KAT6 inhibitors

Abstract

Disclosed herein are compounds used as inhibitors of KAT6 and pharmaceutical compositions comprising the compounds. Also disclosed are methods for treating a disorder or disease responsive to the inhibition of KAT6 activity in a subject. In an embodiment, the compounds are of formula (I) or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or an N-oxide thereof, or a tautomer thereof, wherein values for the variables (e.g., ring B, A', A2, A3, A4, A5, Xl, L, R62, R63, R64, R7, and n) are disclosed herein.

Description

inhibitors KAT6 The technical field of invention

[0001] This document reveals compounds used as KAT6 inhibitors. It also reveals the use of these compounds to inhibit KAT6 activity and to treat breast cancer. Technical background of the invention

[0002] Acetylization of lysine at the epsilon (ε) site is one of the key mechanisms controlling the ability of cells to respond to intracellular and extracellular signals. The levels of lysine acetylization are closely regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). KATs, a highly diverse group of enzymes, transfer the acetyl moiety of acetyl-CoA to lysine structural units, while KDACs remove these moieties. To date, 37 mammalian proteins with endogenous KAT activity have been proposed, including proteins from the MYST family (Moz, Ybf2 / Sas3, Sas2, Tip60), the p300 and CBP families, the SRC / p160 family, and the GCN5 and PCAF families (Sheikh, BN, & Akhtar, A. (2019)). These proteins function 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 acetyltransferase enzyme family, 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, & Akhtar, A. (2019).

[0003] KAT6A is genetically overexpressed in a variety of tumor types (Wiesel-Motiuk, N., & Assaraf, YG (2020)). The lysine acetyltransferases KAT6A and KAT6B play key roles in physiology and pathology. Drug Resist Update, 53 (100729). It is known that the disruption in the regulation of gene expression of KAT6 proteins supports tumor progression, and the abnormal addition of acetyl to histone may lead to tumor formation and cancer progression.

[0004] For example, in breast cancer, KAT6A has been found to be amplified and / or genetically overexpressed in 10–15% of breast cancer cases and in approximately 22% of ER+ HER2 breast cancer cases (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 use in the treatment of breast cancer. Invention Disclosure

[0006] In one of the incarnations, compounds with the formula (I) are revealed in this document: (I)، Or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, where the values ​​of the variables (for example, A) 1 A 2 A 3 A 4 A 5 X 1 Episode B, L, R 62 R 63 R 64 R 7 (n) as described in this document.

[0007] This document also discloses pharmaceutical formulations that include a compound with the formula (I), or a pharmaceutically acceptable salt of it, or a deuterium-treated isotope of it, or N-oxide of it, or a chemical analog of it.

[0008] This document also reveals a method for treating breast cancer, which involves giving a patient in need of treatment a compound with the formula (I), or a pharmaceutically acceptable salt of it, or a deuterium-treated isotope of it, or N-oxide of it, or a chemical analog of it.

[0009] This document also discloses the use of a compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, for the treatment of breast cancer in a patient in need of treatment, involving the administration of a therapeutically effective amount of the compound to the patient.

[0010] This document also discloses a compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, for use in the treatment of breast cancer in a patient in need of treatment, where the treatment involves giving the patient a therapeutically effective amount of the compound.

[0011] This document also discloses the use of a compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or N-oxide thereof, or a chemical analog thereof, to manufacture a drug useful in the treatment of breast cancer in a patient in need of treatment. Detailed description of the invention

[0012] The following terms shall have the meanings indicated throughout the description:

[0013] As used in this document, including the attached aspects, the singular forms of indefinite and definite articles include a reference to the plural unless the context clearly requires otherwise.

[0014] The term “or” is used to mean, and is interchangeably substituted with, the term “and / or” unless the context clearly requires otherwise.

[0015] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms, such as 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, or 1 to 3. Examples of alkyl groups containing 1 to 6 carbon atoms include C1 - 6 alkyl), but not limited to, methyl groups, 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 s-butyl ("s-Bu"), 1,1-dimethylethyl or t-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, as defined in this document, is either deuterated or optionally tritized.

[0016] The term “propyl” refers to 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”).

[0017] The term “butyl” refers to 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl (“t-Bu”).

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

[0019] 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.

[0020] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0021] 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 fluoro, chloro, bromo, and iodo. Examples of haloalkyl include halo C1. - 8 Alkyl, Halo C1 - 6-Alkyl, Halo C1 - 5-Alkyl, Halo C1 - 4-Alkyl or Halogen C1 - 3 alkyl, but not limited to -CF3, -CH2Cl, -CH2CF3, -CHCl2, -CF3, and the like.

[0022] The term "deuterium-treated alkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by one or more deuterium atoms ( 2 H). Examples of deuterium-treated alkyl groups include, but are not limited to, C1 - 8. Deuterium-treated alkyl, C1 - 6 Alkyl Deuterium Treatment, C1 - 4. Deuterium-treated alkyl groups, -CD3, -CHD2, -CH2D, and similar.

[0023] The term "alkoxy" refers to an alkyl group bonded to a molecule via oxygen. This includes radicals in which the alkyl moiety can be linear or branched. For example, the term "C1" - An alkoxy group is an alkyl group bonded to a molecule via oxygen and containing 1, 2, 3, 4, 5, or 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Therefore, an alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, or n-hexoxy.

[0024] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups that includes at least one C=C double bond and between 2 and 18 carbon atoms, such as 2 to 8, or 2 to 6. Examples of an alkyl group include, for example, C2 groups. - 6 Alkenyl, but not limited to ethnyl or vinyl, prop-1-nyl, prop-2-nyl, 2-methylprop-1-nyl, but-1-nyl, but-2-nyl, but-3-nyl, buta-1, 3-dynyl, 2-methylbuta-1, 3-dynyl, hex-1-nyl, hex-2-nyl, hex-3-nyl, hex-4-nyl, and hexa-1, 3-dynyl.

[0025] The term "alkenyl" refers to a hydrocarbon group selected from a linear, branched hydrocarbon group, containing at least one C≡C triple bond and between 2 and 18 carbon atoms, such as 2 to 8, or between 2 and 6. Examples of alkene groups include, for example, C2 groups. - 6. Alkenyl, but not limited to ethinyl, 1-propenyl, 2-propenyl (propargyl), 1-butenyl, 2-butenyl, and 3-butenyl.

[0026] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic groups (e.g., bicyclic and tricyclic) including compact, bridging or spiro cycloalkyl groups.

[0027] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, such as 3 to 10, 3 to 8, 3 to 6, 3 to 5, or 3 to 4. Similarly, a cycloalkyl group may be chosen from a monocyclic group containing 3 to 12 carbon atoms, such as 3 to 10, 3 to 8, or 3 to 6. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Specifically, examples of saturated monocyclic cycloalkyl groups include, for example, C3 groups. - 8. Cycloalkyl groups, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In its preferred form, a cycloalkyl is a single-ring atom containing 3 to 6 carbon atoms (abbreviated as C3). - 6) cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those with 7 to 12 carbon atoms arranged in a compact bicyclic ring chosen from the [4,4], [4,5], [5,5], [5,6], and [6,6] cyclic systems, or in a bridged bicyclic ring chosen from the bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those arranged in a bicyclic ring chosen from the [5,6] and [6,6] cyclic systems.

[0028] The term "cycloalkyl spiro" refers to a ring structure containing carbon atoms and composed of at least two rings sharing one atom. The term "cycloalkyl spiro with 7 to 12 carbon atoms" refers to a ring structure containing 7 to 12 carbon atoms and composed of at least two rings sharing one atom.

[0029] The term “compound cycloalkyl” refers to a bicyclic cycloalkyl group as defined in this document which is a mesh and is formed from two or more rings sharing two adjacent atoms.

[0030] The term "bridged cycloalkyl" refers to a ring structure containing carbon atoms and formed from two rings sharing two non-adjacent carbon atoms. The term "bridged cycloalkyl with 7 to 10 carbon atoms" refers to a ring structure containing 7 to 12 carbon atoms and formed from two rings sharing two non-adjacent carbon atoms.

[0031] The term "cycloalkenyl" refers to non-aromatic cyclic alkyl groups with 3 to 10 carbon atoms, one or more rings, and at least one double bond, preferably 1 to 2 double bonds. In some incarnations, cycloalkenyls are cyclopentenyl or cyclohexenyl, 1-cyclopent-1-nil, 1-cyclopent-2-nil, 1-cyclopent-3-nil, 1-cyclohex-1-nil, 1-cyclohex-2-nil, 1-cyclohex-3-nil, cyclohexadenel, with cyclohexenyl being preferred.

[0032] The term "cycloalkenyl" refers to non-aromatic cycloalkyl groups with between 5 and 10 carbon atoms, containing one or more rings and at least one triple bond.

[0033] The term "Ariel," whether used alone or in combination with other terms, refers to a selected group of:

[0034] Aromatic carbon rings. The rings have 5 or 6 atoms, for example, phenyl;

[0035] Bicyclic cyclic systems such as bicyclic systems with 7 to 12 carbon atoms, where at least one carbon ring is cyclic and aromatic, for example, naphthal and indanyl; and,

[0036] Tricyclic systems such as tricyclic systems have between 10 and 15 atoms where at least one ring is a cyclic and aromatic carbon, for example, fluorinyl.

[0037] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure in this document. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring contains between 5 and 10 ring-forming atoms (i.e., C5 - 10 Aryl). Examples of aromatic hydrocarbon rings include, but are not limited to, monocyclic or bicyclic aromatic hydrocarbons such as phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthryl, and the like. In some incarnations, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some incarnations, the aromatic hydrocarbon ring is a phenyl ring.

[0038] The term "heterogeneous aryl" refers to a group selected from:

[0039] Aromatic single-ring rings with 5, 6 or 7 atoms, including at least one heteroatomic atom, for example, 1 to 4, or in some incarnations, 1 to 3, in some incarnations, 1 to 2, a heteroatomic atom, chosen from nitrogen (N), silver (S) and oxygen (O), with the remaining atoms on the ring being carbon;

[0040] Double-ring rings containing 7 to 12 atoms, including at least one heteroatomic atom, e.g., 1 to 4, or in some incarnations, 1 to 3, or in others, 1 or 2, chosen from N, O, and S, with the remaining atoms on the ring being carbon, and where at least one ring is aromatic and there is at least one heteroatomic atom in the aromatic ring; and

[0041] Trivalent rings containing 11 to 14 atoms, including at least one heteroatomic atom, for example, 1 to 4, or in some incarnations, 1 to 3, or in other incarnations, 1 or 2, a heteroatomic atom, chosen from N, O, and S, with the remaining atoms on the ring being carbon, and where at least one ring is aromatic and there is at least one heteroatomic atom in the aromatic ring.

[0042] When the total number of S and O atoms in an aryl heterogroup exceeds 1, these heteroatoms are not adjacent to each other. In some incarnations, the total number of S and O atoms in an aryl heterogroup does not exceed 2. In some incarnations, the total number of S and O atoms in an aromatic heteroring ring does not exceed 1. When an aryl heterogroup contains more than one heteroring atom in its ring, the heteroring atoms may be identical or different. The nitrogen atoms in the aryl heteroring ring(s) can be oxidized to form N-oxides.

[0043] The terms "heterocyclic aromatic ring" and "heterocyclic aryl" are used interchangeably throughout the disclosure in this document. In some embodiments, a heterocyclic monocyclic or heterocyclic aromatic ring contains 5, 6, 7, 8, 9, or 10 ring-forming atoms with 1, 2, 3, or 4 heterocyclic ring atoms selected separately from nitrogen (N), sulfur (S), and oxygen (O), and the remaining atoms on the ring are carbon. In other embodiments, a heterocyclic monocyclic or heterocyclic aromatic ring is a monocyclic or bicyclic ring containing 1 or 2 heterocyclic ring atoms selected separately from nitrogen (N), sulfur (S), and oxygen (O). In some incarnations, the aromatic monocyclic or bicyclic heterocyclic ring is a heterocyclic aryl ring with 5 to 6 atoms, which is monocyclic and contains 1 or 2 heterocyclic ring atoms chosen separately from nitrogen (N), silver (S) and oxygen (O).In some incarnations, the aromatic monocyclic or bicyclic heterocyclic ring is an 8- to 10-atom heterocyclic aryl ring, which is bicyclic and contains 1 or 2 heterocyclic ring atoms selected separately from nitrogen, silver and oxygen.

[0044] Examples of heterocyclic aryl groups or monocyclic or bicyclic aromatic rings include, but are not limited to, (in order of numbering starting from the priority binding position 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazoyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazoyl, theinyl (e.g., thein-2-yl, thein-3-yl), triazinyl, benzothienyl, furyl or furanyl; Benzofuryl, benzoimidazolyl, indolyl, isoindolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalassinyl, pyrazinyl, pyridazinyl, pyrrolilyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl);Benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 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, furazanil (e.g., furazanil-2-yl, furazanil-3-yl), benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphtheridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), and indazolyl (e.g., 1H-Indazol-5-yl).

[0045] The terms “heterocyclic,” “heterocyclic,” or “heterocyclic” are used interchangeably and refer to a non-aromatic heterocyclic alkyl group comprising one or more heteroatoms chosen from nitrogen, oxygen, or selectively oxidized sulfur in the form of the ring-forming atoms, with the remaining atoms on the ring being carbon, including monocyclic, compact, bridged, and spiro-containing heterocyclic groups.

[0046] The term “selectively oxidized silver”, as used in this document, refers to S, SO or SO2.

[0047] The term "monocyclic heterocyclic" refers to monocyclic groups in which at least one ring-forming atom (e.g., 1-3 heterocyclic atoms, 1 or 2 heterocyclic atoms) is a heterocyclic atom chosen from selectively oxidized nitrogen, oxygen, or sulfur. The heterocyclic ring may be saturated or partially saturated.

[0048] Monocyclic heterocyclic groups containing 4 to 9 illustrative atoms include, but are not limited to, (in order of numbering starting from the given priority bonding position 1) pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, aziridine-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl; Azokan-5-yl, Theranil, Azetidine-1-yl, Azetidine-2-yl, Azetidine-3-yl, Axitanil, Thetanil, 1,2-Dithetanil, 1,3-Dithetanil, Dihydropyridinil, Tetrahydropyridinil, Thiomorpholinil, Thioxanil, Piperazinil, Piperazinil homolog, Piperidinil homolog, Azepan-1-yl, Azepan-2-yl, Azepan-3-yl, Azepan-4-yl, Axipanil, Thepanil, 1,4-Axathianil, 1,4-Diaxapanil, 1,4-Axazepanil, 1,4-Dithepanil, 1,4-Thiazepanil and 1,4-Diaxapanil 1, 4-daythianyl, 1,4-aza thianyl, axa zipinyl, daya zipinyl, thia zipinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyranyl 2-pyrrolinyl, 3-pyrrolinyl, indolenyl, 2H-pyranyl, 4H-pyranyl, 1, 4-diaxanyl, 1, 3-diaxolanyl, pyrazolenyl, pyrazolidinyl, diethianyl, dithiolanyl, pyrazoledinyl, imidazolidine, pyrimelin, 1 1-Diaxo-Thiomorpholinyl.

[0049] The term "spiro heterocyclic" refers to a polycyclic heterocyclic with 5 to 20 atoms, where the rings are connected by a single common carbon atom (called the spiro atom). These rings contain one or more heteroatoms, chosen from nitrogen, oxygen, or selectively oxidized sulfur, with the remaining atoms being carbon. One or more rings in a spiro heterocyclic group may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Spiro heterocyclic groups are typically composed of 6 to 14 atoms, with 7 to 12 being the most desirable.According to the number of spiro atoms shared, heterocyclic spiro is divided into monospiro heterocyclic, dispiro heterocyclic, or polyspiro heterocyclic, preferably referring to monospiro heterocyclic or dispiro heterocyclic, and most preferably monospiro heterocyclic with 4 atoms / 3 atoms, 4 atoms / 4 atoms, 3 atoms / 5 atoms, 4 atoms / 5 atoms, 4 atoms / 6 atoms, 5 atoms / 5 atoms, or 5 atoms / 6 atoms. Representative examples of heterocyclic cyclic groups include, but are not limited to, the following: 2,3-dihydrospiro[indine-1,2'-pyrrolidine] (e.g., 2,3-dihydrospiro[indine-1,2'-pyrrolidine]-1'-yl), 1,3-dihydrospiro[indine-2,2'-pyrrolidine] (e.g., 1,3-dihydrospiro[indine-2,2'-pyrrolidine]-1'-yl), azaspiro[2,4]heptane (e.g., 5-azaspiro[2,4]heptane-5-yl), 2-axa-6-azaspiro[3,3]heptane (e.g., 2-axa-6-azaspiro[3,3]heptane-6-yl), and azaspiro[3,4]octane (e.g. For example, 6-Aza Spiro [3.[4] Octane-6-yl), 2-Axa-6-Aza Spiro[3.4] Octane (e.g., 2-Axa-6-Aza Spiro[3.4] Octane-6-yl), Aza Spiro[3.4] Octane (e.g., 6-Aza Spiro[3.4] Octane-6-yl), Aza Spiro[3.4] Octane (e.g., 6-Aza Spiro[3.4] Octane-6-yl), 1,7-Diaxa Spiro[4.5] Decane, 2-Axa-7-Aza-Spiro[4.4] Nonan (e.g., 2-Axa-7-Aza-Spiro[4.4] Non-7-yl), 7-Axa-Spiro[3.5] Nonel and 5-Axa-Spiro[2.4] Heptyl. The term "compound heterocyclic cycloid" refers to a polycyclic heterocyclic cycloidal system containing 5 to 20 atoms. Each ring in the system shares an adjacent pair of atoms (carbon-carbon or carbon-nitrogen), with the other ring containing one or more heteroatoms chosen from nitrogen, oxygen, or selectively oxidized sulfur as the ring-forming atoms. The remaining atoms on the ring are carbon. One or more rings of a compact heterocyclic cycloidal system may contain one or more double bonds, but the compact heterocyclic cycloidal system does not have a fully conjugated pi-electron system. Ideally, compact heterocycloidal cycloids contain 6 to 14 atoms, but even more preferably 7 to 12 atoms, or 7 to 10 atoms. According to the number of atoms that make up the ring, fused heterocycles are divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycles.The group can be linked to the rest of the molecule through any ring.

[0051] Specifically, the term "bicyclic integrated heterocyclic" refers to a cyclic heterocyclic containing 7 to 12 atoms, preferably 7 to 10 atoms, or even more preferably 9 or 10 atoms as defined in this document, that comprises two integrated rings and includes 1 to 4 heteroatoms chosen from nitrogen, oxygen, or optionally oxidized sulfur in the form of the ring atoms. Typically, a bicyclic integrated heterocyclic is a 5 / 5, 5 / 6, 6 / 6, or 6 / 7 atom bicyclic integrated heterocyclic.Representative examples of fused (bicyclic) heterocyclic groups include, but are not limited to, the following: octahydrocyclopenta[c]pyrrole, octahydropyrolo[3,4-c]pyrrole, octahydroisoindolyl, isoindolyl, octahydrobenzo[b][1,4]dioxene, indolinyl, isoindolyl, benzopyrane, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzoimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzodioxolyl, benzodioxonyl, crominyl, crominyl, octahydrocrominyl, dihydrobenzodioxenyl, dihydrobenzoxazinyl, dihydrobenzodioxpenyl, di Hydrothinodioxinyl, dihydrobenzoaxazepinyl, tetrahydrobenzoaxazepinyl, dihydrobenzoazepynyl, tetrahydrobenzoazepynyl, isocromanyl, cromonyl, or tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-yl).

[0052] The term “integrated heterocyclic benzocyclyl” refers to a bicyclic integrated heterocyclyl in which the monocyclic heterocyclyl atoms have between 4 and 9 atoms as defined in this document (preferably 5 or 6 atoms) integrated with a benzene ring.

[0053] The term "bridged heterocyclic cyclic molecule" refers to a polycyclic heterocyclic alkyl group containing 5 to 14 atoms, where each pair of rings in the system shares two separate atoms. These atoms include one or more heteroatoms chosen from nitrogen, oxygen, or selectively oxidized sulfur, with the remaining atoms being carbon. One or more rings in a bridged heterocyclic molecule may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Ideally, bridged heterocyclic molecules contain 6 to 14 atoms, and even more preferably 7 to 10.Based on the number of atoms in the ring, bridging heterocyclic ...

[0054] If the amine has a replacement with R 5 This means that the nitrogen atom present in the formulas or Not related to hydrogen.

[0055] The term "at least one substitution group" as defined in this document refers, for example, to a number from 1 to 4, such as 1 to 3, and also to 1 or 2 substitution groups, provided the equivalence theory is satisfied. For example, the expression "at least one substitution group R" includes 6” "What was revealed in this document ranges from 1 to 4, such as 1 to 3, and also 1 or 2 replacement groups chosen from the R list." 6 As revealed in this document.

[0056] The compounds identified in this document may contain an asymmetric center and therefore may exist as isomers. “Isomers” refers to two isomers of a compound that are non-identical mirror images of each other. When compounds identified in this document contain two or more asymmetric centers, they may also exist as diisomers. Isomers and diisomers fall within a broader category of isomers. All such possible isomers are assumed to be included as largely pure hydrolyzed isomers, racemic mixtures thereof, and mixtures of diisomers. All isomers of the compounds identified in this document and / or pharmaceutically acceptable salts thereof are assumed to be included. Unless specifically indicated otherwise, a reference to one isomer applies to any of the possible isomers. Where the isomerization is not specified, all possible isomers are included.

[0057] The term “highly pure” as used in this document means that the target isomorph contains no more than 35%, no more than 30%, no more than 25%, or no more than 20%, by weight, of any other isomorph(s). In some incarnations, the term “highly pure” means that the target isomorph contains no more than 10%, for example, no more than 5%, or no more than 1%, by weight, of any other isomorph(s).

[0058] When the compounds identified in this document contain olefinic dimers, unless otherwise specified, these dimers are assumed to include both the E and Z geometric isomers.

[0059] When the compounds disclosed in this document contain a cyclohexyl or cyclobutyl group with a disubstitution, the substitution groups on the cyclohexyl or cyclobutyl ring can take on different forms. Sis and Trans The term means "authority". Sis Both substitution groups are located on the upper side of the substitution group positions on the carbon, while the form means Trans They are located on opposite sides.

[0060] It may be beneficial to separate the reaction products from each other and / or from the starting materials. The product required for each step or set of steps is separated and / or purified (hereinafter referred to as separation) to the required degree of homogeneity using techniques commonly used in the field. Typically, these separation processes include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reversed-phase and normal-phase; volume-based exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and apparatus; small-scale analysis; simulated moving layer (“SMB”); and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer or flash chromatography techniques. A skilled professional will apply the techniques most likely to achieve the required separation.

[0061] “Pharmaceuticalally acceptable salt” refers to salts that, within the bounds of sound medical judgment, are deemed suitable for contact with human and lower animal tissues without causing undue toxicity, irritation, allergic reactions, or similar adverse effects, and are proportionate to a reasonable benefit / risk ratio. A pharmaceutically acceptable salt may be prepared on-site during the final separation and purification of the compounds identified in this document, or separately by the reaction of the functionalized free base group with a suitable organic acid or by the reaction of the acid group with a suitable base.

[0062] Furthermore, if a compound identified in this document is obtained as an addition salt of an acid, the free base can be obtained by converting a solution of the acid salt to a base. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and / or water and treating the solution with an acid, according to the conventional procedures for preparing addition salts of acids from basic compounds. Skilled professionals in the field will recognize the various synthetic methods that can be employed, without undue experimentation, to prepare non-toxic, pharmaceutically acceptable addition salts.

[0063] As defined in this document, the expression “pharmaceuticalally acceptable salt of which” includes salts of a compound having at least one formula (I), and salts of the isomers of the compound having the formula (I), such as salts of isomers, and / or salts of diisomers.

[0064] The term "under treatment" in this document means a human being.

[0065] The term “effective dose” or “therapeutally effective dose” refers to the amount of an active substance, such as a compound, which, when administered to a patient for the treatment of a disease, or at least one clinical symptom of a disease or disorder, is sufficient to cure the disease, disorder, or symptom. The therapeutically effective dose can vary with the compound, the disease, the disorder, and / or the symptoms of the disease or disorder, the severity of the disease, the disorder, and / or the symptoms of the disease or disorder, the age of the patient to be treated, and / or the weight of the patient to be treated. In some formulations, the therapeutically effective dose is the amount of at least one compound and / or at least one homolog thereof, and / or at least one pharmacologically acceptable salt thereof disclosed in this document that is effective to “cure,” as defined above, a disease or disorder in a patient.

[0066] The pharmaceutical formulation containing the compound disclosed in this document may be administered orally to a patient undergoing treatment who requires it. The pharmaceutical formulation may be a standard solid form such as tablets, capsules, and the like.

[0067] All pharmaceutical formulations disclosed in this document can be produced using conventional methods employed in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, and the required formulation can then be prepared. "Pharmaceuticalally acceptable excipient" refers to conventional pharmaceutical carriers suitable for the required formulation.

[0068] The term “disease” refers to any illness, discomfort, affliction, symptom or indication, and may be used interchangeably with the term “disorder” or “morbid condition”.

[0069] Throughout the present description and subsequent aspects, unless the context otherwise requires, the term “includes” and its variations such as “includes” and “contains” are intended to indicate the presence of the attributes listed after it, but do not preclude the presence or addition of one or more other attributes. When used in this document, the term “includes” may be substituted with “contains,” “includes,” or sometimes “with.”

[0070] Throughout the present description and the following aspects, the term "C" refers to n - m "To a range that includes endpoints, where n and m are integers and denote the number of carbon atoms. Examples include C1 - 8, C1 - 6, and the like.

[0071] Unless specifically defined elsewhere in this document, all other technical and scientific terms used in this document have the meaning normally understood by a person of ordinary skill in the field to which this invention belongs.

[0072] Aspects and manifestations

[0073] The following aspects and embodiments are not intended to be an express or implied acknowledgment that they are independent or distinct, nor should they be interpreted as such. Rather, they are intended to convey information so that the full scope of the present invention may be understood. Furthermore, the following aspects and embodiments are not intended to limit the full scope of the invention as stated in Structural Form I.

[0074] Side 1. A compound with the formula (I): (I) Or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, where: A 1 CR 1 Or N, A 2 CR 2 Or N, A 3 CR 3 Or N, A 4 CR 4 Or N, A 5 CR 5 Or N, provided that at most two are A 1 A 2 A 3 A 4 and A 5 It is N; Each of R 1 R 2 R 3 R 4 and R 5 Separately, it consists of hydrogen, deuterium, halogen, and -C. 1- 10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, 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 ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic cyclyl, aryl or heterocyclic aryl mentioned above have no substitution or have been substituted by 1, 2, or 3 of R 1 d ; Or it forms (R 3 and R 4 ) or (R 4 and R 5 Together), in addition to the atoms to which they are bonded, separately C3 - 10 Cycloalkyl, C3 - 10 Cycloalkenyl, a heterocyclic ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; aryl, containing 5 to 12 atoms; or a heterocyclic aryl ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, where each of the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, a heterocyclic cyclyl ring containing 5 to 12 atoms, an aryl ring containing 5 to 12 atoms, or a heterocyclic aryl ring containing 5 to 12 atoms, the aforementioned has no substitution or has a substitution of 1, 2, 3, or 4 of R. 1 d ; Each of R 1a R 1b and R 1c Separately, it consists of hydrogen, deuterium, and -C 1-10 Alkyl, -C 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic aryl, or heterocyclic aryl, where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl compounds listed have no substitution or are substituted with 1, 2, or 3 of R. 1 j ; Each of R 1d and R 1j Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, 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 ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned above have no substitution or have a substitution with at least one substitution group chosen from a halogen, -CN, -C 1- 10 Alkyl, -OR 1h -NR 1h R 1i Cycloalkyl, heterocyclic cyclyl, aryl, and heteroaryl; or two R-forms 1d Or two R 1j By substitution on the same atom, either exo; or Two Rs form 1d They involve substitution on identical or different atoms, together with the atom(s) they are bonded to and any overlapping atoms, C3 - 10 A cycloalkyl, a heterocyclic ring containing 4 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; an aryl containing 6 to 12 atoms; or a heterocyclic aryl ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; where C 3-10 Cycloalkyl, a heterocyclic ring containing 4 to 12 atoms, an aryl ring containing 6 to 12 atoms, or a heterocyclic aryl ring containing 5 to 12 atoms. The aforementioned has no substitution or is substituted by 1, 2, or 3 of R. 1 k ; Each of R 1e R 1f R 1g R 1h and R 1i Separately, it is a hydrogen-based compound, -C 1-10 Alkyl, -Halo C1 - 10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, heterocyclic cyclyl, aryl, or heterocyclic aryl; Each R 1k Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -Halo C1 - 10 Alkyl, or -C 1-10 Alcox; X 1 CR 61 or N; L is a direct bond, -(CR) L1 R L2 ) p -, -O-, -S- or -NR L3 -; The B ring is an isoxazolyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyridazinyl or pyrimidinyl; Each R 61 R 62 R 63 R 64 R 7 R L1 and R L2 Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, 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 ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl compounds listed have no substitution or are substituted with 1, 2, or 3 of R. 3d ; Each of R 3a R 3b and R 3c Separately, it consists of hydrogen, deuterium, and -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic cyclyl, aryl, or heterocyclic aryl; where each of these is -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 Alkenyl, cycloalkyl, heterocyclic cyclyl, aryl, or heterocyclic aryl mentioned above are either without substitution or with an R substitution 3 j ; Each of R 3d and R 3j Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, 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 ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 Alkenyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group mentioned above has no substitution or has a substitution with at least one substitution group chosen from a halogen, -C 1-10 Alkyl, -OR 3h -NR 3h R 3i Cycloalkyl, heterocyclic cyclyl, aryl, or heterocyclic aryl; or two R-forms 3d Or two R 3j By substitution on the same atom, either exo; or Each of R 3e R 3f R 3g R 3h and R 3i Separately, it is a hydrogen-based compound, -C 1-10 Alkyl, -Halo C1 - 10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, heterocyclic cyclyl, benzyl with substitution by alkoxy, aryl, or heterocyclic aryl; R L3 It is hydrogen, -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, or heterocyclic aryl; p can be 0, 1, 2, or 3 (optionally, p can be 1 or 2; also optionally, p can be 1); and n can be 0, 1, 2, or 3 (optionally, n can be 1 or 2; also optionally, n can be 1).

[0075] In one of the incarnations side 1 A 3 CR 3 A 4 CR 4 A 5 CR 5 Optionally, R 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 R 3 and R 5 It is hydrogen, and R is the hydrogen-based compound. 4 -C 1-10 Alkyl, -C 1-10 Alkoxy, cycloalkyl, heterocyclic cyclyl, aryl, or heteroaryl, where each of -C 1-10 The alkyl, cycloalkyl, heterocyclic cyclyl, aryl, or heteroaryl groups mentioned above are either without a substitution or with an R substitution group. 1d At least one; each R 1d Separately, it is a halogen, -C 1-10 Alkyl, -C 1-10 Alkyne -C 1-10 Alkox, -C 1-10 Alcox, or -COOC 1-10 Alkyl.

[0076] In a preferred incarnation, R is chosen 4 from -C 1-6 Alkyl; -C 1-6 Alkyne -C 1-3 Alcox; C3 - 10 Cycloalkyl groups have 1, 2, or 3 substitution groups chosen separately from F, Cl, Br, and -C. 1-6 Alkyl, and -C 1-6 Alkoxie and heterocyclic compounds containing 3 to 7 monocyclic or bicyclic atoms (optionally fused ring, spiro, or bridged bicyclic) and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and selectively oxidized sulfur, and having no substitution or having a substitution of 1, 2, or 3 substitution groups selected separately from F, Cl, Br, and -C. 1-6 Alkyl, and -C 1-6 Alcox.

[0077] In another favorite incarnation, R is chosen 4 from -C 1-6 Alkyl, -C 1-6 Alkyne -C 1-3 Alcox, cyclopropanel, 3-Aza-by-cyclo[3.1.0]hexanil, and oxytanil; where each of these is -C 1-6 Alkyl, -C 1-6 Alkyne -C 1-3 Alcox, cyclopropanyl, 3-Aza-by-cyclo[3.1.0]hexanyl, and oxytanyl mentioned have no substitution or have been substituted by 1, 2, or 3 substitution groups chosen separately from methyl, ethyl, propyl, F, Cl, Br, methoxy, ethoxy, or -COOCH3.

[0078] In one of Side 1's incarnations, R 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 It is hydrogen, and A 3 CR 3 A 4 CR 4 A 5 CR 5 Optionally, R 1 It is -C1 - 5. Alkoxy, R 2 It is hydrogen, forming (R 3 and R 4 (or R) 4 and R 5 Together, in addition to the atoms to which they are bonded, C3 - 10 Cycloalkyl, C3 - 10 Cycloalkenyl, a heterocyclic ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; aryl, containing 6 to 12 atoms; or a heterocyclic aryl ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, with no substitution or with 1, 2, 3, or 4 R atoms. 1 d Each R 1d Separately, it is a halogen, -C 1-10 Alkyl, -C 1-10 Alcox, or -COOC 1-10 Alkyl. In a preferred incarnation, it forms (R 3 and R 4 (or R) 4 and R 5 Together, in addition to the atoms to which they are attached, a dihydrofuran ring, or a pyrrole ring; where each of the dihydrofuran or pyrrole rings has no substitution or has a substitution of 1, 2, 3, or 4 substitution groups chosen from methyl, ethyl, propyl, F, Cl, Br, methoxy, ethoxy, or -COOCH3.

[0079] In a favorite incarnation, R 1 It is -C1 - 5. Alkoxy, R 2 It is hydrogen, and A 3 CR 3 A 4 CR 4 A 5 CR 5 Optionally, R 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 It is hydrogen, and R is the hydrogen-based compound. 3 It is hydrogen, forming (R 4 and R 5 Together, in addition to the atoms to which they are bonded, C3 - 10 Cycloalkyl, C3 - 10 Cycloalkenyl, a heterocyclic ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; aryl, containing 6 to 12 atoms; or a heterocyclic aryl ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, with no substitution or with 1, 2, 3, or 4 R atoms. 1 d Each R 1d Separately, it is a halogen, -C 1-10 Alkyl, -C 1-10 Alkoxie, heterocyclic ring, or -COOC 1-10 Alkyl.

[0080] In a preferred incarnation, R 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 It is hydrogen, and A 3 CR 3 A 4 CR 4 A 5 CR 5 Optionally, R 1 It is -C1 - 5. Alkoxy, R 2 It is hydrogen, and R is the hydrogen-based compound. 5 It is hydrogen, forming (R 3 and R 4 Together, in addition to the atoms to which they are bonded, C3 - 10 Cycloalkyl, C3 - 10 Cycloalkenyls are heterocyclic rings containing 5 to 12 atoms and 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; aryls are rings containing 6 to 12 atoms; or heterocyclic aryls are rings containing 5 to 12 atoms and 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, with no substitution or with 1, 2, 3, or 4 R substitutions. 1 d Each R 1d Separately, it is a halogen, -C 1-10 Alkyl, -C 1-10 Alkoxie, heterocyclic ring, or -COOC 1-10 Alkyl.

[0081] In one of Side 1's incarnations, R 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 It is hydrogen, and A 3 CR 3 A 4 CR 4 A 5 It is N. Optionally, R is 1 It is -C1 - 5-Alcoxy (optionally -OC) 1-5 (Alkyl treated with deuterium), R 2 R 3 and R 5 It is hydrogen, and R is the hydrogen-based compound. 4 -C 1-10 Alkyl, -C 1-10 Alkoxy, cycloalkyl, heterocyclic cyclyl, aryl, or heteroaryl, where each of -C 1-10 The alkyl, cycloalkyl, heterocyclic cyclyl, aryl, or heteroaryl groups mentioned above are either without a substitution or with an R substitution group. 1d At least one; each R 1d Separately, it is a halogen, -C 1-10 Alkyl, -C 1-10 Alkyne -C 1-10 Alkox, -C 1-10 Alcox, or -COOC 1-10 Alkyl.

[0082] side 2 The compound According to the side 1 where it is It is , , , , , , or In one of the incarnations side 2 It is It is , , , , , , , , or In one of the incarnations side 2 It is It is In one of the incarnations side 2 It is It is .

[0083] In a first incarnation according to For the side 2 Loop B has no substitution or has a substitution of 1 or 2 from R 7 (i.e., n has a value of 0, 1 or 2). In one of the incarnations of side 2, n has a value of 0 or 1. In one of the incarnations of side 2, loop B has no substitution (i.e., n has a value of 0).

[0084] In a second incarnation according to For the side 2 , being It is , , , , , , , , or In a third incarnation according to For the side 2 It is It is .

[0085] In a fourth incarnation according to For the side 2 It is It is .

[0086] side 2 ’ A compound with formula (I) is a compound with formula (II-1): (II-1).

[0087] In some incarnations, the compound has the formula (II-1), where A 1 CR 1 R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5 alkyl); A 2 CR 2 And R 2 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; A 3 CR 3 Or N, A 4 CR 4 Or N, A 5 CR 5 Or N, provided that it is at most one of A's 3 A 4 and A 5 It is N; If found, each of R 3 R 4 and R 5 Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -OR 1a -SO2R 1a -COR 1 a -CO2R 1 a -CONR 1 a R 1 b -C(=NR 1a NR 1 b R 1 c -NR 1 a R 1 b -NR 1 a COR 1 b -NR 1 a CONR 1 b R 1 c -NR 1 a CO2R 1 b -NR 1 a SONR 1 b R 1 c -NR 1 a SO2NR 1 b R 1 c -P(=O)R 1 a R 1 b -NR 1 a SO2R 1 b or -SOR 1 a (=NR 1b ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic aryl, or heterocyclic aryl mentioned above have no substitution or have been substituted by 1, 2, or 3 of R 1 d ; Or it forms (R 3 and R 4 ) or (R 4 and R 5 Together), in addition to the atoms to which they are bonded, separately C3 - 10 Cycloalkyl, C3 - 10 Cycloalkenyl, a heterocyclic ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; aryl, containing 5 to 12 atoms; or a heterocyclic aryl ring containing 5 to 12 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, where each of the C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, a heterocyclic cyclyl ring containing 5 to 12 atoms, an aryl ring containing 5 to 12 atoms, or a heterocyclic aryl ring containing 5 to 12 atoms, the aforementioned has no substitution or has a substitution of 1, 2, 3, or 4 of R. 1 d ; Each of R 1a R 1b and R 1c Separately, it is a hydrogen-based compound, -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic aryl, or heterocyclic aryl, where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl compounds listed have no substitution or are substituted with 1, 2, or 3 of R. 1 j ; Each of R 1d and R 1j Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, 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 ), where each of -C 1-10 Alkyl, -C 2-10 Alknell, -C 2-10 The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups mentioned above have no substitution or have a substitution with at least one substitution group chosen from a halogen, -CN, -C 1-10 Alkyl, -OR 1h -NR 1h R 1i Cycloalkyl, heterocyclic cyclyl, aryl, and heteroaryl; or two R-forms 1d Or two R 1j By substitution on the same atom, either exo; or Two Rs form 1d They involve substitution on identical or different atoms, together with the atom(s) they are bonded to and any overlapping atoms, C3 - 10 A cycloalkyl is a heterocyclic ring containing 4 to 12 atoms and 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; an aryl is a ring containing 6 to 12 atoms; or an aryl is a heterocyclic ring containing 5 to 12 atoms and 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; where each of the C 3-10 Cycloalkyl, a heterocyclic ring containing 4 to 12 atoms, an aryl ring containing 6 to 12 atoms, or a heterocyclic aryl ring containing 5 to 12 atoms. The aforementioned has no substitution or is substituted by 1, 2, or 3 of R. 1 k ; Each of R 1e R 1f R 1g R 1h and R 1i Separately, it is a hydrogen-based compound, -C 1-10 Alkyl, -Halo C1 - 10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, cycloalkyl, heterocyclic cyclyl, aryl, or heterocyclic aryl; R 1 k Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -Halo C1 - 10 Alkyl, or -C 1-10 Alcox.

[0088] In some incarnations, the compound has the formula (II-1), where X 1 It is N or CR 61 , Each of R 61 R 62 R 63 and R 64 Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, monocyclic heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, monocyclic aryls containing 5 or 6 atoms, -CN, or -NR 3 a R 3 b Where each of -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C1 - 10 Cycloalkyl monocyclic, C1 - 10 Cyclo-alkyl monocyclic, C1 - 10 Monocyclic cycloalkenyls, heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms chosen separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, or monocyclic aryls containing 5 or 6 atoms, the aforementioned have no substitution or have been substituted by 1, 2, or 3 R atoms 3d ; Each of R 3a and R 3b Separately, it is a hydrogen-based compound, -C 1-5 Alkyl, -C2 - 5-Alkenyl, -C2 - 5-Alkenyl, or C3 - 6. Monocyclic cycloalkyl; Each of R 3d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknell, -C 1-10 Alcox, -C2 - 10 Alkenyl or C3 - 6. Monocyclic alkyl groups.

[0089] In some incarnations, the compound has the formula (II-1), where X is 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 62 R 63 and R 64 Separately, it consists of hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, azitidinyl, -NH2, -NH(C1) - 6-alkyl), -N(C 1-6 Alkyl(2), -CN, F, Cl, Br or I; where each of the following is an alkyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, or azitidinyl mentioned is either not substituted or is substituted by 1, 2, or 3 of R 3d ؛ Each of R 3d Separately, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1, 1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxyranyl, oxytanyl, F, Cl, Br or I.

[0090] In some incarnations, the compound has the formula (II-1), where X is 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 62 R 63 and R 64 Separately, it is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2 or -CH2OCH3.

[0091] In some incarnations, the compound has the formula (II-1), where X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is either hydrogen or deuterium; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0092] In some incarnations, the compound has the formula (II-1), where X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Each is a methyl, ethyl, cyclopropyl, ethyl, or methoxy.

[0093] side 3 The compound according to For the side 1 or side 2 L is -CH2-, or -(CH2)2.

[0094] In one of the Side 3 incarnations, L is -CH2-.

[0095] side 4 The compound according to which of Aspects 1 - 3 X 1 CR 61 , Each of R 61 R 62 R 63 and R 64 Separately, it consists of hydrogen, deuterium, halogen, and -C. 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, monocyclic heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, monocyclic aryls containing 5 or 6 atoms, -CN, or -NR 3 a R 3 b Where each of -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C1 - 10 Cycloalkyl monocyclic, C1 - 10 Cyclo-alkyl monocyclic, C1 - 10 Monocyclic cycloalkenyls, heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms chosen separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, or monocyclic aryls containing 5 or 6 atoms, the aforementioned have no substitution or have been substituted by 1, 2, or 3 R atoms 3d ; Each of R 3a and R 3b Separately, it is a hydrogen-based compound, -C 1-5 Alkyl, -C2 - 5-Alkenyl, -C2 - 5-Alkenyl, or C3 - 6. Monocyclic cycloalkyl; Each R 3d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknell, -C 1-10 Alcox, -C2 - 10 Alkenyl or C3 - 6. Monocyclic alkyl groups.

[0096] In a favorite incarnation, both R 61 R 63 and R 64 Separately, it is hydrogen. In another preferred incarnation, R 62 It is a halogen, -C 1-5 Alkyl, -OC 1-5 Deuterium-treated alkyl, -C2 - 5-Alkenyl, -C1 - 5-Alcoxy, or C3 - 6. Monocyclic cycloalkyl groups; where each of C1 - 5-alkyl, -C2 - 5-Alkenyl, -C1 - 5-Alcoxy, or C3 - The 6-cycloalkyl monocyclic alkyl groups mentioned have no substitution or are substituted with 1, 2, or 3 of R. 3d ;

[0097] Each R 3d Each is a hydrogen, F, Cl, Br, I, methoxy, ethoxy, methyl, or ethyl group.

[0098] In a favorite incarnation, both R 61 and R 63 Separately, it is hydrogen.

[0099] In a favorite incarnation, both R 62 R 63 and R 64 Separately, it is hydrogen.

[0100] In a favorite incarnation, both R 63 and R 64 Separately, it is hydrogen.

[0101] In a favorite incarnation, both R 61 R 62 and R 64 Separately, it is hydrogen.

[0102] In a first incarnation according to For the side 4 X 1 CR 61 , Each of R 61 R 62 R 63 and R 64 Separately, it consists of hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, azitidinyl, -NH2, -NH(C1) - 5-alkyl), -N(C 1-5 Alkyl(2), -CN, F, Cl, Br or I; where each of the following is an alkyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, or azitidinyl mentioned is either not substituted or is substituted by 1, 2, or 3 of R 3d ; Each of R 3d Separately, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1, 1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxyranyl, oxytanyl, F, Cl, Br or I.

[0103] In a second incarnation according to For the side 4 X 1 CR 61 , Each of R 61 R 62 R 63 and R 64 Separately, it consists of hydrogen, deuterium, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2 or -CH2OCH3.

[0104] In a third incarnation according to For the side 4 X 1 CR 61 , R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0105] In a fourth incarnation according to For the side 4 X 1 CR 61 , Each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Separately, it is methyl, ethyl, I, cyclopropyl, ethyl, or methoxy.

[0106] side 5 The compound according to which of Aspects 1 - 3 X 1 It is N, Each of R 62 R 63 and R 64 Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; monocyclic aryls containing 6 atoms; monocyclic aryls containing 5 or 6 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; or -NR 3 a R 3 b Where each of -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, monocyclic heterocyclic cyclosalkenes containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur; monocyclic aryls containing 6 atoms; monocyclic aryls containing 5 or 6 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur. The aforementioned aryls have no substitution or have been substituted by 1, 2, or 3 R atoms. 3d ; Each of R 3a and R 3b Separately, it is a hydrogen-based compound, -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, or cycloalkyl; Each R 3d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknell, -C 1-10 Alcox, -C2 - 10 Alkenyl, or cycloalkyl. In a favorite incarnation, both R 63 and R 64 Separately, it is hydrogen. In a preferred embodiment, R 62 It is C3 - 6-C1-monocyclic alkyl groups - 5. Alkoxy, where each of C3 is present - 6-C1-monocyclic alkyl groups - The alkoxy listed has no substitution or is substituted with 1, 2 or 3 of R 3d ; Each R 3d Each is a hydrogen, F, Cl, Br, I, methoxy, ethoxy, methyl, or ethyl group.

[0107] In a first incarnation according to For the side 5 X 1 It is N, Each of R 62 R 63 and R 64 Separately, it consists of hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, -NH2, -NH(C1) - 6-alkyl), -N(C 1-6 Alkyl(2, F, Cl, Br or I); where each of the following is an alkyl, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl mentioned has no substitution or has been substituted with 1, 2, or 3 of R 3d ; Each of R 3d Separately, it is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1, 1-dimethylethyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, 2-propenyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxyranyl, oxytanyl, F, Cl, Br or I.

[0108] In a second incarnation according to For the side 5 X 1 It is N, Each of R 62 R 63 and R 64 Separately, it is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

[0109] In a third incarnation according to For the side 5 X 1 It is N, R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

[0110] In a fourth incarnation according to For the side 5 X 1 It is N, R 63 and R 64 It is hydrogen; R 62 It is a cyclopropyl or methoxy. In a fifth incarnation according to For the side 5 X1 is N, R 63 and R 64 It is hydrogen; R 62 It is -OCD3.

[0111] side 6 The compound according to which of Aspects 1 - 5 Each R 7 Separately, it is a hydrogen-based compound, -C 1-10 alkyl, -NH2, -NH(-C 1-6 alkyl) or -N(-C 1-6 Alkyl)2.

[0112] In a first incarnation according to For the side 6 n's value is 0, 1, 2, or 3; each R 7 Separately, it consists of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, or -NH2. In a second incarnation according to For the side 6 n has a value of 2, or 3; each of R 7 Separately, it is a methyl group; R 7 The other is hydrogen. In a third incarnation according to For the side 6 n is either 2 or 3; one of the R values ​​is 2. 7 It is -NH2; and R 7 The other is hydrogen. In a fourth incarnation according to For the side 6 R 7 It is hydrogen.

[0113] side 7 The compound according to which of Aspects 1 - 6 R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5. Alkyl).

[0114] In some incarnations side 7 A compound with the formula (I) is a compound with the formula (III-1): (III-1).

[0115] In some incarnations of the compound which has the formula (I) or the formula (III-1), A 5 It is N or CR 5 If found, it will be R 5 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Deuterium-treated alkyl; preferably, -CD3), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl (more preferably, methyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5. Alkyl; preferably, -CF3, -CH2F, or -CHF2); R 2 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl (preferably hydrogen or halogen; most preferably hydrogen); R 3 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 4 -C 1-10 Alkyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl, aryl containing 6 atoms, heterocyclic aryl containing 5 to 6 atoms and containing 1, 2 or 3 heterocyclic atoms selected separately from nitrogen, oxygen and optionally oxidized sulfur, or heterocyclic cyclic atom containing 4 to 8 atoms and containing 1, 2 or 3 heterocyclic atoms selected separately from nitrogen, oxygen and optionally oxidized sulfur; Where -C 1-10 The alkyl group mentioned has no substitution or is substituted by 1, 2, or 3 substitution groups chosen separately from the halogen, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C 1-10 Alkyl)2, -NH(C 1-10 Alkyl), and -NH2; Where each of C 3-10 Cycloalkyl aryls containing 6 atoms, heterocyclic aryls containing 5 to 6 atoms, or heterocyclic cycloids containing 4 to 8 atoms. The aforementioned aryls have no substitutions or are substituted with 1, 2, or 3 R atoms. 1 d ; R is selected 1d From halogen, -C 1-10 Alkyl, -C 1-10 Alkoxy, f-halo C1 - 10 Alkyl; Where -C 1-10 The alkyl group mentioned has no substitution or has a substitution of 1, 2, or 3 substitution groups chosen separately from -CN, -OR 1h and -NR 1h R 1i ; Both R and 1h and R 1i Separately from hydrogen, methyl, ethyl, 1-propyl, and 2-propyl; X 1 It is N or CR 61 R 61 If found, it is hydrogen, or -C 1-10 Alcox; R 62 It consists of hydrogen, halogen, deuterium, and -C 1-10 Alkyl, -SC 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, monocyclic heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, monocyclic aryls containing 5 or 6 atoms, -CN, or -NR 3 a R 3 b Where each of -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C1 - 10 Cycloalkyl monocyclic, C1 - 10 Cyclo-alkyl monocyclic, C1 - 10 Monocyclic cycloalkenyls, heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms chosen separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, or monocyclic aryls containing 5 or 6 atoms, the aforementioned have no substitution or have been substituted by 1, 2, or 3 R atoms 3 d; Each of R 3a and R 3b Separately, it is a hydrogen-based compound, -C 1-5 Alkyl, -C2 - 5-Alkenyl, -C2 - 5-Alkenyl, or C3 - 6. Monocyclic cycloalkyl; Each of R 3d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknell, -C 1-10 Alcox, -C2 - 10 Alkenyl or C3 - 6. Monocyclic alkyl groups. R 63 It is hydrogen or deuterium; R 64 These are hydrogen, deuterium, halogen, -CN, -C 1-10 Alkyl, or -C 1-10 Alcox.

[0116] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 If found, it will be R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5 alkyl); R 2 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 4 It is a 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, oxetanyl, tetrahydrofuranyl, dioxanyl, oxazolyl, 8-oxa-3-aza-bycyclo[3.2.1]octanyl, 2-oxaspiro[3.3]heptanyl, or pyrazolyl; Where each of the following is present: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, either without substitution or with substitution by 1, 2, or 3 substitution groups chosen separately from the halogen, -C 1-10 Alkyl, -Halo C1 - 10 Alkyl, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C 1-10 Alkyl)2, -NH(C 1-10 Alkyl), and -NH2; and Where each of the following is present: cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinel, piperidinyl, tetrahydropyranil, oxetanil, tetrahydrofuranil, dioxanil, oxazolyl, or pyrazolyl mentioned, it is either unsubstituted or substituted with 1, 2, or 3 of the R 1 d ; and R is selected 1d From halogen, -C 1-10 Alkyl, -C 1-10 Alkoxy, f-halo C1 - 10 Alkyl; Where -C 1-10 The alkyl mentioned has no substitution or has a substitution of 1, 2, or 3 substitution groups chosen separately from -CN, hydroxy, methoxy, -NH2, and -N(CH3)2.

[0117] In some incarnations of the compound with the formula (I) or the formula (III-1), R 4 It is 2-oxa-bicyclo[2.1.1]hexanil, or bicyclo[1.1.1]pentanil.

[0118] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 If found, it will be R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5 alkyl); R 2 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It consists of hydrogen, deuterium, halogen, and -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 4 It is - t Bu, , , , , , , , , , , , , , , , , , , or ; X 1 It is N or CR 61 , If R 61 It exists, R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0119] In some incarnations of the compound with the formula (I) or the formula (III-1), R 4 It is or .

[0120] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 If found, it will be R 5 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl;R 4 It is - t Bu, , , or ; R 61 R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0121] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 R 5 It is hydrogen, R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 alkyl(-C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (-Halo C1 - 5 alkyl); R 2 It is hydrogen; R 3 It is hydrogen; R 4 -C 1-5 Alkyl or -halo C1 - 5 alkyl; X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Separately, it is -C 1-5 Alkyl, -C2 - 5Alkenyl, C3 - 6-C1-cyclic alkyl monocyclic alkyl group, or -C1 - 5. Alkoxy.

[0122] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 R 5 It is hydrogen, R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl, -C 1-10 Alkyl or -halo C1 - 10 Alkyl; R 2 It is hydrogen; R 3 It is hydrogen; R 4 -C 1-5 Alkyl or -halo C1 - 5 alkyl; X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Separately, it is -OC 1-10 Deuterium-treated alkyl.

[0123] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 R 5 It is hydrogen, R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 alkyl(-C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (-Halo C1 - 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-methylpropanyl; X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Each of these is a methyl, ethyl, cyclopropyl, ethnyl, -OCD3, or methoxy.

[0124] In some incarnations of the compound with the formula (I) or the formula (III-1), A 5 It is N or CR 5 R 5 It is hydrogen, R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-5 Deuterium-treated alkyl, -C 1-5 Alkyl or -halo C1 - 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-methylpropanyl; X 1 It is N or CR 61 , If R 61 It exists; each of R 61 R 63 and R 64 Separately, it is hydrogen; Each R 62 Separately, it is -OCD3.

[0125] In some incarnations side 1 The compound has the formula (VI): (WE), Or a salt, a deuterium-treated isotope, N-oxide, or a pharmaceutically acceptable chemical analog thereof, where: X 1 It is N or C(H); R 62 It is ethyl, ethnyl, cyclopropyl, -OCD3, or methoxy; R 4 It is or ; A 5 CR 5 Or N; if present, R 5 It is hydrogen; and R 4 c It is a methyl or -CF3; or R forms 5 and R 4c Together with the atoms they are bonded to and the intervening atoms, the dihydrofuranyl or dihydropyranyl ring has no substitution or is substituted by 1 or 2 R atoms. 1 d ; R 1d It is a methyl.

[0126] In some incarnations side 7 A compound with the formula (I) is a compound with the formula (III-2): (III-2). In some incarnations of the compound which has the formula (III-2), R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl, -C 1-10 Alkyl or -halo C1 - 10 Alkyl; R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; The C ring is a heterocyclic cyclic molecule containing between 5 and 7 atoms and containing 1, 2 or 3 heteroatoms selected separately from nitrogen, oxygen and selectively oxidized sulfur; Each R 1d Separately, it consists of hydrogen, halogen, and -C. 1-5 Alkyl, or -halo C1 - 5-alkyl; or Two Rs form 1d They involve substitution on identical or different atoms, together with the atom(s) they are bonded to and any overlapping atoms, C3 - 10 A monocyclic alkyl, or a monocyclic heterocyclic, contains between 4 and 10 atoms and contains 1, 2 or 3 heteroatoms selected separately from nitrogen, oxygen and optionally oxidized sulfur; X 1 It is N or CR 61 R 61 If found, it is hydrogen, or -C 1-10 Alcox; R 62 It is hydrogen, halogen, -C 1-10 Alkyl, -OC 1-10 Deuterium-treated alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl monocyclic, C3 - 10 Cyclo-alkyl monocyclic, C3 - 10 Monocyclic cycloalkenyls, monocyclic heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, monocyclic aryls containing 5 or 6 atoms, -CN, or -NR 3 a R 3 b Where each of -C 1-10 Alkyl, -C2 - 10 Alknel, -C2 - 10 Alkenyl, -C 1-10 Alcox, C1 - 10 Cycloalkyl monocyclic, C1 - 10 Cyclo-alkyl monocyclic, C1 - 10 Monocyclic cycloalkenyls, heterocyclic cyclyls containing 4 to 10 atoms and containing 1, 2, or 3 heteroatoms selected separately from nitrogen, oxygen, and optionally oxidized sulfur, monocyclic aryls containing 6 atoms, or monocyclic aryls containing 5 or 6 atoms mentioned above, either without substitution or with 1, 2, or 3 substitutions of R 3d ; Each of R 3a and R 3b Separately, it is a hydrogen-based compound, -C 1-5 Alkyl, -C2 - 5-Alkenyl, -C2 - 5-Alkenyl, or C3 - 6. Monocyclic cycloalkyl; Each of R 3d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C2 - 10 Alknell, -C 1-10 Alcox, -C2 - 10 Alkenyl or C3 - 6. Monocyclic cycloalkyl. R 63 It is hydrogen; R 64 It is hydrogen, halogen, -CN, -C 1-10 Alkyl, or -C 1-10 Alcox.

[0127] In some incarnations of the compound with the formula (III-2), the C ring is a dihydrofuranil or dihydropyranil; Each R 1d Separately, it consists of hydrogen, halogen, -C1 - 4-Alkyl, -Halo C1 - 4-alkyl, or -C1 - 4. Alkoxie; or two R 1d They have a substitution on an identical or different atom(s), together with the atom(s) they are bonded to and any overlapping atoms, a cyclobutyl ring, or tetrahydropyranyl.

[0128] In some incarnations of the compound with the formula (III-2), the compound has the formula (IV-1): (IV-1).

[0129] In some incarnations of the compound with the formula (IV-1), R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (-Halo C1 - 5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; Each R 1d Separately, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; or Two Rs form 1d They involve substitution on an identical or different atom(s), together with the atom(s) they are bonded to and any overlapping atoms, a cyclobutyl ring, or tetrahydropyranyl; X 1 It is N or CR 61 ; R 61 If you find a form of hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, -OCD3, methyl, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

[0130] In some incarnations of the compound with the formula (III-2), the compound has the formula (V-1): (V-1).

[0131] In some incarnations of the compound with the formula (III-2), the compound has the formula (V-2): (V-2).

[0132] In some incarnations of the compound with the formula (III-2), the compound has the formula (V-3): (V-3).

[0133] In some incarnations of the compound which has the formula (V-1), the formula (V-2), or the formula (V-3), R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 Alkyl (preferably, -C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (preferably, -Halo C1) - 5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; X 1 It is N or CR 61 ; R 61 If you find a form of hydrogen; Each R 1d Separately, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; or Two Rs form 1d They involve substitution on an identical or different atom(s), together with the atom(s) they are bonded to and any overlapping atoms, a cyclobutyl ring, or tetrahydropyranyl; X 1 It is N or CR 61 ; R 61 If you find a form of hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxytanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

[0134] In some incarnations of the compound with the formula (III-2), the compound has the formula (IV-4): (IV-4).

[0135] In some incarnations of the compound which has the formula (V-4), R 1 It is -OR 1a And R 1a It is hydrogen, -C 1-10 Deuterium-treated alkyl (preferably, -C 1-5 Alkyl (deuterium-treated), -C 1-10 alkyl(-C 1-5 Alkyl) or -Halo C1 - 10 Alkyl (-Halo C1 - 5 alkyl); R 2 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; R 3 It is hydrogen, halogen, -C 1-3 Alkyl or -halo C1 - 3. Alkyl; Each R 1d Separately, 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 It is N or CR 61 ; R 61 If you find a form of hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0136] In some incarnations of compound (III-2), the compound has the formula (V-4): (V-4).

[0137] In some incarnations of compound (III-2), the compound has the formula (V-5): (V-5).

[0138] In some incarnations of the compound which has the formula (V-4), or the formula (V-5), X 1 It is N or CR 61 ; R 61 If you find a form of hydrogen; R 63 and R 64 It is hydrogen; R 62 It is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethnyl, prop-1-nyl, prop-2-nyl, ethinyl, 1-propenyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, -OCD3, ethoxy, propoxy, pyrrolidinyl, furanil, pyrazolyl, oxazolyl, oxytanyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

[0139] In some incarnations of the compound which has the formula (III-2), the formula (IV-1), the formula (IV-4), the formula (V-1), the formula (V-2), the formula (V-4), or the formula (V-5), R 1 It is -OR 1a And R 1a It is a 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.

[0140] In some incarnations of the compound which has the formula (III-2), the formula (IV-1), the formula (IV-4), the formula (V-1), the formula (V-2), the formula (V-4), or the formula (V-5), R 1 It is -OR 1a And R 1a It is a methyl; R 2 It is hydrogen; R 3 It is hydrogen; R 63 and R 64 It is hydrogen; R 62 It is a methyl, ethyl, cyclopropyl, methoxy, -OCD3, or ethoxy.

[0141] In some incarnations of the compound having the formula (III-2), formula (IV-1), formula (IV-4), formula (V-1), formula (V-2), formula (V-4), or formula (V-5), R 1 It is -OR 1a And R 1a It is a 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 methyl, ethnyl, cyclopropyl, methoxy, or ethoxy.

[0142] In some incarnations of the compound which has the formula (III-2), the formula (IV-1), the formula (IV-4), the formula (V-1), the formula (V-2), the formula (V-4), or the formula (V-5), R 1 It is -OR 1a And R 1a It is a 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.

[0143] In the first incarnation according to For the side 7 R 1 It is -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.

[0144] In a second incarnation according to For side 7 R 1 It is -OR 1a And R 1a It is methyl, ethyl, 1-propyl, or 2-propyl.

[0145] In a third incarnation according to For side 7 R 1 It is -OR 1a And R 1a It is a methyl.

[0146] In a fourth incarnation according to For side 7 R 1 It is -OR 1a And R 1a It is a CD3.

[0147] side 8 The compound according to which of Aspects 1 - 7 R 2 It is hydrogen.

[0148] side 9 The compound according to which of Aspects 1 - 8 A 5 CR 5 A 4 CR 4 A 3 CR 3 .

[0149] side 10 The compound according to which of Aspects 1 - 9 R 3 and R 5 It is hydrogen; and R 4 -C 1-10 Alkyl, -C 1-10 Alcox, C3 - 10 Cycloalkyl, aryl containing 6 atoms, heterocyclic aryl containing 5 to 6 atoms and containing 1, 2 or 3 heteroatoms selected separately from nitrogen, oxygen and optionally oxidized sulfur, or heterocyclic cyclic aryl containing 4 to 6 atoms and containing 1, 2 or 3 heteroatoms selected separately from nitrogen, oxygen and optionally oxidized sulfur; Where -C 1-10 The alkyl group mentioned has no substitution or is substituted by 1, 2, or 3 substitution groups chosen separately from the halogen, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C 1-10 Alkyl)2, -NH(C 1-10 Alkyl), and -NH2; Where C3 - 10 Cycloalkyl aryls containing 6 atoms, heterocyclic aryls containing 5 to 6 atoms, or heterocyclic cycloids containing 4 to 6 atoms, are either unsubstituted or have one, two, or three separately selected substitution groups from a halogen, -C 1-10 Alkyl, -C 1-10 Alkoxy, f-halo C1 - 10 Alkyl.

[0150] In a first incarnation according to For the side 10 where R 3 and R 5 It is hydrogen; R 4 It is a 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, oxytanyl, tetrahydrofuranyl, dixanyl, oxazolyl, or pyrazolyl; Where each of the aforementioned methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, has no substitution or is substituted by 1, 2, or 3 substitution groups chosen separately from the halogen, -OC 1-10 Alkyl, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C 1-10 Alkyl)2, -NH(C 1-10 Alkyl), and -NH2; and Where each of the aforementioned cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, oxazolyl, or pyrazolyl has no substitution or has a substitution of 1, 2, or 3 substitution groups chosen separately from the halogen, -C 1-10 Alkyl, --OC 1-10 Alkyl, and Halo C1 - 10 Alkyl.

[0151] In a second incarnation according to For the side 10 R 3 and R 5 It is hydrogen; R 4 It is - t Bu, , , , , , , , , , , , , , , or .

[0152] In a third incarnation according to For the side 10 R 3 and R 5 It is hydrogen; R 4 It is - t Bu, , , or .

[0153] In a fourth incarnation according to For the side 10 R 3 and R 5 It is hydrogen; R 4 It is - t Bu.

[0154] side 11 The compound according to which of Aspects 1 - 8 R 3 It is hydrogen; and it forms (R 4 and R 5 Together with the atoms to which they are bonded, a heterocyclic ring containing 5 to 6 atoms and 1, 2, or 3 atoms of nitrogen, oxygen, and selectively oxidized sulfur is formed, where the aforementioned heterocyclic ring has no substitution or is substituted by 1, 2, 3, or 4 of R. 1 d ; and Each R 1d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C 1-10 Alkoxy, heterocyclic compounds containing 4 to 6 atoms, or -halo C1 - 10 Alkyl.

[0155] In a first incarnation according to For the side 11 R 3 It is hydrogen; and it forms (R 4 and R 5 Together, in addition to the atoms to which they are bonded, dihydrofuranyl or dihydropyranyl; Where each of the aforementioned dihydrofuranil or dihydropyranil is either unsubstituted or substituted with 1, 2, 3, or 4 of R 1 d ; and Each R 1d Separately, it consists of hydrogen, halogen, -C1 - 4-Alkyl, -Halo C1 - 4-alkyl, or -C1 - 4. Alkoxy.

[0156] In a second incarnation according to For the side 11 R 3 It is hydrogen; it forms (R 4 and R 5 ), together with the atoms to which they are bonded, or Which has no substitution or has a substitution of 1, 2, 3, or 4 of R 1 d ; and Each R 1d Separately, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl.

[0157] In a third incarnation according to For the side 11 R 3 It is hydrogen; and it forms (R 4 and R 5 ), together with the atoms to which they are bonded, , or .

[0158] In a fourth incarnation according to For the side 11 R 5 It is hydrogen; and it forms (R 3 and R 4 Together with the atoms to which they are bonded, the cycloalkyl ring contains 5 to 6 atoms, and the heterocyclic ring contains 5 to 6 atoms and 1, 2, or 3 heteroatoms chosen separately from nitrogen, oxygen, and selectively oxidized sulfur, where the aforementioned heterocyclic ring contains no substitution or is substituted by 1, 2, 3, or 4 R atoms. 1 d ; and Each R 1d Separately, it consists of hydrogen, halogen, and -C. 1-10 Alkyl, -C 1-10 Alcox, or -Halo C1 - 10 Alkyl.

[0159] In a fifth incarnation according to side 11, R 5 It is hydrogen; and it forms (R 3 and R 4 Together, in addition to the atoms to which they are bonded, cyclopentyl or cyclopropanel; Where each of the dihydro-pyrrolelyl or pyrrolidinyl mentioned has no substitution or has a substitution of 1, 2, 3, or 4 of R 1 d ; and Each R 1d Separately, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl.

[0160] In a sixth incarnation according to For the side 11 R 3 It is hydrogen; and it forms (R 4 and R 5 ), together with the atoms to which they are bonded, Which also has no substitution or has a substitution of 1 or 2 of R d ; and Each R 1d Separately, it is hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl.

[0161] side 12 The compound according to which of Aspects 1 - 8 A 5 It is N; A is 4 CR 4 A 3 CR 3 R 3 It is H; R is 4 -C 1-10 Alkyl, C3 - 10 A cycloalkyl, or heterocyclic cycloalkyl, contains between 4 and 6 atoms and contains 1, 2 or 3 heteroatoms selected separately from nitrogen, oxygen and optionally oxidized sulfur; Where each of -C 1-10 The alkyl group mentioned has no substitution or is substituted by 1, 2, or 3 substitution groups chosen separately from the halogen, C1 - 10 Alkox, cycloalkyl, cycloalkenyl, cycloalkenyl, heterocyclic, aryl, heterocyclic, -CN, -NO2, -CO2C 1-10 Alkyl, -N(C 1-10 Alkyl)2, -NH(C 1-10 Alkyl), or -NH2; where each of C3 - 10 A heterocyclic alkyl or cyclyl atom contains 4 to 6 atoms, either without substitution or with 1, 2, or 3 substitution groups chosen separately from a halogen, -C 1-10 Alkyl, -C 1- 10 Alkoxy, f-halo C1 - 10 Alkyl.

[0162] In the first incarnation according to For the side 12 A 5 It is N; A is 4 It is -CR 4 A 3 It is -CR 3 R 3 It is H; R is 4 It is a methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, or cyclopentyl; Where each of the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, or cyclopentyl mentioned has no substitution or has a substitution by 1, 2, or 3 substitution groups chosen separately from methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0163] In a second incarnation according to For the side 12 A 5 It is N; A is 4 CR 4 A 3 CR 3 R 3 It is H; and R is 4 It is - t Bu, or .

[0164] In a third incarnation according to For the side 12 A 5 It is N; A is 4 CR 4 A 3 CR 3 (R) 3 and R 4 Together with the atoms to which they are bonded, a heterocyclic ring containing 5 to 6 atoms and 1, 2, or 3 heteroatoms chosen separately from nitrogen, oxygen, and selectively oxidized sulfur, where the aforementioned heterocyclic ring containing 5 to 6 atoms has no substitution or has a substitution of 1, 2, or 3 R atoms 1 d ; and Each R 1d Separately, it is hydrogen, or -C 1-10 Alkyl.

[0165] In a fourth incarnation according to For the side 12 A 5 It is N; A is 4 CR 4 A 3 CR 3 And it forms (R 3 and R 4 Together, in addition to the atoms to which they are bonded, dihydro-pyrrolelyl or pyrroledinyl; Where each of the dihydro-pyrrolelyl or pyrrolidinyl mentioned has no substitution or has a substitution of 1, 2 or 3 of R 1 d ; and Each R 1d Separately, it consists of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl.

[0166] In a fifth incarnation according to For the side 12 A 5 It is N; A is 4 CR 4 A 3 CR 3 And it forms (R 3 and R 4 ), together with the atoms to which they are bonded, Which also has no substitution or has a substitution of 1, 2 or 3 of R 1 d ; and Each R 1d Separately, it consists of hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl.

[0167] In a sixth incarnation according to For the side 12 A 3 It is N; A is 4 CR 4 A 5 CR 5 R 4 It is H; and R is 5 -C 1-10 Alcox.

[0168] In a seventh incarnation according to For the side 12 A 3 It is N; A is 4 CR 4 A 5 CR 5 R 4 It is H; and R is 5 It is methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0169] In an eighth incarnation according to side 12, A 4 It is N; A is 3 CR 3 A 5 CR 5 R 3 It is H; and R is 5 -C 1-10 Alcox.

[0170] In a ninth incarnation according to side 12, A 4 It is N; A is 3 CR 3 A 5 CR 5 R 3 It is H; and R is 5 It is methoxy, ethoxy, propoxy, isopropoxy, or butoxy.

[0171] In some incarnations according to any of the aspects 1-12, each R 7 It is hydrogen.

[0172] side 13 A compound with the formula (I), where the compound has the formula (VI): (WE), Or a salt, a deuterium-treated isotope, N-oxide, or a pharmaceutically acceptable chemical analog thereof, where: X 1 It is N or CH; R 62 It is ethyl, ethnyl, cyclopropyl, or methoxy; A 5 It is N or CR 5 If found, it will be R 5 It is hydrogen; R 4 It is or ; and A 5 CR 5 Or N; if present, R 5 It is hydrogen.

[0173] side 14 A compound that is selected from Or a pharmaceutically acceptable salt of it, or a deuterium-treated isotope of it, or N-oxide of it, or a chemical analog of it.

[0174] side 14 ’ A compound that is selected from Or a pharmaceutically acceptable salt of it, or a deuterium-treated isotope of it, or N-oxide of it, or a chemical analog of it.

[0175] side 15 A pharmaceutical formulation containing a compound according to any of the Aspects 1 - 14 , or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or N-oxide thereof, or a chemical analog thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0176] side 16 A method for treating breast cancer involves giving a patient in need of treatment a compound according to any of the aspects 1-14, or a pharmaceutically acceptable salt of it, or a deuterium-treated isotope of it, or N-oxide of it, or a chemical analog of it.

[0177] side 17 The use of a compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, to treat breast cancer in a patient in need of treatment, involves giving the patient a therapeutically effective amount of the compound.

[0178] side 18 A compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, for use in the treatment of breast cancer in a patient in need of treatment, where the treatment involves giving the patient a therapeutically effective amount of the compound.

[0179] side 19 A compound with the formula (I), or a pharmaceutically acceptable salt thereof, or a deuterium-treated isotope thereof, or an N-oxide thereof, or a chemical analog thereof, for the manufacture of a drug useful in the treatment of breast cancer in a patient undergoing treatment who needs it. Examples

[0180] The examples below are intended to be purely illustrative and should not be considered restrictive in any way. Efforts have been made to ensure accuracy with respect to the figures used (e.g., quantities, temperature, etc.), but some experimental errors and deviations should be taken into account. Unless otherwise specified, temperature is measured in degrees Celsius. The reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.

[0181] Unless otherwise indicated, the reactions described below were carried out under positive pressure of nitrogen or argon or using a drying tube in anhydrous solvents; reaction flasks were fitted with rubber baffles for the introduction of substrates and reagents using a syringe; and glassware was dried in an oven and / or by heat.

[0182] Unless otherwise indicated, the reactions described below were carried out under positive pressure of nitrogen or argon or using a drying tube in anhydrous solvents; reaction flasks were fitted with rubber baffles for the introduction of substrates and reagents using a syringe; and glassware was dried in an oven and / or by heat.

[0183] Unless otherwise indicated, purification was performed with a chromatography column on a Biotage system (manufacturer: Dyax Corporation) containing a silica gel column or on a SepPak silica cartridge (Waters), or was performed on a Teledyne Isco Combiflash purification system using pre-filled silica gel cartridges.

[0184] 1H NMR spectra were recorded on a Varian meter operating at a frequency of 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 solvent (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) in the reference standard image. When reporting a large number of peaks, the following abbreviations are used: s (single), d (double), t (triple), q (quadruple), qn (pentruple), sx (hex), m (multiple), br (wide), dd (double pairs), dt (double triples). Coupling constants, where provided, are expressed in hertz (Hz). Compound names, excluding reagents, were generated using ChemDraw version 12.0.

[0185] Abbreviations: EDCI AcOH ACN 1-Ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride acetic acid acetonitrile Aq AIBN water 2,2'-Azo-Base (2-methylpropionitrile) Brian Saturated aqueous sodium chloride solution Bn Benzel BnBr (Boc)2O Cy3P benzyl bromide Di-tert-butyl dicarbonate Tricyclohexylphosphine DMF BPO N,N-Dimethylformamide Dibenzoyl peroxide Dppf 1,1"-Base (Diphenylfosphenol) Virusen DBU 1,8-Diaza by Cyclo[5.4.0]Undis-7-ene DIEA or DIPEA N-Ethyl-N-isopropylpropane-2-amine DMAP DMAC 4-N,N-Dimethylaminopyridine Dimethylacetamide DMF N,N-Dimethylformamide DMSO DME Dtbpy DCM DIC DABCO Dimethyl sulfoxide 1,2-Dimethoxyethane 4,4-Di-tert-butylpyridin Dichloromethane N,N'-Diisopropylcarbodiimide 1, 4-DiAza by Cyclo [2.2.2] Octane EA Ethyl acetate EtOH ethanol Et2O or Ether Et3N Diethyl ether Triethylamine HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluranium hexafluorophosphate HPLC High-performance liquid chromatography IPA LDA 2-Propanol Lithium diisopropylamide i-PrOH Isopropyl alcohol ms or MS Mass spectrum MTBE 2-Methoxy-2-methylpropane NaHMDS NBS Sodium hexamethylene dicellazane N-Bromosuccinimide PE petroleum ether PPA polyphosphoric acid p-TSA p-Toluenesulfonic acid Rt Time of detention rt Room temperature TBAF Tetra-butyl ammonium fluoride TBSCl Tert-butyldimethylsilyl chloride TFA TEA Trifluoroacetic acid Triethylamine THF TLC Pre-TLC hr / hrs Tetrahydrofuran Thin-layer chromatography Preparatory thin-layer chromatography hour

[0186] Example A:

[0187] Example A1: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoic acid

[0188]

[0189] Step 1: Methyl 4-(bromomethyl)-3-iodobenzoate

[0190] AIBN (0.24 g, 1.45 mmol) was added at room temperature 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). The resulting mixture was stirred at 70 °C for 6 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain 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).

[0191] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate

[0192] 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), K₂CO₃ (2.80 g, 20.28 mmol) was added at room temperature. The resulting mixture was stirred briefly at 70 °C. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to obtain a product (2.5 g, 72%). MS (ESI) m / e [M+H]+ = 343.

[0193] Step 3: 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoic acid

[0194] 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), NaOH (2 nM, 5 mL) was added by distillation. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated and acidified with HCl (3 nM) to a pH of ~4. The precipitate was collected by filtration to obtain the desired compound (730 mg, 95%). MS (ESI) m / e [M+H]+ = 329.

[0195] Example A2: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-ethinylbenzoic acid

[0196] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-((trimethylsilyl)ethinyl)benzoate

[0197] 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) was stirred in ACN (5 mL) at 80 °C under a nitrogen atmosphere for a short time. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and sequentially filtered using PE / EA (10:1) to obtain the product (260 mg, 95%). MS (ESI) m / e [M+H]+ = 313.1.

[0198] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-ethinylbenzoic acid

[0199] To a stirred solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-((trimethylsilyl)ethinyl)benzoate (260 mg, 0.83 mmol) in THF (6 mL) and H₂O (2 mL), LiOH (40 mg, 1.67 mmol) was added in fractions at 0°C. The resulting mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the mixture was acidified to pH 2 using HCl (1 nM). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18; mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% in 20 minutes). The fractions containing the product were collected and evaporated to obtain 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.

[0200] Example A3: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoic acid

[0201] Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate

[0202] A solution of methyl 3-bromo-4-methyl benzoate (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 hours. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted using DCM. The organic layer was concentrated, and the crude material 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.

[0203] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate

[0204] 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) was stirred in DMF (100 mL) at 60 °C for 2 hours. After cooling to room temperature, 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 = 4:1) to obtain the product (3.7 g, 82%). MS (ESI) m / e [M+H]+ = 295, 297.

[0205] Step 3: 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoic acid

[0206] 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), NaOH (2 nM, 5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated under vacuum. The pH of the reaction was adjusted to 3 with HCl (3 nM). The precipitate was collected by filtration and dried to obtain the desired compound (800 mg, 84%). MS (ESI) m / e [M+H]+ = 281, 283.

[0207] Example A4: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoic acid

[0208] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoate

[0209] 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) was stirred in THF (10 mL) at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated. Water was added, and the mixture was extracted with EA. The organic layer was concentrated, and the crude was purified by silica gel column chromatography (PE / EA = 4:1) to obtain the product (240 mg, 97%). MS (ESI) m / e [M+H] + = 243.

[0210] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoic acid

[0211] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoate (240 mg, 1 mmol) in MeOH (5 mL) and THF (5 mL), NaOH (2 nM, 5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction was complete, the mixture was concentrated. The pH of the reaction was adjusted to 3 with HCl (3 nM). The precipitate was collected by filtration to obtain the desired compound (180 mg, 80%). MS (ESI) m / e [M+H] + = 229.

[0212] Example A5: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoic acid

[0213] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropyl benzoate

[0214] 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) was stirred in DMAc (5 mL) at 140 °C under an N2 atmosphere for 4 hours in a microwave reactor. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted with EA. The organic layer was concentrated, and the crude was purified by preparative TLC (PE / EA = 1:3) to obtain the product (20 mg, 11.5%). MS (ESI) m / e [M+H] + = 257.

[0215] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropylbenzoic acid

[0216] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropyl benzoate (20 mg, 0.08 mmol) in MeOH (2 mL) and THF (2 mL), NaOH (2 nM, 2 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction was complete, the mixture was concentrated. The pH of the reaction was adjusted to 3 with HCl (3 nM). The precipitate was collected by filtration to obtain the desired compound (15 mg, 79%). MS (ESI) m / e [M+H] + = 243.

[0217] Example A6: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoic acid

[0218] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoate

[0219] Bubbles of N2 were passed through a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (100 mg, 0.34 mmol), potassium methoxymethyl trifluoroborate (62 mg, 0.41 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8 mg, 0.007 mmol), NiCl2.glyme (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 DMAC (2 mL) for 2 minutes and then stirred at room temperature under a blue LED for 6 hours. Immediately after the reaction, the mixture was diluted with EA. The organic layer was washed with water, rinsed, dried with Na2SO4, filtered, and concentrated. The remaining material was purified by silica gel column chromatography with PE / EA (sequential filtration from PE to EA) to obtain the desired product (25 mg, 26%). MS (ESI) m / e [M+H]+ = 261.2.

[0220] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(methoxymethyl)benzoic acid

[0221] 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), NaOH (0.2 mL, 1 nM, 0.2 mmol) was added by distillation. The solution was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was diluted with EA and citric acid solution. The organic layer was washed with Brine, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (23 mg, crude). MS (ESI) m / e [M+H] + = 247.1.

[0222] Example 7: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoic acid

[0223] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoate

[0224] Bubbles of N2 were passed through a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (150 mg, 0.5 mmol), dimethylamine hydrogen chloride salt (61 mg, 0.75 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (11 mg, 0.01 mmol), NiCl2.glyme (11 mg, 0.05 mmol), and DABCO (196 mg, 1.75 mmol) in DMAC (5 mL) for 2 minutes and then stirred briefly at room temperature under a blue LED. Immediately after the reaction, the mixture was diluted with EA. The organic layer was washed with water, bleached, dried with Na2SO4, filtered, and concentrated. The remaining material was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the desired product (27 mg, 21%). MS (ESI) m / e [M+H] + = 260.1.

[0225] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(dimethylamino)benzoic acid

[0226] 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), NaOH (0.2 mL, 1 nM, 0.2 mmol) was added by distillation. The solution was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was acidified with HCl (1 nM) to a pH of 4 and concentrated. The residue was suspended in DCM / MeOH (10:1, 5 mL) for 5 minutes and filtered. The filtrate was concentrated, and the residue was used directly in the next step. (25 mg, crude). MS (ESI) m / e [M+H]+ = 246.3.

[0227] Example A8: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid

[0228] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoate

[0229] 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) was stirred briefly in DMF (100 mL) at 60 °C. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted with EA. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 3:7) to obtain the product (576 mg, 60.4%). MS (ESI) m / e [M+H]+ = 247.

[0230] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid

[0231] 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), NaOH (2 nM, 10 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated. The pH of the reaction mixture was adjusted to 3 with HCl (3 nM). The precipitate was collected by filtration to obtain the desired compound (460 mg, 84.7%). MS (ESI) m / e [M+H]+ = 233.

[0232] Example A9: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoic acid

[0233] Step 1: Methyl 5-bromo-2-fluoro-4-methyl benzoate

[0234] To a solution of 5-bromo-2-fluoro-4-methylbenzoic acid (1 g, 4.5 mmol) in MeOH (10 mL), concentrated H₂SO₄ (5 drops) was added, and the solution was stirred at 80 °C for 16 hours. After cooling to room temperature, the solvent was evaporated, and the residue was dissolved in EA. The organic layer was washed with NaHCO₃ solution, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the desired product (1 g, 95%). MS (ESI) m / e [M+H]+ = 247, 249.

[0235] Step 2: Methyl 5-bromo-4-(bromomethyl)-2-fluorobenzoate

[0236] 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) was stirred in CCl4 (20 mL) at 80 °C for 16 hours. After cooling to room temperature, the solids were separated by filtration. The filtrate was washed with NaHCO3 solution, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the desired product (1.2 g, 90%). MS (ESI) m / e [M+H]+ = 325, 327.

[0237] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoate

[0238] 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), tBuOK (134 mg, 1.2 mmol) was added in batches. The reaction mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was diluted with EA. The organic layer was washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by PE / EA silica gel column chromatography (sequential filtration from PE to EA) to obtain the desired product (330 mg, 100%). MS (ESI) m / e [M+H]+ = 313, 315.

[0239] Step 4: 4-((1H-pyrazol-1-yl)methyl)-5-bromo-2-fluorobenzoic acid

[0240] 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), NaOH (0.34 mL, 6 nN, 2 mmol) was added by distillation. The solution was stirred at room temperature for 16 hours. Immediately after the reaction, the mixture was diluted with EA and citric acid solution. The organic layer was washed with Brine, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (300 mg, 99%). MS (ESI) m / e [M+H]+ = 299, 301.

[0241] Example A10: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoic acid

[0242] Step 1: 3-Bromo-2-fluoro-4-methylbenzoic acid

[0243] To a solution of 2-bromo-1-fluoro-3-methylbenzene (1.89 g, 10 mmol) in THF (30 mL), LDA (5.25 mL, 10.5 mmol, at a concentration of 2 M in THF) was added by distillation at less than -65 °C, and the solution was stirred at this temperature for 30 minutes. Crushed dry ice was added to the solution, and the solution was stirred at -65 °C for 1 hour. The mixture was then allowed to warm to room temperature and stirred briefly. The reaction mixture was diluted with EA, washed with citric acid solution, evaporated, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (2.1 g, crude). MS (ESI) m / e [M+H]+ = 233, 235.

[0244] Step 2: Methyl 3-bromo-2-fluoro-4-methyl benzoate

[0245] To a solution of 3-bromo-2-fluoro-4-methylbenzoic acid (2.1 g, 10 mmol) in MeOH (10 mL), SOCl2 (2 mL) was carefully added by distillation, and the solution was stirred at 80 °C for 3 hours. After cooling to room temperature, the solvent was evaporated, and the residue was purified by silica gel column chromatography (PE:EA = 10:1) to obtain the desired product (1.4 g, 57% in two steps). MS (ESI) m / e [M+H]+ = 247, 249.

[0246] Step 3: Methyl 3-Bromo-4-(bromomethyl)-2-fluorobenzoate

[0247] 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) was stirred in CCl4 (10 mL) at 80 °C for 16 hours. After cooling to room temperature, the solids were separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain the desired product (140 mg, 90%). MS (ESI) m / e [M+H]+ = 325, 327.

[0248] Step 4: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoate

[0249] 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), tBuOK (58 mg, 0.51 mmol) was added in batches. The reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, the mixture was concentrated. The residue was purified by PE / EA silica gel column chromatography (sequential filtration from PE to EA) to obtain the desired product (80 mg, 60%). MS (ESI) m / e [M+H]+ = 313, 315.

[0250] Step 5: 4-((1H-pyrazol-1-yl)methyl)-3-bromo-2-fluorobenzoic acid

[0251] 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), NaOH (0.1 mL, 6 nN, 0.6 mmol) was added by distillation. The solution was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was diluted with EA and citric acid solution, washed with Brine, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (60 mg, 77%). MS (ESI) m / e [M+H]+ = 299, 301.

[0252] Example A11: 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpiculinic acid

[0253] Step 1: 2-Bromo-3-(chloromethyl)pyridine

[0254] To a solution of (2-bromopyridine-3-yl)methanol (1.87 g, 10 mmol) in DCM (10 mL), SOCl2 (2.38 g, 20 mmol) was added by distillation at 0°C. The mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was diluted with water and extracted with DCM. The organic layer was concentrated to obtain the product (2.00 g, 97%). MS (ESI) m / e [M+H]+ = 206, 208.

[0255] Step 2: 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine

[0256] 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) was stirred briefly in DMF (10 mL) at 80 °C. Immediately after the reaction, the solvent was removed under vacuum. The crude material 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.

[0257] Step 3: 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine

[0258] 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 briefly at 140 °C under an N2 atmosphere. Immediately after the reaction, the mixture was concentrated. The crude material 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.

[0259] Step 4: 3-((1H-pyrazol-1-yl)methyl)-2-cyclopropylpyridine 1-oxide

[0260] 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) was briefly stirred in DCM (10 mL) at room temperature. Immediately after the reaction, the mixture was concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the product (1 g, 71%). MS (ESI) m / e [M+H]+ = 216.2.

[0261] Step 5: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-cyclopropylpyridine

[0262] The 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) was stirred briefly in DCE (10 mL) at 90 °C. Immediately after the reaction, the solution was diluted with water and extracted with EA. The organic layer was concentrated, and the crude material was purified with a C18 column (0.1% FA in water / ACN) to obtain 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.

[0263] Step 6: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinate

[0264] 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) was stirred in MeOH (10 mL) at 110 °C under a CO₂ (gas) atmosphere (15 atm) for a short time. After cooling to room temperature, the solution was concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the product (200 mg, 61%). MS (ESI) m / e [M+H]+ = 258.2.

[0265] Step 7: 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinic acid

[0266] A solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinate (200 mg, 0.78 mmol) and LiOH.H2O (100 mg, 2.38 mmol) was briefly stirred in THF / H2O (1:1) (10 mL) at 50 °C. After cooling to room temperature, the solution was concentrated under vacuum. The crude material was purified by column C18 (0.1% FA in water / ACN) to obtain the product (150 mg, 79%). MS (ESI) m / e [M+H]+ = 244.1.

[0267] Example A12: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-2-yl)benzoic acid

[0268] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-2-yl)benzoate

[0269] Bubbles of N2 were passed through a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-bromobenzoate (294 mg, 1 mmol), oxytane-2-carboxylic acid (204 mg, 4 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (22 mg, 0.02 mmol), NiCl2.glyme (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 DMAC (10 mL) for 2 minutes and then stirred at room temperature under a blue LED for a period of time. Briefly, immediately after the reaction, the mixture was diluted with EA, washed with water, dried with Na2SO4, filtered, and concentrated. The residue was purified using a silica gel column with PE / EA (sequential filtration from PE to EA) to obtain the desired product (140 mg, 51%). MS (ESI) m / e [M+H]+ = 273.2.

[0270] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-2-yl)benzoic acid

[0271] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-2-yl)benzoate (140 mg, 0.51 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (1 mL, 1 nM, 1 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, 1 nM HCl was added to the reaction mixture to a pH of 4, and the resulting solution was extracted with EA, washed with Brine, dried, concentrated, and distilled to obtain the product (80 mg, 61%). MS (ESI) m / e [M+H]+ = 259.0.

[0272] Example A13: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-3-yl)benzoic acid

[0273] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-3-yl)benzoate

[0274] To a mixture of oxetane-3-ol (111 mg, 1.5 mmol) and 5,7-di-tert-butyl-3-phenylbenzo[d]oxazol-3-imtetrafluoroborate (NHC, 553 mg, 1.4 mmol) in 2-methoxy-2-methylpropane (MTBE, 5 mL), pyridine (110 mg, 1.4 mmol) was added and the mixture was stirred at room temperature under an N2 atmosphere for 20 minutes. In another flask, bubbles of N2 were passed through 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), quinoclidine (122 mg, 1.1 mmol), and LiBr (87 mg, 1 mmol) in DMAC (5 mL) for 2 minutes. The MTBE reaction mixture was filtered, and the filtrate was added to the DMAC solution. Bubbles of N2 were passed through the resulting mixture for another 2 hours and stirred briefly at room temperature under a blue LED. Immediately after the reaction, the mixture was diluted with EA, washed with water, rinsed, dried with Na2SO4, filtered, and concentrated.The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to PE / EA = 1:2) to obtain the desired product (130 mg, 48%). MS (ESI) m / e [M+H]+ = 273.1.

[0275] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-3-yl)benzoic acid

[0276] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(oxytane-3-yl)benzoate (130 mg, 0.48 mmol) in THF (3 mL), MeOH (3 mL), and water (3 mL), NaOH (0.96 mL, 1 nM, 0.96 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was diluted with EA and citric acid solution, washed with Brine, dried with Na2SO4, filtered, and concentrated to obtain the desired product (90 mg, crude). MS (ESI) m / e [M+H]+ = 259.1.

[0277] Example A14: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(azitidine-1-yl)benzoic acid

[0278] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(azitidine-1-yl)benzoate

[0279] Bubbles of N2 were passed through a mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-iodobenzoate (342 mg, 1 mmol), azetidine (114 mg, 2 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (22 mg, 0.02 mmol), NiCl2.glyme (22 mg, 0.1 mmol), and DABCO (392 mg, 3.5 mmol) in DMAC (10 mL) for 2 minutes and then stirred briefly at room temperature under a blue LED. Immediately after the reaction, the mixture was diluted with EA, washed with water, rinsed, dried with Na2SO4, filtered, and concentrated. The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to EA) to obtain the desired product (200 mg, 74%). MS (ESI) m / e [M+H]+ = 272.2.

[0280] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(azitidine-1-yl)benzoic acid

[0281] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-(azitidine-1-yl)benzoate (200 mg, 0.74 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (1.5 mL, 1 nM, 1.48 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, citric acid solution to pH 4 was added to the reaction mixture, diluted with EA, washed with Brine, dried, and concentrated to obtain the product (120 mg, 63%). MS (ESI) m / e [M+H]+ = 258.1.

[0282] Example A15: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoic acid

[0283] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoate

[0284] To a mixture of cyclobutanol (108 mg, 1.5 mmol) and 5,7-Di-tert-butyl-3-phenylbenzo[d]oxazol-3-imtetrafluoroborate (NHC, 553 mg, 1.4 mmol) in 2-methoxy-2-methylpropane (MTBE, 5 mL), pyridine (110 mg, 1.4 mmol) was added and the mixture was stirred at room temperature under an N2 atmosphere for 20 minutes. In another flask, bubbles of N2 were passed through 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), quinoclidine (122 mg, 1.1 mmol), and LiBr (87 mg, 1 mmol) in DMAC (5 mL) for 2 minutes. The MTBE reaction mixture was filtered, and the filtrate was added to the DMAC solution. Bubbles of N2 were passed through the resulting mixture for another 2 hours and stirred briefly at room temperature under a blue LED. Immediately after the reaction, the mixture was diluted with EA, washed with water, rinsed, dried with Na2SO4, filtered, and concentrated.The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to PE / EA = 1:1) to obtain the desired product (220 mg, 81%). MS (ESI) m / e [M+H]+ = 271.1.

[0285] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-cyclobutylbenzoic acid

[0286] 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, 6 N, 1.8 mmol) was added, and the solution was stirred at room temperature for 3 hours. Immediately after the reaction, the reaction mixture was diluted with EA and washed with citric acid solution, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (150 mg, 72%). MS (ESI) m / e [M+H]+ = 257.1.

[0287] Example A16: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoic acid

[0288] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoate

[0289] 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) was stirred in DMF (20 mL) at 80 °C for 1 hour. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified with a silica gel column (PE / EA = 7:3) to obtain the product (800 mg, 93%). MS (ESI) m / e [M+H]+ = 251.

[0290] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-chlorobenzoic acid

[0291] 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), NaOH (2 N, 5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated, the pH was adjusted to 7 using HCl, and the precipitate was collected by filtration to obtain the desired compound (700 mg, 93%). MS (ESI) m / e [M+H]+ = 237.

[0292] Example A17: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinic acid

[0293] Step 1: Methyl 6-methoxy-5-methyl picolinate

[0294] To a solution of methyl 6-chloro-5-methyl picolinate (500 mg, 2.69 mmol) in MeOH (2 mL), a NaOMe / MeOH solution (2 mL, 30% w / w) was added, and the solution was stirred at 85 °C for 3 hours. After cooling to room temperature, the solution was diluted with EA, washed with citric acid solution, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (350 mg, 72%). MS (ESI) m / e [M+H]+ = 182.1.

[0295] Step 2: Methyl 5-(bromomethyl)-6-methoxypicolineate

[0296] A mixture of methyl 6-methoxy-5-methyl picolinate (326 mg, 1.8 mmol), NBS (325 mg, 1.89 mmol), and BPO (22 mg, 0.09 mmol) was stirred in CCl4 (10 mL) at 80 °C for 4 hours. After cooling to room temperature, the solids were separated by filtration, and the filtrate was washed with NaHCO3, pyridinized, dried with Na2SO4, filtered, and concentrated. The residue was dissolved in THF (10 mL) and diethyl phosphite (496 mg, 3.6 mmol) followed by TEA (363 mg, 3.6 mmol). The resulting solution was stirred at room temperature for 1 hour and diluted with EA. The solution was washed with citric acid, pyridinized, dried with Na2SO4, filtered, and concentrated. The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 2:1) to obtain the desired product (400 mg, 86%). MS (ESI) m / e [M+H]+ = 260, 262..

[0297] Step 3: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolineate

[0298] To a mixture of methyl 5-(bromomethyl)-6-methoxypicolineate (400 mg, 1.54 mmol) and 1H-pyrazole (315 mg, 4.63 mmol) in THF (10 mL), tBuOK (519 mg, 4.63 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, the mixture was diluted with EA, washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 1:4) to obtain the desired product (180 mg, 47%). MS (ESI) m / e [M+H]+ = 248.1.

[0299] Step 4: 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinenic acid

[0300] To a solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolineate (170 mg, 0.69 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (0.22 mL, 6 nN, 1.32 mmol) was added, and the solution was stirred briefly at room temperature. Immediately after the reaction, the reaction mixture was diluted with EA and citric acid solution, washed with Brine, dried with Na₂SO₄, filtered, and concentrated to obtain the desired 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 = 2.0 Hz, 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.

[0301] Example A18: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoic acid

[0302] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoate

[0303] 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) was stirred in DMF (10 mL) at 80 °C for 2 hours. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on a silica gel column (sequential filtration with 10%–50% EA in PE) to obtain the desired product (400 mg, 84%). MS (ESI) m / e [M+1]+ = 235.

[0304] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoic acid

[0305] A mixture of methyl 4-((1H-pyrazol-1-yl)methyl)-3-fluorobenzoate (400 mg, 1.70 mmol) and NaOH (340 mg, 8.51 mmol) was stirred in MeOH (5 mL) and H₂O (5 mL) at room temperature for 16 hours. Immediately after the reaction, the pH of the resulting mixture was adjusted to 4–5 with HCl (1 N). The resulting solution was extracted by DCM. The organic layer was concentrated. The residue was purified by reverse-phase flash chromatography (column, C18 reverse-phase; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 100% in 30 minutes; reagent, UV 254 nm) to obtain the desired product (200 mg, 53%). MS (ESI) m / e [M+1]+ = 221.

[0306] Example A19: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoic acid

[0307] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoate

[0308] 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) was stirred in DMF (5 mL) at 80 °C for 1 hour. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on a silica gel column (sequential filtration with 10%–50% EA in PE) to obtain the desired product (70 mg, 91%). MS (ESI) m / e [M+1]+ = 285.

[0309] Step 2: 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoic acid

[0310] 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) was stirred in MeOH (3 mL) and H₂O (3 mL) at room temperature for 16 hours. Immediately after the reaction, the pH of the resulting mixture was adjusted to 4–5 with HCl (1 N). The resulting solution was extracted by DCM. The organic layer was concentrated. The residue was purified by reverse-phase flash chromatography (column, C18 reverse-phase; mobile phase, MeCN in water (0.1% FA), gradient from 10% to 100% in 30 minutes; reagent, UV 254 nm) to obtain the desired product (40 mg, 60%). MS (ESI) m / e [M+1]+ = 271.

[0311] Example A20: Synthesis of 3-methyl-4-(pyridine-2-ylmethyl)benzoic acid

[0312] Step 1: Methyl 3-methyl-4-(pyridine-2-ylmethyl)benzoate

[0313] A mixture of methyl 4-bromo-3-methyl benzoate (350 mg, 1.5 mmol), potassium picolinate (340 mg, 1.8 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and xanthophos (36 mg, 0.06 mmol) was stirred in a 3 mL diglyme at 150 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EA and filtered through silica gel, washed with water, and bland. The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified with a silica gel column (PE / EA = 2:1) to obtain the desired product (230 mg, 64%). MS (ESI) m / e [M+H]+ = 242.

[0314] Step 2: 3-methyl-4-(pyridine-2-ylmethyl)benzoic acid

[0315] A mixture of methyl 3-methyl-4-(pyridine-2-ylmethyl)benzoate (230 mg, 0.95 mmol) and LiOH-H₂O (210 mg, 5 mmol) was stirred in THF (5 mL) / H₂O (5 mL) at room temperature for 24 hours. Immediately after the reaction, the reaction mixture was adjusted to pH 6 using 1 M aqueous HCl and extracted with EA. The organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated to obtain the desired compound (120 mg, 55%). MS (ESI) m / e [M+H]+ = 228.

[0316] Example A21: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoic acid

[0317] Step 1: Methyl 3-(difluoromethoxy)-4-methylbenzoate

[0318] To a solution of methyl 3-hydroxy-4-methyl benzoate (1.66 g, 10 mmol) in ACN (20 mL), KOH solution (10 mL, 5 N, 50 mmol) was added, and the solution was stirred at 0 °C for 5 minutes. Diethyl (bromodifluoromethyl) phosphonate (5.34 g, 20 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 3 hours. Immediately after the reaction, the solution was diluted with EA, washed with citric acid solution, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column using PE / EA (sequential filtration from PE to PE:EA = 4:1) to obtain the desired product (1.5 g, 69%). MS (ESI) m / e [M+H]+ = 216.9.

[0319] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethoxy)benzoate

[0320] 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) was briefly stirred in CCl4 (20 mL) at 80 °C. After cooling to room temperature, the solid was separated by filtration, and the filtrate was washed with NaHCO3, pyridinized, dried with Na2SO4, filtered, and concentrated. The residue was dissolved in THF (20 mL) and diethyl phosphite (1.9 g, 13.8 mmol), followed by TEA (1.39 g, 13.8 mmol). The resulting solution was stirred at room temperature for 1 h and diluted with EA. The solution was washed with citric acid, pyridinized, dried with Na2SO4, filtered, and concentrated. The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 4:1) to obtain the desired product (1 g, 49%). MS (ESI) m / e [M+H]+ = 295, 297.

[0321] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoate

[0322] 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), tBuOK (571 mg, 5.1 mmol) was added, and the reaction mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was diluted with EA, washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 1:2) to obtain the desired product (800 mg, 73%). MS (ESI) m / e [M+H]+ = 283.0.

[0323] Step 4: 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoic acid

[0324] 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), NaOH (0.9 mL, 6 nN, 5.4 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was diluted with EA and citric acid solution, washed with Brine, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (600 mg, 79%). MS (ESI) m / e [M+H]+ = 268.9.

[0325] Example A22: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoic acid

[0326] Step 1: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoate

[0327] 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) was stirred in 1,4-dioxane (20 mL) at 70 °C for 16 h. After cooling to room temperature, the solution was diluted with EA, washed with Brine, dried with Na₂SO₄, concentrated, and filtered. The residue was purified by silica gel column using PE / EA (sequential filtration from PE to PE:EA = 1:1) to obtain the desired product (600 mg, 83%). MS (ESI) m / e [M+H]+ = 242.9.

[0328] Step 2: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-formyl benzoate

[0329] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoate (600 mg, 2.48 mmol) in THF (20 mL) and water (10 mL), K₂OsO₄·2H₂O (46 mg, 0.12 mmol) was added, and the solution was stirred at room temperature for 10 minutes. NaIO₄ (1.6 g, 7.44 mmol) was then added, and the mixture was stirred at room temperature for 16 hours. Immediately after the reaction, the mixture was diluted with EA, washed with water, Na₂S₂O₃ solution, pyrene, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 1:4) to obtain the desired product (500 mg, 82%). MS (ESI) m / e [M+H]+ = 245.1.

[0330] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(hydroxymethyl)benzoate

[0331] To a solution of methyl 4-((1H-pyrazol-1-yl)methyl)-3-formyl benzoate (300 mg, 1.23 mmol) in MeOH (10 mL), NaBH4 (70 mg, 1.84 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was diluted with EA, washed with water, rinsed, dried with Na2SO4, filtered, and concentrated to obtain the desired product (280 mg, 92%). MS (ESI) m / e [M+H]+ = 247.0.

[0332] Step 4: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoate

[0333] 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-imtetrafluoroborate (NHC, 474 mg, 1.2 mmol) in 2-methoxy-2-methylpropane (MTBE, 4 mL), pyridine (118 mg, 1.5 mmol) was added and the mixture was stirred at room temperature under an N2 atmosphere for 30 minutes. In another flask, N2 bubbles were passed through a mixture of 2-((difluoromethyl)sulfonyl)benzo[d]thiazol (274 mg, 1.1 mmol), Cu(TMHD)2 (43 mg, 0.1 mmol), Ir(ppy)2(dtbbpy)PF6 (46 mg, 0.05 mmol), t-Butyrosulfate (44 mg, 0.11 mmol), and tetrabutylammonium benzoate (437 mg, 1.2 mmol) in DMSO (20 mL) for 2 minutes. The MTBE reaction mixture was filtered, and the filtrate was added to the DMSO solution. N2 bubbles were passed through the resulting mixture for another 2 hours and stirred briefly at room temperature under a blue LED. Once the reaction was complete, the mixture was diluted with EA, washed with water, dried with Na2SO4, filtered, and concentrated.The remaining material was purified by a silica gel column using PE / EA (sequential filtration from PE to EA) to obtain the desired product (200 mg, 71%). MS (ESI) m / e [M+H]+ = 281.0.

[0334] Step 5: 4-((1H-pyrazol-1-yl)methyl)-3-(2,2-difluoroethyl)benzoic acid

[0335] 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), NaOH (0.24 mL, 6 N, 1.44 mmol) was added, and the solution was stirred at room temperature for 16 hours. Immediately after the reaction, the reaction mixture was adjusted to a pH of 5 using citric acid solution and then diluted with EA. The mixture was washed with Brine, dried with Na2SO4, filtered, and concentrated to obtain the desired product (170 mg, 90%). MS (ESI) m / e [M+H]+ = 267.1.

[0336] Example A23: Synthesis of 3-methoxy-4-(pyridine-2-ylmethyl)benzoic acid

[0337] Step 1: Methyl 3-methoxy-4-(pyridine-2-ylmethyl)benzoate

[0338] A mixture of methyl 4-bromo-3-methoxybenzoate (100 mg, 0.4 mmol), potassium picolinate (80 mg, 0.48 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and xanthophos (24 mg, 0.04 mmol) was stirred in a 5 mL diglyme at 150 °C for 16 hours. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted using DCM. The organic layer was concentrated, and the crude material was purified using a silica gel column (PE / EA = 1:1) to obtain the product (65 mg, 62%). MS (ESI) m / e [M+H]+ = 258.

[0339] Step 2: 3-Methoxy-4-(pyridine-2-ylmethyl)benzoic acid

[0340] To a solution of methyl 3-methoxy-4-(pyridine-2-ylmethyl)benzoate (65 mg, 0.25 mmol) in MeOH (5 mL) and THF (5 mL), NaOH (2 nM, 5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated, the pH was adjusted to 7 using HCl, and the precipitate was collected by filtration to obtain the desired compound (55 mg, 89%). MS (ESI) m / e [M+H]+ = 244.

[0341] Example A24: Synthesis of 3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoic acid

[0342] Step 1: Methyl 4-(bromomethyl)-3-methoxybenzoate

[0343] A mixture of methyl 3-methoxy-4-methyl benzoate (1.0 g, 5.56 mmol), NBS (1.09 g, 6.11 mmol), and AIBN (183 mg, 1.11 mmol) was stirred in CCl4 (20 mL) at 90 °C for 2 hours. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted using DCM. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 10:1) to obtain the product (1.0 g, 70%). MS (ESI) m / e [M+H]+ = 259, 261.

[0344] Step 2: Methyl 3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoate

[0345] 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 room temperature for 30 minutes. Methyl 4-(bromomethyl)-3-methoxybenzoate (100 mg, 0.39 mmol) was then added, and the resulting mixture was stirred at room temperature for 30 minutes. Immediately after the reaction, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified with a silica gel column (PE / EA = 1:1) to obtain the product (70 mg, 69%). MS (ESI) m / e [M+H]+ = 261.

[0346] Step 3: 3-Methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzoic acid

[0347] 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), NaOH (2 N, 0.5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated, the pH was adjusted to 7 using HCl, and the precipitate was collected by filtration to obtain the desired compound (60 mg, 91%). MS (ESI) m / e [M+H]+ = 247.

[0348] Example A25: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethoxypicolinic acid

[0349] Step 1: Methyl 6-ethoxy-5-methyl picolinate

[0350] To a solution of methyl 6-chloro-5-methyl picolinate (500 mg, 2.69 mmol) in toluene (10 mL), a NaOEt / EtOH solution (2.75 g, 8.1 mmol, 20% w / w) was added, and the solution was stirred at 100 °C for 16 hours. After cooling to room temperature, the solution was diluted with EA, washed with citric acid solution, dried with Na2SO4, filtered, and concentrated. The residue was purified by a silica gel column using PE / EA (sequential filtration from PE to PE:EA = 1:1) to obtain the desired product (450 mg, 80%). MS (ESI) m / e [M+H]+ = 196.0.

[0351] Step 2: Methyl 5-(bromomethyl)-6-ethoxypicolineate

[0352] A mixture of methyl 6-ethoxy-5-methyl picolinate (450 mg, 2.29 mmol), NBS (421 mg, 2.37 mmol), and BPO (51 mg, 0.21 mmol) was stirred in CCl4 (10 mL) at 80 °C for 3 hours. After cooling to room temperature, the solids were separated by filtration, and the filtrate was washed with NaHCO3 solution, dried with Na2SO4, filtered, and concentrated. The residue was dissolved in THF (10 mL) and diethyl phosphite (581 mg, 2.29 mmol), followed by TEA (233 mg, 2.29 mmol). The resulting solution was stirred at room temperature for 2 hours and diluted with EA. The solution was washed with citric acid, dried with Na2SO4, filtered, and concentrated. The residue was purified using a silica gel column with PE / EA (sequential filtration from PE to EA) to obtain the desired product (350 mg, 56%). MS (ESI) m / e [M+H]+ = 273.9.

[0353] Step 3: 5-((1H-pyrazol-1-yl)methyl)-6-ethoxypicolinic acid

[0354] To a mixture of methyl 5-(bromomethyl)-6-ethoxypicolinate (350 mg, 1.28 mmol) and 1H-pyrazole (166 mg, 2.44 mmol) in THF (20 mL), tBuOK (273 mg, 2.44 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Immediately after the reaction, NaOH solution (1 mL, 6 nN, 6 mmol) was added to the reaction mixture, and it was stirred for an additional 2 hours. The mixture was adjusted to pH 5 using citric acid solution and diluted with EA, washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The remaining material was purified by column C18 using 0.1% FA in water / ACN (sequential filtration of 10% of 0.1% FA in water to ACN) to obtain the desired product (100 mg, 31%). MS (ESI) m / e [M+H]+ = 248.0.

[0355] Example A26: Synthesis of 6-methyl-5-(pyridine-2-ylmethyl)piculinic acid

[0356] Step 1: Methyl 6-methyl-5-(pyridine-2-ylmethyl)picolenate

[0357] A mixture of methyl 5-bromo-6-methyl picolinate (350 mg, 1.5 mmol), potassium picolinate (340 mg, 1.8 mmol), Pd2dba3 (20 mmol, 0.02 mmol), and xanthophos (36 mg, 0.06 mmol) was stirred in diglyme (3 mL) at 150 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with EA and filtered through silica gel, washed with water, and bland. The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by a silica gel column (PE / EA = 1:1 to 1:3) to obtain the desired product (160 mg, 44%). MS (ESI) m / e [M+H]+ = 243.

[0358] Step 2: 6-methyl-5-(pyridine-2-ylmethyl)piculinic acid

[0359] A mixture of methyl 6-methyl-5-(pyridine-2-ylmethyl)picolinate (120 mg, 0.5 mmol) and LiOH-H₂O (210 mg, 5 mmol) was stirred in THF (5 mL) / H₂O (5 mL) at room temperature for 24 hours. Immediately after the reaction, the reaction mixture was adjusted to pH 6 using 1 M aqueous HCl and extracted with EA. The organic phase was dried with anhydrous Na₂SO₄, filtered, and concentrated to obtain the desired compound (60 mg, 52%). MS (ESI) m / e [M+H]+ = 229.

[0360] Example A27: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoic acid

[0361] Step 1: Methyl 3-(difluoromethyl)-4-methyl benzoate

[0362] To a solution of methyl 3-formyl-4-methyl benzoate (300 mg, 1.69 mmol) in DCM (5 mL), DAST (2.7 g, 16.9 mmol) was added. The resulting mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the mixture was poured into ice water and extracted with EA. The organic layer was washed with saturated NaHCO3, Bryn, and concentrated to obtain the product (300 mg, 89%). MS (ESI) m / e [M+H]+ = 201.

[0363] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethyl)benzoate

[0364] A mixture of methyl 3-(difluoromethyl)-4-methyl benzoate (280 mg, 1.4 mmol), NBS (300 mg, 1.68 mmol), and AIBN (23 mmol, 0.14 mmol) was stirred in CCl4 (5 mL) at 90 °C for 2 hours. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified with a silica gel column (PE / EA = 10:1) to obtain the product (380 mg, 98%). MS (ESI) m / e [M+H]+ = 279, 281.

[0365] Step 3: Methyl 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoate

[0366] To a solution of 1H-pyrazole (91 mg, 1.34 mmol) in THF (10 mL), NaH (60% in mineral oil, 68 mg, 0.55 mmol) was added at 0°C. The resulting mixture was stirred at room temperature for 30 minutes. Methyl 4-(bromomethyl)-3-(difluoromethyl)benzoate (310 mg, 1.12 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Immediately after the reaction, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified with a silica gel column (PE / EA = 7:3) to obtain the product (50 mg, 17%). MS (ESI) m / e [M+H]+ = 267.

[0367] Step 4: 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethyl)benzoic acid

[0368] 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), NaOH (2 N, 0.5 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated, the pH was adjusted to 7 using HCl, and the precipitate was collected by filtration to obtain the desired compound (40 mg, 94%). MS (ESI) m / e [M+H]+ = 253.

[0369] Example A28: Synthesis of 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypicolinenic acid

[0370] Step 1: Methyl 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypicolineate

[0371] To a mixture of tert-butyl(1H-pyrazol-3-yl)carbamate (100 mg, 0.55 mmol) in THF (10 mL), tBuOK (62 mg, 0.55 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. Methyl 5-(bromomethyl)-6-methoxypicolineate (130 mg, 0.5 mmol) was added, and the reaction mixture was stirred briefly at room temperature. Immediately after the reaction, the reaction mixture was diluted with EA, washed with citric acid, water, and pyrene, dried with Na₂SO₄, filtered, and concentrated to obtain the crude product (240 mg, crude). MS (ESI) m / e [M+H]+ = 363.0.

[0372] Step 2: 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypicolinenic acid

[0373] To a solution of methyl 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypicolineate (240 mg, 0.5 mmol) in THF (5 mL), MeOH (5 mL), and water (5 mL), NaOH (0.17 mL, 6 nN, 1.02 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was diluted with EA and citric acid solution, washed with Brine, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column using DCM / MeOH (sequential filtration from DCM to DCM:MeOH = 5:1) to obtain the desired product (80 mg, 46% in two steps). MS (ESI) m / e [M+H]+ = 349.0.

[0374] Example A29: Synthesis of 4-((4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid

[0375] Step 1: Methyl 4-((4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoate

[0376] 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) was stirred in DMF (10 mL) at 70 °C for 1 hour. After cooling to room temperature, the mixture was quenched with water. The aqueous layer was extracted with DCM. The organic layer was concentrated, and the crude material was purified with a silica gel column (PE / EA = 3:2) to obtain the product (400 mg, 95%). MS (ESI) m / e [M+H]+ = 362.

[0377] Step 2: 4-((4-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid

[0378] 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), NaOH (2 nM, 1 mL) was added. The resulting mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was concentrated, the pH was adjusted to 7 using HCl, and the precipitate was collected by filtration to obtain the desired compound (330 mg, 86%). MS (ESI) m / e [M+H]+ = 348.

[0379] Example A30: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethylpicolinic acid

[0380] Step 1: 2-Bromo-3-(chloromethyl)pyridine

[0381] To a solution of (2-bromopyridine-3-yl)methanol (1.87 g, 10 mmol) in DCM (10 mL), SOCl2 (2.38 g, 20 mmol) was added at 0 °C and stirred briefly at room temperature. Immediately after the reaction, the mixture was diluted with water and extracted with EA. The organic layer was concentrated to obtain the crude product (2.00 g, 97%). MS (ESI) m / e [M+H]+ = 206, 208.

[0382] Step 2: 3-((1H-pyrazol-1-yl)methyl)-2-bromopyridine

[0383] تم تقليب محلول من 2-برومو-3-(كلورو ميثيل) بيريدين (2.00 جم، 9.76 مللي مول)، 1H-إيميدازو [1، 2-a] إيميدازول (680 مجم، 10.00 مللي مول) وCs2CO3 (6.52 جم، 10 مللي مول) في DMF (10 ملليلتر) عند 80 درجة مئوية لمدة لفترة وجيزة. فور انتهاء التفاعل، تم تركيز المحلول وتمت تنقيته بعمود استشراب هلام السيليكا (PE / EA = 3: 1) للحصول على المنتج (2.00 جم، 86%). MS (ESI) m / e [M+H]+ = 238, 240.

[0384] الخطوة 3: 3-((1H-بيرازول-1-يل) ميثيل)-2-ڤينيل بيريدين

[0385] تم تقليب محلول من 3-((1H-بيرازول-1-يل) ميثيل)-2-برومو بيريدين (2.00 جم، 8.43 مللي مول)، ملح تراي فلورو بورات بوتاسيوم لحمض ڤينيل بورونيك (2.26 جم، 16.86 مللي مول)، Pd(PPh3)4 (924 مجم، 0.8 مللي مول) وK2CO3 (2.33 جم، 16.86 مللي مول) في دايوكسان / ماء (10 ملليلتر، حجم / حجم = 5: 1) عند 100 درجة مئوية في ظل جو من N2 لفترة وجيزة. فور انتهاء التفاعل، تم تركيز الخليط وتمت تنقيته باستشراب عمود هلام السيليكا (PE / EA = 3: 1) للحصول على المنتج (1 جم، 64%). MS (ESI) m / e [M+H]+ = 186.2.

[0386] الخطوة 4: 3-((1H-بيرازول-1-يل) ميثيل)-2-إيثيل بيريدين

[0387] A solution of 3-((1H-pyrazol-1-yl)methyl)-2-phenylpyridine (2.00 g, 10.81 mmol) and Pd / C (10% on carbon, hydrated) (200 mg) was stirred in MeOH (10 mL) at room temperature under an H2 atmosphere (2 atm pressure) for 4 hours. Immediately after the reaction, the mixture was filtered. The filtrate was concentrated to obtain the product (2 g, 99%). MS (ESI) m / e [M+H]+ = 188.3.

[0388] Step 5: 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine 1-oxide

[0389] 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) was briefly stirred in DCM (20 mL) at room temperature. Immediately after the reaction, the mixture was concentrated. The raw material 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.

[0390] Step 6: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-ethylpyridine

[0391] A solution of 3-((1H-pyrazol-1-yl)methyl)-2-ethylpyridine 1-oxide (406 mg, 2 mmol) and POCl3 (918 mg, 6.00 mmol) was stirred briefly in DCE (10 mL) at 100 °C. Immediately after the reaction, the solution was diluted with water and extracted with EA. The organic layer was concentrated and purified by Combi-Flash (column C18 containing 20–35 μm spherical silica particles; mobile phase: [water (0.1% FA)-ACN], % B = 5%–80%; 7.0 mins) to obtain 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.

[0392] Step 7: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-ethyl picolinate

[0393] 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) was stirred briefly in MeOH (10 mL) at 100 °C under a CO₂ atmosphere (15 atm). After cooling to room temperature, the solution was concentrated. The crude material 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.

[0394] Step 8: 5-((1H-pyrazol-1-yl)methyl)-6-ethylpiculenic acid

[0395] A solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-ethyl picolinate (100 mg, 0.81 mmol) and LiOH.H2O (100 mg, 2.38 mmol) was stirred in THF / H2O (10 mL, v / v = 1 / 1) at 50 °C for 2 hours. Immediately after the reaction, the solution was concentrated. The crude material was purified by Combi-Flash (column C18 containing 20–35 µm spherical silica particles; mobile phase: [water (0.1% FA)-ACN], % B = 5%–80%; 5.0 mins) to obtain the product (100 mg, 53%). MS (ESI) m / e [M+H]+ = 232.2.

[0396] Example A31: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)piculenic acid

[0397] Step 1: Methyl-d3 6-chloro-5-methyl picolinate

[0398] To a solution of 6-chloro-5-methylpiculinic acid (5 g, 29.2 mmol) in DMF (50 mL), K₂CO₃ (4.43 g, 32.1 mmol) was added, followed by CD₃I (4.66 g, 32.1 mmol). The mixture was stirred briefly at room temperature. Immediately after the reaction, the mixture was poured into ice-cold water (200 mL) and extracted twice with EA. The extracts were washed with citric acid solution, dried with Na₂SO₄, filtered, and concentrated to obtain the desired product (4.8 g, 87%). MS (ESI) m / e [M+H]+ = 189.1.

[0399] Step 2: Methyl 6-(methoxy-d3)-5-methyl picolinate

[0400] To a solution of CD3OD (4.79 g, 106 mmol) (4 g, 21.3 mmol) in THF (100 mL), NaH (60% in mineral oil, 2.13 g, 53 mmol) was added at 0°C and stirred at 0°C for 30 minutes. D-methyl-d3-6-chloro-5-methylpicolinate (4 g, 21.3 mmol) was added, and the solution was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice-cold water and citric acid solution (500 mL) and extracted twice with EA. The extract was washed with Bran, dried with Na2SO4, filtered, concentrated, and the remaining material was purified by silica gel column chromatography (PE:EA = 1:0 to 1:1) to obtain the desired product (2.3 g, 58%). MS (ESI) m / e [M+H]+ = 185.2.

[0401] Step 3: Methyl 5-(bromomethyl)-6-(methoxy-d3)picolineate

[0402] A mixture of methyl 6-(methoxy-d3)-5-methyl picolinate (2.3 g, 12.4 mmol), NBS (2.43 g, 13.7 mmol), and BPO (150 mg, 0.62 mmol) was stirred in CCl4 (50 mL) at 80 °C for 4 hours. After cooling to room temperature, the solids were separated by filtration, and the filtrate was washed with NaHCO3 solution, dried with Na2SO4, filtered, and concentrated. The residue was dissolved in THF (50 mL) and diethyl phosphite (1.67 g, 12.4 mmol), followed by TEA (1.25 g, 12.4 mmol). The resulting solution was stirred at room temperature for 4 hours and diluted with EA. The solution was washed with water, rinsed, dried with Na2SO4, filtered and concentrated to obtain the desired product (3 g, crude). MS (ESI) m / e [M+H]+ = 263, 265.

[0403] Step 4: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)picolineate

[0404] To a mixture of methyl 5-(bromomethyl)-6-(methoxy-d3)picolenate (3 g, 11.45 mmol) and 1H-pyrazole (1.24 g, 18.32 mmol) in DMF (50 mL), Cs₂CO₃ (3.92 g, 12 mmol) was added, and the reaction mixture was stirred at 80 °C for 4 hours. After cooling to room temperature, the reaction mixture was poured into ice-cold water and citric acid solution and extracted twice with EA. The collected organic layers were washed with water, brine, dried with Na₂SO₄, filtered, and concentrated. The residue was purified with a silica gel column using PE / EA (sequential filtration from PE to EA) to obtain the desired product (1.1 g, 38%). MS (ESI) m / e [M+H]+ = 251.2.

[0405] Step 5: 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)piculenic acid

[0406] To a solution of methyl 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)picolenate (1.1 g, 4.4 mmol) in THF (10 mL), MeOH (10 mL), and water (10 mL), NaOH (1.1 mL, 6 nN, 6.6 mmol) was added, and the solution was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was diluted with water, adjusted to pH 5 using citric acid solution, and extracted twice with EA. The extracts were washed with water, rinsed, dried, and concentrated to obtain 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 = 2.0 Hz, 1H), 5.37 (s, 2H).MS (ESI) m / e [M+H]+ = 237.1.

[0407] Example B:

[0408] Example B1: Synthesis of 5-(tert-butyl)-2-methoxybenzenesulfonamide.

[0409] To a solution of 1-(tert-butyl)-4-methoxybenzene (82 g, 0.5 mol) in DCM (200 mL), sulfochloric acid (115 mL, 1.75 mol) in DCM (120 mL) was added by distillation at 0°C. The mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. The mixture was then poured into ice water and extracted with DCM. The organic layer was dried with Na₂SO₄ and filtered. The filtrate was concentrated, and the crude material was re-dissolved in CH₃CN (250 mL). NH₃H₂O (80 mL) was then added by distillation at 0°C. The mixture was stirred at room temperature for 10 hours. The solvent was removed, and the crude material was purified by silica gel chromatography column to obtain 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.

[0410] Example B2: Synthesis of 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide

[0411] Step 1: 6-(tert-butyl)-2-fluoro-3-methoxypyridine

[0412] To a mixture of CuI (18.5 g, 97 mmol) and tert-butylmagnesium bromide (1 M in THF, 97 mL), a solution of 6-bromo-2-fluoro-3-methoxypyridine (5 g, 24 mmol) in THF (3 mL) was added by distillation at 0 °C. The reaction mixture was allowed to warm and stirred at 20 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (150 mL) and extracted with EA (100 mL × 3). The collected organic layers were washed with Bryn, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 100 / 1 to 0 / 1) to obtain the desired compound (3.4 g, yield 77%). MS(ESI) m / e [M+H]+ = 184.4.

[0413] Step 2: 2-(benzylthio)-6-(tert-butyl)-3-methoxypyridine

[0414] To a solution of phenylmethanethiol (3.5 g, 28 mmol) in THF (70 mL), NaH (60% in mineral oil, 1.12 g, 28 mmol) was slowly added and stirred for 30 minutes at 0°C. 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 hours. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL), extracted with EA (300 mL × 3). The collected organic layers were washed with Bryn, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE:EA = 100 / 1 to 10 / 1) to obtain the desired compound (4.05 g, yield of 75%). 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.

[0415] Step 3: 6-(tert-butyl)-3-methoxypyridine-2-sulfonamide

[0416] 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), NCS (5.44 g, 40.7 mmol) was added at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. After the addition of 7 M NH₃ in MeOH (9.7 mL), the reaction mixture was stirred at 20 °C for an additional 1 h. The reaction mixture was then diluted with 10 mL of H₂O and extracted with EA (30 mL × 3). The collected organic layers were washed with Braine, dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The collected organic layers were filtered and concentrated under reduced pressure. The remaining material was purified by silica gel column chromatography (PE / THF = 100 / 1 to 0 / 1) to obtain the desired compound (1 g, yield of 62%). 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.

[0417] Example B3: Synthesis of 2-methoxy-5-(4-methoxypiperidine-1-yl)benzenesulfonamide

[0418] 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) was stirred in dioxane (10 mL) at 120 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography followed by sequential filtration with 5%–10% MeOH in DCM to obtain the desired product (200 mg, 71%). MS (ESI) m / e [M+H]+ = 301.

[0419] Example B4: Synthesis of 6-methoxy-2,3-dihydro-1H-indene-5-sulfonamide

[0420] To a solution of methyl 5-methoxy-2,3-dihydro-1H-indine (148 mg, 1 mmol) in 10 mL of DCM, sulfuryl chloride (232 mg, 2 mmol) was added at 0 °C and stirred for 2 hours at room temperature. The reaction mixture was washed with water. The organic phase was concentrated. The residue was dissolved in acetonitrile (5 mL), 25% aqueous NH3 (1 mL) was added, and the mixture was stirred at room temperature for another 1 hour. Immediately after the reaction, the mixture was diluted with water and extracted with EA. The collected organic layers were washed with Bryn, dried with anhydrous Na2SO4, filtered, and concentrated to obtain the desired compound (50 mg, yield 22%). MS (ESI) m / e [M+H]+ = 227.9.

[0421] Example B5: Synthesis of 2-methoxy-5-(1-methoxycyclopropyl)benzenesulfonamide

[0422] Step 1: 1-(3-Bromo-4-methoxyphenyl)cyclopropane-1-ol

[0423] A mixture of methyl 3-bromo-4-methoxybenzoate (4 g, 16.3 mmol) and tetraisopropoxytitanium (6.5 g, 23 mmol) was stirred in THF (40 mL) for 30 minutes at 25 °C under an N₂ atmosphere. Bromo(ethyl)magnesium (1 M in THF, 45.7 mL) was added by distillation at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched with H₂O (40 mL), filtered, and extracted with EA (40 mL × 3). The collected organic layers were washed with Bryn, dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The remaining material was purified by silica gel column chromatography (PE:EA = 1 / 0 to 3 / 1) to obtain the product (2.23 g, yield of 56%). 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).

[0424] Step 2: Synthesis of -methoxy-5-(1-methoxycyclopropyl)benzenesulfonamide

[0425] To a solution of 1-(3-bromo-4-methoxyphenyl)cyclopropanol (2.58 g, 10.6 mmol) in THF (26 mL), NaH (60% in mineral oil, 424 mg, 10.6 mmol) was added and stirred for 30 minutes at 0°C. MeI (1.66 g, 11.7 mmol) was added by distillation. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with H₂O (20 mL). The aqueous phase was extracted with EA (20 mL × 3). The collected organic phases were washed with Bryn, dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE:EA = 3:1) to obtain 2-bromo-1-methoxy-4-(1-methoxycyclopropyl)benzene (1 g). To a solution of 2-bromo-1-methoxy-4-(1-methoxycyclopropyl)benzene (500 mg, 1.94 mmol) in THF (5 mL), n-BuLi (1.6 M in hexane, 1.2 mL) was added by distillation and stirred at -60 °C for 30 minutes. Sulfuryl chloride (262 mg, 1 g) was added to the reaction mixture.At -60°C, the reagent (94 mmol) was stirred at 25°C for 30 minutes. 7 mM NH3 was added in MeOH (2.8 mL). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O and extracted with EA (5 mL × 3). The collected organic layers were washed with Brine, dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18; mobile phase: [H2O(NH4HCO3 at 10 mmol)-ACN]; gradient: 15%–55% B over 8.0 minutes) to obtain the desired compound (152 mg, yield 30%). 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.

[0426] Example B6: Synthesis of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0427] Step 1: 1-Bromo-4-methoxy-2-((2-methylallyl)oxy)benzene

[0428] To a solution of 2-bromo-5-methoxyphenol (5 g, 24.6 mmol) and K₂CO₃ (8.5 g, 61.6 mmol) in ACN (50 mL), 3-bromo-2-methylprop-1-in (3.66 g, 27.1 mmol) was added at 25 °C. The solution was then stirred at 85 °C for 12 hours. 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 obtain the desired 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).

[0429] Step 2: 6-Methoxy-3,3-Dimethyl-2,3-Dihydrobenzofuran

[0430] To a solution of 1-bromo-4-methoxy-2-(2-methylalyloxy)benzene (3 g, 11.6 mmol) in toluene (30 mL), Bu3SnH3 (5.1 g, 17.50 mmol) and AIBN (250 mg, 1.5 mmol) were successively added at 25 °C. The solution was then stirred at 110 °C for 12 h. The reaction mixture was cooled to room temperature and quenched with aqueous KF. It was then extracted with DCM (30 mL × 3). The collected organic layers were washed with Bryn, dried with 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 obtain the desired compound (1.78 g, yield 86%). 1H NMR: (400 MHz, 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).

[0431] Step 3: 7-Bromo-6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran

[0432] To a solution of 6-methoxy-3,3-dimethyl-2H-benzofuran (1.43 g, 8 mmol) in THF (28 mL), n-BuLi (1.6 M in hexane, 6.5 mL) was added at 0°C. The reaction mixture was refluxed at 45°C for 90 minutes. The mixture was then 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 hours. The solution was quenched with H₂O (30 mL) and extracted with EA (30 mL × 3). The collected organic layers were washed with Bryn, dried with Na₂SO₄, filtered, and concentrated under reduced pressure. The remaining material was purified by silica gel column chromatography (PE:EA = 1 / 0 to 0 / 1) to obtain the desired compound (1.2 g, yield of 58%). 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).

[0433] Step 4: 6-Methoxy-3,3-Dimethyl-2,3-Dihydrobenzofuran-7-sulfonamide

[0434] To a solution of 7-bromo-6-methoxy-3,3-dimethyl-2H-benzofuran (600 mg, 2.3 mmol) in THF (6 mL) under an N2 atmosphere, the mixture was cooled to -60 °C, followed by the distillation of a solution of n-BuLi (1.6 M in n-hexane, 1.46 mL). The mixture was stirred at -60 °C for 30 min. To the reaction mixture, sulfuryl chloride (315 mg, 2.3 mmol) was added at -60 °C, and the solution was stirred at 25 °C for 30 min. To the reaction mixture, 7 M NH3 in MeOH (3.33 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with H2O and extracted with EA (5 mL × 3). The collected organic layers were washed with Bran, dried with Na2SO4, filtered, and concentrated under reduced pressure. The remaining material was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O(NH4HCO3 at 10 mM)-ACN]; gradient: 15%–55% B over 8.0 minutes) to obtain the desired compound (100 mg, yield 16%). 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.

[0435] Example B7: Synthesis of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonamide

[0436] Step 1: Methyl 2-(3-methoxyphenoxy)acetate

[0437] A solution of 3-methoxyphenol (3.00 g, 24.19 mmol), methyl 2-bromoacetate (4.41 g, 29.03 mmol), Cs2CO3 (15.77 g, 48.38 mmol) was stirred briefly in 10 mL of DMF at room temperature. Immediately after the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 5:1) to obtain the product (3.80 g, 80%). MS (ESI) m / e [M+H]+ = 197.2.

[0438] Step 2: 1-(3-Methoxyphenoxy)-2-methylpropane-2-ol

[0439] To a solution of methyl 2-(3-methoxyphenoxy)acetate (3.80 g, 19.39 mmol) in 20 mL of THF, CH3MgBr (at a concentration of 3 M, 12.93 mL, 38.78 mmol) was added at 0 °C and stirred for 2 hours. Immediately after the reaction, the solution was diluted with water and extracted with EA. The collected organic layers were washed with Bryn, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain the desired compound (3.80 g, 100%). MS (ESI) m / e [M+H]+ = 197.1.

[0440] Step 3: 6-Methoxy-2,2-Dimethyl-2,3-Dihydrobenzofuran

[0441] To a solution of 1-(3-methoxyphenoxy)-2-methylpropane-2-ol (3.80 g, 19.38 mmol) in 10 mL of methanesulfonic acid, P₂O₅ (8.66 g, 61.00 mmol) was added at room temperature and stirred for 2 hours. Immediately after the reaction, the solution was diluted with water and extracted with EA. The collected organic layers were washed with Bryn, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10:1) to obtain the desired 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.

[0442] Step 4: 6-Methoxy-2,2-Dimethyl-2,3-Dihydrobenzofuran-7-sulfenic acid

[0443] 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, n-BuLi (12 mL, 30 mmol) was added at 0°C and stirred for 10 minutes. The mixture was then cooled to -78°C and SO2 bubbles were passed through it for 5 minutes. Immediately after the reaction, the mixture was quenched with water. The solution was concentrated and purified by a reverse-phase chromatography column (column C18 containing 20–35 µm spherical silica particles; mobile phase: [water (0.1% FA)-ACN], % B = 5%–80%) to obtain the desired compound (1.80 g, 74%). MS (ESI) m / e [M+Na]+ = 243.2.

[0444] Step 5: 6-Methoxy-2,2-Dimethyl-2,3-Dihydrobenzofuran-7-sulfonylchloride

[0445] To a solution of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran (1.80 g, 7.4 mmol) in 10 mL of DCM, sulfuryl dichloride (992 mg, 7.4 mmol) was added by distillation at 0°C and stirred for 1 hour. Immediately after the reaction, the mixture was poured into ice water and extracted with DCM. The organic layer was concentrated to obtain the desired compound (1.80 g, 88%). MS (ESI) m / e [M+Na]+ = 276.1.

[0446] Step 6: 6-Methoxy-2,2-Dimethyl-2,3-Dihydrobenzofuran-7-sulfonamide

[0447] To a solution of 6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-sulfonylchloride (200 mg, 0.72 mmol) in 1 mL acetonitrile, NH3•H2O (1 mL) was added by distillation at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, H2O was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain the desired 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.

[0448] Example B8: Synthesis of 7-methoxy-4,4-dimethylchromane-8-sulfonamide

[0449] Step 1: 1-Bromo-4-methoxy-2-((3-methylbut-2-en-1-yl)oxy)benzene

[0450] A mixture of 2-bromo-5-methoxyphenol (3.00 g, 14.78 mmol), 3-methylbut-2-in-1-ol (1.50 g, 17.73 mmol), PPh3 (5.80 g, 22.17 mmol), and 1,2-ditert-butyl-diazine (5.10 g, 22.17 mmol) was stirred in THF (30 mL) 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 silica gel flash chromatography followed by sequential filtration with 10%–40% EA in PE to obtain the desired product (2.00 g, 50%). MS (ESI) m / e [M+H]+ = 271.

[0451] Step 2: 7-Methoxy-4,4-Dimethylchrome

[0452] 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), tetraethyl ammonium chloride (732 mg, 4.44 mmol), and Pd(OAc)2 (331 mg, 1.48 mmol) was stirred in DMF (30 mL) 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 silica gel flash chromatography followed by sequential filtration with 5%–20% EA in PE to obtain the desired product (280 mg, 49%). MS (ESI) m / e [M+H]+ = 193.

[0453] Step 3: 7-Methoxy-4,4-Dimethylchromane-8-sulfenic acid

[0454] To a stirred mixture of 7-methoxy-4,4-dimethylchrome (280 mg, 1.46 mmol) and TMEDA (169 mg, 1.46 mmol) in n-hexane (15 mL), n-BuLi (2.5 M in n-hexane) (1.75 mL, 4.38 mmol) was added by distillation at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes. The mixture was then cooled to -78 °C and SO2 bubbles were passed through for 5 minutes. Immediately after the reaction, the mixture was quenched with water and extracted with DCM. The collected organic layers were washed with Bryn, dried with Na2SO4, filtered, and concentrated to obtain the desired product (200 mg, 53%). MS (ESI) m / e [M+H]+ = 257.

[0455] Step 4: 7-Methoxy-4,4-Dimethylchromane-8-sulfonylchloride

[0456] To a stirred mixture of 7-methoxy-4,4-dimethylchromane-8-sulfinic acid (200 mg, 0.78 mmol) in DCM (10 mL), SO2Cl2 (105 mg, 0.78 mmol) was added by distillation at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. Immediately after the reaction, H2O was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Bryn, dried with Na2SO4, filtered, and concentrated to obtain the desired product (200 mg, 88%). MS (ESI) m / e [M+H]+ = 291.

[0457] Step 5: 7-Methoxy-4,4-Dimethylcromon-8-sulfonamide

[0458] To a solution of 7-methoxy-4,4-dimethylchromane-8-sulfonyl chloride (200 mg, 0.69 mmol) in THF (5 mL), NH3•H2O (2 mL) was added by distillation at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, H2O was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain 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.

[0459] Example B9: Synthesis of 3-methoxy-6-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-2-sulfonamide

[0460] Step 1: 1-(6-Bromo-5-methoxypyridine-2-yl)ethane-1-one

[0461] 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), iPrMgCl (48 mL, 96 mmol) was added by distillation at -40 °C under an N2 atmosphere. The mixture was stirred at -40 °C for 2 hours. Immediately after the reaction, the mixture was quenched with H2O. The mixture was extracted with EA. The organic layer was concentrated, and the crude material was purified by silica gel column chromatography (PE / EA = 5:1) to obtain the desired compound (21.1 g, 96%). MS (ESI) m / e [M+H]+ = 230.

[0462] Step 2: 2-Bromo-3-methoxy-6-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propane-2-yl)pyridine

[0463] To a solution of 1-(6-bromo-5-methoxypyridine-2-yl)ethane-1-one (21 g, 91.3 mmol) and KOAc (8.9 g, 91.3 mmol) in DMSO (100 mL), TMSCF3 (26 g, 183 mmol) was added by distillation at 0°C. The mixture was stirred at room temperature for 5 hours. Immediately after the reaction, the mixture was quenched with H₂O and extracted with EA. The organic layer was dried and concentrated to obtain the raw material. The raw material was used in the next step without purification (34 g, crude). MS (ESI) m / e [M+H]+ = 374.

[0464] Step 3: 2-(6-Bromo-5-methoxypyridine-2-yl)-1,1,1-trifluoropropane-2-ol

[0465] A solution of 2-bromo-3-methoxy-6-(1,1,1-trifluoro-2-((trimethylsilyl)oxy)propane-2-yl)pyridine (34 g, 91.3 mmol) and K₂CO₃ (25.3 g, 183 mmol) was stirred in MeOH (200 mL) at room temperature for 2 hours. Immediately after the reaction, the mixture was filtered and concentrated. The crude material was purified by silica gel column chromatography (PE / EA = 3:1) to obtain the desired compound (22 g, 80.3%). MS (ESI) m / e [M+H]+ = 300.

[0466] Step 4: 2-(6-Bromo-5-methoxypyridine-2-yl)-1,1,1-trifluoropropane-2-ylmethanesulfonate

[0467] To a solution of 2-(6-bromo-5-methoxypyridine-2-yl)-1,1,1-trifluoropropane-2-ol (22 g, 73.3 mmol) in DCM (200 mL), MsCl (11 g, 95.3 mmol) was added by distillation at 0 °C, followed by TEA (14.8 g, 147 mmol). The mixture was stirred at 0 °C for 2 hours. Immediately after the reaction, the mixture was washed with H₂O. The organic layer was dried and concentrated. The raw material was used in the next step without purification (27 g, crude). MS (ESI) m / e [M+H]+ = 378.

[0468] Step 5: 2-Bromo-3-methoxy-6-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine

[0469] To a solution of 2-(6-bromo-5-methoxypyridine-2-yl)-1,1,1-trifluoropropane-2-ylmethanesulfonate (27 g, crude) in DCM (200 mL), AlMe3 (73.3 mL, 146.6 mmol) was added at 0 °C under an N2 atmosphere. The mixture was stirred at 0 °C for 3 hours. Immediately after the reaction, the mixture was quenched with H2O. The organic layer was dried and concentrated. The crude material was purified by silica gel column chromatography (PE / EA = 10:1) to obtain the desired compound (9 g, 41.2%). MS (ESI) m / e [M+H]+ = 298.

[0470] Step 6: 3-Methoxy-6-(1,1,1-Trifluoro-2-methylpropane-2-yl)pyridine-2-sulfonamide

[0471] To a solution of 2-bromo-3-methoxy-6-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine (9 g, 30.2 mmol) in THF (200 mL), n-BuLi (13.3 mL, 33.2 mmol) was added at -78 °C under an N2 atmosphere. The mixture was stirred at -78 °C for 0.5 h. Bubbles of SO2 (gas) were then passed through the reaction mixture at a temperature below -40 °C. Immediately after the reaction, the mixture was quenched with H2O (20 mL). The mixture was concentrated to the dry stage. The feedstock was re-dissolved in NH3.H2O (12.5%) (70 mL), and THF (70 mL) and I2 (7.5 g, 60 mmol) were added at room temperature in batches. The mixture was stirred at room temperature for 1 hour. It was then diluted with EA. The organic layer was washed with H2O, dried, and concentrated. The raw material was purified by silica gel column chromatography (PE / EA = 2:1) to obtain the desired 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.

[0472] Example B10: Synthesis of 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonamide

[0473] 1-Methoxy-4-[1-(trifluoromethyl)cyclopropyl]benzene (5 g, 23 mmol) was added to chlorosulfonic acid (13.5 g, 115 mmol) at 0 °C by distillation under an atmosphere of N2. The reaction mixture was stirred at this temperature for 1 hour. The reaction mixture was then added to ice-cold water by distillation. The precipitate was filtered and purified by silica gel column chromatography (PE:EA = 3:1) to obtain 2-Methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonylchloride (3.0 g, 41%). To a solution of 2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)benzenesulfonylchloride (2.0 g, 6.4 mmol) in THF (20 mL), NH3•H2O (10.0 mL) was added by distillation at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the desired 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.

[0474] Example B11: Synthesis of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonamide

[0475] Step 1: 1-(4-Methoxyphenyl)cyclobutane-1-ol

[0476] To a solution of 1-bromo-4-methoxybenzene (3.0 g, 16.1 mmol) in THF (50 mL), n-BuLi (2.5 M, 7.1 mL, 17.7 mmol) was added by distillation at -70 °C. The mixture was stirred at -70 °C for 30 minutes. Cyclobutanone (1.36 g, 19.4 mmol) was added in THF (5 mL) at -70 °C. The resulting mixture was stirred at -70 °C for 1 hour. After heating to room temperature, the mixture was quenched with saturated NH4Cl and extracted with EA. The organic layer was washed with Bryn, dried with Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 1:3) to obtain the desired product (2.57 g, 90%).

[0477] Step 2: 1-Methoxy-4-(1-methylcyclobutyl)benzene

[0478] To a solution of 1-(4-methoxyphenyl)cyclobutane-1-ol (2.5 g, 14.0 mmol) in DCM (100 mL), TiCl4 (5.34 g, 28.1 mmol) was added at -70 °C. The mixture was stirred at -70 °C for 1 h. ZnMe2 (1.0 M, 42.1 mL, 42.1 mmol) was added by distillation at -70 °C. The resulting mixture was stirred at -70 °C for 2 h. After heating to room temperature, the mixture was quenched with Braine and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to obtain the desired product (2.4 g, 97%).

[0479] Step 3: 2-Methoxy-5-(1-methylcyclobutyl)benzenesulfonic acid

[0480] To a solution of 1-methoxy-4-(1-methylcyclobutyl)benzene (2.2 g, 12.5 mmol) in DCM (50 mL), ClSO3H (1.8 g, 15.0 mmol) in DCM (10 mL) was added at -10 °C. The resulting mixture was stirred at -10 °C for 1 hour. The mixture was quenched with ice water and concentrated. The raw material was purified with C18 silica (ACN / H2O = 15:85) to obtain the desired product (3.2 g, 100%). MS (ESI) m / e [MH]- = 255.

[0481] Step 4: 2-Methoxy-5-(1-Methylcyclobutyl)benzenesulfonylchloride

[0482] A solution of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonic acid (3.1 g, 12.1 mmol) was stirred in SOCl2 (40 mL) at 85 °C for 2 hours. The mixture was concentrated to obtain the crude product (3.2 g).

[0483] Step 5: 2-Methoxy-5-(1-methylcyclobutyl)benzenesulfonamide

[0484] To a solution of 2-methoxy-5-(1-methylcyclobutyl)benzenesulfonylchloride (3.2 g, 11.7 mmol) in THF (50 mL), NH3.H2O (20 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with EA, the organic layer was washed with Brine, dried with Na2SO4, and concentrated. The crude material 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.

[0485] Example B12: Synthesis of 2-methoxy-5-(3-methyloxytene-3-yl)benzenesulfonamide

[0486] Step 1: 1,3-Dioxyisoindolene-2-yl 3-methyloxytene-3-carboxylate

[0487] To a solution of 3-methyloxytane-3-carboxylic acid (1 g, 8.6 mmol) and 2-hydroxyisoindolene-1,3-dione (1.4 g, 8.6 mmol) in DCM (80 mL), DMAP (105 mg, 861 µmol) and DIC (1.2 g, 9.4 mmol) were added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain crude residue. The residue was pelleted with MeOH (8 mL) to obtain the desired compound (1.3 g, yield 58%). 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).

[0488] Step 2: 3-(4-Methoxyphenyl)-3-methyloxytene

[0489] A solution of NiBr2.glyme (83 mg, 268 µmol) and 4,4-di-tert-butyl-N-cyano-[2,2-bipyridine]-6-carboxymidamide (90 mg, 268 µmol) was stirred in THF (5 mL) at 25 °C for 0.5 h using a glove box, resulting in a homogeneous solution. To 1,3-dioxyisoindolene-2-yl 3-methyloxytane-3-carboxylate (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) in the other vial, 5 mL of the prepared catalyst solution was added. The reaction mixture was stirred at 35°C for 16 hours. The mixture was then 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 obtain the desired compound (390 mg, yield 57%). 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).

[0490] Step 3: 3-(3-Bromo-4-methoxyphenyl)-3-methyloxytene

[0491] To a solution of 3-(4-methoxyphenyl)-3-methyloxytane (0.3 g, 1.6 mmol, 1 equator) in ACN (3 mL), NBS (299.6 mg, 1.7 mmol, 1.05 equator) was added at 25 °C under an N2 atmosphere. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 3:1) to obtain 3-(3-bromo-4-methoxyphenyl)-3-methyloxytane (0.37 g). To a solution of 3-(3-bromo-4-methoxyphenyl)-3-methyloxytane (0.3 g, 1.2 mmol) in THF (3 mL), n-BuLi (2.5 M in hexane, 467 µL) was distilled at -60 °C under an N₂ atmosphere. The reaction mixture was stirred at -60 °C for 30 minutes. Sulphryl 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 minutes. NH₃ (7 M) in MeOH (1.7 mL) was added. The reaction mixture was stirred at 25 °C for 10 minutes. The reaction mixture was concentrated under vacuum.The remaining material was purified by preparative HPLC (Column = Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; Mobile phase: [Water (NH4HCO3) - MeCN], % of B = 2%-40%; 8.0 mins) to obtain the desired compound (61 mg, yield of 19%). 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.

[0492] Example B13: Synthesis of 2-methoxy-5-(3-methoxyoxytetan-3-yl)benzenesulfonamide

[0493] Step 1: 3-(3-Bromo-4-methoxyphenyl)oxytan-3-ol

[0494] To a solution of 2-bromo-4-iodo-1-methoxybenzene (10 g, 32 mmol) and oxytane-3-one (3.45 g, 48 mmol) in THF (100 mL), n-BuLi (2.5 M in hexane, 15.3 mL, 38 mmol) was added by distillation at -65 °C. The resulting mixture was stirred at -65 °C for 3 hours. Immediately after the reaction, the mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with EA. The organic phase was washed with pyrene, dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 50:0 to 10:1) to obtain the desired compound (3.5 g, yield 30%). 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.

[0495] Step 2: 3-(3-Bromo-4-methoxyphenyl)-3-methoxyoxytetan

[0496] To a solution of 3-(3-bromo-4-methoxyphenyl)oxytan-3-ol (2.4 g, 9.3 mmol) in THF (30 mL), NaH (60% in mineral oil, 560 mg, 14 mmol) was added in batches at 0°C. After addition, the mixture was stirred at 0°C for 30 minutes, and then MeI (2 g, 14 mmol) was added by distillation at 0°C. The resulting mixture was stirred at 20°C for 4 hours. Immediately after the reaction, the mixture was poured into aqueous NH4Cl (5 mL) and extracted with EA (3 mL × 3). The collected organic layers were concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to obtain the desired compound (2.85 g, crude). 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.

[0497] Step 3: 3-(3-(benzylthio)-4-methoxyphenyl)-3-methoxyoxytetan

[0498] A mixture of 3-(3-bromo-4-methoxy-phenyl)-3-methoxy-oxytane (1 g, 3.7 mmol), phenylmethanethiol (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 degased and purified with N₂ three times. The reaction mixture was stirred at 110 °C for 16 h under an N₂ atmosphere. Immediately after the reaction, the mixture was quenched with H₂O (30 mL) and extracted with EA. The collected organic layers were concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to obtain the desired compound (1 g, yield of 80%). 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.

[0499] Step 4: 2-Methoxy-5-(3-Methoxyoxytetan-3-yl)benzenesulfonamide

[0500] To a solution of 3-(3-benzylsulfanyl-4-methoxyphenyl)-3-methoxy-oxytane (800 mg, 2.53 mmol) in DCM (15 mL) and H₂O (5 mL), TCCA (1.18 g, 5.06 mmol) was added. The mixture was stirred at 0–15 °C for 16 h. NH₃ / MeOH (7 M, 4.00 mL, 11.07 Eq) was then added. The mixture was stirred for 1 h. Immediately after the reaction, the mixture was concentrated. The crude product was purified by silica gel chromatography (PE:EA = 50:1 to 3:1) to obtain the desired compound (276 mg, yield 39%). 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.

[0501] Example B14: Synthesis of 2-methoxy-5-(6-methyl-2-oxaspiro[3,3]heptane-6-yl)benzenesulfonamide

[0502] Step 1: 6-(4-methoxyphenyl)-2-oxaspiro[3,3]heptane-6-ol

[0503] To a solution of 1-bromo-4-methoxybenzene (2.0 g, 10.8 mmol) in THF (30 mL), n-BuLi (2.5 M, 4.5 mL, 11.3 mmol) was added by distillation at -70 °C. The mixture was stirred at -70 °C for 30 minutes. 2-oxaspiro[3.3]heptane-6-one (1.33 g, 11.9 mmol) was added in THF (5 mL) at -70 °C. The resulting mixture was stirred at -70 °C for 1 hour. After heating to room temperature, the mixture was quenched with saturated NH4Cl and extracted with EA. The organic layer was washed with Bryn, dried with Na2SO4, and concentrated. The raw material was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the desired compound (1.7 g, 72%).

[0504] Step 2: 6-(4-Methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane

[0505] To a solution of 6-(4-methoxyphenyl)-2-oxaspiro[3.3]heptane-6-ol (800 mg, 3.64 mmol) in DCM (40 mL), TiCl4 (1.38 g, 7.27 mmol) was added at -70 °C. The mixture was stirred at -70 °C for 1 h. ZnMe2 (1.0 M in toluene, 11 mL, 10.92 mmol) was added by distillation at -70 °C. The resulting mixture was stirred at -70 °C for 2 h. After heating to room temperature, the mixture was quenched with Braine and extracted with EA. The organic layer was dried with Na2SO4 and concentrated to obtain the desired compound (800 mg).

[0506] Step 3: 6-(3-Bromo-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane

[0507] To a solution of 6-(4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane (580 mg, 2.66 mmol) in ACN (20 mL), NBS (427 mg, 2.39 mmol) was added. The resulting mixture was stirred briefly at room temperature. The mixture was quenched with water and extracted with EA. The organic layer was washed with Brine, dried with Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 4:1) to obtain the desired compound (460 mg, 58%).

[0508] Step 4: 6-(3-(benzylthio)-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane

[0509] A solution of 6-(3-bromo-4-methoxyphenyl)-6-methyl-2-oxaspiro[3.3]heptane (360 mg, 1.22 mmol), phenylmethanethiol (166 mg, 1.34 mmol), Pd2dba3 (112 mg, 0.12 mmol), xanthophos (71 mg, 0.12 mmol) and TEA (247 mg, 2.44 mmol) in 1,4-dioxane (10 mL) was briefly stirred at 100 °C. It was then cooled to room temperature. The mixture was quenched with Braine and extracted with EA. The organic layer was dried with Na2SO4 and concentrated. The raw material was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the desired compound (341 mg, 82%). MS (ESI) m / e [M+H]+ = 341.

[0510] Step 5: 2-Methoxy-5-(6-methyl-2-oxaspiro[3,3]heptane-6-yl)benzenesulfonamide

[0511] 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), NCS (533 mg, 3.97 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then added to THF (20 mL) and NH3.H2O (15 mL) at 0°C. The resulting mixture was stirred briefly at room temperature. The reaction mixture was extracted with EA, the organic layer was washed with Brine, dried with Na2SO4, and concentrated. The crude material was purified by silica gel column chromatography (PE:EA = 7:3) to obtain the desired compound (235 mg, 70%). MS (ESI) m / e [M+H]+ = 298.

[0512] Example B15: Synthesis of 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide

[0513] Step 1: 4-(4-Methoxyphenyl)tetrahydropyran-4-ol

[0514] To a solution of 1-bromo-4-methoxybenzene (3 g, 16 mmol) in THF (30 mL) at -78 °C, n-BuLi (2.5 M in hexane, 7.7 mL) was added by distillation under an N2 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 saturated aqueous NH4Cl (50 mL) at 25 °C. The aqueous phase was extracted with EA. The collected organic phase was washed with Bryn, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The remaining material was purified by a silica gel column (PE:EA = 1:0 to 0:1) to obtain the desired compound (2.3 g, yield of 69%). 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).

[0515] Step 2: 4-(4-Methoxyphenyl)-4-Methyltetrahydro-2H-pyran

[0516] To a solution of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-ol (2 g, 9.6 mmol) in DCM (50 mL), TiCl4 (3.64 g, 19.2 mmol) was added by distillation at -78 °C under an N2 atmosphere. After the addition, the mixture was stirred at -78 °C for 1 h, and then dimethyl zinc (1 M in toluene, 38.4 mL) was added by distillation at -78 °C. The resulting mixture was stirred at -78 °C for 2 h. H2O (50 mL) was added to the reaction mixture and extracted with H2O (35 mL × 3). The collected organic phases were washed with pyrene, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE:EA = 1:0 to 0:1) to obtain the desired compound (600 mg, yield of 29%). 1H NMR: (400 MHz, 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).

[0517] Step 3: 2-Methoxy-5-(4-Methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide

[0518] To a solution of 4-(4-methoxyphenyl)-4-methyltetrahydro-2H-pyrane (500 mg, 2.4 mmol) in DCM (10 mL), sulfochloric acid (847 mg, 7.2 mmol) was added at 0 °C under an atmosphere of N₂. The mixture was stirred at 0 °C for 2 hours. H₂O (10 mL) was added to the reaction mixture and extracted with DCM (7 mL × 2). The collected organic phase was washed with Bryn (7 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain 2-methoxy-5-(4-methyltetrahydro-2H-pyrane-4-yl)benzenesulfonic acid (150 mg, 22% yield). To a solution of 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonic acid (150 mg, 0.5 mmol) in DCM (2 mL), DMF (383 µg) and (COCl)2 (100 mg, 0.75 mmol) were added at 0 °C under an atmosphere of N2. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonylchloride (150 mg, crude).A solution of crude 2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonylchloride (150 mg, 0.5 mmol) in 7 M NH3 in MeOH (1 mL) was stirred at 20 °C for 10 minutes. DCM (10 mL) was added to the reaction mixture. The collected organic phases were washed with Bryn (2 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column = Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN], % of B = 15%–50%; 8.0 minutes) to obtain the desired compound (36 mg, yield 26%). 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).

[0519] Example B16: Synthesis of 2-methoxy-5-(4-methylmorpholine-3-yl)benzenesulfonamide

[0520] Step 1: 2-Methoxy-5-(4-methylmorpholine-3-yl)benzenesulfonic acid

[0521] To a solution of 3-(4-methoxyphenyl)-4-methylmorpholine (1 g, 4.8 mmol) in DCM (20 mL), sulfochloric acid (1.7 g, 14.5 mmol) was added under an N2 atmosphere at 0°C. The mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was quenched with MeOH (2 mL) and concentrated. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250*70 mm, 15 µm); mobile phase: [H2O (0.04% HCl)-ACN]; % B: 0%, isometric sequential filtration pattern) to obtain the desired compound (700 mg, 50% yield). MS(ESI) m / e [M+H]+ = 288.1.

[0522] Step 2: 2-Methoxy-5-(4-methylmorpholine-3-yl)benzenesulfonamide

[0523] To a solution of 2-methoxy-5-(4-methylmorpholine-3-yl)benzenesulfonic acid (600 mg, 2.1 mmol) in DCM (6 mL), DMF (15 mg, 210 µmol) and (COCl)2 (1.06 g, 8.4 mmol) were added at 0°C. The mixture was stirred at room temperature for 12 hours. Then, 7 M NH3 was added in MeOH (3 mL), and the mixture was stirred for a further 0.5 hours. The mixture was then concentrated. The remaining material was purified by preparative HPLC (column: WePure Biotech XP tC18; mobile phase: [H2O(NH4HCO3 at 10 mM concentration)-ACN]; gradient: 1%-30% of B in 8.0 minutes) to obtain the desired compound (242 mg, yield at 40%). 1H NMR (400 MHz, DMSO-d6) δ = 7.71 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 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.

[0524] Example B17: Synthesis of 5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-methoxybenzenesulfonamide

[0525] To a mixture of 5-bromo-2-methoxybenzenesulfonamide (200 mg, 0.8 mmol) and 8-oxa-3-aza-bicyclo[3.2.1]octane (110 mg, 1.0 mmol) in dioxane (10 mL), Pd-PEPPSI-IPent (60 mg, 0.1 mmol) and t-BuOK (110 mg, 1.1 mmol) were added. The resulting mixture was degassing with nitrogen and heated to 120 °C with stirring for 1 hour. The resulting reaction mixture was cooled to room temperature. The solids were separated by filtration. The filtrate was concentrated. The residue was deposited on a silica gel chromatography column (EA:PE to 12:1) to obtain the desired product (100 mg, 44%). MS (ESI) m / e [M+H]+ = 299.

[0526] Example B18: Synthesis of 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0527] Step 1: 1-Bromo-2-(2-Bromoethoxy)-4-methoxybenzene

[0528] To a suspension of 2-bromo-5-methoxyphenol (2.03 g, 10 mmol) and K₂CO₃ (2.1 g, 15 mmol) in CH₃CN (50 mL), 1,2-dibromoethane (9.4 g, 50 mmol) was added at room temperature, and the reaction mixture was stirred at 80 °C for 12 hours. The mixture was filtered, and the filtrate was diluted with EA and washed with citric acid, chloride, dried, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1-3 / 1) to obtain the desired compound (2.1 g, yield 68%). MS(ESI) m / e [M+H] 308.9.

[0529] Step 2: 6-Methoxy-2,3-Dihydrobenzofuran

[0530] To a solution of 1-bromo-2-(2-bromoethoxy)-4-methoxybenzene (1.9 g, 6.2 mmol) in THF (40 mL), n-BuLi (2.7 mL, 6.8 mmol, 2.5 M in hexane) was distilled at -65 °C. The resulting solution was then stirred at -65 °C for 30 minutes, allowed to warm to room temperature, and stirred for 16 hours. The solution was quenched by adding water and extracted twice with EA. The collected organic layers were washed with water, brin, dried with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain the desired compound (550 mg, yield 59%). MS(ESI) m / e [M+H]+ = 151.0.

[0531] Step 3: 6-Methoxy-2,3-Dihydrobenzofuran-7-sulfenic acid

[0532] To a solution of 6-methoxy-2,3-dihydrobenzofuran (300 mg, 2 mmol) and TMEDA (464 mg, 4 mmol) in n-hexane (10 mL), n-BuLi (2.5 M in hexane, 2.4 mL, 6 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour, then cooled to -70°C. SO2 bubbles (gas) were passed through the solution for 1 minute, and then it was stirred at this temperature for 30 minutes. The reaction mixture was quenched by adding water (4 mL) and concentrated. The residue was purified by column C18 [(water (0.1% HCOOH)], % B = 0%–70%, to obtain the desired compound (360 mg, yield 72%). MS(ESI) m / e [M-OH]- = 197.0.

[0533] Step 4: 6-Methoxy-2,3-Dihydrobenzofuran-7-sulfonamide

[0534] To a solution of 6-methoxy-2,3-dihydrobenzofuran-7-sulfinic acid (360 mg, 1.83 mmol) in DCM (10 mL), SO2Cl2 (247 mg, 1.83 mmol) was added by distillation at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. The solution was diluted with DCM and washed with water, dried with Na2SO4, filtered, concentrated, and the residue was dissolved in THF (5 mL) and ammonia water (1 mL) and stirred at room temperature for 1 hour. The solution was concentrated, and the residue was purified by column C18 using 0.1% FA in water / ACN (sequential filtration of 10% to 100%) to obtain the desired 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.

[0535] Example B19: Synthesis of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonamide

[0536] Step 1: 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carbonitrile

[0537] 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), NaH (60% in mineral oil, 3.3 g, 82 mmol) was added at 0 °C. The mixture was stirred at 15 °C for 2 hours. Immediately after the reaction, the reaction mixture was quenched with aqueous NH4Cl (100 mL) and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to obtain the desired 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).

[0538] Step 2: 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carbaldehyde

[0539] To a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carbonitrile (4.4 g, 21 mmol) in THF (90 mL), DIBAL-H (1 M in THF, 43 mL) was added at -70 °C. The mixture was stirred at 15 °C for 16 h. Immediately after the reaction, the mixture was quenched by adding 1 M HCl (45 mL) at -30 °C, then warmed to room temperature and stirred for 0.5 h. The mixture was filtered through a sieve, and the filtrate was extracted with EA, washed with water and brine, dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 30:1 to 5:1) to obtain the desired 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).

[0540] Step 3: (1-(2-fluoro-4-methoxyphenyl)cyclobutyl)methanol

[0541] To a solution of 1-(2-fluoro-4-methoxyphenyl)cyclobutane-1-carbaldehyde (2.5 g, 12 mmol) in MeOH (25 mL), NaBH4 (477 mg, 12.6 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. Immediately after the reaction, the reaction mixture was quenched by adding aqueous NH4Cl and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 20:1 to 5:1) to obtain 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).

[0542] Step 4: 6-Methoxy-2H-Spiro[benzofuran-3,1'-cyclobutane]

[0543] To a solution of (1-(2-fluoro-4-methoxyphenyl)cyclobutyl)methanol (2 g, 9.5 mmol) in THF (20 mL), t-BuOK (1 M in THF, 14.3 mL) was added. The mixture was stirred at 70 °C for 12 hours. Immediately after the reaction, the reaction mixture was cooled to room temperature, quenched with water, and extracted with EA. The collected organic layers were washed with Brine, dried with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 40:1) to obtain 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.

[0544] Step 5: Lithium 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfinate

[0545] To a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane] (1000 mg, 5.26 mmol), TMEDA (610 mg, 5.26 mmol) in 20 mL of hexane, n-BuLi (2.1 mL, 5.26 mmol) was added at 0°C and stirred for 10 minutes. The mixture was then cooled to -78°C and SO2 bubbles were passed through for 5 minutes. Immediately after the reaction, the mixture was filtered, and the paste was collected to obtain the product (1.34 g, 100%). MS (ESI) m / e [M+H]+ = 255.3.

[0546] Step 6: 6-Methoxy-2H-Spiro[benzofuran-3,1'-cyclobutane]-7-sulfonylchloride

[0547] 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), NCS (1.75 g, 13.2 mmol) was added at 0 °C and stirred for 10 minutes. Immediately after the reaction, the solution was diluted with water, and the mixture was filtered. The resulting paste was collected to obtain the desired product (1.51 g, 100%). MS (ESI) m / e [M+H]+ = 288.2.

[0548] Step 7: 6-Methoxy-2H-Spiro[benzofuran-3,1'-cyclobutane]-7-sulfonamide

[0549] To a solution of 6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-sulfonylchloride (1.51 g, 5.26 mmol) in THF (10 mL), NH3•H2O (1 mL) was added by distillation at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, H2O was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated. The residue was diluted with EA (10 mL) and stirred for 1 hour. The mixture was then filtered, and the resulting paste was collected to obtain the desired product (1 g, 71%). MS (ESI) m / e [M+H]+ =270.3.

[0550] Example B20: Synthesis of 6-methoxy-2',3',5',6'-tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-7-sulfonamide

[0551] Step 1: Methyl 4-(2-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-carboxylate

[0552] To a solution of methyl 2-(2-fluoro-4-methoxyphenyl)acetate (6 g, 30 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (35 g, 151 mmol) in DMF (60 mL), t-BuOK (1 M in THF, 121 mL) was added by distillation at 0 °C. The mixture was stirred at 15 °C for 1 h. Immediately after the reaction, the reaction mixture was quenched with water and then extracted with EA. The collected organic layers were washed with Bryn, dried with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the desired compound (7.5 g, 92% yield). 1H NMR (400 MHz, 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).

[0553] Step 2: (4-(2-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-yl)methanol

[0554] To a solution of methyl 4-(2-fluoro-4-methoxyphenyl)tetrahydropyran-4-carboxylate (7.5 g, 28 mmol) in THF (120 mL), LiBH4 (at a concentration of 2 M in THF, 28 mL, 56 mmol) was added at 0 °C. The mixture was stirred at 40 °C for 16 hours. Immediately after the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA. The collected organic layers were washed with Bryn, dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (6.6 g) without 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).

[0555] Step 3: 6-Methoxy-2',3',5',6'-Tetrahydro-2H-Spiro[benzofuran-3,4'-pyran]

[0556] To a solution of [4-(2-fluoro-4-methoxy-phenyl)tetrahydropyran-4-yl]methanol (5.6 g, 23 mmol) in THF (60 mL), t-BuOK (at a concentration of 1 M in THF, 35 mL, 35 mmol) was added at 15 °C. The mixture was stirred at 70 °C for 3 hours. Immediately after the reaction, the mixture was cooled to room temperature, quenched with water, and extracted with EA. The collected organic layers were washed with Bryn, dried with Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was crushed with MTBE and filtered. The resulting filtrate was dried under vacuum to obtain 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.

[0557] Step 4: 6-Methoxy-2',3',5',6'-tetrahydro-2H-spiro[benzofuran-3,4'-pyran]-7-sulfonamide

[0558] 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) was mixed with n-BuLi (2.5 M in n-hexane, 2 mL, 5 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 h and cooled to -60°C. Sulphryl chloride (920 mg, 6.8 mmol) was added to the mixture at -60°C. The mixture was stirred at 15°C for 12 h. Immediately after the reaction, the mixture was poured into a container and extracted with EA. The collected organic layers were washed with Braine, dried with Na₂SO₄, filtered, and concentrated to obtain crude sulfonylureas (1.4 g). To a solution of crude sulfonylureas (1.4 g, 4.4 mmol) in MeOH (10 mL), NH₃ / MeOH (7 M, 5 mL) was added. The mixture was stirred at 15 °C for 0.5 hours. Immediately after the reaction, the mixture was filtered.The filtrate was dried in a vacuum medium to obtain the crude product, which was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [H2O(NH4HCO3 at a concentration of 10 mM)-ACN]; gradient: 1%-40% of B in 8.0 minutes) to obtain the desired 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

[0559] Example B21: Synthesis of 7-methoxy-3,3-dimethylcromon-8-sulfonamide

[0560] Step 1: 7-hydroxy-3,3-dimethylchromon-4-one

[0561] To a suspension of tBuOK (6.72 g, 60 mmol) in THF (70 mL), 7-hydroxycromon-4-one (1.64 g, 10 mmol) and CH3I (7.1 g, 50 mmol) were added by distillation in THF (30 mL) at -70 °C. The solution was stirred at this temperature for 4 hours, allowed to warm to room temperature, and stirred for 1 hour. The solution was diluted with water and citric acid and extracted with EA. The extracted layer was washed with Brine, dried with Na2SO4, filtered, and concentrated to obtain the desired product (3 g, crude). MS (ESI) m / e [M+H]+ = 193.1.

[0562] Step 2: 7-Methoxy-3,3-Dimethylchromane-4-one

[0563] To a suspension of 7-hydroxy-3,3-dimethylchromium-4-one (3 g, 10 mmol) and K₂CO₃ (2.76 g, 20 mmol) in DMF (40 mL), CH₃I (2.84 g, 20 mmol) was added, and the mixture was stirred briefly at 90 °C. After cooling to room temperature, the solution was diluted with EA, washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 4:1) to obtain the desired product (1.6 g, 78% in two steps). MS (ESI) m / e [M+H]+ = 207.0.

[0564] Step 3: 7-Methoxy-3,3-Dimethylchrome

[0565] A suspension of 7-methoxy-3,3-dimethylchroman-4-one (1.6 g, 7.76 mmol) and Zn powder (4 g, 621 mmol) was dissolved in MeOH (30 mL) and concentrated HCl (10 mL) and stirred at room temperature for 4 hours. Immediately after the reaction, the mixture was diluted with EA, washed with water, bleached, dried with Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the desired product (1.1 g, 74%). MS (ESI) m / e [M+H]+ = 193.1.

[0566] Step 4: 7-Methoxy-3,3-Dimethylchromane-8-sulfenic acid

[0567] To a solution of 7-methoxy-3,3-dimethylcroman (576 mg, 3 mmol) and TMEDA (348 mg, 9 mmol) in n-hexane (20 mL), n-BuLi (3.6 mL, 9 mmol, at a concentration of 2.5 M in n-hexane) was added by distillation at less than 10 °C, and the reaction mixture was stirred at 10 °C for 30 minutes. The solution was then cooled to -60 °C, SO2 bubbles (gas) were passed through it for 1 minute, and it was stirred at -60 °C for 30 minutes. Immediately after the reaction was completed, 1 standard of HCl (5 ml) was added to the reaction mixture and the solution was diluted with water, extracted with EA, washed with Braine, dried with Na2SO4, filtered and concentrated to obtain the desired product (600 mg, 78%). MS (ESI) m / e [M+H]+ = 257.0.

[0568] Step 5: 7-Methoxy-3,3-Dimethylchromane-8-sulfonamide

[0569] To a solution of 7-methoxy-3,3-dimethylchromane-8-sulfinic acid (600 mg, 2.34 mmol) in AcOH (10 mL) and H₂O (3 mL), NCS (939 mg, 7 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The solution was diluted with water and extracted with EA. The extracted layer was washed with Braine, dried with Na₂SO₄, filtered, and concentrated. The residue was dissolved in THF (10 mL) and NH₄OH solution (2 mL). After stirring at room temperature for 1 hour, the solution was concentrated, and the residue was purified by a C18 column using 0.1% FA in water / ACN (sequential filtration from 10% to 100%) to obtain the desired product (200 mg, 31%). MS (ESI) m / e [M+H]+ = 272.1.

[0570] Example B22: Synthesis of 2-methoxy-5-(1-methoxy-2-methylpropane-2-yl)benzenesulfonamide

[0571] Step 1: 2-[3-[Bis[(2,4-Dimethoxyphenyl)methyl]sulfamoyl]-4-methoxy-phenyl]-2-methyl-propanoate

[0572] To a solution of methyl 2-[3-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-4-methoxyphenyl]acetate (15 g, 26.8 mmol) in THF (150 mL), tBuOK (9 g, 80.4 mmol) and MeI (11.4 g, 80.4 mmol) were slowly added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. Immediately after the reaction, the mixture was quenched with H₂O and extracted with EA. The collected organic layers were concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10:1 to 1:1) to obtain the desired compound (12 g, yield 76%). 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).

[0573] Step 2: N,N-Bis(2,4-dimethoxybenzyl)-5-(1-hydroxy-2-methylpropane-2-yl)-2-methoxybenzenesulfonamide

[0574] To a solution of methyl 2-[3-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-4-methoxyphenyl]-2-methyl-propanoate (1.5 g, 2.5 mmol) in THF (20 mL), LiBH4 (2 M in THF, 2.55 mL) was added at 0 °C. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was quenched with saturated NH4Cl (30 mL) and extracted with EA. The collected organic layers were washed with Bryn, dried with 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 obtain the desired compound (1.1 g, yield 77%). 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).

[0575] Step 3: N,N-Bis(2,4-dimethoxybenzyl)-2-methoxy-5-(1-methoxy-2-methylpropane-2-yl)benzenesulfonamide

[0576] To a solution of N,N-Bis[(2,4-dimethoxyphenyl)methyl]-5-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxybenzenesulfonamide (1.1 g, 2 mmol) in THF (15 mL), NaH (60% in mineral oil, 120 mg, 3 mmol) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. MeI (418 mg, 3 mmol) was then added to the mixture at 0°C. The reaction mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was quenched with aqueous NH4Cl (20 mL) and extracted with EA. The collected organic layers were washed with Bryn, dried with Na2SO4, filtered, and concentrated under reduced pressure. The remaining material was purified by silica gel column chromatography (PE / EA=10:1 to 4:1) to obtain the desired compound (400 mg, yield of 35%). 1H NMR (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).

[0577] Step 4: 2-Methoxy-5-(1-Methoxy-2-methylpropane-2-yl)benzenesulfonamide

[0578] 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), TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. 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 minutes) to obtain the desired compound (72 mg, yield 43%). 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).

[0579] Example B23: Synthesis of 2-(tert-butyl)-5-methoxypyridine-4-sulfonamide

[0580] To a solution of 2-tert-butyl-5-methoxypyridine (180 mg, 1.1 mmol) and TMEDA (152 mg, 1.3 mmol) in THF (3 mL), n-BuLi (2.5 M in n-hexane, 480 µL) was added by distillation at -60 °C. The mixture was stirred at -60 °C for 1 h, and N-sulfinyl-O-(tert-butyl)-hydroxyamine (221 mg, 1.6 mmol) in THF (0.5 mL) was added by distillation. The reaction mixture was stirred at 15 °C for 16 h. The reaction mixture was quenched with 5 mL of saturated NH4Cl and extracted with EA. The collected organic layers were washed with Bran, dried with Na2SO4, filtered, and concentrated under reduced pressure. The remaining material was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm, mobile phase: [H2O(NH4HCO3 at 10 mM)-ACN]; gradient: 10%–40% B over 8.0 minutes) to obtain the desired compound (8.5 mg, yield 3%). 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).

[0581] Example B24: Synthesis of 6-(tert-butyl)-3-(methoxy-d3)pyridin-2-sulfonamide

[0582] Step 1: 2-Fluoro-6-iodopyridine-3-ol

[0583] To a solution of 2-fluoropyridine-3-ol (5 g, 44.2 mmol) and K₂CO₃ (12.2 g, 88.4 mmol) in water (200 mL), I₂ (12.4 g, 48.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was adjusted to a pH of 6 using citric acid and extracted twice with EA. The collected organic layers were washed with Na₂S₂O₃ solution, dried with anhydrous Na₂SO₄, filtered, and concentrated to obtain the product (11 g, crude). MS(ESI) m / e [M+H]+ = 239.9.

[0584] Step 2: 2-Fluoro-6-iodo-3-(methoxy-d3)pyridine

[0585] To a solution of 2-fluoro-6-iodopyridine-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 room temperature for 30 minutes. CD3I (7 g, 48.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EA, washed with water, bleached, dried with anhydrous Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE to PE / EA = 1:1) to obtain the product (6 g, 53%). MS(ESI) m / e [M+H]+ = 257.0.

[0586] Step 3: 2-(benzylthio)-6-iodo-3-(methoxy-d3)pyridine

[0587] To a solution of phenylmethanethiol (2.79 g, 22.5 mmol) in THF (100 mL), NaH (60% in mineral oil, 900 mg, 22.5 mmol) was slowly added 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 collected organic layers were washed with pyrene, dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE to PE / EA = 3:1) to obtain the compound (5.1 g, 75% yield). MS(ESI) m / e [M+H]+ = 361.1.

[0588] Step 4: 2-(benzylthio)-6-(tert-butyl)-3-(methoxy-d3)pyridine

[0589] To a mixture of CuCN (1.24 g, 13.9 mmol) in THF (20 mL), tert-butyl magnesium chloride (27.8 mL, at a concentration of 1 M in THF, 27.8 mmol) was distilled at -65 °C and stirred at -65 °C for 1 h. 2-(benzylthio)-6-iodo-3-(methoxy-d3)pyridine (2 g, 5.55 mmol) was distilled in THF (5 mL) at -65 °C and stirred at -65 °C for 1 h. The mixture was then allowed to warm to room temperature and stirred for 3 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (100 mL × 2). The collected organic layers were washed with saturated aqueous NH4Cl, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE to PE:EA = 4:1) to obtain the desired compound (1 g, yield 62%). MS(ESI) m / e [M+H]+ = 291.2.

[0590] Step 5: 6-(tert-butyl)-3-(methoxy-d3)pyridine-2-sulfonamide

[0591] 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), NCS (1.38 g, 10.34 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Immediately after the reaction, the solution was poured into ice-cold water and extracted twice with EA. The extracts were washed with water, bleached, dried, concentrated, and the residue was dissolved in THF (10 mL). NH₄OH (25%, 2 mL) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated and the remaining substance was purified by column C18 using 0.1% FA in water / ACN (sequential filtration from 10% to 60%) to obtain the desired 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.

[0592] Example B25: Synthesis of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-sulfonamide

[0593] Step 1: 6-Methoxy-3,3-Dimethyl-2,3-Dihydrobenzofuran-5-sulfonylurea

[0594] To a solution of 6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran (1 g, 5.6 mmol) in DCM (10 mL), sulfochloric acid (651 mg, 5.6 mol) was added by distillation at 0°C and stirred for 1 hour. Immediately after the reaction, the mixture was poured into ice water and extracted with DCM. The organic layer was concentrated to obtain the desired product (1 g, 64%). MS (ESI) m / e [M+Na]+ = 277.2.

[0595] Step 2: 6-Methoxy-3,3-Dimethyl-2,3-Dihydrobenzofuran-5-sulfonamide

[0596] 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), NH3•H2O (5 mL) was added by distillation at 0°C. The reaction mixture was stirred at room temperature for 1 hour. Immediately after the reaction, H2O was added to the reaction mixture and extracted with EA. The collected organic layers were washed with Brine, dried with Na2SO4, filtered, and concentrated. The residue was diluted with EA (10 mL) and stirred for 1 hour. The mixture was filtered, and the resulting filtrate was collected to obtain 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.

[0597] Example B26: Synthesis of 5-(2-oxa-pycyclo[2.1.1]hexane-4-yl)-2-methoxybenzenesulfonamide

[0598] Step 1: 4-(4-Methoxyphenyl)-2-oxa-pyricyclo[2.1.1]hexane

[0599] To a solution of 3-(hydroxymethyl)-3-(4-methoxyphenyl)cyclobutane-1-ol (1 g, 4.8 mmol) in pyridine (3.2 mL) and DCM (8 mL), 4-toluene sulfonyl chloride (1.37 g, 7.2 mmol, 1.5 Eq) was added at 0 °C under an N2 atmosphere. The reaction mixture was stirred at 25 °C for 2 hours. Immediately after the reaction, the mixture was diluted with DCM, washed with water, 1 N of aqueous HCl and pyridine, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain crude (3-hydroxy-1-(4-methoxyphenyl)cyclobutyl)methyl 4-methylbenzenesulfonate.

[0600] To a solution of crude (3-hydroxy-1-(4-methoxyphenyl)cyclobutyl)methyl 4-methylbenzenesulfonate in THF (80 mL), NaH (60% in mineral oil, 320 mg, 8 mmol) was added at 0 °C under an N₂ atmosphere. The reaction mixture was stirred at 0 °C for 30 minutes, then heated to 80 °C and stirred at this temperature for 12 hours. After cooling to room temperature, 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 obtain the desired compound (0.2 g, yield 19%). 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).

[0601] Step 2: 4-(3-Bromo-4-methoxyphenyl)-2-oxa-pyricyclo[2.1.1]hexane

[0602] To a solution of 4-(4-methoxyphenyl)-2-oxa-bicyclo[2.1.1]hexane (0.2 g, 1.0 mmol) in ACN (3 mL), NBS (187.1 mg, 1.0 mmol, 1 Eq) was added. The reaction mixture was stirred at 20 °C for 12 hours. Immediately after the reaction, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:0 to 1:1) to obtain the desired compound (0.2 g, yield 71%). 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)

[0603] Step 3: 4-(3-(benzylthio)-4-methoxyphenyl)-2-oxa-pyricyclo[2.1.1]hexane

[0604] To a solution of 4-(3-bromo-4-methoxyphenyl)-2-oxa-bicyclo[2.1.1]hexane (150 mg, 557 µmol) in dioxane (2 mL), Pd2(dba)3 (51 mg, 56 µmol) and xantphos (65 mg, 112 µmol) were added. The mixture was stirred at room temperature for 30 minutes under an N2 atmosphere. A solution of phenylmethanethiol (139 mg, 1.1 mmol) and DIEA (144 mg, 1.1 mmol) in dioxane (2 mL) was then added to the reaction mixture. The reaction mixture was stirred at 110 °C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE:EA = 1:0 to 3:1) to obtain the desired compound (140 mg, yield of 80%). 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).

[0605] Step 4: 5-(2-Axa-pyricyclo[2.1.1]hexane-4-yl)-2-methoxybenzenesulfonamide

[0606] To a solution of 4-(3-(benzylthio)-4-methoxyphenyl)-2-oxa-bicyclo[2.1.1]hexane (140 mg, 448 µmol) in AcOH (2.4 mL), ACN (0.6 mL), and H₂O (0.06 mL), sulfuryl chloride (181 mg, 1.3 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Immediately after the reaction, the mixture was concentrated under vacuum to obtain crude 5-(2-oxa-bicyclo[2.1.1]hexane-4-yl)-2-methoxybenzene sulfonyl chloride, which was dissolved in

[0607] NH3 at a concentration of 7 M in MeOH (2.6 mL). The reaction mixture was stirred at room temperature for 10 minutes. Immediately after the reaction, the mixture was filtered through a sieve and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 75 × 40 mm × 3 µm; mobile phase: [H2O(NH4HCO3)ACN]; gradient: 5%–30% B over 8.0 minutes) to obtain the desired compound (85.3 mg, yield 70%). 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.

[0608] Example B27: Synthesis of 7-methoxy-3,4-dihydro-2H-2,4-methanocromon-8-sulfonamide

[0609] Step 1: 2-(3-(benzyloxy)cyclobutyl)-5-methoxyphenol

[0610] To a solution of 2-bromo-5-methoxyphenol (1.1 g, 5.4 mmol) in DME (330 mL) ((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) at 25 °C under an N2 atmosphere. The solution was injected into a photoflux reactor (FEP, reactor coils, 3.175 (1 / 8") mm, 55 mL, 395 nm, 200 W * 2, 40 °C) at a flow rate of 40 mL / min. Three reactions were carried out in parallel. Immediately after the reaction was complete, the combined mixture of the three reactions was poured into H₂O and extracted with EA. The collected organic layers were washed with Bryn, dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, PE:EA = 10:1 to 3:1) to obtain the desired compound (0.9 g, yield 20%). MS(ESI) m / e [M+H]+ = 285.1.

[0611] Step 2: 2-(3-hydroxycyclobutyl)-5-methoxyphenol

[0612] To a mixture of 2-(3-benzyloxycyclobutyl)-5-methoxyphenol (0.9 g, 3.2 mmol) and Pd / C (0.4 g, 10% w / w) in MeOH (12 mL) and EA (48 mL), concentrated HCl (0.3 mL) was added. The suspension was degassing and purified with H₂ three times, then stirred under an H₂ atmosphere (15 psi) at 25 °C for 16 h. Immediately after the reaction, the mixture was filtered through silica gel. The filtrate was concentrated under vacuum. The residue was purified by preparative TLC (silica gel, PE:EA = 1:1) to obtain the desired compound (0.45 g, 72% yield). MS(ESI) m / e [M-OH]+ = 177.1.

[0613] Step 3: 7-Methoxy-3,4-Dihydro-2H-2,4-Methanochrome

[0614] A mixture of 2-(3-hydroxycyclobutyl)-5-methoxyphenol (250 mg, 1.3 mmol) and 2-(tributylphosphoranilydine)acetonitrile (Tsunoda reagent, 940 mg, 3.9 mmol) was stirred in dioxane (7.5 mL) at 150 °C under microwave conditions for 1 hour. After cooling to room temperature, the solution was diluted with EA and washed with Brine, dried with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the desired 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.

[0615] Step 4: 7-Methoxy-3,4-Dihydro-2H-2,4-Methanochrome-8-sulfonamide

[0616] To a mixture of 7-methoxy-3,4-dihydro-2H-2,4-methanocrom (80 mg, 0.46 mmol) in n-hexane (10 mL), TMEDA (106 mg, 0.92 mmol) and n-BuLi (1.6 M in n-hexane, 0.40 mL, 0.56 mmol) were added at 0°C and stirred at 0°C for 30 minutes. The solution was cooled to -70°C, and SO2 (gas) bubbles were passed through for 1 minute. The reaction mixture was then stirred further at -70°C for 30 minutes. Immediately after the reaction, the mixture was concentrated under vacuum to obtain crude 7-methoxy-3,4-dihydro-2H-2,4-methanocrom-8-sulfinic acid.

[0617] To a mixture of crude 7-methoxy-3,4-dihydro-2H-2,4-methanocromon-8-sulfonic acid in acetic acid (12 mL) and water (4 mL), NCS (190 mg, 0.84 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was concentrated to remove the acetic acid. The residue was extracted with EA. The collected organic phases were washed with Bryn, dried with anhydrous Na2SO4, and concentrated under vacuum to obtain the crude 7-methoxy-3,4-dihydro-2H-2,4-methanocromon-8-sulfonyl chloride.

[0618] To a mixture of crude 7-methoxy-3,4-dihydro-2H-2,4-methanocromon-8-sulfonyl chloride in THF (6 mL), NH3.H2O (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain the desired compound (60 mg, yield 51%). MS(ESI) m / z [M + H]+ = 256.0.

[0619] Example B28: Synthesis of 6-(bicyclo[1.1.1]pentane-1-yl)-3-methoxypyridine-2-sulfonamide

[0620] Step 1: 6-(Bycyclo[1.1.1]pentane-1-yl)-2-fluoro-3-methoxypyridine

[0621] To a mixture of 6-bromo-2-fluoro-3-methoxypyridine (412 mg, 2 mmol) in DMA (10 mL), 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) were added. The mixture was exchanged with N2 three times and stirred at room temperature under blue light (440 nm) for 16 hours. Immediately after the reaction, the mixture was concentrated under vacuum. The remaining material was purified by silica gel column chromatography (PE:EA = 2:1) to obtain the desired compound (70 mg, 18%). MS(ESI) m / z [M + H]+ = 194.2.

[0622] Step 2: 2-(benzylthio)-6-(bicyclo[1.1.1]pentane-1-yl)-3-methoxypyridine

[0623] To a mixture of phenylmethanethiol (35 mg, 0.26 mmol) in THF (10 mL), NaH (60% in mineral oil, 11.2 mg, 0.26 mmol) was added and stirred at 0°C for approximately 30 minutes. 6-(bicyclo[1.1.1]pentane-1-yl)-2-fluoro-3-methoxypyridine (50 mg, 0.26 mmol) in THF (2 mL) was then added to the above mixture at 0°C. The reaction mixture was heated to 60°C and stirred at this temperature for 3 hours. Immediately after the reaction, the mixture was cooled to room temperature, quenched with H₂O, and extracted with EA. The collected organic phases were washed with pyrene, dried with Na₂SO₄, and concentrated. The remaining material was purified by silica gel column chromatography (PE:EA = 3:1) to obtain the desired compound (60 mg, 78%). MS(ESI) m / z [M + H]+ = 298.2.

[0624] Step 3: 6-(Bycyclo[1.1.1]pentane-1-yl)-3-methoxypyridine-2-sulfonamide

[0625] To a mixture of 2-(benzylthio)-6-(bicyclo[1.1.1]pentan-1-yl)-3-methoxypyridine (60 mg, 0.20 mmol) in acetic acid (6 mL) and water (2 mL), NCS (180 mg, 0.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the mixture was concentrated under vacuum to remove the acetic acid. The residue was diluted with H₂O and extracted with EA. The collected organic phases were washed with ryne, dried with anhydrous Na₂SO₄, and concentrated to obtain crude 6-(bicyclo[1.1.1]pentan-1-yl)-3-methoxypyridine-2-sulfonyl chloride.

[0626] To a mixture of crude 6-(bicyclo[1.1.1]pentan-1-yl)-3-methoxypyridine-2-sulfonyl chloride in THF (5 mL), NH3.H2O (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was concentrated under vacuum. The residue was diluted with DCM and water. The aqueous phase was adjusted to pH 2–3 using 1 N HCl (aqueous), which was then extracted with DCM. The collected organic phases were washed with Bryn, dried with anhydrous Na2SO4, and concentrated to obtain the desired compound without further purification (50 mg, 99%). MS(ESI) m / z [M + H]+ = 255.1.

[0627] Example C:

[0628] Example C1: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-iodobenzamide

[0629] 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) was briefly stirred in DCM (20 mL) at room temperature. Immediately after the reaction, 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 obtain the desired 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.

[0630] Example C2: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-cyclopropylbenzamide

[0631] 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 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the remaining material was purified by preparative HPLC (Waters Sunfire C18, 55%-70% ACN in H2O / 0.1% FA) to obtain 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.

[0632] Examples C3 below (Table 1) were synthesized starting from the corresponding precursors according to the similar procedures described for Example C2.

[0633] Table 1: Example The compound chemical name Data 1 H NMR LC / MS m / z (M+1) Part 3 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-methylbenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.34 (s, 1H), 7.85-7.74 (m, 2H), 7.73-7.69 (m, 1H), 7.69-7.54 (m, 2H), 7.49-7.45 (m, 1H), 7.17-7.00 (m, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.28 (s, 1H), 5.38 (s, 2H), 3.77 (s, 3H), 2.30 (s, 3H), 1.27 (s, 9H). MS (ESI) m / e [M+H] + = 442.

[0634] Example C4: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-phenylbenzamide

[0635] 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) was stirred briefly in THF (10 mL) at 80 °C. After cooling to room temperature, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude 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.

[0636] Examples C5 below (Table 2) were synthesized starting from the corresponding precursors according to the similar procedures described for Example C4.

[0637] Table 2: Example The compound chemical name Data 1 H NMR LC / MS m / z (M+1) J5 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(furan-2-yl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.56 (s, 1H), 8.22 (s, 1H), 7.91-7.82 (m, 2H), 7.81-7.76 (m, 1H), 7.74-7.62 (m, 2H), 7.54-7.49 (m, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.00-6.93 (m, 1H), 6.73-6.65 (m, 2H), 6.31 (s, 1H), 5.62 (s, 2H), 3.81 (s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H] + = 494.

[0638] Example C6: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-ethylbenzamide

[0639] To a solution of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-phenylbenzamide (50 mg, 0.11 mmol) and Pd / C (10 mg, 10%) in MeOH (5 mL), H2 (1 atm) was introduced. The resulting mixture was stirred at 30 °C for 4 hours. After cooling to room temperature, the reaction mixture was separated by filtration, and the filtrate was concentrated. The residue was purified by preparative HPLC (Waters Sunfire C18, 50%–70% ACN in H2O / 0.1% FA) to obtain 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.

[0640] Example C7: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-methoxybenzamide

[0641] 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) was stirred briefly in DCM (50 mL) at room temperature. Immediately after the reaction, 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 in H2O / 0.1% FA) to obtain the product (21 mg, 42%). 1 H NMR (400 MHz, DMSO- d 6) 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 = 8.7 Hz, 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.

[0642] Examples C8-C17 below (Table 3) were synthesized starting from the corresponding precursors according to similar procedures described for Example C7.

[0643] Table 3: Example Structural formula chemical name Data 1 H NMR LC / MS m / z (M+H) J8 5-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-cyclopropyl picolineamide 1 H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.72-7.66 (m, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.32-6.29 (m, 1H), 5.63 (s, 2H), 3.80 (s, 3H), 2.42-2.34 (m, 1H), 1.27 (s, 9H), 1.24-1.18 (m, 2H), 1.06-0.97 (m, 2H).MS (ESI) m / e [M+1] + = 469.3. Q9 4-((1H-pyrazol-1-yl)methyl)-3-ethinyl-N-((6-methoxy-2,3-dihydro-1H-indine-5-yl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO-d6)δ 12.46 (s, 1H), 7.99 (s, 1H), 7.86-7.74 (m, 2H), 7.70-7.55 (m, 1H), 7.53-7.45 (m, 1H), 7.15-7.69 (m, 1H), 6.90-6.75 (m, 1H), 6.30-6.26 (s, 1H), 5.48 (s, 2H), 4.70-4.40 (m, 1H), 3.85-3.55 (m, 3H), 2.95-2.75 (m, 4H), 2.06-1.94 (m, 2H). MS (ESI) m / e [M+1] + = 436.3. J10 4-((1H-pyrazol-1-yl)methyl)-5-bromo-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-2-fluorobenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.73 (s, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.84 – 7.80 (m, 2H), 7.75 – 7.67 (m, 1H), 7.55 (s, 1H), 7.22 – 7.15 (m, 1H), 6.57 (d, J = 10.7 Hz, 1H), 6.37 – 6.33 (m, 1H), 5.44 (s, 2H), 3.86 (s, 3H), 1.29 (s, 9H). MS (ESI) m / e [M+H] + = 524.2. J11 4-((1H-pyrazol-1-yl)methyl)-3-bromo-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-2-fluorobenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.74 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.75 – 7.68 (m, 1H), 7.54 (s, 1H), 7.48 – 7.42 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.36 – 6.32 (m, 1H), 5.49 (s, 2H), 3.86 (s, 3H), 1.29 (s, 9H). MS (ESI) m / e [M+H] + = 524.2. J12 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(methoxymethyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.51 (s, 1H), 7.91 – 7.88 (m, 1H), 7.85 – 7.82 (m, 1H), 7.81 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.64 – 7.54 (m, 1H), 7.49 (s, 1H), 7.11 – 7.00 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.32 – 6.27 (m, 1H), 5.43 (s, 2H), 4.54 (s, 2H), 3.75 (s, 3H), 3.33 (s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H] + = 472.4. J13 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(dimethylamino)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.50 (s, 1H), 7.87 – 7.83 (m, 2H), 7.72 – 7.65 (m, 2H), 7.49 (s, 1H), 7.46 – 7.41 (m, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.32 – 6.29 (m, 1H), 5.45 (s, 2H), 3.83 (s, 3H), 2.70 (s, 6H), 1.29 (s, 9H). MS (ESI) m / e [M+H] + = 471.4. J14 4-((1H-pyrazol-1-yl)methyl)-3-bromo-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.61 (s, 1H), 8.17-8.13 (m, 1H), 7.89-7.86 (m, 1H), 7.85-7.81 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.13 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 5.45 (s, 2H), 3.81 (s, 3H), 1.28 (s, 9H). MS (ESI) m / e [M+H] + = 506. J15 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-ethinylbenzamide 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.01 (s, 1H), 7.85 -7.81 (m, 2H), 7.79 (br d, J = 7.8 Hz, 1H), 7.68 (br s, 1H), 7.48 (s, 1H), 7.13 (br d, J = 7.8 Hz, 1H), 6.85 (br d, J = 8.8 Hz, 1H), 6.29 (br s, 1H), 5.50 (s, 2H), 4.64 (s, 1H), 3.79 (s, 3H), 1.27 (s, 9H). MS (ESI) m / e [M+H]+ = 452.4. J16 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-phenylbenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.37 (s, 1H), 8.18-8.13 (m, 1H), 7.83-7.78 (m, 1H), 7.75-7.68 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.51-7.46 (m, 1H), 7.16 (dd, J = 17.2, 11.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.29 (s, 1H), 5.89 (d, J = 17.3 Hz, 1H), 5.50 (s, 2H), 5.45 (d, J = 11.1 Hz, 1H), 3.90 (s, 3H), 1.13 (s, 9H). MS (ESI) m / e [M+H] + = 455. J17 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropyl-N-((2-methoxy-5-(4-methoxypiperidine-1-yl)phenyl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.43 (s, 1H), 7.80 (s, 1H), 7.60-7.51 (m, 2H), 7.50-7.45 (m, 1H), 7.41-7.35 (m, 1H), 7.31-7.16 (m, 1H), 7.13-6.98 (m, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.29 (s, 1H), 5.55 (s, 2H), 3.73 (s, 3H), 3.25 (s, 3H), 2.87-2.76 (m, 2H), 2.49 (s, 3H), 2.09-2.01 (m, 1H), 1.98-1.89 (m, 2H), 1.59-1.48 (m, 2H), 0.94 (d, J = 7.4 Hz, 2H), 0.83-0.66 (m, 2H). MS (ESI) m / e [M+H] + = 525. J18 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(oxytane-2-yl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.62 (s, 1H), 8.18 – 8.16 (m, 1H), 7.88 – 7.85 (m, 1H), 7.80 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.72 – 7.67 (m, 1H), 7.48 (s, 1H), 7.16 (s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.31 – 6.29 (m, 1H), 6.09 – 6.03 (m, 1H), 5.31 (s, 2H), 4.74 – 4.68 (m, J = 6.4 Hz, 1H), 4.60 – 4.53 (m, 1H), 3.83 (s, 3H), 2.96 – 2.87 (m, 1H), 2.46 – 2.38 (m, 1H), 1.30 (s, 9H). MS (ESI) m / e [M+H] + = 484.4. J19 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-(oxytane-3-yl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.48 (s, 1H), 8.22 (s, 1H), 7.80 – 7.76 (m, 1H), 7.75 – 7.64 (m, 3H), 7.53 – 7.49 (m, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.32 – 6.29 (m, 1H), 5.34 (s, 2H), 4.91 – 4.84 (m, 2H), 4.75 – 4.63 (m, 3H), 3.93 (s, 3H), 1.16 (s, 9H). MS (ESI) m / e [M+H] + = 485.4. J20 4-((1H-pyrazol-1-yl)methyl)-3-(azitidine-1-yl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.26 (s, 1H), 7.78 – 7.64 (m, 3H), 7.53 (s, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.07 – 7.04 (m, 1H), 6.46 (d, J = 7.9 Hz, 1H), 6.34 – 6.31 (m, 1H), 5.31 (s, 2H), 3.98 (t, J = 6.9 Hz, 4H), 3.92 (s, 3H), 2.29 – 2.21 (m, 2H), 1.17 (s, 9H). MS (ESI) m / e [M+H] + = 484.4. J21 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-cyclobutylbenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.39 (s, 1H), 7.93 (s, 1H), 7.83 – 7.77 (m, 1H), 7.76 – 7.60 (m, 3H), 7.51 (s, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.34 – 6.28 (m, 1H), 5.39 (s, 2H), 3.92 (s, 3H), 3.85 – 3.76 (m, 1H), 2.35 – 2.24 (m, 2H), 2.22 – 2.10 (m, 2H), 2.05 – 1.93 (m, 1H), 1.87 – 1.76 (m, 1H), 1.16 (s, 9H). MS (ESI) m / e [M+H] + = 483.4. J22 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-chlorobenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.44 (s, 1H), 8.00 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.67 – 7.60 (m, 2H), 7.51 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 5.49 (s, 2H), 3.86 (s, 3H), 1.11 (s, 9H). MS (ESI) m / e [M+H] + = 463. J23 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-ethylbenzamide 1 H NMR (400 MHz, DMSO- d 6) δ12.26 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.66-7.59 (m, 2H), 7.47 (d, J = 2.0 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.28 (t, J = 2.0 Hz, 1H), 5.43 (s, 2H), 3.88 (s, 3H), 2.75-2.67 (m, 2H), 1.15-1.08 (m, 12H). MS (ESI) m / e [M+H] + = 457. J24 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-fluorobenzamide 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (brs, 1H), 7.85 – 7.84 (m, 1H), 7.75 – 7.68 (m, 3H), 7.63 (d, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.15 – 7.11 (m, 1H), 6.28 – 6.27 (m, 1H), 5.45 (s, 2H), 3.88 (s, 3H), 1.11 (s, 9H). MS (ESI) m / e [M+H] + =447. J25 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-(trifluoromethyl)benzamide 1 H NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 8.30 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.67 – 7.63 (m, 2H), 7.54 – 7.53 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.35 – 6.34 (m, 1H), 5.61 (s, 2H), 3.88 (s, 3H), 1.10 (s, 9H). MS (ESI) m / e [M+H] + =497. J26 4-((1H-pyrazol-1-yl)methyl)-3-bromo-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.44 (s, 1H), 8.17 (s, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 8.1, 1H), 7.70 – 7.60 (m, 2H), 7.52 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.46 (s, 2H), 3.88 (s, 3H), 1.11 (s, 9H). MS (ESI) m / e [M+H] + = 507. J27 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-methoxybenzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.30 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.55 (d, J = 1.3 Hz, 1H), 7.46 (d, J = 1.3 Hz, 1H), 7.41 (d, J = 7.9, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.27 (t, J = 2.0 Hz, 1H), 5.32 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 1.12 (s, 9H). MS (ESI) m / e [M+H] + = 459. J28 4-((1H-pyrazol-1-yl)methyl)-3-methoxy-N-((2-methoxy-5-(1-methoxycyclopropyl)phenyl)sulfonyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.51 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.37 (d, J = 7.9, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.25 (t, J = 2.0 Hz, 1H), 5.29 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.12 (s, 3H), 1.14 (t, J = 5.1 Hz, 2H), 0.92 (t, J = 5.4 Hz, 2H). MS (ESI) m / e [M+H] + = 472. J29 N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-methyl-4-(pyridine-2-ylmethyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.28 (br s, 1H), 8.43 (d, J = 4.1 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.65 – 7.57 (m, 2H), 7.25 – 7.13 (m, 3H), 7.07 (br s, 1H), 4.10 (s, 2H), 3.75 (s, 3H), 2.23 (s, 3H), 1.26 (s, 9H). MS (ESI) m / e [M+H] + = 453.4. J30 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-(difluoromethoxy)benzal 1 H NMR (400 MHz, DMSO- d 6) δ 12.47 (s, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.77 – 7.63 (m, 4H), 7.52 (d, J = 1.3 Hz, 1H), 7.31 (t, J = 73.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 5.45 (s, 2H), 3.91 (s, 3H), 1.15 (s, 9H). MS (ESI) m / e [M+H] + = 495.3. J31 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-(2,2-difluoroethyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.33 (s, 1H), 7.89 – 7.86 (m, 1H), 7.86 – 7.83 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.73 – 7.58 (m, 2H), 7.52 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.34 – 6.28 (m, 1H), 6.21 – 5.99 (m, 1H), 5.51 (s, 2H), 3.89 (s, 3H), 3.47 – 3.37 (m, J = 14.2 Hz, 2H), 1.16 (s, 9H). MS (ESI) m / e [M+H] + = 493.3. J32 N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-methoxy-4-(pyridine-2-ylmethyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.23 (s, 1H), 8.41 (d, J = 4.0 Hz, 1H), 7.77 – 7.53 (m, 3H), 7.50 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.23 – 7.05 (m, 3H), 4.04 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 1.11 (s, 9H). MS (ESI) m / e [M+H] + = 470. J33 N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.28 (s, 1H), 7.73 – 7.58 (m, 3H), 7.56 – 7.50 (m, 1H), 7.39 (t, J = 6.8 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.01 (d, J = 1.8 Hz, 1H), 5.20 (s, 2H), 3.86 (s, 6H), 2.10 (s, 3H), 1.10 (d, J = 2.1 Hz, 9H). MS (ESI) m / e [M+H] + = 473. J34 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-ethoxypicolineamide 1 H NMR (400 MHz, DMSO- d 6) δ 11.71 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.37 (s, 2H), 4.61 (q, J = 6.8 Hz, 2H), 3.93 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H). MS (ESI) m / e [M+H] + = 474.3. J35 N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-methyl-5-(pyridine-2-ylmethyl)picolineamide 1 H NMR (400 MHz, DMSO- d 6) δ 11.34 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.74 – 7.61 (m, 4H), 7.25 (d, J = 7.4 Hz, 1H), 7.19 (dd, J = 7.4, 5.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 4.19 (s, 2H), 3.75 (s, 3H), 2.51 (s, 3H), 1.24 (s, 9H). MS (ESI) m / e [M+H] + = 454.3. J36 4-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-(difluoromethyl)benzamide 1 H NMR (400 MHz, DMSO- d 6) δ 12.51 (s, 1H), 8.12 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.52 – 7.46 (m, 1H), 7.40 – 7.20 (m, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.29 (t, J = 2.0 Hz, 1H), 5.57 (s, 2H), 3.86 (s, 3H), 1.07 (s, 9H). MS (ESI) m / e [M+H] + = 479.

[0644] Example C37: Synthesis of 5-((3-amino-1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-methoxypicolineamide

[0645] Step 1: Tert-butyl (1-((6-(((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)carbamyl)-2-methoxypyridine-3-yl)methyl)-1H-pyrazole-3-yl)carbamate

[0646] A solution of 5-((3-((tert-butoxycarbonyl)amino)-1H-pyrazol-1-yl)methyl)-6-methoxypicolinic 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) was briefly stirred in DCM (2 mL) at room temperature. Immediately after the reaction, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 20% to 100%, to obtain the product (15 mg, 29%). MS (ESI) m / e [M+H]+ = 574.9.

[0647] Step 2: 5-((3-Amino-1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-methoxypicolineamide

[0648] To a solution of tert-butyl(1-((6-(((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)carbamoyl)-2-methoxypyridine-3-yl)methyl)-1H-pyrazol-3-yl)carbamate (15 mg, 0.03 mmol) in DCM (4 mL), TFA (1 mL) was added, and the solution was stirred at room temperature for 4 hours. Immediately after the reaction, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 20% to 100%, to obtain the product (15 mg, 29%). 1H NMR (400 MHz, 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.

[0649] Examples C38 below (Table 4) were synthesized starting from the corresponding precursors in accordance with the similar procedures described for Example C37.

[0650] Table 4:

[0651] Example The compound chemical name Data 1H NMR LC / MS m / z (M+H) J38 4-((4-Amino-1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-3-methoxybenzamide 1H NMR (400 MHz, DMSO-d6) δ 7.58 – 7.47 (m, 3H), 7.38 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 5.09 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 1.12 (s, 9H). MS (ESI) m / e [M+H]+ = 474.

[0652] Example C39: Synthesis

[0653] 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((7-methoxy-4,4-dimethylcroman-8-yl)sulfonyl)picolineamide

[0654] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic acid (15 mg, 0.06 mmol), 7-methoxy-4,4-dimethylcromon-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 hours. Immediately after the reaction, the DCM was removed under vacuum. The residue was subjected to preparative HPLC (column: Sunfire C18; mobile phase: [H2O (0.1% FA)-ACN]; gradient: 48%–63% B over 11.0 minutes) to obtain the desired compound (7 mg, 23%). 1H NMR (400 MHz, 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.

[0655] Example C40: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolineamide

[0656] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic 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) was briefly stirred in DCM (2 mL) at room temperature. Immediately after the reaction, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 20% to 100%, to obtain the product (10 mg, 22%). 1H NMR (400 MHz, 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.

[0657] Example C41: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-methoxypicolineamide

[0658] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic 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) was stirred in DCM (2 mL) at room temperature for 4 hours. Immediately after the reaction, the mixture was concentrated, and the residue was purified by a C18 column (mobile phase, ACN in water (0.1% FA), 20% to 100% dilution) to obtain the product (7 mg, 15%). 1H NMR (400 MHz, 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.

[0659] Example C42: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0660] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic 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) was stirred in DCM (2 mL) at 45 °C for 4 hours. Immediately after the reaction, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 20% to 100%, to obtain 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.

[0661] Example C43: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0662] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic 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) was stirred in DCM (2 mL) at 45 °C for 4 hours. Immediately after the reaction, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 20% to 100%, to obtain 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.

[0663] Example C44: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-phenylbenzamide

[0664] A solution of 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoic 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by silica gel column chromatography (MeOH / DCM = 1:10) to obtain the crude product (70 mg). The crude product was further purified by preparative HPLC (Waters Sunfire C18, 43%-63% ACN in H2O / 0.1% FA) to obtain the product (12 mg). 1H NMR (400 MHz, DMSO-d6) δ 12.25 (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.

[0665] 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

[0666] 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by preparative HPLC (Waters Sunfire C18, 40%–60% ACN in 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.

[0667] Example C46: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0668] A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinic 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by preparative HPLC (Waters Sunfire C18, 48%–68% ACN in H2O / FA) to obtain the product (22 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 10.95 (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.

[0669] Example C47: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0670] A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinic 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by preparative HPLC (Waters Sunfire C18, 48%–68% ACN in H2O / FA) to obtain the product (23 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 11.16 (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.

[0671] Example C48: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-cyclopropyl picolineamide

[0672] A solution of 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropyl picolinic 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by preparative HPLC (Waters Sunfire C18, 53%–73% ACN in H2O / FA) to obtain the product (14 mg, 24%). 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.

[0673] 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

[0674] 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by preparative HPLC (Waters Sunfire C18, 43%–58% ACN in 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.

[0675] Example C50: Synthesis of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-phenylbenzamide

[0676] A solution of 4-((1H-pyrazol-1-yl)methyl)-3-phenylbenzoic 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) was briefly stirred in DCM (5 mL) at room temperature. Immediately after the reaction, the reaction mixture was concentrated, water was added, the mixture was extracted with MeOH / DCM, the organic layer was concentrated, and the crude was purified by silica gel column chromatography (MeOH / DCM = 1:20) to obtain the crude product (40 mg). The raw material (10 mg) was purified by preparative HPLC (Waters Sunfire C18, 45%-65% of ACN in H2O / FA) to obtain the 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.

[0677] 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

[0678] To a solution of 4-((1H-pyrazol-1-yl)methyl)-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)-3-phenylbenzamide (30 mg, 0.13 mmol) in MeOH (10 mL), Pd / C (30 mg) was added, followed by the introduction of H2. The resulting mixture was stirred at room temperature for 2 hours. Immediately after the reaction, the reaction mixture was separated by filtration and concentrated. The crude material was purified by preparative HPLC (Waters Sunfire C18, 45%–65% ACN in 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.

[0679] 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

[0680] Examples C52 were synthesized starting from the corresponding precursors in accordance with the similar procedures described for Example C51.

[0681] 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.

[0682] Example C53: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-ethyl-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0683] 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-ethylpiculinic acid (23 mg, 0.10 mmol), EDCI (36 mg, 0.20 mmol) and DMAP (36 mg, 0.30 mmol) was stirred briefly in DCM (1 mL) at room temperature. Immediately after the reaction was complete, the mixture was concentrated. The raw material was purified by Combi-Flash (column = C18 containing spherical silica particles 20-35 μm; mobile phase: [water (0.1% FA) - ACN], % of B = 5%-80%; 6.0 mins) to obtain the 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.

[0684] Example C54: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((3-methoxy-6-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridine-2-yl)sulfonyl)picolineamide

[0685]

[0686] A solution of 3-methoxy-6-(1,1,1-trifluoro-2-methylpropane-2-yl)pyridin-2-sulfonamide (30 mg, 0.1 mmol), 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinic acid (23 mg, 0.1 mmol), EDCI (38.4 mg, 0.2 mmol) and DMAP (24.4 mg, 0.2 mmol) was stirred briefly in DCM (5 mL) at room temperature. The solvent was removed, and the remaining material was purified by preparative HPLC (column: Sunfire C18; mobile phase: [H2O (0.1% FA)-ACN]; gradient: 55%-70% B in 11.0 minutes) to obtain the desired product (26 mg, 50.6%). 1H NMR (400 MHz, DMSO-d6) δ 11.94 (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.

[0687] Example C55: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((7-methoxy-3,3-dimethylcromon-8-yl)sulfonyl)picolineamide

[0688] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic acid (23 mg, 0.1 mmol), 7-methoxy-3,3-dimethylchromane-8-sulfonamide (27 mg, 0.1 mmol), DMAP (37 mg, 0.3 mmol), and EDCI (29 mg, 0.15 mmol) was stirred in DCM (2 mL) at 45 °C for 4 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by column C18 (mobile phase, ACN in water (0.1% FA), 10% to 70%, to obtain 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.

[0689] Example C56: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-methoxycyclopropyl)phenyl)sulfonyl)picolineamide

[0690] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic 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) was stirred in DCM (2 mL) at 45 °C for 6 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by a C18 column (mobile phase, ACN in water (0.1% FA), 10% to 70%, to obtain the product (21 mg, 44%). 1H NMR (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.

[0691] Example C57: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-methoxy-2-methylpropane-2-yl)phenyl)sulfonyl)picolineamide

[0692] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypiculinic acid (13 mg, 0.055 mmol), 2-methoxy-5-(1-methoxy-2-methylpropane-2-yl)benzenesulfonamide (15 mg, 0.055 mmol), DMAP (20 mg, 0.164 mmol), and EDCI (16 mg, 0.082 mmol) was stirred in DCM (2 mL) at 45 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by a C18 column (mobile phase, ACN in water (0.1% FA), 20% to 80%, to obtain 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.

[0693] Example C58: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide

[0694] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinic 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) was stirred in DCM (2 mL) at 45 °C for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by a C18 column (mobile phase, ACN in water (0.1% FA), 10% to 80%, to obtain 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.

[0695] Example C59: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(1-(trifluoromethyl)cyclopropyl)phenyl)sulfonyl)picolineamide

[0696] A mixture of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinenic 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) was stirred in DCM (2 mL) at 45 °C for 2 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified by a C18 column (mobile phase, ACN in water (0.1% FA), 15% to 70%, to obtain the product (36 mg, 70%). 1H NMR (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.

[0697] Example C60: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2H-spiro[benzofuran-3,1'-cyclobutane]-7-yl)sulfonyl)picolineamide

[0698] 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-methoxypiculinic acid (23 mg, 0.10 mmol), EDCI (38 mg, 0.20 mmol), and DMAP (36 mg, 0.30 mmol) was briefly stirred in DCM (1 mL) at room temperature. Immediately after the reaction, the mixture was concentrated and purified (column = C18 containing spherical silica particles 20–35 μm; mobile phase: [water (HCOOH)-ACN], % B = 5%–80%; 7.0 min) to obtain 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.

[0699] Example C61: Synthesis of 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)picolineamide

[0700] 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-methoxypiculinic acid (23 mg, 0.10 mmol), EDCI (38 mg, 0.20 mmol), and DMAP (36 mg, 0.30 mmol) was briefly stirred in DCM (1 mL) at room temperature. Immediately after the reaction, the mixture was concentrated and purified (column C18 containing 20–35 µm spherical silica particles; mobile phase: [water (HCOOH)-ACN], % B = 5%–80%; 7.0 min) to obtain 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 = 7.5 Hz, 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.

[0701] Examples C62-C76 below (Table 9) were synthesized starting from the corresponding precursors according to similar procedures described for Example C61.

[0702] Table 9: Example The compound chemical name Data 1H NMR LC / MS m / z (M+H) J62 5-((1H-pyrazol-1-yl)methyl)-N-((5-(8-oxa-3-azapycyclo[3.2.1]octane-3-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypicolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.52 – 7.49 (m, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.21 – 7.15 (m, 2H), 7.13 – 7.09 (m, 1H), 6.31 (t, J = 2.0 Hz, 1H), 5.36 (s, 2H), 4.44 (m, 2H), 4.12 (s, 3H), 3.75 (s, 3H), 3.36 – 3.35 (m, 1H), 3.33 – 3.31 (m, 1H), 2.83 – 2.76 (m, 2H), 1.89 – 1.81 (m, 4H). MS (ESI) m / e [M+H]+ = 514.3. J63 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-methoxypyridine-2-yl)sulfonyl)-6-(methoxy-d3)picolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.75 – 7.69 (m, 1H), 7.68 – 7.62 (m, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.53 – 7.50 (m, 1H), 7.24 – 7.19 (m, 1H), 6.33 – 6.30 (m, 1H), 5.36 (s, 2H), 3.92 (s, 3H), 1.10 (s, 9H). MS (ESI) m / e [M+H]+ = 463.3. J64 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)-N-((6-methoxy-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.22 – 7.17 (m, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.36 (s, 2H), 4.29 (s, 2H), 3.74 (s, 3H), 1.26 (s, 6H). MS (ESI) m / e [M+H]+ = 476.3. J65 5-((1H-pyrazol-1-yl)methyl)-6-(methoxy-d3)-N-((6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)picolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.32 (t, J = 2.0 Hz, 1H), 5.37 (s, 2H), 3.77 (s, 3H), 2.91 (s, 2H), 1.24 (s, 6H). MS (ESI) m / e [M+H]+ = 476.3. J66 5-((1H-pyrazol-1-yl)methyl)-N-((6-(tert-butyl)-3-(methoxy-d3)pyridine-2-yl)sulfonyl)-6-methoxypicolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.87 – 7.84 (m, 1H), 7.75 – 7.70 (m, 1H), 7.69 – 7.63 (m, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.52 (br s, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.33 – 6.31 (m, 1H), 5.38 (s, 2H), 4.10 (s, 3H), 1.10 (s, 9H). MS (ESI) m / e [M+H]+ = 463.3. J67 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(3-methoxyoxyoxytane-3-yl)phenyl)sulfonyl)picolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.91 – 7.89 (m, 1H), 7.85 – 7.83 (m, 1H), 7.81 – 7.76 (m, 1H), 7.51 – 7.48 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.30 (t, J = 2.0 Hz, 1H), 5.35 (s, 2H), 4.81 (d, J = 7.2 Hz, 2H), 4.72 (d, J = 7.2 Hz, 2H), 4.13 (s, 3H), 3.88 (s, 3H), 3.06 (s, 3H). MS (ESI) m / e [M+H]+ = 489.2. J68 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxyphenyl)sulfonyl)picolinamide 1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 7.87 (br d, J = 6.8 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.23 – 7.14 (m, 2H), 7.11 (t, J = 7.8 Hz, 1H), 6.26 (t, J = 2.0 Hz, 1H), 5.31 (s, 2H), 4.08 (s, 3H), 3.80 (s, 3H). MS (ESI) m / e [M+H]+ = 403.4. J69 5-((1H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.54 – 7.43 (m, 3H), 7.16 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.27 (t, J = 2.0 Hz, 1H), 5.32 (s, 2H), 4.07 (s, 3H), 3.73 (s, 6H). MS (ESI) m / e [M+H]+ = 433.3. J70 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)phenyl)sulfonyl)picolineamide 1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.83 – 7.75 (m, 2H), 7.64 (br dd, J = 8.7, 2.0 Hz, 1H), 7.49 -7.43 (m, 2H), 7.20 – 7.10 (m, 2H), 6.26 (t, J = 2.0 Hz, 1H), 5.31 (s, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 3.67 – 3.56 (m, 2H), 3.53 – 3.39 (m, 2H), 1.96 – 1.83 (m, 2H), 1.73 – 1.63 (m, 2H), 1.20 (s, 3H). MS (ESI) m / e [M+H]+ = 501.3. J71 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((6-methoxy-2',3',5',6'-tetrahydro-2H-spiro[benzof...

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:A1 is CR1 or N, A2 is CR2 or N, A3 is CR3 or N, A4 is CR4 or N, A5 is CR5 or N, provided that at most two of A1, A2, A3, A4 and A5 are N;R1,R2, R3, R4 and R5 are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR1a, -SO2R1a, -COR1a, -CO2R1a, -CONR1aR1b, -C(=NR1a)NR1bR1c, -NR1aR1b, -NR1aCOR1b, -NR1aCONR1bR1c, -NR1aCO2R1b, -NR1aSONR1bR1c, -NR1aSO2NR1bR1c, -P(=O)R1aR1b, –NR1aSO2R1b or -SOR1a(=NR1b), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R1d;or (R1 andR2), (R2 and R3), (R3 andR4), or (R4 and R5), together with the atoms to which they are attached, independently form a C3-10 cycloalkyl, C3-10 cycloalkenyl, 5- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, 5- to 12- membered aryl, or 5- to 12- membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, wherein each of said C3-10 cycloalkyl, C3-10 cycloalkenyl, 5- to 12-membered heterocyclyl ring, 5- to 12- membered aryl, or 5- to 12- membered heteroaryl ring is unsubstituted or substituted with 1, 2, 3, or 4 R1d;R1a, R1b, and R1c are each independently hydrogen, deuterium, -C1-10alkyl, -C1-10deuteroalkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R1j;R1d and R1j are each independently hydrogen, deuterium, halogen, -C1-10alkyl, , -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR1e, -SO2R1e, -COR1e, -CO2R1e, -CONR1eR1f, -C(=NR1e)NR1fR1g, -NR1eR1f, -NR1eCOR1f, -NR1eCONR1fR1g, -NR1eCO2R1f, -NR1eSONR1fR1g, -NR1eSO2NR1fR1g, -P(=O)R1eR1f, -NR1eSO2R1f, or-SOR1e(=NR1f), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with at least one substituent selected from halogen, -CN, -C1-10alkyl, -OR1h, -NR1hR1i, cycloalkyl, heterocyclyl, aryl, and heteroaryl; ortwo R1d or two R1j substituted at same atom form an oxo; ortwo R1d substituted at same or different atom(s), together with the atom(s) to which they are attached and any intervening atoms, form a C3-10 cycloalkyl, 4- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; wherein said C3-10 cycloalkyl, 4- to 12-membered heterocyclyl ring, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring is unsubstituted or substituted with 1, 2, or 3 R1k;R1e, R1f, R1g,R1h and R1i are each independently hydrogen, -C1-10alkyl, -haloC1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;each R1k is independently hydrogen, halogen, -C1-10alkyl, -haloC1-10alkyl, or -C1-10alkoxy;X1 is CR61 or N;L is a direct bond, -(CRL1RL2)p-, -O-, -S- or -NRL3-;ring B is isoxazolyl, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrizinyl or pyrimidinyl;R61, R62, R63, R64, R7, RL1 and RL2 are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -OC1-10deuteroalkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR3a, -SR3a, -SO2R3a, -COR3a, -CO2R3a, -CONR3aR3b, -C(=NR3a)NR3bR3c, -NR3aR3b, -NR3aCOR3b, -NR3aCONR3bR3c, -NR3aCO2R3b, -NR3aSONR3bR3c, -NR3aSO2NR3bR3c, -P(=O)R3aR3b, -NR3aSO2R3b, or -SOR3a(=NR3b), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R3d;R3a, R3b and R3c are each independently hydrogen, deuterium, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl; wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with R3j;R3d and R3j are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR3e, -SO2R3e, -COR3e, -CO2R3e, -CONR3eR3f, -C(=NR3e)NR3fR3g, -NR3eR3f, -NR3eCOR3f, -NR3eCONR3fR3g, -NR3eCO2R3f, -NR3eSONR3fR3g, -NR3eSO2NR3fR3g, -P(=O)R3eR3f, -NR3eSO2R3f, or -SOR3e(=NR3f), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with at least one substituent selected from halogen, -C1-10alkyl, -OR3h, -NR3hR3i, cycloalkyl, heterocyclyl, aryl, or heteroaryl; ortwo R3d or two R3j substituted at same atom form an oxo; orR3e, R3f, R3g,R3h and R3i are each independently hydrogen, -C1-10alkyl, -haloC1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, alkoxy substituted benzyl, aryl, or heteroaryl;RL3 is hydrogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl;p is 0, 1, 2, or 3; andn is 0, 1, 2, 3, or 4.

2. The compound of claim 1, wherein is , , , , , , , or . 3. The compound of claim 1, wherein is , , , , , , , , , or .

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

5. The compound of any one of claims 1-4, wherein A1 is CR1; R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;A2 is CR2; and R2 is hydrogen, deuterium, halogen, -C1-3alkyl or -haloC1-3alkyl;A3 is CR3 or N, A4 is CR4 or N, A5 is CR5 or N, provided that at most one of A3, A4 and A5 are N;if present, R3, R4 and R5 are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR1a, -SO2R1a, -COR1a, -CO2R1a, -CONR1aR1b, -C(=NR1a)NR1bR1c, -NR1aR1b, -NR1aCOR1b, -NR1aCONR1bR1c, -NR1aCO2R1b, -NR1aSONR1bR1c, -NR1aSO2NR1bR1c, -P(=O)R1aR1b, -NR1aSO2R1b, or -SOR1a(=NR1b), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R1d;or (R3 andR4) or (R4 and R5), together with the atoms to which they are attached, independently form a C3-10 cycloalkyl, C3-10 cycloalkenyl, 5- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, 5- to 12- membered aryl, or 5- to 12- membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, wherein each of said C3-10 cycloalkyl, C3-10 cycloalkenyl, 5- to 12-membered heterocyclyl ring, 5- to 12- membered aryl, or 5- to 12- membered heteroaryl ring is unsubstituted or substituted with 1, 2, 3, or 4 R1d;R1a, R1b, and R1c are each independently hydrogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with 1, 2, or 3 R1j;R1d and R1j are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -OR1e, -SO2R1e, -COR1e, -CO2R1e, -CONR1eR1f, -C(=NR1e)NR1fR1g, -NR1eR1f, -NR1eCOR1f, -NR1eCONR1fR1g, -NR1eCO2R1f, -NR1eSONR1fR1g, -NR1eSO2NR1fR1g, -P(=O)R1eR1f, -NR1eSO2R1f, or-SOR1e(=NR1f), wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with at least one substituent selected from halogen, -CN, -C1-10alkyl, -OR1h, -NR1hR1i, cycloalkyl, heterocyclyl, aryl, and heteroaryl; ortwo R1d substituted at same or different atom(s), together with the atom(s) to which they are attached and any intervening atoms, form a C3-10 cycloalkyl, 4- to 12-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; wherein each of said C3-10 cycloalkyl, 4- to 12-membered heterocyclyl ring, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl ring is unsubstituted or substituted with 1, 2, or 3 R1k;R1e, R1f, R1g,R1h and R1i are each independently hydrogen, deuterium, -C1-10alkyl, -haloC1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;each R1k is independently hydrogen, deuterium, halogen, -C1-10alkyl, -haloC1-10alkyl, or -C1-10alkoxy.

6. The compound of any one of claims 1-5, wherein X1 is N or CR61,R61, R62, R63 and R64 are each independently hydrogen, deuterium, halogen, -C1-10alkyl, -SC1-10alkyl, -OC1-10deuteroalkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C3-10 monocyclic cycloalkyl, C3-10 monocyclic cycloalkenyl, C3-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 -NR3aR3b; wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C1-10 monocyclic cycloalkyl, C1-10 monocyclic cycloalkenyl, C1-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 is unsubstituted or substituted with 1, 2 or 3 R3d;R3a and R3bare each independently hydrogen, -C1-5alkyl, -C2-5alkenyl, -C2-5alkynyl, or C3-6 monocyclic cycloalkyl;each R3d is independently hydrogen, halogen, -C1-10alkyl, -C2-10alkenyl, -C1-10alkoxy, -C2-10alkynyl or C3-6 monocyclic cycloalkyl.

7. The compound of any one of claims 1-5, wherein X1 is N or CR61,if R61 is present, R61, R62, R63 and R64 are each independently hydrogen, methyl, -OCD3, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, azetidinyl, -NH2, -NH(C1-5alkyl), -N(C1-5alkyl)2, -CN, F, Cl, Br or I; wherein each of said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl or azetidinyl is unsubstituted or substituted with 1, 2 or 3 R3d;each R3d is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, 2-propynyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxiranyl, oxetanyl, F, Cl, Br or I.

8. The compound of any one of claims 1-5, wherein X1 is N or CR61,if R61 is present, R61, R62, R63 and R64 are each independently hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, -CN, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, -CH(CH3)OCH3, -OCHF2 or -CH2OCH3.

9. The compound of any one of claims 1-5, wherein X1 is N or CR61,if R61 is present, R61, R63, and R64 are each independently hydrogen or deuterium;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

10. The compound of any one of claims 1-5, wherein X1 is N or CR61,if R61 is present, R61, R63 and R64 are each independently hydrogen or deuterium ;R62 is each independently methyl, ethyl, cyclopropyl, ethynyl or methoxy.

11. The compound of claim 1, wherein the compound having formula (III-1):(III-1),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof , wherein:A5 is N or CR5; if present, R5 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, deuterium, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, deuterium, halogen, -C1-3alkyl or -haloC1-3alkyl;R4 is -C1-10alkyl, -C1-10alkoxy, C3-10cycloalkyl, 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 heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur; wherein said -C1-10alkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, -OC1-10alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -CO2C1-10alkyl, -N(C1-10alkyl)2, -NH(C1-10alkyl), and -NH2;wherein each of said C3-10cycloalkyl, 6- membered aryl, 5- to 6- membered heteroaryl, or 4- to 8- membered heterocyclyl is unsubstituted or substituted with 1, 2, or 3 R1d;each R1d is independently halogen, -C1-10alkyl, -C1-10alkoxy, or -haloC1-10alkyl;wherein said -C1-10alkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from -CN, -OR1h, and-NR1hR1i;each R1h and R1i is independently selected from hydrogen, methyl, ethyl, 1-propyl, and 2-propyl; X1 is N or CR61;if present, R61 is hydrogen or -C1-10alkoxy;R62 is hydrogen, deuterium, halogen, -C1-10alkyl, -SC1-10alkyl, -OC1-10deuteroalkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C3-10 monocyclic cycloalkyl, C3-10 monocyclic cycloalkenyl, C3-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 -NR3aR3b; wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C1-10 monocyclic cycloalkyl, C1-10 monocyclic cycloalkenyl, C1-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 is unsubstituted or substituted with 1, 2 or 3 R3d;R3a and R3b are each independently hydrogen, -C1-5alkyl, -C2-5alkenyl, -C2-5alkynyl, or C3-6 monocyclic cycloalkyl;each R3d is independently hydrogen, halogen, -C1-10alkyl, -C2-10alkenyl, -C1-10alkoxy, -C2-10alkynyl or C3-6 monocyclic cycloalkyl;R63 is hydrogen or deuterium; andR64 is hydrogen, deuterium, halogen, -CN, -C1-10alkyl, or -C1-10alkoxy.

12. The compound of any one of claims 1-11, wherein A5 is N or CR5; if present, R5 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, deuterium, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R4 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, oxetanyl, tetrahydrofuranyl, dioxanyl, oxazolyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxaspiro[3.3]heptanyl, or pyrazolyl; wherein each of said methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, 1,1-dimethylethyl, is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halogen, -C1-10alkyl, -haloC1-10alkyl, -OC1-10alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl, -CN, -NO2, -CO2C1-10alkyl, -N(C1-10alkyl)2, -NH(C1-10alkyl), and -NH2;and wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, oxazolyl, or pyrazolyl is unsubstituted or substituted with 1, 2, or 3 R1d; andeach R1d is independently selected from halogen, -C1-10alkyl, -C1-10alkoxy, and -haloC1-10alkyl;wherein said -C1-10alkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from -CN, hydroxy, methoxy, -NH2, and -N(CH3)2.

13. The compound of any one of claims 1-11, wherein A5 is N or CR5; if present, R5 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl, or -haloC1-10alkyl;R2 is hydrogen, halogen, deuterium, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, deuterium, -C1-3alkyl or -haloC1-3alkyl;R4 is , -tBu, , , , , , , , , , , , , , , , , , , or ;X1 is N or CR61,if R61 is present, R61, R63, and R64 are hydrogen;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

14. The compound of any one of claims 1-11, wherein A5 is N or CR5; R5 is hydrogen,R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen;R3 is hydrogen;R4 is -C1-5alkyl or -haloC1-5alkyl;X1 is N or CR61,if R61 is present, R61, R63 and R64 are each independently hydrogen; andR62 is each independently -C1-5alkyl, -OC1-5deuteroalkyl, -C2-5alkenyl, C3-6 monocyclic cycloalkyl, or -C1-5alkoxy.

15. The compound of any one of claims 1-11, wherein A5 is N or CR5; R5 is hydrogen,R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen;R3 is hydrogen;R4 is 1,1-dimethylethyl, or 1,1,1-trifluoro-2-methylpropanyl;X1 is N or CR61,if R61 is present, R61, R63 and R64 are each independently hydrogen; andR62 is each independently methyl, ethyl, cyclopropyl, ethyl，-OCD3, or methoxy.

16. The compound of claim 1, wherein the compound is of Formula (VI):(VI),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:X1 is N or C(H);R62 is ethyl, ethenyl, cyclopropyl, -OCD3, or methoxy;R4 is or ; andA5 is CR5 or N; if present, R5 is hydrogen.

17. The compound of claim 1, wherein the compound is of formula (III-2):(III-2),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;ring C is 5- to7- membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur;each R1d is independently hydrogen, halogen, -C1-5alkyl, or -haloC1-5alkyl; or two R1d substituted at same or different atom(s), together with the atom(s) to which they are attached and any intervening atoms, form C3-10 monocyclic cycloalkyl, or 4- to 10- membered monocyclic heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and optionally oxidized sulfur;X1 is N or CR61;.if present R61 is hydrogen, or -C1-10alkoxy;R62 is hydrogen, halogen, -C1-10alkyl, -OC1-10deuteroalkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C3-10 monocyclic cycloalkyl, C3-10 monocyclic cycloalkenyl, C3-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 -NR3aR3b; wherein each of said -C1-10alkyl, -C2-10alkenyl, -C2-10alkynyl, -C1-10alkoxy, C1-10 monocyclic cycloalkyl, C1-10 monocyclic cycloalkenyl, C1-10 monocyclic cycloalkynyl, 4- to 10- membered monocyclic heterocyclyl 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 is unsubstituted or substituted with 1, 2 or 3 R3d;R3a and R3b are each independently hydrogen, -C1-5alkyl, -C2-5alkenyl, -C2-5alkynyl, or C3-6 monocyclic cycloalkyl;each R3d is independently hydrogen, halogen, -C1-10alkyl, -C2-10alkenyl, -C1-10alkoxy, -C2-10alkynyl or C3-6 monocyclic cycloalkyl.R63 is hydrogen;R64 is hydrogen, halogen, -CN, -C1-10alkyl, or -C1-10alkoxy.

18. The compound of claim 17, wherein ring C is dihydrofuranyl or dihydro-pyranyl;each R1d is independently hydrogen, halogen, -C1-4alkyl, -haloC1-4alkyl, or -C1-4alkoxy; or two R1d substituted at same or different atom(s), together with the atom(s) to which they are attached and any intervening atoms, form a cyclobutyl or tetrahydropyranyl ring.

19. The compound of claim 17, wherein the compound is of formula (IV-1):(IV-1),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;each R1d is independently hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl; or two R1d substituted at same or different atom(s), together with the atom(s) to which they are attached and any intervening atoms, form a cyclobutyl or tetrahydropyranyl ring;X1 is N or CR61;if present R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, pyrrolidinyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

20. The compound of claim 17, wherein the compound is of formula (V-1):(V-1),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;X1 is N or CR61;if present, R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

21. The compound of claim 17, wherein the compound is of formula (V-2):(V-2),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;X1 is N or CR61;if present R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, methoxycyclopentyl, -CH2F, -CH2CHF2, or -CH2OCH3.

22. The compound of claim 17, wherein the compound is of formula (IV-4):(IV-4),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:R1 is -OR1a; and R1a is hydrogen, -C1-10deuteroalkyl, -C1-10alkyl or -haloC1-10alkyl;R2 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;R3 is hydrogen, halogen, -C1-3alkyl or -haloC1-3alkyl;each R1d is independently hydrogen, hydrogen, F, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 1-methylpropyl, or 1,1-dimethylethyl;X1 is N or CR61;if present, R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, -OCD3, ethyl, n-propyl, isopropyl, ethenyl, prop-1-enyl, prop-2-enyl, ethynyl, 1-propynyl, cyclopropyl, F, Cl, Br, I, -N(CH3)2, methoxy, ethoxy, propoxy, pyrrolidinyl, furanyl, pyrazolyl, oxazolyl, oxetanyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

23. The compound of claim 17, wherein the compound is of formula (V-4):(V-4),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:X1 is N or CR61;if present, R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethenyl, 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, oxetanyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

24. The compound of claim 17, wherein the compound is of formula (V-5):(V-5),or a pharmaceutically acceptable salt, deuterated analog, N-oxide, or tautomer thereof, wherein:X1 is N or CR61;if present, R61 is hydrogen;R63 and R64 are hydrogen;R62 is hydrogen, methyl, ethyl, n-propyl, isopropyl, ethenyl, 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, oxetanyl, methoxycyclopentyl, -CH2F, -CH2CHF2 or -CH2OCH3.

25. The compound of any one of claims 17-24, wherein R1 is -OR1a; and R1a is methyl;R2 is hydrogen;R3 is hydrogen;X1 is N or CR61;if present, R61 is hydrogen;R63 and R64 are hydrogen;R62 is methyl, ethyl, cyclopropyl, methoxy, -OCD3, or ethoxy.

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

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

28. The compound of any one of claims 1-27, wherein each R7 is independently hydrogen, -C1-10alkyl, -NH2, -NH(-C1-6alkyl) or -N(-C1-6alkyl)2.

29. The compound of any one of claims 1-28, whereineach R7 is independently hydrogen, methyl, ethyl, 1-propyl, 2-propyl or -NH2;preferably, each R7 is hydrogen.

30. A compound selected from or a pharmaceutically acceptable salt thereof, or a deuterated analog thereof, or an N-oxide thereof, or a tautomer thereof.

31. A pharmaceutical composition comprising a compound of 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, comprising administering to a subject in need thereof a compound of any one of claims 1-30, or a pharmaceutically acceptable salt, or a deuterated analog thereof, or an N-oxide thereof, or a tautomer thereof.  

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