PRMT5 inhibitors and their use

Abstract

The present invention provides compounds and compositions that modulate or inhibit PRMT5.

Description

[Technical Field]

[0001] [Cross reference] This application claims the rights of International Application PCT / CN2023 / 098094 filed on 2 June 2023, International Application PCT / CN2023 / 133986 filed on 24 November 2023, International Application PCT / CN2024 / 071562 filed on 10 January 2024, and International Application PCT / CN2024 / 091509 filed on 7 May 2024, which in whole form constitute part of this specification by reference. [Background technology]

[0002] Conventional chemotherapy agents exhibit broad cytotoxicity, and many of their side effects may stem from their harmful effects on healthy cells. Targeted therapy, on the other hand, selects tumor cells, often leading to improved clinical outcomes. Several targeted therapies, such as tyrosine kinase inhibitors targeting BCR-ABL tyrosine kinase, which is uniquely expressed in cancer cells, have been developed and have achieved significant clinical success. While the protein arginine N-methyltransferase (PRMT5) has been identified as another potential target for selective chemotherapy, PRMT5 inhibitors are not yet approved for clinical use.

[0003] The protein arginine N-methyltransferase (PRMT5) catalyzes the sequential electrophilic transfer of two methyl groups from two equivalents of S-adenosyl-L-methionine (SAM) to each terminal nitrogen of the guanidine moiety of an arginine residue. This reaction produces symmetric dimethylarginine (sDMA). Furthermore, PRMT5 regulates gene expression by methylating several histones. PRMT5 is an essential enzyme for cells and is intricately related to the loss of p16 / CDKN2A, a genetic feature common to cancer cells. Therefore, PRMT5 inhibitors are of interest as selective chemotherapeutic agents.

[0004] Approximately 15% of all cancer cells lack the p16 / CDKN2A gene and co-delete the adjacent gene encoding methylthioadenosine phosphorylase (MTAP). Methylthioadenosine phosphorylase (MTAP) catalyzes the conversion of methylthioadenosine (MTA) to methionine. Therefore, cells that do not express MTAP face increased MTA concentration due to reduced processing of MTA to methionine. Because MTA is structurally similar to SAM, it competes with SAM for the active site of PRMT5. Consequently, cancer cells lacking the gene for MTAP face enhanced PRMT5 inhibition, decreased methylation activity, and increased sensitivity to PRMT5 depletion or loss of activity. This effect makes cancer cells selectively vulnerable to PRMT5 inactivation by exogenous inhibitors.

[0005] PRMT5 is necessary for the survival of normal tissue cells, and studies suggest that inhibition of PRMT5 in normal tissues may lead to serious disadvantages such as pancytopenia, infertility, skeletal muscle loss, and / or cardiac hypertrophy. Therefore, any PRMT5 inhibitor must exhibit very high selectivity against cancer cells. Since MTA is more concentrated in tumor cells lacking MTAP and less concentrated in healthy cells, MTA-coordinated PRMT5 inhibitors (inhibitors that bind to the MTA-PRMT5 complex) are expected to target cancer cells with high selectivity. Therefore, the development of MTA-coordinated PRMT5 inhibitors is needed. [Overview of the project]

[0006] This specification discloses compounds of formula (I) as described herein, or pharmaceutically acceptable salts or stereoisomers thereof. [ka]

[0007] Furthermore, the compound of formula (Ia) described herein, or its pharmaceutically acceptable salts or stereoisomers, are disclosed herein. [ka]

[0008] Furthermore, the compound of formula (Ib) described herein, or its pharmaceutically acceptable salts or stereoisomers, are disclosed herein. [ka]

[0009] Furthermore, this specification discloses pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0010] Furthermore, methods of treatment and use of the disclosed compounds and compositions are disclosed herein, including administering them to a subject.

[0011] Reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated to be incorporated by reference. [Modes for carrying out the invention]

[0012] definition The following description includes certain details to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention may be carried out without these details. In other examples, known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless otherwise specified in the context, the word “comprise” and its variations such as “comprises” and “comprising” throughout this specification and the appended claims should be interpreted in an open and comprehensive sense as “including, but not limited to.” Furthermore, the headings presented herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0013] Throughout this specification, any reference to “several embodiments” or “an embodiment” means that any particular feature, structure, or characteristic described in relation to that embodiment is included in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, any particular feature, structure, or characteristic can be combined in any suitable way in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms ("a," "an," and "the") include multiple references unless explicitly indicated otherwise. It should also be noted that the term “or” is generally used in its meaning including “and / or” unless explicitly indicated otherwise.

[0014] As used herein, the following terms have the meanings set forth below, unless otherwise indicated.

[0015] "Oxo" refers to =O.

[0016] "Carboxyl" refers to the -COOH group.

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to a linear or branched saturated hydrocarbon monovalent group having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl and octyl. Where applicable in this specification, "C1-C6 alkyl" or "C 1~6 Numerical ranges such as "alkyl" mean that an alkyl group can consist of one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, or six carbon atoms, but the definition here also includes the appearance of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C 1~10 It is alkyl. In some embodiments, alkyl is C 1~6 It is alkyl. In some embodiments, alkyl is C 1~5 It is alkyl. In some embodiments, alkyl is C 1~4 It is alkyl. In some embodiments, alkyl is C 1~3It is alkyl. Unless otherwise specified herein, alkyl groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0019] "Alkenyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group may be in either a cis or trans configuration with respect to the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Where used herein, "C2-C6 alkenyl" or "C 2~6The numerical ranges for "alkenyl," etc., mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition herein also includes the appearance of the term "alkenyl" without a specified numerical range. Unless otherwise specified herein, the alkenyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] "Alkynyl" refers to a linear or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and containing 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiinyl. Where used herein, it is referred to as "C2-C6 alkynyl" or "C 2~6The numerical ranges for "alkynyl," etc., mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition here also includes the appearance of the term "alkynyl" without a specified numerical range. Unless otherwise specified herein, the alkynyl group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0021] "Alkylene" refers to a linear or branched divalent hydrocarbon chain. Unless otherwise specified herein, alkylene groups may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0022] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined above. Unless otherwise specifically stated herein, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkoxy is optionally substituted with halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to a cycloalkyl ring or a heterocycloalkyl ring, aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is C6-C 10The aryl is an aryl group. In some embodiments, the aryl is a six-membered aryl(phenyl) group. Examples of aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluorantene, fluorene, as-indacene, s-indacene, indan, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified herein, the aryl may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, the aryl is optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0024] "Cycloalkyl" refers to a partially or completely saturated monocyclic or polycyclic carbon ring, which may include fused ring systems (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via a non-aromatic ring atom), spiro ring systems, or bridging ring systems. In some embodiments, the cycloalkyl is completely saturated. Typical cycloalkyls include cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C3). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyls, cycloalkyls having 3 to 10 carbon atoms (e.g., C3-C3) 10 Fully saturated cycloalkyl or C3-C 10Examples include, but are not limited to, cycloalkenyls, cycloalkyls having 3 to 8 carbon atoms (e.g., C3-C8 fully saturated cycloalkyls or C3-C8 cycloalkenyls), cycloalkyls having 3 to 6 carbon atoms (e.g., C3-C6 fully saturated cycloalkyls or C3-C6 cycloalkenyls), cycloalkyls having 3 to 5 carbon atoms (e.g., C3-C5 fully saturated cycloalkyls or C3-C5 cycloalkenyls), or cycloalkyls having 3 or 4 carbon atoms (e.g., C3 or C4 fully saturated cycloalkyls or C3 or C4 cycloalkenyls). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- or 6-membered fully saturated cycloalkyl or a 5- or 6-membered cycloalkenyl. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyls may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen. As used herein, "cycloalkylene" refers to the divalent cycloalkyl radical described herein. In some embodiments, if the cycloalkylene includes a cycloalkyl condensed with an aryl ring or a heteroaryl ring, the cycloalkylene is bonded with cycloalkyl and aryl, or with cycloalkyl and heteroaryl. In some embodiments, if the cycloalkylene includes a cycloalkyl condensed with an aryl ring or a heteroaryl ring, the cycloalkylene is bonded with cycloalkyl alone.

[0025] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0026] "Haloalkyl" refers to an alkyl radical as defined above, which is substituted with one or more halo radicals as defined above. Examples include trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0027] "Hydroxyalkyl" refers to an alkyl radical as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Examples of hydroxyalkyls include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl radical as defined above, which is substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Examples of aminoalkyls include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] "Heteroalkyl" refers to an alkyl group in which one or more of the alkyl backbone atoms are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. In a heteroalkyl group, the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group, which consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group containing one or two oxygen, nitrogen, or sulfur atoms, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. In one embodiment, the heteroalkyl group is a C1-C6 heteroalkyl group containing one oxygen, nitrogen, or sulfur atom, and the carbon atoms of the heteroalkyl group are bonded to the rest of the molecule. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified herein, heteroalkyls are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyls are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted with a halogen.

[0030] A "heterocycloalkyl" refers to a 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom. In some embodiments, the heterocycloalkyl contains 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, including fused ring systems (when fused with an aryl ring or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom), spirocyclic ring systems, or bridging ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Typical heterocycloalkyls include heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2-C2). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyls, heterocycloalkyls having 2 to 10 carbon atoms (e.g., C2-C2) 10 Fully saturated heterocycloalkyl or C2-C 10Examples include, but are not limited to, heterocycloalkenyls, heterocycloalkyls having 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyls or C2-C8 heterocycloalkenyls), heterocycloalkyls having 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), heterocycloalkyls having 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyls or C2-C7 heterocycloalkenyls), heterocycloalkyls having 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyls or C2-C5 heterocycloalkenyls), or heterocycloalkyls having 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyls or C2-C4 heterocycloalkenyls). Examples of such heterocycloalkyl radicals include azilidinyl, azetidinyl, oxetanyl, dioxolanil, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperadinyl, 4-piperidonyl, and pylori. Examples include, but are not limited to, dinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbon atoms in the ring.When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms constituting the heterocycloalkyl (including heteroatoms) (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- or 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-membered or 6-membered heterocycloalkenyl. Unless otherwise specified herein, the heterocycloalkyl may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.As used herein, “heterocycloalkylene” refers to the divalent heterocycloalkyl radical as described herein. In some embodiments, if the heterocycloalkylene includes an aryl ring or a heterocycloalkyl condensed with a heteroaryl ring, the heterocycloalkylene is bonded with a heterocycloalkyl and an aryl, or with a heterocycloalkyl and a heteroaryl. In some embodiments, if the heterocycloalkylene includes an aryl ring or a heterocycloalkyl condensed with a heteroaryl ring, the heterocycloalkylene is bonded with a heterocycloalkyl alone.

[0031] A "heteroaryl" refers to a 5- to 14-membered cyclic radical comprising 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a condensed ring system (when condensed with a cycloalkyl ring or heterocycloalkyl ring, the heteroaryl is bonded via an aromatic ring atom) or a bridging ring system, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl.Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, isoin Examples include, but are not limited to, drill, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with, for example, halogens, aminos, nitriles, nitros, hydroxyls, alkyls, alkenyls, alkynyls, haloalkyls, alkoxys, carboxyls, carboxylates, aryls, cycloalkyls, heterocycloalkyls, heteroaryls, etc. In some embodiments, heteroaryls are optionally substituted with halogens, methyls, ethyls, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with a halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.

[0032] The terms “optional” or “optionally” mean that the events or situations described thereafter may or may not occur, and the description includes both cases in which such events or situations occur and cases in which they do not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at a level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, it will be understood by those skilled in the art that such a group is not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unrealizable. Therefore, any substituents described should be understood to generally have a maximum molecular weight of up to about 1000 daltons, and more typically up to about 500 daltons.

[0033] When referring to any substituent, the term "one or more" means that the group in question is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the group in question is optionally substituted with one, two, three, or four substituents. In some embodiments, the group in question is optionally substituted with one, two, or three substituents. In some embodiments, the group in question is optionally substituted with one or two substituents. In some embodiments, the group in question is optionally substituted with one substituent. In some embodiments, the group in question is optionally substituted with two substituents.

[0034] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, that is effective in producing the desired therapeutic effect.

[0035] As used herein, the terms “to treat,” “to treat,” or “to cure” include alleviating, suppressing, or improving at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, mitigating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or cessating the symptoms of a disease or condition.

[0036] As used herein, “PRMT5-related disease or disorder,” or alternatively “PRMT5-mediated disease or disorder,” means any disease or other adverse condition in which PRMT5 or its mutants are known or suspected to be involved.

[0037] compound This specification describes compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, that are useful in the treatment of diseases related to PRMT5.

[0038] In this specification, formula (I): [ka] (In the formula, Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl, Each R 4 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SRa -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and arbitrarily substituted, or Two R atoms on the same atom 4 They combine to form an oxo, or, Two R atoms on the same atom 4 They combine to form arbitrarily substituted cycloalkyl or heterocycloalkyl groups, n is 1, 2, 3, 4, 5, or 6. R 5 is -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b -C(=O)R a, -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally and independently substituted, W is N or CR W and R W is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b , -NR c C(=O)NR d R b , -NR a C(=O)R b , -NR b C(=O)OR b , -NR a S(=O)2R b , -N=S(=O)(R a ), -C(=O)R b , -C(=O)OR c R d , -P(=O)(R b)2. It is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs, U is N or CR U and is R U is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. T is N or CR T And, R T These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. X is C, and Y is C, or X is C, and Y is N, or X is N and Y is C, Z 1 O, S, N, NR 1a CR 1b , or C(R 1c )2, Z 2 O, S, N, NR 2a CR 2b , or C(R 2c )2, Z 3 O, S, N, NR 3a CR 3b , or C(R 3c )2, Each R 1a , R 2a , and R 3a These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R 1b , R 2b , and R 3b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. Each R 1c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 1c They come together to form an oxo, Each R 2c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R2c They come together to form an oxo, Each R 3c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 3c They come together to form an oxo, Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R b These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R, or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. L is either absent or a C1-C4 alkylene arbitrarily substituted with one or more Rs, and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1~C3 alkyl, -S(=O)2C1~C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C3 alkyl, -S(=O)2N(C1~C3 alkyl)2, -S(=O)(=NC1~C3 alkyl)(C1~C3 alkyl), -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -N=S(=O)(C1~C3 alkyl)2, -O-C1~C4 alkylene-OH, -O-C1~C4 alkylene-NH2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, -P(=O)(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, C3~C6 cycloalkyl, or 3-membered to 6-membered heterocycloalkyl, or Compounds of which (two R atoms on the same atom form an oxo) or their pharmaceutically acceptable salts or stereoisomers are described.

[0039] In this specification, formula (I): [ka] (In the formula, Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl, Each R 4 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 4a It is arbitrarily replaced with, or Two R atoms on the same atom 4They combine to form an oxo, or, Two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a cycloalkyl or heterocycloalkyl group with arbitrary substitutions. Each R 4a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 4aThey come together to form an oxo, Each R 4b These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 4b They come together to form an oxo, n is 1, 2, 3, 4, 5, or 6. R 5 is -S(=O)R a -S(=O)2Ra -S(=O)2NR c R d -S(=O)(=NR b )R b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 5a It is arbitrarily replaced with, Each R 5a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(Rb )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 5a They come together to form an oxo, W is N or CR W And, R W These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. U is N or CR U And, R U These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. T is N or CR T And, R T These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. X is C, and Y is C, or X is C, and Y is N, or X is N and Y is C, Z 1 O, S, N, NR 1a CR 1b , or C(R 1c )2, Z 2 O, S, N, NR 2a CR 2b , or C(R 2c )2, Z 3 O, S, N, NR 3a CR 3b , or C(R 3c )2, Each R 1a , R 2a , and R 3a These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R 1b , R 2b , and R 3b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. Each R 1c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 1c They come together to form an oxo, Each R 2c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R2c They come together to form an oxo, Each R 3c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 3c They come together to form an oxo, Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R b These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R, or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. L is either absent or a C1-C4 alkylene arbitrarily substituted with one or more Rs, and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1~C3 alkyl, -S(=O)2C1~C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C3 alkyl, -S(=O)2N(C1~C3 alkyl)2, -S(=O)(=NC1~C3 alkyl)(C1~C3 alkyl), -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -N=S(=O)(C1~C3 alkyl)2, -O-C1~C4 alkylene-OH, -O-C1~C4 alkylene-NH2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, -P(=O)(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, C3~C6 cycloalkyl, or 3-membered to 6-membered heterocycloalkyl, or Compounds of which (two R atoms on the same atom form an oxo) or their pharmaceutically acceptable salts or stereoisomers are described.

[0040] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 4a It is arbitrarily replaced.

[0041] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4 These are, independently, halogen, -ORa , C1~C6 alkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 4a It is arbitrarily replaced.

[0042] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4 These are independently -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently one or more R 4a It is arbitrarily replaced.

[0043] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, R 4 independently, -L-aryl, where aryl is independently one or more R 4a It is arbitrarily replaced.

[0044] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, R 4 These are independently -L-heteroaryls, where the heteroaryl is independently one or more R 4a It is arbitrarily replaced.

[0045] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -SF5, -SH, -SR a , -NR c R d , -NR b C(=O)R a -C(=O)R a , -C(=O)ORb -C(=O)NR c R d -C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 hydroxyalkyl, C1~C6 aminoalkyl, C1~C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 4a It is arbitrarily replaced.

[0046] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 They come together to form an oxo.

[0047] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a cycloalkyl or heterocycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 These combine to form a cycloalkyl or heterocycloalkyl group, each optionally and independently substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a cycloalkyl group with optional substitutions. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a fully saturated cycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a partially saturated cycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4bThis forms a 4- to 6-membered fully saturated cycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a 4- to 6-membered partially saturated cycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a heterocycloalkyl which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a fully saturated heterocycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a partially saturated heterocycloalkyl which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b This forms a 4- to 6-membered fully saturated heterocycloalkyl group which is optionally substituted. In some embodiments, two R atoms on the same atom 4 They come together as one or more R 4b It forms a 4- to 6-membered partially saturated heterocycloalkyl group which is optionally substituted.

[0048] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a 5-membered or 6-membered cycloalkyl or 5-membered or 6-membered heterocycloalkyl group which is optionally substituted.

[0049] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a 5-membered cycloalkyl group with arbitrary substitutions.

[0050] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a 6-membered cycloalkyl group with arbitrary substitutions.

[0051] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a 5-membered heterocycloalkyl group with arbitrary substitutions.

[0052] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b This forms a 6-membered heterocycloalkyl group with arbitrary substitutions.

[0053] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4 Together, they each have one or more R 4b A cycloalkyl or heterocycloalkyl group is optionally substituted with a cycloalkyl or heterocycloalkyl group, where the cycloalkyl or heterocycloalkyl group is condensed with an aryl or heteroaryl group. In some embodiments, two R groups on the same atom 4 Together, they each have one or more R 4b A cycloalkyl group is formed by optionally substituting a cycloalkyl group, where the cycloalkyl group is condensed with an aryl or heteroaryl group. In some embodiments, two R groups on the same atom 4 Together, they each have one or more R 4b This forms an optionally substituted heterocycloalkyl, where the heterocycloalkyl is condensed with an aryl or heteroaryl.

[0054] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted. In some embodiments, each R 4a These are, independently, halogen, -CN, -OH, and -OR a -SF5, -S(=O)2R a , -NR c R d -C(=O)R a, -C(=O)OR b -C(=O)NR c R d , -C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 hydroxyalkyl, C1~C6 aminoalkyl, C1~C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, each R 4a These are, independently, halogen, -CN, -OH, and -OR a -SF5, -S(=O)2R a , -NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, where each alkyl, cycloalkyl, or heterocycloalkyl is independently substituted with one or more R atoms.

[0055] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4a They come together to form an oxo.

[0056] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4b These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b, -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and arbitrarily substituted.

[0057] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, each R 4b These are, independently, halogen, -CN, -NO2, -OH, -OR a -SF5, -NR c R d -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, each R 4bThese are, independently, halogen, -OH, and -OR a , -NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl, where each alkyl, cycloalkyl, and heterocycloalkyl is independently substituted with one or more R atoms.

[0058] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, two R atoms on the same atom 4b They come together to form an oxo.

[0059] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salt or stereoisomer, n is 1, 2, 3, 4, 5, or 6. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 0.

[0060] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound is of formula (Ia): [ka] (In the formula, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a-S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 6 They come together to form an oxo, m is 0, 1, 2, 3, 4, 5, or 6. Each R 7 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NRb )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 7 They come together to form an oxo, p is 0, 1, 2, 3, 4, or 5, and L 1 It is a compound of a C1-C4 alkylene that is either nonexistent or arbitrarily substituted with one or more R atoms.

[0061] In this specification, formula (Ia): [ka] (In the formula, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a, -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 6 They come together to form an oxo, m is 0, 1, 2, 3, 4, 5, or 6. Each R 7 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SRa -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 7 They come together to form an oxo, p is 0, 1, 2, 3, 4, or 5, and L 1 It does not exist, or -NR c - or C1-C4 alkylene, where C1-C4 alkylene is optionally substituted with one or more R atoms. Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl, R 5 is -S(=O)R a -S(=O)2R a -S(=O)2NRc R d -S(=O)(=NR b )R b -C(=O)R a , -C(=O)OR b -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 5a It is arbitrarily replaced with, Each R 5a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 5a They come together to form an oxo, W is N or CR W And, R W These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. U is N or CR U And, R U These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b)2. It is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs, T is N or CR T and is R T is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. X is C, and Y is C, or X is C, and Y is N, or X is N and Y is C, Z 1 O, S, N, NR 1a CR 1b , or C(R 1c )2, Z 2 O, S, N, NR 2a CR 2b , or C(R 2c )2, Z 3 O, S, N, NR 3a CR 3b , or C(R 3c )2, Each R 1a , R 2a , and R 3a These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R 1b , R 2b , and R 3b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NRc R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups. Each R 1c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 1c They come together to form an oxo, Each R 2c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R2c They come together to form an oxo, Each R 3c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or 2 R 3c They come together to form an oxo, Each R a These are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. Each R b These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R groups. R c and R dEach of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R, or R c and R d These, together with the atoms to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. L is either absent or a C1-C4 alkylene arbitrarily substituted with one or more Rs, and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1~C3 alkyl, -S(=O)2C1~C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1~C3 alkyl, -S(=O)2N(C1~C3 alkyl)2, -S(=O)(=NC1~C3 alkyl)(C1~C3 alkyl), -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -N=S(=O)(C1~C3 alkyl)2, -O-C1~C4 alkylene-OH, -O-C1~C4 alkylene-NH2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, -P(=O)(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, C3~C6 cycloalkyl, or 3-membered to 6-membered heterocycloalkyl, or Compounds of which (two R atoms on the same atom form an oxo) or their pharmaceutically acceptable salts or stereoisomers are described.

[0062] In some embodiments of the compound of formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 is absent.

[0063] In some embodiments of the compound of formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 is C1-C4 alkylene optionally substituted with one or more Rs. In some embodiments, L 1 is -CH2-.

[0064] In some embodiments of the compound of formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 is -NR c -. In some embodiments, L 1 is -NH-.

[0065] In some embodiments of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt or stereoisomer thereof, each R 6 is independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -SF5, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)R a , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R dThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R atoms.

[0066] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a , -NR c R d -C(=O)R a , -C(=O)OR b The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R atoms.

[0067] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -SF5, S(=O)2R a , -NR c R dThese are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl groups, where each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, and heteroaryl group is independently substituted with one or more R groups.

[0068] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -SF5, -S(=O)2R a , -NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, where each alkyl, alkynyl, cycloalkyl, or heterocycloalkyl is independently substituted with one or more R groups. In some embodiments, one or more R groups are used. 6 is a halogen. In some embodiments, one or more R 6 is -CN. In some embodiments, one or more R 6 is -NO2. In some embodiments, one or more R 6 is OH. In some embodiments, one or more R 6 is S(=O)2R a In some embodiments, one or more R 6 is NR c R d In some embodiments, one or more R 6 R is an optionally substituted C1-C6 alkyl group. In some embodiments, one or more R 6 R is an optionally substituted C1-C3 alkyl group. In some embodiments, one or more R 6is an optionally substituted C1-C6 alkoxyl which is optionally substituted with one or more halogens. In some embodiments, one or more R 6 is an optionally substituted C1-C3 alkoxyl. In some embodiments, one or more R 6 is a C1-C6 haloalkyl group. In some embodiments, one or more R groups are used. 6 R is an optionally substituted C2-C6 alkynyl. In some embodiments, one or more R 6 is an optionally substituted cycloalkyl. In some embodiments, one or more R 6 R is an optionally substituted 3- to 6-membered cycloalkyl group. In some embodiments, one or more R 6 is an optionally substituted heterocycloalkyl. In some embodiments, one or more R 6 R is an optionally substituted 3- to 6-membered heterocycloalkyl group. In some embodiments, one or more R 6 is an optionally substituted heteroaryl. In some embodiments, one or more R 6 are CN, F, Cl, CH3, CH2CH3, CH(CH3)2, CHF2, CF3, OCH2F, OCF3, [ka] In some embodiments, two R atoms on the same atom 6 They come together to form an oxo.

[0069] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, ring B is a cycloalkyl or heterocycloalkyl. In some embodiments, ring B is a fully saturated cycloalkyl. In some embodiments, ring B is a fully saturated heterocycloalkyl. In some embodiments, ring B is a partially saturated cycloalkyl. In some embodiments, ring B is a partially saturated heterocycloalkyl. In some embodiments, ring B is a 5-membered or 6-membered partially saturated heterocycloalkyl. In some embodiments, ring B is a bridged bicyclic ring. In some embodiments, ring B is a spiro-dicyclic ring. In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, ring B is a 4- to 7-membered ring. In some embodiments, ring B is a biring ring. In some embodiments, ring B is a monoring ring.

[0070] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, ring B is an aryl. In some embodiments, the aryl includes a phenyl condensed with a cycloalkyl or heterocycloalkyl. In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0071] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, ring B is phenyl. In some embodiments, [ka] teeth, [ka] That is the case.

[0072] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0073] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0074] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0075] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, ring B is a heteroaryl. In some embodiments, ring B is a bicyclic heteroaryl. In some embodiments, ring B is a 5-6 condensed, 6-6 condensed, or 6-5 condensed bicyclic heteroaryl. In some embodiments, [ka] teeth, [ka] That is the case.

[0076] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, ring B is a monocyclic heteroaryl. In some embodiments, ring B is a five-membered or six-membered heteroaryl. In some embodiments, ring B is a five-membered heteroaryl. In some embodiments, ring B is pyrazolyl, pyrrolyl, or thiazolyl. In some embodiments, ring B is a six-membered heteroaryl. In some embodiments, ring B is pyridyl, pyrimidinyl, or pyridazinyl.

[0077] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0078] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0079] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0080] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0081] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 2, 3, 4, or 5. In some embodiments, m is 3, 4, or 5. In some embodiments, m is 4 or 5.

[0082] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, the compound is of formula (Ib): [ka] (In the formula, Ring C is cycloalkyl or heterocycloalkyl, Each R 6 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 6 They come together to form an oxo, m is 0, 1, 2, 3, 4, 5, or 6. Each R 7These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom 7 They come together to form an oxo, The compound is (where q is 0, 1, 2, 3, or 4).

[0083] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R6 is a halogen or a -L-heteroaryl, where the heteroaryl is independently optionally substituted with one or more R. In some embodiments, one or more R 6 is a halogen. In some embodiments, one or more R 6 is a -L-heteroaryl compound, where the heteroaryl is independently and arbitrarily substituted with one or more R atoms.

[0084] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, two R atoms on the same atom 6 They come together to form an oxo.

[0085] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, ring C is a 4- to 6-membered cycloalkyl or a 4- to 6-membered heterocycloalkyl. In some embodiments, ring C is a bicyclic ring. In some embodiments, ring C is a monocyclic ring.

[0086] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, ring C is a 4- to 6-membered fully saturated cycloalkyl group. In some embodiments, ring C is a 4- to 6-membered partially saturated cycloalkyl group. In some embodiments, ring C is a partially saturated ring containing one double bond.

[0087] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0088] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0089] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, ring C is a cycloalkyl group containing a condensed aryl or heteroaryl group. In some embodiments, [ka] teeth, [ka] That is the case.

[0090] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, the ring C is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0091] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, ring C is a heterocycloalkyl containing a condensed aryl or heteroaryl. In some embodiments, [ka] teeth, [ka] That is the case.

[0092] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0093] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, ring A is a 4- to 6-membered cycloalkyl group. In some embodiments, ring A is a 4- to 6-membered fully saturated cycloalkyl group. In some embodiments, ring A is a 4-membered fully saturated cycloalkyl group. In some embodiments, ring A is a 5-membered fully saturated cycloalkyl group. In some embodiments, ring A is a 6-membered fully saturated cycloalkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated cycloalkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated cycloalkyl group containing one double bond. In some embodiments, ring A is a 5-membered partially saturated cycloalkyl group. In some embodiments, ring A is a 6-membered partially saturated cycloalkyl group. In some embodiments, ring A contains one double bond within the ring.

[0094] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] That is the case.

[0095] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0096] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, ring A is a 4- to 7-membered heterocycloalkyl group. In some embodiments, ring A is a 4- to 6-membered heterocycloalkyl group. In some embodiments, ring A contains 1 to 3 nitrogen atoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom. In some embodiments, ring A contains 1 to 3 ring nitrogen atoms. In some embodiments, ring A contains 1 or 2 ring nitrogen atoms. In some embodiments, ring A contains 1 ring nitrogen atom. In some embodiments, ring A is a 4- to 6-membered fully saturated heterocycloalkyl group. In some embodiments, ring A is a 4-membered fully saturated heterocycloalkyl group. In some embodiments, ring A is a 5-membered fully saturated heterocycloalkyl group. In some embodiments, ring A is a 6-membered fully saturated heterocycloalkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated heterocycloalkyl group. In some embodiments, ring A is a 4- to 6-membered partially saturated heterocycloalkyl group containing one double bond. In some embodiments, ring A is a 5-membered partially saturated heterocycloalkyl group. In some embodiments, ring A is a 6-membered partially saturated heterocycloalkyl group.

[0097] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, ring A is [ka] That is the case.

[0098] In some embodiments of the compound of formula (I), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0099] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, ring A is a 4- to 6-membered partially saturated heterocycloalkyl.

[0100] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0101] In some embodiments of the compound of formula (Ia), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0102] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0103] In some embodiments of the compound of formula (Ib), or its pharmaceutically acceptable salts or stereoisomers, [ka] teeth, [ka] That is the case.

[0104] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 7 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a , -OC(=O)OR b -OC(=O)NR c R d -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -S(=O)(=NR b )R b , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a -N=S(=O)(R b )2, -C(=O)R a , -C(=O)OR b -C(=O)NR c R d -P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R atoms.

[0105] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 7 These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -SF5, -SH, -SR a , -NR c R d , -NR b C(=O)R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R atoms.

[0106] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, each R 7 These are, independently, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 7 These are, independently, halogen, -OH, and -OR a , amino, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 7 R is independently a halogen, -OH, C1-C6 alkoxyl, C1-C6 alkyl, or C1-C6 haloalkyl, where the alkoxyl is optionally substituted with one or more halogens. In some embodiments, each R7 These are independently a halogen, a C1-C6 alkoxyl, or a C1-C6 alkyl, where the alkoxyl is optionally substituted with one or more halogens.

[0107] In some embodiments of the compound of formula (Ia) or formula (Ib), or its pharmaceutically acceptable salt or stereoisomer, two R atoms on the same atom 7 They come together to form an oxo.

[0108] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 5a It is optionally replaced by R. In some embodiments, 5 is one or more R 5a It is a C1-C6 alkyl which is optionally substituted with R. In some embodiments, 5 is a C1-C6 haloalkyl group. In some embodiments, R 5 R is a C1-C6 hydroxyalkyl group. In some embodiments, R 5 R is a C1-C6 aminoalkyl group. In some embodiments, R 5 R is a C1-C6 heteroalkyl group. In some embodiments, R 5 is one or more R 5a It is a C2-C6 alkenyl which is optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C2-C6 alkynyl which is optionally substituted with R. In some embodiments, 5is an L-cycloalkyl group, where the cycloalkyl group consists of one or more R groups. 5a It is optionally replaced by R. In some embodiments, 5 is a -L-heterocycloalkyl, where the heterocycloalkyl is one or more R 5a It is optionally replaced by R. In some embodiments, 5 is an -L-aryl, where aryl is one or more R 5a It is optionally replaced by R. In some embodiments, 5 is a -L-heteroaryl, where the heteroaryl is one or more R 5a It is arbitrarily replaced.

[0109] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 The alkyl group is a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C1-C6 hydroxyalkyl group, where the alkyl group has one or more R groups. 5a It is arbitrarily replaced.

[0110] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 It is methyl.

[0111] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 It is ethyl.

[0112] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 is an -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 5aIt is optionally replaced by R. In some embodiments, 5 is -L-(3- to 6-membered cycloalkyl), -L-(3- to 6-membered heterocycloalkyl), -L-phenyl, or -L-(5- or 6-membered heteroaryl), where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R 5a It is arbitrarily replaced.

[0113] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, L is absent or -CH2-. In some embodiments, L is absent. In some embodiments, L is -CH2-. In some embodiments, L is a C1-C4 alkylene optionally substituted with one or more R groups.

[0114] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 teeth, [ka] That is the case.

[0115] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 5a These are, independently, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -SF5, -SH, -SR a -S(=O)R a -S(=O)2R a , -NR c R d , -NR b C(=O)R a -C(=O)R a , -C(=O)OR b -C(=O)NR c R dThe elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where the alkyl is independently substituted with one or more R atoms.

[0116] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 5a These are, independently, halogen, -CN, -NO2, -OH, -OR a The elements are -SF5, -SH, -C1~C6 alkyl, C1~C6 haloalkyl, C1~C6 hydroxyalkyl, C1~C6 aminoalkyl, or C1~C6 heteroalkyl, where the alkyl is independently and arbitrarily substituted with one or more R atoms.

[0117] In some embodiments of compounds of formula (I), formula (Ia), or (Ib), or their pharmaceutically acceptable salts or stereoisomers, R 5 CH3, CHF2, CF3, CH2CH3, CH2CH(CH3)2, CH2CHF2, CH2CF3, [ka] That is the case.

[0118] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, W is N.

[0119] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, W is CR. W That is the case.

[0120] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R W These are hydrogen, halogen, -CN, -NO2, -OH, -OR a-SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where the alkyl is optionally substituted with one or more R. In some embodiments, R W R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R W is a C1-C6 alkyl group. In some embodiments, R W R is hydrogen. In some embodiments, R W It is a halogen.

[0121] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, U is N.

[0122] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, U is CR. U That is the case.

[0123] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R U These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R atoms.

[0124] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R U These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where the alkyl is optionally substituted with one or more R. In some embodiments, R U R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R U is a C1-C6 alkyl group. In some embodiments, R U R is hydrogen. In some embodiments, R U is a halogen. In some embodiments, R U These are C1-C6 alkyl groups.

[0125] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, T is N.

[0126] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, T is CR. T That is the case.

[0127] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R T These are hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -NR c R d -C(=O)R a , -C(=O)ORb -C(=O)NR c R d The elements are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments, R T R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R T These are C1-C6 alkyl groups.

[0128] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R T These are hydrogen, halogen, -CN, -NO2, -OH, -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0129] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R T is hydrogen, halogen, -C1-C3 alkyl, C1-C3 haloalkyl, or C2 or C3 alkynyl. In some embodiments, R T R is hydrogen. In some embodiments, R T is a halogen. In some embodiments, R T is a C1-C3 alkyl group. In some embodiments, R T is a C1-C3 haloalkyl group. In some embodiments, RT It is a C2 or C3 alkynyl.

[0130] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, R T It is hydrogen.

[0131] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, X is C and Y is C. In some embodiments, X is C and Y is N. In some embodiments, X is N and Y is C.

[0132] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, Z 1 is O. In some embodiments, Z 1 is S. In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, Z 1 is N. In some embodiments, Z 1 is NR 1a In some embodiments, Z 1 CR 1b In some embodiments, Z 1 is C(R 1c )2.

[0133] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, Z 2 is O. In some embodiments or stereoisomers thereof, Z 2 In some embodiments, Z 2 is N. In some embodiments, Z 2 is NR 2a In some embodiments, Z 2 CR 2bIn some embodiments, Z 2 is C(R 2c )2.

[0134] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, Z 3 is O. In some embodiments, Z 3 In some embodiments, Z 3 is N. In some embodiments, Z 3 is NR 3a In some embodiments, Z 3 CR 3b In some embodiments, Z 3 is C(R 3c )2.

[0135] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0136] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0137] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0138] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0139] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 1a , R 2a , and R 3a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 1a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 2a R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 3a These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0140] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R1a , R 2a , and R 3a R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 1a R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 2a R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 3a R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 1a R is hydrogen. In some embodiments, R 1a is methyl. In some embodiments, R 2a R is hydrogen. In some embodiments, R 2a is methyl. In some embodiments, R 3a R is hydrogen. In some embodiments, R 3a It is methyl.

[0141] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 1b , R 2b , and R 3b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 1b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 2bThese are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, R 3b These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0142] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 1b , R 2b , and R 3b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R 1b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R 1b R is hydrogen. In some embodiments, R 1b is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 2b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R 2b R is hydrogen. In some embodiments, R 2b is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 3b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments, R 3b R is hydrogen. In some embodiments, R 3bThese are C1-C6 alkyl or C1-C6 haloalkyl.

[0143] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 1b , R 2b , and R 3b R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 1b R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 1b is methyl. In some embodiments, R 2b R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 2b is methyl. In some embodiments, R 3b R is independently hydrogen or a C1-C3 alkyl group (e.g., methyl). In some embodiments, R 3b It is methyl.

[0144] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 1c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 1c R is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R 1c It is, independently, hydrogen.

[0145] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, two R1c They come together to form an oxo.

[0146] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 2c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 2c These are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0147] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 2c It is, independently, hydrogen.

[0148] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, two R 2c They come together to form an oxo.

[0149] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 3c These are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a -SF5, -SH, -SR a , -NR c R d These are C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 3cThese are independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0150] In several embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, each R 3c It is, independently, hydrogen.

[0151] In some embodiments of the compounds of formula (I), formula (Ia), or formula (Ib), or their pharmaceutically acceptable salts or stereoisomers, two R 3c They come together to form an oxo.

[0152] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0153] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0154] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0155] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] That is the case.

[0156] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0157] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0158] In some embodiments of compounds of formula (I), formula (Ia), or formula (Ib), or pharmaceutically acceptable salts or stereoisomers thereof, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] That is the case.

[0159] In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently -L-cycloalkyl or -L-heterocycloalkyl, where each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl or a C1-C6 haloalkyl, where each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R aR is independently a C1-C6 alkyl or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a R is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R a These are independently C1-C6 haloalkyl groups.

[0160] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, -L-cycloalkyl, or -L-heterocycloalkyl, where each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, where each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R bR is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, where each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, each R b R is hydrogen. In some embodiments of the compounds disclosed herein, each R b R is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, each R b These are independently C1-C6 haloalkyl groups.

[0161] In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R dEach of these is independently hydrogen, -L-cycloalkyl, or -L-heterocycloalkyl, where each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, or a C1-C6 heteroalkyl group, where each alkyl group is independently optionally substituted with one or more R atoms.

[0162] In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl, where each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each is independently hydrogen or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d Each of these is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently a C1-C6 alkyl group. In some embodiments of the compounds disclosed herein, R c and R d Each of these is independently a C1-C6 haloalkyl group.

[0163] In some embodiments of the compounds disclosed herein, R c and R d These atoms, together with the atoms to which they are bonded, form heterocycloalkyl groups optionally substituted with one or more R atoms.

[0164] In some embodiments of the compounds disclosed herein, L is absent. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene optionally substituted with one or more R atoms. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene. In some embodiments of the compounds disclosed herein, L is -CH2-. In some embodiments of the compounds disclosed herein, L is -CH2CH2-. In some embodiments of the compounds disclosed herein, L is -CH2CH2CH2-.

[0165] In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, or C3~C6 cycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, or C3~C6 cycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -SF5, -NH2, -NHC1~C3 alkyl, -N(C1~C3 alkyl)2, -C(=O)C1~C3 alkyl, -C(=O)OH, -C(=O)OC1~C3 alkyl, -C(=O)NH2, -C(=O)NHC1~C3 alkyl, -C(=O)N(C1~C3 alkyl)2, C1~C3 alkyl, or C1~C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -SF5, C1~C3 alkyl, C1~C3 alkoxy, C1~C3 haloalkyl, C1~C3 haloalkoxy, C1~C3 hydroxyalkyl, C1~C3 aminoalkyl, C1~C3 heteroalkyl, or C3~C6 cycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently a halogen, -CN, -OH, -SF5, C1-C3 alkyl, C1-C3 alkoxy, or C1-C3 haloalkyl.

[0166] In this specification, all combinations of the groups described above are assumed for various variable elements. Throughout this specification, groups and their substituents are selected by those skilled in the art so as to yield stable moieties and compounds.

[0167] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds in Table 1.

[0168] [Table 1] TIFF2026519609000122.tif228170TIFF2026519609000123.tif244170TIFF2026519609000124.tif25217 0TIFF2026519609000125.tif232170TIFF2026519609000126.tif251170TIFF2026519609000127.tif23717 0TIFF2026519609000128.tif238170TIFF2026519609000129.tif254170TIFF2026519609000130.tif22117 0TIFF2026519609000131.tif253170TIFF2026519609000132.tif252170TIFF2026519609000133.tif75170

[0169] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts or stereoisomers, are one of the compounds in Table 2.

[0170] [Table 2] TIFF2026519609000135.tif240170TIFF2026519609000136.tif174170

[0171] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis isomers, trans isomers, syn isomers, anti isomers, entgegen(E) isomers, and zusammen(Z) isomers, as well as their corresponding mixtures. In some situations, the compounds described herein have one or more chiral centers, each center existing in either an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, as well as their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomer compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these dissimilarity. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolving techniques based on differences in solubility. Then, in some embodiments, the optically pure enantiomers are recovered together with the resolving agent by any practical means that do not result in racemization.

[0172] isotopically enriched compounds Unless otherwise stated, the compounds described herein may represent their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but with atomic masses or mass numbers different from those primarily found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen, 1 H (light hydrogen), 2 H (deuterium), and 3 It has three naturally occurring isotopes, denoted by H (tritium). Light hydrogen is the most abundant hydrogen isotope in nature. Enrichment with deuterium may result in several therapeutic benefits, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating in vivo pathways of drug excretion and metabolism.

[0173] For example, the compounds described herein may be artificially enriched with one or more specific isotopes. In some embodiments, the compounds described herein may be artificially enriched with one or more isotopes not primarily found in nature. In some embodiments, the compounds described herein may be deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 The compounds may be artificially enriched with one or more isotopes selected from C). In some embodiments, the compounds described herein are 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S,36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 I, and 125 It is artificially enriched with one or more isotopes selected from I. In some embodiments, the abundance of the enriched isotope is, independently, at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0174] In some embodiments, the compound is deuterated at at least one position. In some embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 It is substituted with a hydrogen atom.

[0175] Methods for synthesizing deuterium-containing compounds are known in the art and are not limited to the present examples, but include the methods described in U.S. Patents No. 5,846,514 and No. 6,334,997, as well as the following synthesis methods. For example, deuterium-substituted compounds can be synthesized using various methods, as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0176] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0177] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a number of inorganic or organic bases, as well as either inorganic or organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by reacting the purified compounds separately in their free form with suitable acids or bases and then isolating the salts thus formed.

[0178] Examples of pharmaceutically acceptable salts include salts prepared by the reaction of the compounds described herein with mineral acids, organic acids, or inorganic bases, such as acetates, acrylates, adipicates, alginates, aspartates, benzoates, benzenesulfons, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dioate, camphorates, camphorsulfons, capronates, caprylates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucons, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptanoates, glycerophosphates, glycolates, hemisulfates, heptanoates, hexanoates, hexyn-1,6-dioate, hydroxybenzoates, γ-hydroxybutyrates, hydrochlorides, and bromine. Examples include hydrochlorides, hydroiodides, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malons, methanesulfonates, mandelates, metaphosphates, methanesulfonates, methoxybenzoates, methylbenzoates, monohydrogen phosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmoate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrinates, pivalates, propions, pyrosulfates, pyrophosphates, propiolates, phthalates, phenylacetates, phenylbutyrates, propanesulfonates, salicylates, succinates, sulfates, sulfites, succinates, suberinates, sebacinates, sulfonates, tartrates, thiocyanates, tosylates, undecanoates, and xylenesulfonates.

[0179] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, such as inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, and manic acid. Examples of organic acids include, but are not limited to, delicates, aryl sulfonic acids, methanesulfonic acids, ethanesulfonic acids, 1,2-ethanedisulfonic acids, 2-hydroxyethanesulfonic acids, benzenesulfonic acids, 2-naphthalenesulfonic acids, 4-methylbicyclo-[2.2.2]octa-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid are used in the preparation of salts that are useful as intermediates in obtaining the compounds disclosed herein, or their stereoisomers, and their pharmaceutically acceptable acid addition salts, although they are not pharmaceutically acceptable in themselves.

[0180] In some embodiments, the compounds described herein containing a free acid group react with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, or sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Typical salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2. + (C 1~4 Examples include alkyl(4) and others.

[0181] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. It should be understood that the compounds described herein also include those in which any basic nitrogen-containing group contained in the compound has been quaternized. In some embodiments, such quaternization yields water-soluble or oil-soluble or water-dispersible or oil-dispersible products.

[0182] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. A tautomer is a compound that can be interconverted by the movement of hydrogen atoms, involving the switching of a single bond with an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomers of the compounds disclosed herein are intended. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0183] Treatment method This specification discloses a method for treating cancer, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject.

[0184] In some embodiments, a method for treating cancer involves administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject.

[0185] Furthermore, this specification discloses a method for inhibiting PRMT5 activity in a subject, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0186] This specification discloses a method for modulating protein arginine methyltransferase 5 (PRMT5) in a subject requiring modification, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the subject.

[0187] This specification discloses a method for inhibiting protein arginine methyltransferase 5 (PRMT5) in a subject requiring inhibition, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the subject has cancer.

[0188] This specification discloses a method for treating a disease or condition comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment, wherein the disease or condition is related to the overexpression of PRMT5. In some embodiments, the disease or disorder is cancer.

[0189] This specification discloses a method for treating cancer, comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, cervical cancer, testicular germ cell cancer, and non-small cell lung cancer, and multiple myeloma, diffuse large B-cell lymphoma, rhabdomyosarcoma, and cutaneous squamous cell carcinoma. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is malignant mesothelioma.

[0190] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are effective in inhibiting the proliferation of cancer cells, including cancer cells lacking the MTAP gene.

[0191] In some embodiments, the cancer is a cancer in which the MTAP gene is deleted.

[0192] In some embodiments, cancer is MTAP (methylthioadenosine phosphorylase) null. In some embodiments, cancer shows accumulation of methylthioadenosine (MTA), which is an MTAP substrate.

[0193] In some embodiments, the method targets PRMT5 in MTAP null tumors while preserving PRMT5 in normal tissue (MTAP WT). In some embodiments, the compounds disclosed herein are MTA-coordinated small molecule inhibitors that preferentially target the MTA-binding state of PRMT5, which is abundant in MTAP null tumor cells, while providing an improved therapeutic index compared to normal cells where MTAP is intact and MTA levels are low.

[0194] In some embodiments, cancer is mesothelioma, breast cancer, multiple myeloma, leukemia, lymphoma, glioblastoma, lung cancer, liver cancer, colorectal cancer, melanoma, ovarian cancer, kidney cancer, pancreatic cancer, gastric cancer, cervical cancer, esophageal cancer, nasopharyngeal cancer, laryngeal cancer, skin cancer, prostate cancer, breast cancer, or gastrointestinal cancer.

[0195] In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is estrogen receptor-negative (ER) - ) or progesterone receptor negative (PR - )

[0196] In some embodiments, the breast cancer is HER2-negative. In some embodiments, the breast cancer is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative, which is also referred to herein as “triple-negative breast cancer.”

[0197] In some embodiments, breast cancer is a different breast cancer including but not limited to lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, papillary Paget's disease, phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, or triple-negative, HER-positive, estrogen receptor-positive, progesterone receptor-positive, HER and estrogen receptor-positive, HER and progesterone receptor-positive, estrogen and progesterone receptor-positive, and HER and estrogen and progesterone receptor-positive.

[0198] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is NSCLC (non-small cell lung cancer). In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the cancer is adenocarcinoma. In some embodiments, the cancer is glioblastoma (GBM). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is DLBCL, HNSCC, or cholangiocarcinoma.

[0199] In some embodiments, cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangiosarcoma, hemangioendothelioma), appendiceal carcinoma, benign monoclonal gammaglobulinemia, biliary tract carcinoma (e.g., cholangiocarcinoma), bladder carcinoma, brain carcinoma (e.g., meningioma, glioma, e.g., astrocytoma, oligodendroglioma, medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical carcinoma (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal carcinoma (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endosarcoma (e.g., carcinoma), Posi sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma), familial eosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), pharyngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematopoietic cancer (e.g., acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute bone cancer) Leukemias such as myelin leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma ( For example, T-cell NHL such as Waldenström macroglobulinemia, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, as well as precursor T lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (for example, cutaneous T-cell lymphoma (CTCL) (for example, mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma),Mixed forms of one or more of the above-mentioned leukemia / lymphomas, and multiple myeloma (MM), heavy chain disease (e.g., alpha chain disease, gamma chain disease, muon chain disease), hemangioblastoma, inflammatory myofibroblastic neoplasm, immunocellular amyloidosis, renal cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatocellular carcinoma), lung cancer (e.g., bronchial cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma), slender lung cancer Myosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), idiopathic myelogenesis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), eosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis type 1 (NF)) Or type 2, schwannomatous), neuroendocrine carcinoma (e.g., gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, penile cancer (e.g., Paget's disease of the penis and scrotum), pineal gland tumor, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCO), keratoacanthoma (KA)) These include melanoma, basal cell carcinoma (BCC), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synoviomas, testicular cancer (e.g., seminomas, testicular embryonic carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., vulvar Paget's disease).

[0200] In some embodiments, the disclosed compounds are useful for treating any PRMT5-mediated or PRMT5-responsive proliferative cell disorder, such as PRMT5-responsive cancer.

[0201] dosage In certain embodiments, compositions comprising the compounds(s) described herein are administered for therapeutic purposes. In certain therapeutic uses, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially block at least one of the symptoms of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0202] Route of administration Appropriate routes of administration include, but are not limited to, oral administration, intravenous administration, rectal administration, aerosol administration, parenteral administration, ocular administration, pulmonary administration, transmucosal administration, transdermal administration, transvaginal administration, transaural administration, transnasal administration, and local administration. Furthermore, parenteral delivery, for example, includes intramuscular injection, subcutaneous injection, intravenous injection, intrathecal injection, as well as intrathecal injection, direct intraventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.

[0203] Pharmaceutical composition / formulation The compounds described herein are administered to subjects requiring them, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in accordance with standard pharmacopoeias, in pharmaceutical compositions. In some embodiments, the compounds described herein are administered to animals.

[0204] In another embodiment, pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient are provided herein. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) (such disclosures are incorporated herein by reference). [Examples]

[0205] The following embodiments are provided to illustrate, and not to limit, the invention described in the claims. The following embodiments further illustrate the invention, but of course should not be construed as limiting its scope in any way.

[0206] The following synthesis schemes are provided for illustrative purposes only, not limitation. The following examples illustrate various methods for producing the compounds described herein. Those skilled in the art will understand that these compounds can be produced by similar methods or by combining them with other methods known to those skilled in the art. They will also understand that they can be produced in a manner similar to those described below, using appropriate starting materials and, as necessary, modifying the synthesis route. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein.

[0207] Examples Unless otherwise specified, all materials were obtained from commercial suppliers and used without further refinement.

[0208] The following abbreviations are used to refer to various reagents and solvents: [Table 3] TIFF2026519609000138.tif160170

[0209] Example A Intermediate A01 [ka]

[0210] To a solution of A01-01 (90.0 g, 452 mmol) in CH3CN (800 mL), 2-methyl-1H-imidazole (44.5 g, 542 mmol) and K2CO3 (125 g, 904 mmol) were added. The reaction mixture was stirred at 85°C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with H2O (1.00 L) and extracted with DCM (800 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A01-02 (87.8 g, 74.4% yield). 1H NMR (400MHz, CDCl3) δ 8.29 (dd, J = 8.4, 1.6 Hz, 1H), 8.09 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 3.99 (s, 3H), 2.22 (s, 3H).

[0211] To a solution of A01-02 (50.0 g, 191 mmol) in EtOH (500 mL) and H2O (250 mL), Fe (32.0 g, 574 mmol) and CaCl2 (21.2 g, 191 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with H2O (500 mL) and extracted with DCM (500 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A01-03 (40 g, 90.3% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.74 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 6.94 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.85 (s, 2H), 3.75 (s, 3H), 2.08 (s, 3H).

[0212] To a solution of A01-03 (40.0 g, 173 mmol) in 1,2-dichlorobenzene (400 mL), CDI (61.7 g, 380 mmol) was added. The reaction mixture was stirred at 180 °C for 4 hours. After cooling to 20 °C, the reaction mixture was filtered, the solid was washed with THF (100 mL), and dried under vacuum to obtain A01-04 (40 g, 89.9% yield). LCMS: MS m / z (ESI) [M+H] + = 258.1.

[0213] To a solution of A01-04 (40.0 g, 155 mmol) in CH3CN (400 mL), BOP (138 g, 311 mmol) and DBU (71.0 g, 467 mmol) were added. The mixture was stirred at 25°C for 30 minutes, after which (2,4-dimethoxyphenyl)methaneamine (39.0 g, 233 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with H2O (2 L), and extracted with DCM (1 L x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 2 / 3) to obtain A01-05 (23.0 g, 36.4% yield). LCMS: MS m / z (ESI) [M+H] + = 406.9.

[0214] A mixture of A01-05 (23.0 g, 56.6 mmol) in TFA (150 mL) was stirred at 80°C for 2 hours and then concentrated. The residue was triturated at 25°C with a solution (petroleum ether / siRNA = 1 / 1, 200 mL) for 2 hours, filtered, and the solid was dried under vacuum to obtain A01-06 (14.0 g, 96.5% yield). LCMS: MS m / z (ESI) [M+H] + = 257.3.

[0215] To a solution of A01-06 (14.0 g, 54.6 mmol) in THF (150 mL) and H2O (100 mL), LiOH (13.1 g, 546 mmol) was added. The mixture was stirred at 70 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=3 with 3 M HCl (100 mL). The mixture was then filtered, the solid was washed with THF (80 mL), and dried under vacuum to obtain A01 (13.2 g, 99.8% yield). LCMS: MS m / z (ESI) [M+1] + = 243.1; 1H NMR (400MHz, DMSO-d6) δ 10.12 (brs, 1H), 9.53 (brs, 1H), 8.64 (s, 1H), 8.55 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 3.08 (s, 3H).

[0216] Intermediate A02 [ka]

[0217] To a solution of A02-01 (15 g, 75.3 mmol) in CH3CN (150 mL), methyl aminoacetate hydrochloride (37.9 g, 301 mmol) and DIPEA (58.4 g, 452 mmol) were added. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (SiO2, petroleum ether / THF 0% → 20%) to obtain A02-02 (5.3 g, 26.2% yield). 1 H NMR (400MHz, CDCl3) δ 8.38 (brs, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.34 (dd, J = 8.8, 1.6 Hz, 1H), 4.18 (d, J = 5.2 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 3H).

[0218] To a solution of A02-02 (5.00 g, 18.6 mmol) in EtOH (50 mL) and H2O (10 mL), Fe (4.20 g, 74.6 mmol) and CaCl2 (2.10 g, 18.6 mmol) were added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain A02-03 (3.00 g, 78.1% yield). 1H NMR (400MHz, DMSO-d6) δ 10.58 (s, 1H), 7.28 (s, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.25 (s, 1H), 3.78 (s, 3H).

[0219] To a solution of A02-03 (3.00 g, 14.5 mmol) in THF (30 mL), MnO2 (5.10 g, 58.2 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with warm THF (30 mL). The filtrate was concentrated to obtain A02-04 (1.60 g, 53.9% yield). 1 H NMR (400MHz, DMSO-d6) δ 12.71 (brs, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.25(s, 1H), 8.09 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H).

[0220] To a suspension of NaH (196 mg, 4.90 mmol, 60% purity) in DMF (5 mL), A02-04 (500 mg, 2.45 mmol) was added under an N2 atmosphere at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then PMB-Cl (499 mg, 3.18 mmol) was added, and the mixture was stirred for a further 12 hours. The reaction solution was quenched with NH4Cl (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel chromatography (SiO2, petroleum ether / THF 0% → 30%) to obtain A02-05 (420 mg, 52.9% yield). LCMS: MS m / z (ESI) [M+H] + = 325.2. 1H NMR (400MHz, DMSO-d6) δ 8.44 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 8.8, 2.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.44 (s, 2H), 3.89 (s, 3H), 3.72 (s, 3H).

[0221] To a solution of A02-05 (400 mg, 1.23 mmol) in DMF (10 mL), NaH (123.3 mg, 3.08 mmol) and TosMIC (482 mg, 2.47 mmol) were added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched with H2O (40 mL), and HCl (2 M) was added until the pH reached 3-4. The mixture was then extracted with siRNA (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / THF = 0% → 50%) to obtain A02-06 (210 mg, 46.9% yield). LCMS: MS m / z (ESI) [M+H] + = 350.3.

[0222] To a solution of A02-06 (210 mg, 0.601 mmol) in DMF (5 mL), K2CO3 (166 mg, 1.20 mmol) and CH3I (171 mg, 1.20 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with H2O (20 mL) and extracted with  (15 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by column chromatography (SiO2, PE / THF = 0% → 33%) to obtain A02-07 (200 mg, 91.5% yield). LCMS: MS m / z (ESI) [M+H] + = 364.3.

[0223] To a solution of A02-07 (270 mg, 0.74 mmol) in TFA (3 mL), TfOH (0.300 mL, 0.200 mmol) was added. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated, and the crude product was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 20 / 1) to obtain A02-08 (130 mg, 80.6% yield). LCMS: MS m / z (ESI) [M+H] + = 244.1.

[0224] To a solution of A02-08 (100 mg, 0.410 mmol) in CH3CN (3 mL), (2,4-dimethoxyphenyl)methaneamine (103 mg, 0.620 mmol), BOP (364 mg, 0.820 mmol), and DBU (188 mg, 1.23 mmol) were added. The reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O (10 mL) and extracted with  (10 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 20 / 1) to obtain A02-09 (130 mg, 80.6% yield). LCMS: MS m / z (ESI) [M+H] + = 393.3; 1 H NMR (400MHz, CDCl3) δ 8.61 (s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.05 (dd, J = 8.4, 2.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 5.75 (brs, 1H), 4.83 (d, J = 4.8 Hz, 2H), 3.98 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H).

[0225] A solution of A02-09 (130 mg, 0.330 mmol) in TFA (3 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated, the residue was triturated with solution (10 mL, PE:Â=1:1), filtered, and the solid was dried under vacuum to obtain A02-10 (65.0 mg, 81.0% yield). LCMS: MS m / z (ESI) [M+H] + = 243.2.

[0226] A solution of A02-10 (55.0 mg, 0.230 mmol) in THF (3 mL) and H2O (1 mL) was mixed with LiOH (47.7 mg, 1.14 mmol). The mixture was stirred at 70°C for 12 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=3 with 3 M HCl. The mixture was filtered, the solid was washed with THF (1 mL), and dried under vacuum to obtain A02 (36.0 mg, 69.5% yield). LCMS: MS m / z (ESI) [M+H] + = 229.1.

[0227] Intermediate A03 [ka]

[0228] To a solution of A03-01 (5.00 g, 18.0 mmol) and 5-bromo-1H-imidazole (3.20 g, 21.7 mmol) in dioxane (80 mL) and H2O (8 mL), Cs2CO3 (11.8 g, 36.1 mmol) and Pd(PPh3)4 (2.1 g, 1.80 mmol) were added, and the mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction product was filtered, and the filtrate was removed under vacuum to obtain the residue. The residue was diluted with saturated H2O (200 mL) and extracted with SiO2 (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (using a 0% to 20% THF / DCM eluent at 100 mL / min) to obtain A03-02 (500 mg, 12.8% yield). LCMS: MS m / z (ESI) [M+H] += 218.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (brs, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.17 (s, 2H), 6.71 (d, J = 8.4 Hz, 1H), 3.77 (s, 3H).

[0229] To a mixture of A03-02 (500 mg, 2.30 mmol) in THF (10 mL), CDI (747 mg, 4.60 mmol) was added, and the mixture was stirred at 70°C for 12 hours. The reaction product was filtered, and the filtered cake was concentrated under reduced pressure to obtain A03-03 (200 mg, 35.7% yield). LCMS: MS m / z (ESI) [M+H] + = 243.9; 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (brs, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.96 (dd, J = 8.4, 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H).

[0230] A mixture of A03-03 (370 mg, 1.52 mmol) in POCl3 (4 mL, 43.1 mmol) was mixed with DIPEA (0.76 mL, 4.56 mmol), and the mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluent: 0% → 6% THF / DCM gradient at 50 mL / min) to obtain A03-04 (80 mg, 20.1% yield). LCMS: MS m / z (ESI) [M+H] + = 262.0.

[0231] A mixture of A03-04 (76.7 mg, 0.459 mmol) in THF (2 mL) was mixed with TEA (95.4 μL, 0.688 mmol), and the mixture was stirred at 60°C for 2 hours. The reaction product was concentrated to obtain the residue. The residue was tritulated in DCM (2 mL) at 25°C for 1 hour, filtered, and the solid was dried under vacuum to obtain A03-05 (70 mg, 77.8% yield). LCMS: MS m / z (ESI) [M+H] + = 393.3.

[0232] A mixture of A03-05 (60 mg, 0.153 mmol) in TFA (1 mL, 0.153 mmol) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the residue. The residue was diluted with THF (1 mL), adjusted to a pH above 7 with saturated NaHCO3, and then filtered. The solid was dried under vacuum to obtain A03-06 (30 mg, 81.0% yield). LCMS: MS m / z (ESI) [M+H] + = 243.0.

[0233] A mixture of A03-06 (30 mg, 0.124 mmol) in THF (0.5 mL) was mixed with LiOH·H2O (2.89 mL, 2.89 mmol), and the mixture was stirred at 50°C for 5 hours. The reaction mixture was adjusted to pH 4 with 1 M HCl and then filtered. The solid was dried under vacuum to obtain A03 (30 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 228.9.

[0234] Intermediate A04 [ka]

[0235] The title compound was prepared from methyl 2,5-difluoro-4-nitrobenzoate (A04-01) using a procedure similar to that described for the synthesis of A01. LCMS: MS m / z (ESI) [M+H] + = 261.1.

[0236] Intermediate A05 [ka]

[0237] To a solution of A05-01 (15.0 g, 59.0 mmol) in CH3CN (150 mL), K2CO3 (24.4 g, 177 mmol) and 2-methyl-1H-imidazole (5.80 g, 70.8 mmol) were added. The reaction mixture was stirred at 85°C for 2 hours. The reaction mixture was concentrated to remove CH3CN, diluted with H2O (500 mL), and extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain A05-02 (18.0 g, 96.5% yield). LCMS: MS m / z (ESI) [M+H] + = 315.9; 1 H NMR (400MHz, CDCl3) δ 8.18 (s, 1H), 7.74 (s, 1H), 7.05 (d, J = 1.2 Hz, 1H), 6.88 (d, J = 1.2 Hz, 1H), 2.23 (s, 3H).

[0238] To a solution of A05-02 (17.0 g, 53.7 mmol) in EtOH (180 mL) and H2O (90 mL), CaCl2 (6.00 g, 53.7 mmol) and Fe (9.0 g, 161 mmol) were added. The reaction mixture was stirred at 75°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated to remove EtOH. The resulting mixture was diluted with H2O (300 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product A05-03 (14.0 g, 90.9% yield). LCMS: MS m / z (ESI) [M+H] + = 285.8; 1H NMR (400MHz, DMSO-d6) δ 7.39 (s, 1H), 7.08 (s, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 5.42 (s, 2H), 2.11 (s, 3H).

[0239] To a solution of A05-03 (13.6 g, 47.4 mmol) in 1,2-dichlorobenzene (150 mL), CDI (16.9 g, 104 mmol) was added. The reaction mixture was stirred at 180 °C for 4 hours. The reaction mixture was cooled to 30 °C and filtered. The filter cake was washed with THF (100 mL x 2) and dried under vacuum to obtain A05-04 (14.4 g, 97.1% yield). LCMS: MS m / z (ESI) [M+H] + = 311.8; 1 H NMR (400MHz, DMSO-d6) δ 11.52 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 2.93 (s, 3H).

[0240] To a solution of A05-04 (12.4 g, 39.7 mmol) in CH3CN (200 mL), BOP (35.1 g, 79.3 mmol) and DBU (18.1 g, 119 mmol) were added, and the mixture was stirred at 25°C for 0.5 hours, after which (2,4-dimethoxyphenyl)methaneamine (9.90 g, 59.5 mmol) was added. The mixture was stirred at 50°C for 15.5 hours. The reaction mixture was concentrated to remove CH3CN, the residue was dissolved in DCM (300 mL), and filtered. The filtrate was washed with H2O (500 mL) and extracted with DCM (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (330 g silica flash column, 100 mL / min eluent of 0% to 60% THF / petroleum ether gradient) to obtain A05-05 (15.7 g, 85.7% yield). LCMS: MS m / z (ESI) [M+H] + = 460.7; 1H NMR (400MHz, CDCl3) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.43 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.49 (d, J = 2.0 Hz, 1H), 6.46 (dd, J = 8.4, 2.4 Hz, 1H), 5.56 (t, J = 5.2 Hz, 1H), 4.75 (d, J = 5.6 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H), 2.98 (s, 3H).

[0241] To a solution of A05-05 (2.00 g, 4.33 mmol) in MeOH (30 mL), Pd(dppf)Cl2 (317 mg, 0.433 mmol) and sodium methanelate (4.01 mL, 21.6 mmol) were added. The mixture was stirred at 80°C for 16 hours under CO (50 psi). The reaction solution was filtered. The filter cake was washed with SiO (10 mL x 2) and dried under vacuum to obtain A05-06 (1.80 g, 47.1% yield). LCMS: MS m / z (ESI) [M+H] + = 441.1.

[0242] A solution of A05-06 (1.50 g, 3.40 mmol) in TFA (20 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under vacuum to remove the TFA, and the mixture was tritulated with SiO (10 mL) at 25°C for 20 minutes. The mixture was filtered, and the solid was dried under vacuum to obtain A05-07 (1.30 g, 47.2% yield). LCMS: MS m / z (ESI) [M+H] + = 291.0.

[0243] A mixture of A05-07 (900 mg, 3.10 mmol) in THF (8 mL) and H2O (4 mL) was mixed with LiOH (780 mg, 18.6 mmol). The reaction was stirred at 80°C for 16 hours. The reaction was concentrated to remove THF. The resulting mixture was adjusted to pH 3-4 with 1 M HCl and then filtered. The filtration cake was washed with THF (10 mL x 2) and dried in vacuum to obtain A05 (600 mg, 70.0% yield). LCMS: MS m / z (ESI) [M+H] + = 276.8.

[0244] Intermediate A06 [ka]

[0245] To a solution of A06-01 (10.0 g, 44.5 mmol) in DCE (200 mL), m-CPBA (27.1 g, 134 mmol) was added. The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with DCM (100 mL), washed with water (50 mL), and then washed with saturated Na2SO3 aqueous solution (200 mL x 3). The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0% → 6% ethyl acetate in petroleum ether), the compound was dissolved in MTBE (50 mL), and stirred for 10 minutes. The mixture was then filtered, and the filtrate was concentrated under reduced pressure to obtain A06-02 (7.0 g, 61.8% yield). 1 H NMR (400MHz, CDCl3) δ 7.53 (t, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.0 Hz, 1H).

[0246] A06 was prepared from A06-02 using the same procedure as described for the synthesis of A05. LCMS: MS m / z (ESI) [M+H] + = 277.0.

[0247] Intermediate A07 [ka]

[0248] To a solution of 5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (4.50 g, 24.2 mmol) in dioxane (100 mL) and H2O (20 mL), A03-01 (9.40 g, 33.9 mmol), Xphos (2.30 g, 4.84 mmol), XPhos Pd G3 (2.00 g, 2.42 mmol), and K3PO4 (15.4 g, 72.6 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated. The residue was triturated with siRNA / H2O (100 ml / 50 ml) at 25°C for 2 hours, filtered, and the solid was dried under vacuum to obtain A07-01 (6.08 g, 71.6% yield). LCMS: MS m / z (ESI) [M+H] + = 257.3.

[0249] To a solution of A07-01 (6.00 g, 23.4 mmol) in THF (60 mL) and H2O (60 mL), LiOH (9.80 g, 234 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to obtain A07 (5.60 g, 97.4% yield). LCMS: MS m / z (ESI) [M+H] + = 243.0.

[0250] Intermediate A08 [ka]

[0251] To a solution of A08-01 (500 mg, 4.50 mmol) in DCM (5 mL), DIPEA (0.940 mL, 5.45 mmol) was added, and the reaction mixture was cooled to -78°C. Then, Tf2O (0.760 mL, 4.50 mmol) was added dropwise at -78°C, and the reaction mixture was stirred at the same temperature for 15 minutes. After completion, the reaction mixture was quenched with water (5 mL), extracted with DCM (10 mL x 2), the combined organic layer was washed with brine (10 mL), dried through sodium sulfate, filtered, and concentrated to obtain A08-02 (1.00 g, 91.4% yield). 1 H NMR (400 MHz, CDCl3) δ 4.94 - 4.80 (m, 4H).

[0252] To a solution of A08-02 (1.00 g, 2.22 mmol) and A03-01 (492 mg, 1.77 mmol) in dioxane (20 mL) and H2O (2 mL), K2CO3 (920 mg, 6.66 mmol) and Pd(PPh3)4 (256 mg, 0.222 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated, and the residue was diluted with siRNA (20 mL) and water (20 mL). The mixture was stirred at 25°C for 30 minutes, and then filtered. The solid was washed with siRNA (10 mL) and dried under vacuum to obtain A08-03 (128 mg, 23.6% yield). LCMS: MS m / z (ESI) [M+H] + = 245.3.

[0253] A mixture of A08-03 (128 mg, 0.524 mmol) in THF (1 mL) and H2O (1 mL) was mixed with lithium hydroxide (50.1 mg, 2.10 mmol). The mixture was stirred at 75°C for 3 hours. The reaction mixture was concentrated, and the residue was acidified to pH 6.0 with 1.5 M HCl. The mixture was filtered, the solid was washed with methanol (5 ml), and dried under vacuum to obtain A08 (83 mg, 68.8% yield). LCMS: MS m / z (ESI) [M+H] + = 231.3.

[0254] Intermediate A09 [ka]

[0255] The title compound was prepared from methyl 6-chloro-5-nitropicolinate (A09-01) using a procedure similar to that described for the synthesis of A01. LCMS: MS m / z (ESI) [M+1] + = 244.0.

[0256] Intermediate A10 [ka]

[0257] To a solution of 5-bromo-1H-pyrazole-4-carbonitrile (466 mg, 2.71 mmol) in dioxane (15 mL) and H2O (4 mL), A03-01 (500 mg, 1.80 mmol), XPhos Pd G3 (153 mg, 0.18 mmol), XPhos (86.0 mg, 0.18 mmol), and K3PO4 (1.15 g, 5.41 mmol) were added. The reaction mixture was stirred at 110°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated. The residue was triturated with siRNA / H2O (20 ml:10 ml) at 25°C for 2 hours and filtered. The solid was dried under vacuum to obtain A10-01 (130 mg, 29.7% yield). LCMS: MS m / z (ESI) [M+H] + = 243.1.

[0258] To a solution of A10-01 (110 mg, 0.45 mmol) in THF (8 mL), H2O (3 mL) and LiOH (191 mg, 4.54 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to obtain A10 (100 mg, 96.5% yield). LCMS: MS m / z (ESI) [M+H] + = 229.1.

[0259] Intermediate A11 [ka]

[0260] To a solution of A11-01 (20 g, 118 mmol) in DMF (200 mL), NBS (21.0 g, 118 mmol) was added. The mixture was stirred at 25°C for 3 hours. The reaction suspension was diluted with water (3 L) and extracted with siRNA (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether / siRNA = 100 / 0 → 95 / 5) to obtain A11-02a (17.0 g, 58.0% yield) and A11-02b (3.0 g, 10.2% yield).

[0261] A11-02a: LCMS: MS m / z (ESI) [M+H] + = 248.0; 1 H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 12.0 Hz, 1H), 4.59 (brs, 2H), 3.88 (s, 3H).

[0262] A11-02b: LCMS: MS m / z (ESI) [M+H] + = 247.9; 1 H NMR (400 MHz, CDCl3) δ 7.76 (t, J= 8.4 Hz, 1H), 6.56 (dd, J = 8.4, 1.2 Hz, 1H), 4.60 (brs, 2H), 3.91 (s, 3H).

[0263] A11 was prepared from A11-02b using the same procedure as described for the synthesis of A07. LCMS: MS m / z (ESI) [M+1] + = 260.1; 1H NMR (400 MHz, DMSO-d6) δ 9.82 (brs, 1H), 9.25 (brs, 1H), 8.70 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 4.48 - 4.37 (m, 3H).

[0264] Intermediate A12 [ka]

[0265] To a solution of A11-02a (6 g, 24.2 mmol) in dioxane (100 mL), (PinB)2 (9.2 g, 36.3 mmol), Pd(dppf)Cl2 (1.8 g, 2.42 mmol), and KOAc (5.9 g, 60.5 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under vacuum, washed with siRNA / H2O (80 ml / 20 ml) at 25 °C for 2 hours, and filtered. The solid was dried under vacuum to obtain A12-01 (4.80 g, 67.2% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.99 (d, J = 9.2 Hz, 1H), 6.47 (s, 2H), 6.38 (d, J = 14.4 Hz, 1H), 3.73 (s, 3H), 1.29 (s, 12H).

[0266] To a solution of 5-bromo-1-methylpyrazole-4-carbonitride (3.00 g, 16.1 mmol) in dioxane (100 mL) and H2O (20 mL), A12-01 (4.80 g, 16.1 mmol), Xphos (0.80 g, 1.61 mmol), XPhos Pd G3 (0.70 g, 0.134 mmol), and K3PO4 (8.60 g, 40.3 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours under an N2 atmosphere. After concentrating the reaction mixture under vacuum, it was triturated with siRNA / H2O (60 ml / 20 ml) at 25°C for 2 hours, filtered, and the solid was dried under vacuum to obtain A12-02 (3.50 g, 79.1% yield). LCMS: MS m / z (ESI) [M+H] + = 275.2; 1 H NMR (400MHz, DMSO-d6) δ 8.72 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 7.56 (s, 2H), 7.28 (d, J = 13.2 Hz, 1H), 4.39 (s, 3H), 3.89 (s, 3H).

[0267] A solution of A12-02 (3.5 g, 12.8 mmol) in THF (30 mL) and H2O (15 mL) was mixed with LiOH (5.40 g, 128 mmol). The reaction mixture was stirred at 80 °C for 12 hours. After cooling to room temperature, the reaction mixture was adjusted to pH=5 with 3 M HCl. The mixture was filtered, the solid was washed with THF (10 mL), and dried under vacuum to obtain A12 (2.7 g, 81.3% yield). LCMS: MS m / z (ESI) [M+H] + = 261.0.

[0268] Intermediate A13 [ka]

[0269] The title compound was prepared from 5-bromo-1-fluoro-3-methyl-2-nitrobenzene using a procedure similar to that described for the synthesis of A05. LCMS: MS m / z (ESI) [M+H]+ = 257.3.

[0270] Intermediate A14 [ka]

[0271] A solution of A14-01 (9.5 g, 69.8 mmol) and NBS (12.42 g, 69.8 mmol) in acetonitrile (100 ml) was stirred at 65°C for 4 hours under a nitrogen atmosphere. The reaction mixture was quenched at room temperature by adding saturated Na2S2O3 (50 mL) and NaHCO3 (50 mL). The mixture was extracted with HCl (100 mL x 3), and the combined organic layer was washed with brine (100 mL) and dried through anhydrous Na2SO4. After filtration, the filtrate was concentrated to obtain the residue, which was purified by flash silica gel chromatography using PE / HCl (13:1) to obtain A14-02 (5.46 g, 36.4% yield). LCMS: MS m / z (ESI) [M+H] + = 215.0; 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 6.4 Hz, 1H), 6.52 (d, J = 10.4 Hz, 1H), 4.84 (brs, 2H).

[0272] To a solution of A14-02 (2g, 9.30 mmol) in DMF (20 ml), 1H-pyrazole (0.76 g, 11.2 mmol) and K2CO3 (3.86 g, 27.9 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction solution was diluted with H2O (300 mL) and extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography with elution using PE / THF (8:1) to obtain A14-03 (2.02 g, 83% yield). LCMS: MS m / z (ESI) [M+H] + = 263.0; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.4 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.14 (s, 1H), 6.51 (s, 1H), 4.95 (brs, 2H).

[0273] To a solution of A14-03 (2.02 g, 7.68 mmol) and (PinB)2 (2.93 g, 11.5 mmol) in 1,4-dioxane (30 ml), PdCl2 (dppf) (562 mg, 0.768 mmol) and potassium acetate (1.51 g, 15.4 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the residue, which was purified by flash silica gel chromatography using PE / THF (6:1) to obtain compound A14-04 (1.98 g, 83% yield). LCMS: MS m / z (ESI) [M+H] + = 311.1; 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 2.4 Hz, 1H), 7.99 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 6.99 (s, 1H), 6.50 (t, J = 2.0 Hz, 1H), 5.45 (brs, 2H), 1.36 (s, 12H).

[0274] To a solution of A14-04 (1.98 g, 6.38 mmol), K2CO3 (1.765 g, 12.77 mmol), and A08-02 (6.21 g, 12.8 mmol) in 1,4-dioxane (30 ml) and water (6.00 ml), Pd(Ph3P)4 (0.738 g, 0.638 mmol) was added. The reaction mixture was stirred at 80°C for 12 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain the residue. The residue was dissolved in SiO2O = 1:1 (20 mL) and stirred for 1 hour. The mixture was then filtered, and the filtered cake was concentrated to obtain A14-05 (570 mg, 32.2% yield). LCMS: MS m / z (ESI) [M+H] + = 278.1; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.4 Hz, 1H), 8.27 (s, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H), 7.23 (brs, 2H), 6.62 (t, J = 2.0 Hz, 1H), 5.37 (t, J = 3.6 Hz, 2H), 5.02 (t, J = 3.2 Hz, 2H).

[0275] Sodium hydroxide (288 mg, 7.21 mmol) was added to a solution of A14-05 (200 mg, 0.721 mmol) in water (3 ml). The reaction mixture was stirred in a MW at 120°C for 2.5 hours. The mixture was adjusted to pH=6 with 1 M HCl. The mixture was then filtered, and the filtered cake was concentrated to obtain A14 (110 mg, 51.5% yield). LCMS: MS m / z (ESI) [M+H] + = 296.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 6.92 (brs, 2H), 6.50 - 6.44 (m, 1H), 5.39 (t, J = 3.2 Hz, 2H), 5.03 (t, J = 3.2 Hz, 2H).

[0276] Intermediate A15 [ka]

[0277] To a solution of A15-01 (5g, 30.3 mmol) in 25 ml of THF at 40°C, PinBH (6.55 ml, 45.4 mmol) was added over 10 minutes under N2 while maintaining an internal temperature of less than approximately 50°C. The mixture was stirred at 50°C for 1 hour and then cooled to 25°C. To the cooled solution, solutions of dtbbpy (812 mg, 3.03 mmol), bis(pinacorato)diborone (4.61 g, 18.16 mmol), and [Ir(COD)(OMe)2] (1.00 g, 1.51 mmol) in 25 ml of THF were added. The reaction mixture was heated at 65°C for 3 hours. The mixture was then cooled to 40°C and quenched by adding i-PrOH (5 ml). The mixture was used directly in the next step as a solution of A15-02 in THF. LCMS: MS m / z (ESI) [M+H] + = 292.1.

[0278] To a solution of A15-02 (8.00 g, 27.5 mmol) in THF (50 mL) and water (50 mL), 4-cyano-2,5-dihydrofuran-3-yl-4-methylbenzenesulfonate (7.00 g, 28.8 mmol), Pd(xanthophos)Cl2 (1.00 g, 1.37 mmol), and tripotassium phosphate (17.50 g, 82 mmol) were added. The mixture was stirred at 65°C for 16 hours under an N2 atmosphere. After cooling to 25°C, the mixture was diluted with MeCN (25 mL) and stirred for 2 hours. The mixture was filtered, the solid was washed with water (20 mL) and MeCN (10 mL), and dried under vacuum to obtain A15-03 (1.6 g, 22.6% yield). LCMS: MS m / z (ESI) [M+H] + = 258.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.41 (s, 1H), 6.83 (s, 2H), 5.34 (t, J = 3.2 Hz, 2H), 4.99 (t, J = 3.2 Hz, 2H), 3.83 (s, 3H), 2.60 (s, 3H).

[0279] To a solution of A15-03 (1.6 g, 6.19 mmol) in THF (8.00 ml) and water (8.00 ml), NaOH (1.6 g, 40.0 mmol) was added. The mixture was stirred at 80°C for 16 hours. The mixture was adjusted to pH=5 with HCl (1 M). The mixture was filtered through a Celite pad, and the residue was concentrated to obtain A15. LCMS: MS m / z (ESI) [M+H] + = 245.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.38 (s, 1H), 6.78 (s, 2H), 5.33 (s, 2H), 4.99 (s, 2H), 2.61 (s, 3H).

[0280] Intermediate A16 [ka]

[0281] The title compound was prepared from A16-01 using the same procedure as described for the synthesis of A15.

[0282] Intermediate A17 [ka]

[0283] To a solution of A17-01 (20.0 g, 108 mmol) in THF (200 mL), NBS (23.0 mg, 129 mmol) was added. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. The resulting mixture was quenched at 25°C by adding H2O (200 mL) and extracted with siRNA (200 mL x 3). The combined organic layers were sequentially washed with 10% sodium thiosulfate solution (200 mL) and saturated sodium chloride solution (200 mL), dried via MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 5% THF / petroleum ether gradient at 40 mL / min) to obtain A17-02 (10.0 g, 35.1% yield). LCMS: MS m / z (ESI) [M+H] + = 263.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.86 (s, 1H), 6.38 (s, 2H), 3.76 (s, 3H).

[0284] To a solution of A17-02 (10.0 g, 37.8 mmol) in dioxane (100 mL), (PinB)2 (28.8 g, 113 mmol), KOAc (11.1 g, 113 mmol), and Pd(dppf)Cl2 (401 mg, 3.78 mmol) were added. The mixture was stirred at 100 °C for 12 hours under an N2 atmosphere. The reaction mixture was quenched with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried through anhydrous Mg2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 5% EA / petroleum ether gradient at 40 mL / min) to obtain A17-03 (8.00 g, 67.9% yield). LCMS: MS m / z (ESI) [M+H] + = 312.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 6.74 (s, 1H), 6.36 (s, 2H), 3.75 (s, 3H), 1.30 (s, 12H).

[0285] To a solution of A17-03 (6.00 g, 19.3 mmol) in dioxane (60 mL) and H2O (20 mL), A08-02 (4.68 g, 19.3 mmol), K2CO3 (7.97 g, 57.8 mmol), and Pd(PPh3)4 (2.23 g, 1.93 mmol) were added, and the mixture was stirred at 80°C for 4 hours under an N2 atmosphere. The reaction mixture was diluted with SiO (60 mL) and H2O (60 mL) at 25°C, the mixture was filtered, and the filtered cake was concentrated under reduced pressure to obtain A17-04 (4.00 g, 74.5% yield). LCMS: MS m / z (ESI) [M+H] + = 279.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.60 (s, 1H), 7.08 (brs, 2H), 5.35 (t, J = 3.2 Hz, 2H), 5.00 (t, J = 3.2 Hz, 2H), 3.86 (s, 3H).

[0286] To a solution of A17-04 (4.00 g, 14.4 mmol) in THF (40 mL) and H2O (20 mL), LiOH·H2O (5.74 g, 144 mmol) was added. The reaction mixture was stirred at 85°C for 4 hours. The reaction mixture was filtered to remove the black solids. The filtrate was adjusted to pH=6 with 1 M HCl. The mixture was filtered, and the filtrate cake was concentrated under reduced pressure to obtain A17. LCMS: MS m / z (ESI) [M+H] + = 265.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.60 (s, 1H), 7.12 (brs, 2H), 5.36 (s, 2H), 5.01 (s, 2H).

[0287] Intermediate B01 [ka]

[0288] A mixture of B01-01 (900 mg, 4.49 mmol) and 4-fluorobenzene-1-carbonitrile (544 mg, 4.49 mmol) in DMSO (15 mL) was mixed with K2CO3 (1.86 g, 13.5 mmol), and the mixture was stirred at 100 °C for 12 hours under an N2 atmosphere. The reaction mixture was filtered, the filtrate was diluted with H2O (200 mL), and extracted with ELISA (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography to obtain B01-02 (1.00 g, 73.8%). 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 3.55 - 3.40 (m, 2H), 3.32 - 3.20 (m, 2H), 2.73 (s, 3H), 2.20 - 2.01 (m, 2H), 1.41 (s, 9H).

[0289] A mixture of B01-02 (400 mg, 1.33 mmol) in DCM (4 mL) was mixed with 4 M HCl / dioxane (4 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain B01 (310 mg, HCl salt). LCMS: MS m / z (ESI) [M+1] + = 202.1;

[0290] Intermediate B02 [ka]

[0291] The title compound was prepared from B02-01 using the same procedure as described for the synthesis of B01. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (br s, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.07 - 3.97 (m, 2H), 3.28 - 3.13 (m, 1H), 2.96 - 2.83 (m, 2H), 2.53 - 2.51 (m, 3H), 2.11 - 2.01 (m, 2H), 1.63 - 1.47 (m, 2H).

[0292] Intermediate B03 [ka]

[0293] The title compound was prepared from B03-01 using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+1] + = 202.2.

[0294] Intermediate B04 [ka]

[0295] The title compound was prepared from B04-01 using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+1] + = 216.0.

[0296] Intermediate B05 [ka]

[0297] The title compound was prepared from B05-01 using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 216.1.

[0298] Intermediate B06 [ka]

[0299] The title compound was prepared from B01-01 and 2-fluoropyridine using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 178.0; 1 H NMR: (400 MHz, DMSO-d6) δ 9.74 - 9.42 (m, 2H), 8.07 - 7.97 (m, 2H), 7.10 (d, J = 9.2 Hz, 1H), 7.00 - 6.86 (m, 1H), 4.05 - 3.92 (m, 2H), 3.90 - 3.78 (m, 2H), 3.70 - 3.58 (m, 1H), 2.60 (t, J = 5.2 Hz, 3H), 2.45 - 2.36 (m, 2H).

[0300] Intermediates B07a and B07b [ka]

[0301] To a solution of B07-01 (10.0 g, 64.0 mmol) in THF (100 mL), potassium bis(trimethylsilyl)azanide (96.0 mL, 96.0 mmol) was added at -78°C under an N2 atmosphere. The mixture was stirred at -78°C for 40 minutes, and then 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (34.3 g, 96.0 mmol) in THF (50 mL) was added. The mixture was warmed to 20°C and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with ELISA (150 mL x 3). The combined organic layers were washed with brine (100 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether, 0% → 6% siRNA) to obtain compound B07-02 (3.04 g, 16.5% yield). 1 H NMR: (400 MHz, CDCl3) δ 5.74 - 5.62 (m, 1H), 4.05 - 3.95 (m, 4H), 2.59 - 2.51 (m, 2H), 2.44 - 2.39 (m, 2H), 1.91 (t, J = 6.4 Hz, 2H).

[0302] To a solution of B07-02 (9.00 g, 31.2 mmol) in MeOH (90 mL), TEA (6.49 mL, 46.8 mmol) and Pd(dppf)Cl2 (2.30 g, 3.12 mmol) were added. The reaction mixture was stirred at 25°C for 18 hours under a CO atmosphere (50 psi). The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether with 0% → 2% THF) to obtain compound B07-03 (3.20 g, 48.5% yield). 1 H NMR: (400 MHz, CDCl3) δ 6.95 - 6.83 (m, 1H), 4.01 (s, 4H), 3.75 (s, 3H), 2.57 - 2.52 (m, 2H), 2.47 - 2.44 (m, 2H), 1.81 (t, J = 6.4 Hz, 2H).

[0303] To a solution of B07-03 (3.50 g, 17.7 mmol) in THF (50 mL), LiAlH4 (0.700 g, 17.7 mmol) was added at 0°C under an N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with H2O (0.7 mL), 15% NaOH (0.7 mL) was added, dried through Mg2SO4, filtered, and concentrated under reduced pressure to obtain crude product B07-04 (2.90 g, 96.5%). 1 ¹H NMR: (400 MHz, chloroform-d) δ = 5.65 - 5.57 (m, 1H), 4.04 (s, 2H), 3.99 (s, 4H), 2.34 - 2.23 (m, 4H), 1.80 (t, J = 6.5 Hz, 2H).

[0304] To a solution of B07-04 (1.50 g, 8.81 mmol) in THF (30 mL), 2-bromophenol (1.80 g, 10.6 mmol) and PPh3 (3.50 g, 13.2 mmol) were added, followed by the slow addition of DIAD (2.70 g, 13.2 mmol) at 0°C under an N2 atmosphere. The mixture was stirred at 25°C for 16 hours. The residue was quenched with H2O (50 mL) and extracted with SiO2 (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether with 0% → 10% SiO2) to obtain compound B07-05 (1.80 g, 62.8% yield). LCMS: MS m / z (ESI) [M+H] + = 324.8; 1 H NMR: (400 MHz, CDCl3) δ 7.55 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 - 7.25 (m, 1H), 6.91 (dd, J = 8.4, 1.2 Hz, 1H), 6.85 (td, J = 7.6, 1.2 Hz, 1H), 5.87 - 5.75 (m, 1H), 4.50 (s, 2H), 4.02 (s, 4H), 2.46 - 2.31 (m, 4H), 1.86 (t, J = 6.4 Hz, 2H).

[0305] To a solution of B07-05 (1.60 g, 4.92 mmol) in toluene (20 mL), tri-n-butyltin hydride (1.72 g, 5.91 mmol) and AIBN (100 mg, 0.492 mmol) were added, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was diluted with H2O (50 mL) and extracted with siRNA (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (0% → 40% siRNA in SiO2, petroleum ether) to obtain compound B07-06 (900 mg, 74.3% yield). 1 H NMR: (400 MHz, CDCl3) δ 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 7.16 (td, J = 7.6, 1.2 Hz, 1H), 6.90 (td, J = 7.6, 0.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H), 4.01 (s, 4H), 2.09 - 1.98 (m, 2H), 1.91 - 1.81 (m, 4H), 1.74 - 1.65 (m, 2H).

[0306] To a solution of B07-06 (800 mg, 3.25 mmol) in H2O (10 mL), AcOH (8 mL, 139 mmol) was added. The reaction mixture was stirred at 60°C for 5 hours. The reaction mixture was concentrated, the residue was diluted with NaHCO3 aqueous solution (20 mL), and extracted with RINKAN (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product B07-07 (600 mg, 91.3% yield). LCMS: MS m / z (ESI) [M+H] + = 203.0.

[0307] To a solution of B07-07 (270 mg, 1.34 mmol) in MeOH (5 mL), methanamine hydrochloride (451 mg, 6.67 mmol) was added at 25°C for 1 hour, followed by the addition of sodium cyanoboranoid (168 mg, 2.67 mmol). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM with 0% → 10% MeOH) to obtain a mixture of compounds B07a and B07b, which was used in the next step. LCMS: MS m / z (ESI) [M+H] + = 217.9.

[0308] Intermediates B08a and B08b [ka]

[0309] To a solution of B08-01 (2g, 10.7 mmol) in THF (20 mL), n-BuLi (2.5 M in hexane, 9.41 mL, 23.5 mmol) was slowly added at -78°C, and the mixture was stirred at -78°C for 30 minutes. Then, 1,4-dioxaspiro[4.5]decan-8-one (1.70 g, 10.7 mmol) in THF (5 mL) was slowly added at -78°C, and the reaction mixture was then warmed to 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (40 mL x 3), and the combined organic layers were washed with water (20 mL) and brine (20 mL). The mixture was dried through anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash silica gel chromatography (using a 0% to 18% THF / petroleum ether gradient eluent at 40 mL / min) to obtain B08-02 (1.82 g, 64.4% yield). LCMS: MS m / z (ESI) [M+Na] + = 287.2; 1H NMR (400 MHz, CD3OD) δ 7.48 - 7.41 (m, 2H), 7.26 - 7.19 (m, 2H), 4.92 (s, 2H), 3.97 (s, 4H), 2.23 - 2.06 (m, 4H), 1.98 - 1.91 (m, 2H), 1.70 - 1.60 (m, 2H).

[0310] Compound B08-02 (1.82 g, 6.89 mmol) was dissolved in TFA (23 mL), and the reaction mixture was stirred overnight at 30°C. The reaction mixture was cooled to -20°C, and THF (4.6 mL) was added. NaOH (25 wt% aqueous solution) was carefully added to adjust the pH to approximately 11. H₂O (4.6 mL) was added to induce precipitation. The solution was filtered and rinsed thoroughly with H₂O. The resulting solid was concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluent: 0% → 2% THF / petroleum ether gradient at 25 mL / min) to obtain B08-03 (0.91 g, 65.3% yield). 1 H NMR (400 MHz, CD3OD) δ 7.35 - 7.18 (m, 4H), 5.15 (s, 2H), 2.97 - 2.82 (m, 2H), 2.39 - 2.17 (m, 4H), 2.14 - 2.05 (m, 2H).

[0311] To a solution of B08-03 (280 mg, 1.38 mmol) in MeOH (6 mL), a solution of 30 wt% methylamine / MeOH (6 mL, 6.92 mmol) was added. The reaction mixture was stirred for 1 hour, and then NaBH3CN (174 mg, 2.77 mmol) was added. The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 4% MeOH / DCM gradient at 25 mL / min) to obtain a mixture of B08a and B08b, which was used in the next step. LCMS: MS m / z (ESI) [M+H] + = 218.0;

[0312] Intermediate B09 [ka]

[0313] To a solution of B09-01 (4.00 g, 30.3 mmol) in toluene (50 mL), potassium allyltrifluoroborate (9.00 g, 60.5 mmol) and TsOH (1.00 g, 6.05 mmol) were added. The reaction mixture was stirred at 40°C for 16 hours. The reaction solution was diluted with H2O (40 mL) and extracted with DCM (40 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B09-02 (5.20 g, 98.7% yield). 1 H NMR (400MHz, CDCl3) δ 7.35 - 7.17 (m, 4H), 6.08 - 5.96 (m, 1H), 5.31 - 5.19 (m, 2H), 3.13 (d, J = 16.4 Hz, 2H), 2.99 (d, J = 16.4 Hz, 2H), 2.56 (d, J = 7.2 Hz, 2H), 2.42 (s, 1H).

[0314] To a solution of B09-02 (3.00 g, 17.2 mmol) in DCM (20 mL), Br2 (2.80 g, 17.2 mmol) was added dropwise at -30°C for 20 minutes. The reaction mixture was stirred at 0°C for 20 minutes. The reaction solution was quenched with NaHSO3 (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B09-03 (5.30 g, 92.1% yield).

[0315] To a solution of B09-03 (5.00 g, 15.0 mmol) in MeOH (30 mL), K2CO3 (4.10 g, 29.9 mmol) was added. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered and concentrated under vacuum to obtain B09-04 (3.1 g, 81.8% yield). 1H NMR (400MHz, CD3OD) δ 7.22 - 7.07 (m, 4H), 4.68 - 4.59 (m, 1H), 4.24 (dd, J = 10.4, 5.2 Hz, 1H), 4.02 (dd, J = 10.4, 4.0 Hz, 1H), 3.26 (dd, J = 43.6, 16.0 Hz, 2H), 3.07 (dd, J = 28.4, 16.0 Hz, 2H), 2.73 (dd, J = 14.4, 7.2 Hz, 1H), 2.47 (dd, J = 14.4, 4.0 Hz, 1H).

[0316] To a solution of B09-04 (1.50 g, 5.93 mmol) in EtOH (5 mL), MeNH2 / THF (10 mL, 59.3 mmol) was added. The reaction mixture was stirred at 65°C for 12 hours. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography (SiO2, DCM / MeOH = 100 / 0 → 20 / 1) to obtain B09 (410 mg, 34.0% yield). 1 H NMR (400MHz, CDCl3-d) δ 7.24 - 7.08 (m, 4H), 4.03 (dd, J = 9.2, 6.4 Hz, 1H), 3.70 (dd, J = 9.2, 4.8 Hz, 1H), 3.49 - 3.39 (m, 1H), 3.23 (d, J = 16.4 Hz, 1H), 3.14 (d, J = 15.6 Hz, 1H), 3.11 (d, J = 16.4 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 2.44 (s, 3H), 2.32 (dd, J = 7.5, 12.8, 7.6 Hz, 1H), 1.87 (dd, J (= 12.8, 5.2 Hz, 1H).

[0317] Intermediate B10 [ka]

[0318] The title compound was prepared from B10-01 using the same procedure as described for the synthesis of B09. LCMS: MS m / z (ESI) [M+H] + = 156.1;

[0319] Intermediate B11 [ka]

[0320] The title compound was prepared from 4,4-difluorocyclohexane-1-one (B11-01) using a procedure similar to that described for the synthesis of B09. 1 H NMR: (400MHz, DMSO-d6) δ 4.00 - 3.76 (m, 3H), 2.53 (s, 3H), 2.25 - 2.16 (m, 1H), 2.09 - 1.66 (m, 8H), 1.60 - 1.48 (m, 1H).

[0321] Intermediate B12 [ka]

[0322] To a solution of B01-01 (200 mg, 0.999 mmol) in dioxane (4 mL), bromobenzene (0.13 mL, 1.199 mmol), BINAP (124 mg, 0.200 mmol), Pd2(dba)3 (91.5 mg, 0.100 mmol), and Cs2CO3 (651 mg, 2.00 mmol) were added. After degassing and purging with N2 three times, the reaction mixture was stirred at 100°C for 12 hours. The crude product was purified by column chromatography (SiO2, petroleum ether / siRNA = 100 / 0 → 10 / 1) to obtain compound B12-01 (193 mg, 0.698 mmol, 69.9%). LCMS: MS m / z (ESI) [M+H] + = 277.4.

[0323] Compound B12-01 (193 mg, 0.698 mmol) was dissolved in 4 M HCl / 1,4-dioxane (4.00 mL, 129 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain the desired product B12 (140 mg, 0.658 mmol, 94.25% yield, HCl salt). LCMS: MS m / z (ESI) [M+H] + = 177.0; 1 H NMR: (400 MHz, CDCl3) δ 10.32 (brs, 1H), 10.12 (brs, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.54 - 7.42 (m, 2H), 7.41 - 7.35 (m, 1H), 4.47 - 4.28 (m, 2H), 4.26 - 4.17 (m, 1H), 4.16 - 4.06 (m, 1H), 3.92 - 3.80 (m, 1H), 2.98 - 2.84 (m, 1H), 2.78 (s, 3H), 2.73 - 2.59 (m, 1H).

[0324] Intermediate B13 [ka]

[0325] To a solution of B01-01 (300 mg, 1.50 mmol) and 3-bromopyridine (355 mg, 2.25 mmol) in THF (6 mL), Cs2CO3 (1.46 g, 4.49 mmol) and RuPhos Pd G3 (125 mg, 0.15 mmol) were added. The resulting mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (50 mL), extracted with  (90 mL), and the organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, DCM / THF = 100 / 0 → 2 / 1) to obtain compound B13-01 (400 mg, 1.44 mmol, 96.3%). LCMS: MS m / z (ESI) [M+H] + = 278.1; 1H NMR (400MHz, DMSO-d6) δ 7.96 (d, J = 2.8 Hz, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.16 (dd, J = 8.4, 4.4 Hz, 1H), 6.93 (dd, J = 8.4, 1.6 Hz, 1H), 4.90 - 4.65 (m, 1H), 3.50 - 3.37 (m, 2H), 3.28 - 3.16 (m, 2H), 2.74 (s, 3H), 2.21 - 1.99 (m, 2H), 1.42 (s, 9H).

[0326] A solution of B13-01 (250 mg, 0.90 mmol) in 4 M HCl / dioxane (7 mL) was stirred at 30°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound B13 (160 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 178.1.

[0327] Intermediate B14 [ka]

[0328] The title compound was prepared from tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (B14-01) and 3-iodo-1-methyl-1H-pyrazole using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 179.1.

[0329] Intermediate B15 [ka]

[0330] The title compound was prepared from tert-butyl(1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (B15-01) and 3-iodo-1-methyl-1H-pyrazole using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 179.1.

[0331] Intermediate B16 [ka]

[0332] The title compound was prepared from tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (B16-01) and 3-iodo-1-methyl-1H-pyrazole using a procedure similar to that described for the synthesis of B13.

[0333] Intermediate B17 [ka]

[0334] The title compound was prepared from 3-iodo-1-methyl-1H-pyrazole using a procedure similar to that described for the synthesis of B13.

[0335] Intermediate B18 [ka]

[0336] To a solution of B01-01 (500 mg, 2.50 mmol) in i-PrOH (9 mL), 5-iodo-1-methylpyrazole (623 mg, 3.00 mmol), ethylene glycol (884 mg, 2.50 mmol), K3PO4 (2.12 g, 9.98 mmol), and CuI (95.1 mg, 0.499 mmol) were added. The mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with water (15 ml) and RINKAN (15 ml). The aqueous layer was extracted with RINKAN (20 mL x 3). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 0% → 3% tetrahydrofuran in petroleum ether) to obtain compound B18-01 (450 mg, 64.3% yield). LCMS: MS m / z (ESI) [M+H] + = 281.3.

[0337] To a solution of B18-01 (450 mg, 1.61 mmol) in dioxane (1 ml), HCl / dioxane (4 M, 2 mL, 8.00 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain compound B18 (260 mg, 90% yield).

[0338] Intermediate B19 [ka]

[0339] To a solution of B01-01 (616 mg, 3.08 mmol) in THF (25 mL), 2-bromo-1-methylimidazole (450 mg, 2.80 mmol), BrettPhosPdG3 (253 mg, 0.280 mmol), Brettphos (150 mg, 0.280 mmol), and t-BuONa (806 mg, 8.39 mmol) were added. The mixture was stirred at 50°C for 16 hours under N2 protection. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 40% THF / petroleum ether gradient at 100 mL / min) to obtain B19-01 (350 mg, 87.5% yield). LCMS: MS m / z (ESI) [M+H] + = 280.9.

[0340] A solution of B19-01 (400 mg, 1.427 mmol) in 4 M HCl / dioxane (5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B19 (281 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 181.2.

[0341] Intermediate B20 [ka]

[0342] The title compound was prepared from 1-fluoro-4-(trifluoromethyl)benzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 245.4;

[0343] Intermediate B21 [ka]

[0344] The title compound was prepared from 2,4-difluorobenzonitrile using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 219.9; 1 H NMR: (400 MHz, DMSO-d6) δ 9.26 (brs, 2H), 7.68 - 7.55 (m, 1H), 6.60 (dd, J = 13.2, 2.0 Hz, 1H), 6.50 (dd, J = 8.8, 2.0 Hz, 1H), 3.95 - 3.80 (m, 1H), 3.70 - 3.61 (m, 1H), 3.59 - 3.49 (m, 2H), 3.43 - 3.37 (m, 1H), 2.60 (s, 3H), 2.41 - 2.30 (m, 1H), 2.29 - 2.19 (m, 1H).

[0345] Intermediate B22 [ka]

[0346] The title compound was prepared from 4-fluoro-2-methylbenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 216.0; 1 H NMR: (400 MHz, DMSO-d6) δ 9.43 (brs, 2H), 7.49 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.48 (dd, J = 8.8, 2.4 Hz, 1H), 3.95 - 3.79 (m, 1H), 3.67 - 3.59 (m, 1H), 3.55 - 3.48 (m, 2H), 3.36 - 3.28 (m, 1H), 2.59 (t, J = 5.2 Hz, 3H), 2.38 (s, 3H), 2.36 - 2.29 (m, 1H), 2.29 - 2.18 (m, 1H).

[0347] Intermediate B23 [ka]

[0348] The title compound was prepared from 4-chloropyridine hydrochloride using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 178.0;

[0349] Intermediate B24 [ka]

[0350] The title compound was prepared from 1-fluoro-4-(methylsulfonyl)benzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 255.0;

[0351] Intermediate B25 [ka]

[0352] The title compound was prepared from 1-(cyclopropylsulfonyl)-4-fluorobenzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 281.1;

[0353] Intermediate B26 [ka]

[0354] The title compound was prepared from 2,4-difluoro-1-(methylsulfonyl)benzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 272.9;1 H NMR (400 MHz, DMSO-d6) δ 9.31 (brs, 2H), 7.58 (t, J = 8.4 Hz, 1H), 6.58 (dd, J = 14.4, 2.0 Hz, 1H), 6.52 (dd, J = 8.8, 2.0 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.70 - 3.62 (m, 1H), 3.56 (s, 3H), 3.55 - 3.48 (m, 1H), 3.43 - 3.34 (m, 2H), 3.17 (s, 3H), 2.42 - 2.31 (m, 1H), 2.30 - 2.18 (m, 1H).

[0355] Intermediate B27 [ka]

[0356] The title compound was prepared from 4-bromo-2-methyl-1-(methylsulfonyl)benzene using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+1] + = 268.9.

[0357] Intermediate B28 [ka]

[0358] The title compound was prepared from 1,2-difluoro-4-(methylsulfonyl)benzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 272.9;

[0359] Intermediate B29 [ka]

[0360] The title compound was prepared from 1-(cyclobutylsulfonyl)-4-fluorobenzene using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 295.3;

[0361] Intermediate B30 [ka]

[0362] To a solution of B30-01 (709 mg, 3.53 mmol) in isopropyl alcohol (5 mL), (1S,2S)-2-aminocyclohexane-1-ol (31.3 mg, 0.272 mmol), NaHMDS (5.16 mL, 5.16 mmol), and NiI2 (0.01 mL, 0.272 mmol) were added, and the mixture was degassed with N2 for 5 minutes. Then, 3-iodooxetane (500 mg, 2.72 mmol) was added, and the mixture was heated at 80°C for 30 minutes under microwave irradiation. After cooling to room temperature, the mixture was quenched with saturated NH4Cl solution (5 mL) and extracted with RINKAN (15 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, tetrahydrofuran / petroleum ether = 0 / 100 → 1 / 99) to obtain compound B30-02 (550 mg, 76.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 5.09 (dd, J = 8.4, 6.0 Hz, 2H), 4.73 (t, J = 6.4 Hz, 2H), 4.24 - 4.14 (m, 1H).

[0363] To a solution of B30-02 (388 mg, 1.82 mmol) in dioxane (3.5 mL), B01-01 (350 mg, 1.75 mmol), BINAP (218 mg, 0.349 mmol), Cs2CO3 (1.71 g, 5.24 mmol), and Pd2(dba)3 (160 mg, 0.175 mmol) were added. The mixture was stirred at 120 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with water (2 ml) and SiO2 (2 ml). The aqueous layer was extracted with SiO2 (10 mL x 3). The combined organic layers were washed with brine (5 ml), dried through anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, petroleum ether / tetrahydrofuran = 100 / 0 → 10 / 1) to obtain compound B30-03 (369 mg, 63.5% yield). LCMS: MS m / z (ESI) [M+H] + = 333.2.

[0364] To a solution of B30-03 (100 mg, 0.301 mmol) in DCM (1 ml), TFA (0.5 mL, 6.58 mmol) was added. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain B30. LCMS: MS m / z (ESI) [M+H] + = 232.8.

[0365] Intermediate B31 [ka]

[0366] The title compound was prepared from 1-bromo-4-cyclopropylbenzene using a procedure similar to that described for the synthesis of B12. LCMS: MS m / z (ESI) [M+H] + = 440.9; 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.82 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.75 - 4.50 (m, 1H), 3.65 - 3.38 (m, 3H), 3.23 - 3.10 (m, 1H), 3.08 (s, 3H), 3.05 (s, 3H), 2.39 - 2.24 (m, 2H), 1.85 - 1.72 (m, 1H), 0.89 - 0.77 (m, 2H), 0.58 - 0.45 (m, 2H).

[0367] Intermediate B32 [ka]

[0368] The title compound was prepared from 4-bromo-2-methylpyridine using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 192.3.

[0369] Intermediate B33 [ka]

[0370] The title compound was prepared from 3-bromo-5-methylpyridine using a procedure similar to that described for the synthesis of B13.

[0371] Intermediate B34 [ka]

[0372] To a solution of B01-01 (500 mg, 2.496 mmol) in CH3CN (14 mL), 4-chloro-1,2-diazine hydrochloride (377 mg, 2.50 mmol) and DIPEA (2.07 mL, 12.5 mmol) were added. The mixture was stirred at 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (column, eluent of 50% → 80% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain B34-01 (620 mg, 89.2% yield). LCMS: MS m / z (ESI) [M+H] + = 279.2.

[0373] A solution of B34-01 (500 mg, 1.796 mmol) in 4 M HCl / dioxane (5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound B34. LCMS: MS m / z (ESI) [M+H] + = 179.2.

[0374] Intermediate B35 [ka]

[0375] To a solution of B01-01 (500 mg, 2.50 mmol) in CH3CN (5 mL), 3,6-dichloro-1,2-diazine (372 mg, 2.50 mmol) and DIPEA (1.65 mL, 9.99 mmol) were added, and the mixture was stirred at 90°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using 30% → 50% THF / petroleum ether as the eluent) to obtain B35-01 (780 mg, 99.9% yield). LCMS: MS m / z (ESI) [M+H] + = 313.1.

[0376] To a solution of B35-01 (400 mg, 1.28 mmol) in methanol (10 mL), Pd / C (10%, 40.0 mg) was added under an N2 atmosphere. The suspension was degassed three times and purged with H2. The mixture was stirred at 20°C for 16 hours under H2 (15 Psi). The reaction product was filtered and concentrated under reduced pressure to obtain B35-02 (350 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 279.2.

[0377] A solution of B35-02 (300 mg, 1.078 mmol) in 4 M HCl / dioxane (4 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B35 (230 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 179.1.

[0378] Intermediate B36 [ka]

[0379] The title compound was prepared from 2-chloropyrimidine using a procedure similar to that described for the synthesis of B34. LCMS: MS m / z (ESI) [M+H] + = 179.2.

[0380] Intermediate B37 [ka]

[0381] To a solution of B37-01 (252 mg, 1.23 mmol) in DMSO (5 mL), 4-fluorobenzene-1-carbonitrile (149 mg, 1.23 mmol) and K2CO3 (512 mg, 3.70 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction solution was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 0% → 25% THF / petroleum ether gradient at 100 mL / min) to obtain B37-02 (140 mg, 37.1%). LCMS: MS m / z (ESI) [M+H] + = 306.2.

[0382] To a solution of B37-02 (117 mg, 0.383 mmol) in THF (3 mL), NaH (23.0 mg, 0.575 mmol, 60% purity) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours, and CH3I (0.07 mL, 1.15 mmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched by adding H2O (40 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound B37-03 (102 mg, 83.4% yield). LCMS: MS m / z (ESI) [M+H] + = 320.2.

[0383] A solution of B37-03 (70.0 mg, 0.219 mmol) in HCl / dioxane (4 mol / L, 4 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B37 (52.0 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 220.1

[0384] Intermediate B38 [ka]

[0385] The title compound was prepared from tert-butyl((3S,4R)-4-fluoropyrrolidine-3-yl)carbamate using a procedure similar to that described for the synthesis of B37.

[0386] Intermediate B39 [ka]

[0387] To a solution of B39-01 (3.9 g, 20.9 mmol) in DMSO (10 mL), 4-bromopyridine (2.41 mL, 25.1 mmol), BINAP (2.6 g, 4.19 mmol), Pd2(dba)3 (1.9 g, 2.09 mmol), and Cs2CO3 (13.6 g, 41.9 mmol) were added. The resulting mixture was stirred at 100 °C for 12 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (60 mL), extracted with SiO2 (60 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 10 / 1) to obtain B39-02 (4.85 g, 88.0% yield). LCMS: MS m / z (ESI) [M+1] + = 263.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 6.4 Hz, 1H), 6.42 (d, J = 6.4 Hz, 2H), 4.19 - 4.07 (m, 1H), 3.54 - 3.45 (m, 1H), 3.38 - 3.34 (m, 1H), 3.29 - 3.20 (m, 1H), 3.07 (dd, J = 10.4, 4.8 Hz, 1H), 2.23 - 2.03 (m, 1H), 1.95 - 1.80 (m, 1H), 1.39 (s, 9H).

[0388] To a solution of B39-02 (500 mg, 1.90 mmol) in DMF (8 mL), NaH (98.7 mg, 2.47 mmol) was added, and the mixture was stirred at 20°C for 10 minutes, after which iodoethane (0.18 mL, 2.28 mmol) was added. The resulting mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched with H2O (30 mL) and extracted with siRNA (90 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 10 / 1) to obtain B39-03 (260 mg, 47.0% yield). LCMS: MS m / z (ESI) [M+1] + = 291.9; 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.0 Hz, 2H), 6.47 (br d, J = 6.0 Hz, 2H), 4.74 - 4.37 (m, 1H), 3.46 - 3.42 (m, 2H), 3.30 - 3.20 (m, 1H), 3.19 - 3.11 (m, 3H), 2.18 - 2.07 (m, 2H), 1.41 (s, 9H), 1.06 (t, J = 7.2 Hz, 3H).

[0389] Compound B39-03 (260 mg, 0.892 mmol) was dissolved in HCl / dioxane (4.00 mol / L, 8.00 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and dried under vacuum to obtain B39 (161 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 192.3.

[0390] Intermediate B40 [ka]

[0391] The title compound was prepared from 1-iodo-3-(trifluoromethyl)benzene using a procedure similar to that described for the synthesis of B13.

[0392] Intermediate B41 [ka]

[0393] To a solution of B41-01 (1.00 g, 4.80 mmol) in dioxane (8 mL) and water (2 mL), 1,4-dibromobenzene (1.25 g, 5.29 mmol), K2CO3 (2.00 g, 14.4 mmol), and Pd(PPh3)4 (0.550 g, 0.480 mmol) were added. The mixture was stirred at 80°C for 3 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with water (5 mL) and HCl (5 mL). The aqueous layer was extracted with HCl (20 mL × 3). The combined organic layers were washed with brine (5 mL), dried through anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 0 / 100 → 36 / 64) to obtain B41-02 (1.0 g, 87.8% yield). LCMS: MS m / z (ESI) [M+H] + = 237.0.

[0394] To a solution of B41-02 (500 mg, 2.11 mmol) in THF (10 mL), B01-01 (465 mg, 2.32 mmol), t-BuONa (608 mg, 6.33 mmol), and RuPhos Pd G3 (177 mg, 0.211 mmol) were added. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (2 mL), extracted with siRNA (20 mL × 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 95 / 5) to obtain B41-03 (45 mg, 6.0% yield). LCMS: MS m / z (ESI) [M+H] + = 357.2.

[0395] To a solution of B41-03 (45 mg, 0.126 mmol) in dioxane (1 ml), HCl / dioxane (4 M, 0.5 mL, 2.00 mmol) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain B41 (35 mg, 94.7% yield).

[0396] Intermediate B42 [ka]

[0397] The title compound was prepared from 3-bromo-2-methylbenzonitrile using a procedure similar to that described for the synthesis of B12. LCMS: MS m / z (ESI) [M+H] + = 216.1.

[0398] Intermediate B43 [ka]

[0399] To a solution of B43-01 (5.00 g, 42.3 mmol) in dioxane (50 mL), a solution of NBS (7.50 g, 42.3 mmol) in dioxane (50 mL) was slowly added over 30 minutes at room temperature. The mixture was stirred for a further 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using 0% → 22% ethyl acetate / petroleum ether as the eluent) to obtain B43-02 (2.54 g, 30.5% yield). LCMS: MS m / z (ESI) [M+Na] + = 196.7; 1 H NMR (400 MHz, DMSO-d6) δ 7.23 (dd, J = 8.4, 7.6 Hz, 1H), 7.08 - 7.04 (m, 1H), 7.04 - 7.01 (m, 1H), 5.87 (s, 2H).

[0400] A mixture of B43-02 (4.00 g, 20.3 mmol) and cyclopropylboranediol (3.50 g, 40.6 mmol) in toluene (40 mL) and H2O (20 mL) was mixed with K3PO4 (12.9 g, 60.9 mmol) and cataCXium A Pd G3 (73.9 mg, 0.101 mmol). The mixture was then stirred at 90°C for 16 hours under an N2 atmosphere. The reaction mixture was extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (5 mL x 2), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using 0% → 10% EA / petroleum ether as the eluent) to obtain B43-03 (3.12 g, 97.1%). LCMS: MS m / z (ESI) [M+H] + = 158.8; 1 H NMR (400 MHz, CDCl3) δ 7.13 - 7.06 (m, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 4.23 (brs, 2H), 1.81 - 1.66 (m, 1H), 1.21 - 1.08 (m, 2H), 0.85 - 0.74 (m, 2H).

[0401] A mixture of B43-03 (3.12 g, 19.7 mmol) in 2 M H2SO4 (48 mL) was heated to dissolve the solids, and then cooled in an ice bath. A solution of sodium nitrite (1.40 g, 20.7 mmol) in H2O (10 mL) was slowly added to the mixture, and the mixture was stirred in an ice bath for 30 minutes. Subsequently, a solution of NaI (3.50 g, 23.7 mmol) in H2O (10 mL) was slowly added at 0°C for 30 minutes, and the mixture was stirred at 20°C for 30 minutes. The reaction mixture was diluted with H2O (60 mL) and extracted with siRNA (60 mL x 3). The combined organic layer was washed with brine (10 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using 0% → 2% EA / petroleum ether as the eluent) to obtain B43-04 (3.00 g, 56.5%). 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J = 8.0, 1.2 Hz, 1H), 7.62 (dd, J = 7.6, 1.2 Hz, 1H), 7.01 (dd, J = 8.0, 7.6 Hz, 1H), 2.01 - 1.89 (m, 1H), 1.37 - 1.26 (m, 2H), 0.94 - 0.84 (m, 2H).

[0402] To a solution of B43-04 (1.00 g, 3.72 mmol) and B01-01 (0.700 g, 3.72 mmol) in dioxane (5 mL), Pd2(dba)3 (0.300 g, 0.372 mmol), BINAP (0.500 g, 0.743 mmol), and Cs2CO3 (3.60 g, 11.2 mmol) were added. The mixture was stirred at 120 °C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using 0% → 10% EA / petroleum ether as the eluent) to obtain B43-05 (1.2 g, 92.3% yield). LCMS: MS m / z (ESI) [M+H] + = 342.2.

[0403] Compound B43-05 (1.20 g, 3.51 mmol) was dissolved in HCl / dioxane (4 M, 12 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B43 (1.00 g, crude product). LCMS: MS m / z (ESI) [M+H] + = 242.2.

[0404] Intermediate B44 [ka]

[0405] To a solution of B44-01 (7.90 g, 60.3 mmol) in toluene (100 mL), potassium allyltrifluoroborate (17.8 g, 121 mmol) and 4-methylbenzenesulfonic acid (2.10 g, 12.1 mmol) were added, and the reaction mixture was stirred at 20°C for 16 hours. The reaction solution was diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product B44-02 (7.50 g, 71.9% yield). 1 H NMR (400MHz, CDCl3) δ 7.63 (d, J = 7.2 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 5.86 - 5.68 (m, 1H), 5.24 - 5.11 (m, 2H), 4.86 - 4.77 (m, 1H), 2.60 - 2.38 (m, 2H), 2.23 (brs, 1H).

[0406] To a solution of B44-02 (3.00 g, 17.3 mmol) in acetone (15 mL) and water (4.5 mL), potassium osmium(VI) dihydrate (0.60 g, 1.73 mmol) and NMO (2.20 g, 19.1 mmol) were added. The mixture was stirred at 20°C for 16 hours. The mixture was quenched with saturated aqueous Na2S2O3 (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using 40% → 50% THF / petroleum ether as the eluent) to obtain B44-03 (0.90 g, 26.9% yield). 1 H NMR (400MHz, DMSO-d6) δ 7.85 - 7.74 (m, 2H), 7.60 - 7.42 (m, 2H), 5.50 - 5.35 (m, 1H), 4.90 - 4.74 (m, 1H), 4.67 - 4.43 (m, 2H), 3.34 - 3.17 (m, 3H), 1.76 - 1.56 (m, 2H).

[0407] To a solution of B44-03 (900 mg, 4.66 mmol) in DCM (54 mL), 4-methylbenzenesulfonyl chloride (977 mg, 5.12 mmol), TEA (0.71 mL, 5.12 mmol), and di-n-butyltin oxide (116 mg, 0.466 mmol) were added. The mixture was stirred at 45°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using a 30% → 40% THF / petroleum ether eluent) to obtain B44-04 (850 mg, 96.4% yield).

[0408] To a solution of B44-04 (1.00 g, 5.285 mmol) in DCM (10 mL), TEA (2.20 mL, 15.9 mmol) and methanesulfonic anhydride (1.47 g, 8.457 mmol) were added. The mixture was stirred at 20°C for 2 hours. The mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B44-05 (1.00 g, 70.8% yield).

[0409] A mixture of B44-05 (1.00 g, 3.741 mmol) was dissolved in methylamine / ethanol solution (10.55 g, 30% purity), and the mixture was stirred at 60°C for 16 hours. The resulting mixture was concentrated. The residue was purified by flash silica gel chromatography (10% → 30% methanol / DCM eluent at 40 mL / min), followed by preparative HPLC (basic conditions, column: C18-1 150 × 30 mm × 5 μm, mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN], B%: 14% → 54%, 9 min) to obtain B44 (56.0 mg, 7.4% yield). LCMS: MS m / z (ESI) [M+H] + = 203.1.

[0410] Intermediate B45 [ka]

[0411] To a solution of B45-01 (2.00 mg, 8.80 mmol) in MeOH (40 mL), NaBH4 (1.00 g, 26.4 mmol) was slowly added at 25°C under an N2 atmosphere. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with H2O (40 mL) and concentrated under reduced pressure to remove the MeOH. The resulting solution was extracted with ELISA (30 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B45-02 (2.00 mg, 99.1% yield). LCMS: MS m / z (ESI) [M+Ht-Bu] + = 174.0; 1 H NMR (400MHz, DMSO-d6) δ 4.90 (d, J = 3.2 Hz, 1H), 4.33 - 4.25 (m, 1H), 3.97 - 3.82 (m, 3H), 3.82 - 3.72 (m, 2H), 3.60 (dd, J = 9.2, 1.6 Hz, 1H), 2.13 - 2.02 (m, 2H), 1.37 (s, 9H).

[0412] A solution of B45-02 (2.00 g, 8.72 mmol) in 5% TFA / HFIP (2 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude product B45-03 (2.10 g, crude).

[0413] To a solution of B45-03 (1.00 g, 7.74 mmol) in DMSO (30 mL), iodobenzene (2.37 g, 11.6 mmol), CuI (295 mg, 1.55 mmol), L-proline (356 mg, 3.10 mmol), and Cs2CO3 (6.30 g, 19.4 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with siRNA (150 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (20 g silica flash column, eluent of ethyl acetate / petroleum ether gradient from 0% to 68% at 30 mL / min) to obtain B45-04 (400 mg, 25.2% yield). LCMS: MS m / z (ESI) [M+H] + = 206.2; 1 H NMR (400MHz, DMSO-d6) δ 7.21 - 7.02 (m, 2H), 6.68 (t, J = 7.2 Hz, 1H), 6.43 (d, J = 7.6, 2H), 4.96 (d, J = 2.8 Hz, 1H), 4.34 (brs, 1H), 3.97 - 3.86 (m, 2H), 3.83 (dd, J = 9.2, 4.4 Hz, 1H), 3.77 (d, J = 8.0 Hz, 1H), 3.71 (d, J = 8.0 Hz, 1H), 3.65 (dd, J = 9.2, 2.0 Hz, 1H), 2.17 (d, J = 3.6 Hz, 2H).

[0414] To a solution of B45-04 (350 mg, 1.70 mmol) in DCM (7 mL), TEA (0.47 mL, 3.41 mmol) was added, followed by the dropwise addition of methanesulfonic anhydride (475 mg, 2.73 mmol) in DCM (3 mL). The resulting mixture was stirred at 0°C for 1 hour. The reaction product was diluted with H2O (10 mL), concentrated under reduced pressure to remove DCM, and extracted with RINKAN (8 mL × 3). The combined organic layers were washed with brine (15 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product B45-05 (460 mg, 95.2% yield). LCMS: MS m / z (ESI) [M+H] + = 284.3; 1 H NMR (400MHz, CDCl3) δ 7.29 - 7.17 (m, 2H), 6.82 (t, J=7.6 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 5.41 - 5.32 (m, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 4.12 (m, 1H), 4.09 - 4.04 (m, 1H), 4.04 - 3.98 (m, 2H), 3.96 (d, J = 8.0 Hz, 1H), 3.10 (s, 3H), 2.76 (d, J = 14.4 Hz, 1H), 2.46 (dd, J = 14.4, 5.6 Hz, 1H).

[0415] To a solution of B45-05 (500 mg, 1.76 mmol) in EtOH (9 mL), CH3NH2 (30% in EtOH) (549 mg, 17.6 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (silica flash column, eluent of 0% to 6% MeOH(NH3) / DCM gradient at 30 mL / min) to obtain B45 (300 mg, 77.9% yield). LCMS: MS m / z (ESI) [M+H] + = 219.3; 1H NMR (400MHz, CDCl3) δ 7.25 - 7.18 (m, 2H), 6.77 (t, J = 7.2 Hz, 1H), 6.48 (d, J = 7.6 Hz, 2H), 4.10 - 3.95 (m, 4H), 3.94 - 3.83 (m, 2H), 3.64 - 3.53 (m, 1H), 2.56 (s, 3H), 2.55 - 2.47 (m, 1H), 2.42 - 2.31 (m, 1H).

[0416] Intermediate B46 [ka]

[0417] To a mixture of B46-01 (3.00 g, 24.3 mmol) in DMSO (60 mL), 4-fluorobenzene-1-carbonitrile (5.90 g, 48.5 mmol) and potassium carbonate (11.7 g, 85.0 mmol) were added. The resulting mixture was stirred at 100°C for 2.5 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL), extracted with HCl (100 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / HCl = 100 / 0 → 4 / 1) to obtain B46-02 (985 mg, 21.6% yield). LCMS: MS m / z (ESI) [M+H] + = 188.8; 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 5.03 (d, J = 3.6 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.48 - 3.35 (m, 3H), 3.14 (d, J = 10.8 Hz, 1H), 2.11 - 1.98 (m, 1H), 1.96 - 1.84 (m, 1H).

[0418] To a solution of B46-02 (780 mg, 4.15 mmol) in DCM (20 mL), TEA (1.15 mL, 8.29 mmol) and methanesulfonic anhydride (1.16 g, 6.63 mmol) were added. The resulting mixture was stirred at 0°C for 1 hour under an N2 atmosphere. The reaction mixture was filtered and dried under vacuum to obtain B46-03 (1.00 g, 90.6% yield). LCMS: MS m / z (ESI) [M+H] + = 266.9.

[0419] To a solution of B46-03 (350 mg, 0.413 mmol) in THF (7 mL), cyclopropanamine (800 mg, 14.0 mmol) and K2CO3 (545 g, 3.94 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL), extracted with RINKAN (50 ml x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA = 100 / 0 → 10 / 1) to obtain B46 (96 mg, 32.1% yield). LCMS: MS m / z (ESI) [M+H] + = 227.9; 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 3.51 - 3.41 (m, 2H), 3.41 - 3.35 (m, 1H), 3.31 - 3.23 (m, 1H), 3.15 - 3.05 (m, 1H), 2.49 - 2.36 (m, 1H), 2.17 - 2.03 (m, 2H), 1.95 - 1.82 (m, 1H), 0.46 - 0.34 (m, 2H), 0.28 - 0.13 (m, 2H).

[0420] Intermediate B47 [ka]

[0421] To a solution of B39-01 (1.7 g, 9.13 mmol) in DMSO (35 mL), 4-fluorobenzene-1-carbonitrile (2.2 g, 18.3 mmol) and potassium carbonate (4.40 g, 31.9 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H₂O (40 mL), extracted with SiO₂ (50 mL x 3), and the organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (PE / EA eluent at 80 mL / min, 27% → 35%) to obtain B47-01 (1.91 g, 72.9% yield). LCMS: MS m / z (ESI) [M+H] + = 287.9; 1 H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 6.4 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 4.20 - 4.09 (m, 1H), 3.56 - 3.47 (m, 1H), 3.46 - 3.38 (m, 1H), 3.34 - 3.24 (m, 1H), 2.21 - 2.09 (m, 1H), 1.95 - 1.84 (m, 1H), 1.39 (s, 9H).

[0422] To a solution of B47-01 (500 mg, 1.74 mmol) in DMF (10 mL), NaH (90.5 mg, 2.26 mmol) was slowly added at 0°C. The mixture was stirred at °C for 10 minutes, and then (bromomethyl)cyclopropane (0.33 mL, 3.48 mmol) was added. The resulting mixture was stirred at room temperature under an N2 atmosphere for 12 hours. The reaction mixture was quenched with H2O (100 mL), extracted with RINKAN (100 mL x 3), the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / EA=5 / 1) to obtain B47-02 (415 mg, 69.9% yield). LCMS: MS m / z (ESI) [M+H] + = 341.9.

[0423] Compound B47-02 (415 mg, 1.22 mmol) was dissolved in HCl / dioxane (4 mol / L, 8 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain B47 (285 mg, crude). LCMS: MS m / z (ESI) [M+1] + = 241.9.

[0424] Intermediate B48 [ka]

[0425] To a solution of B48-01 (152 mg, 0.684 mmol) in THF (20 mL), 4-iodobenzene-1-carbonitrile (157 mg, 0.684 mmol), Cs2CO3 (669 mg, 2.05 mmol), and RuPhos Pd G3 (55.2 mg, 0.066 mmol) were added. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 20% → 40% THF / petroleum ether gradient at 100 mL / min) to obtain B48-02 (201 mg, 90.8% yield). LCMS: MS m / z (ESI) [Mt-Bu+H] + = 268.1.

[0426] To a solution of B48-02 (200 mg, 0.619 mmol) in THF (4 mL), NaH (37.1 mg, 0.928 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. CH3I (0.12 mL, 1.86 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B48-03 (200 mg, 95.8% yield). LCMS: MS m / z (ESI) [Mt-Bu+H] + = 282.1.

[0427] A solution of B48-03 (200 mg, 0.593 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B48 (150 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 238.2.

[0428] Intermediate B49 [ka]

[0429] A solution of B49-01 (580 mg, 2.90 mmol) and 4-iodobenzene-1-carbonitride (553 mg, 2.41 mmol) in dioxane (6 mL) is prepared by adding CuI (46.0 mg, 0.241 mmol), K3PO4 (1.03 g, 4.83 mmol), and N 1 ,N 1 ,N 2 ,N 2 -Tetramethylethane-1,2-diamine (21.3 mg, 0.241 mmol) was added. The mixture was stirred at 100°C for 18 hours under an N2 atmosphere. The mixture was diluted with water (25 mL) and extracted with siRNA (25 mL x 3). The combined organic layer was washed with brine (10 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether / siRNA = 10 / 1 → 3 / 1) to obtain B49-02 (720 mg, 99.0% yield). LCMS: MS m / z (ESI) [M+H] + = 302.1; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 7.2 Hz, 2H), 4.85 (brs, 1H), 4.51 - 4.36 (m, 1H), 4.21 - 4.15 (m, 1H), 3.77 (dd, J = 10.0, 3.2 Hz, 1H), 3.02 (dd, J = 17.6, 8.0 Hz, 1H), 2.55 (dd, J = 17.6, 4.8 Hz, 1H), 1.46 (s, 9H).

[0430] To a solution of B49-02 (300 mg, 0.996 mmol) in DMF (3 mL), NaH (51.8 mg, 1.29 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 10 minutes, after which CH3I (184 mg, 1.29 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was quenched with NH4Cl (20 mL) and extracted with  (20 mL x 3). The combined organic layer was washed with brine (15 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether /  = 10 / 1 → 3 / 1) to obtain B49-03 (230 mg, 73.2% yield). LCMS: MS m / z (ESI) [M+H] + = 316.1.

[0431] A solution of B49-03 (230 mg, 0.729 mmol) in 4 M HCl / dioxane (4 mL) was stirred at 25°C for 18 hours. The solution was concentrated to obtain B49 (120 mg, 76.4% yield). LCMS: MS m / z (ESI) [M+H] + = 216.1.

[0432] Intermediate B50 [ka]

[0433] The title compound was prepared from 4-fluoro-3-methylbenzonitrile using a procedure similar to that described for the synthesis of B01. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (br s, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 4.07 - 3.97 (m, 2H), 3.28 - 3.13 (m, 1H), 2.96 - 2.83 (m, 2H), 2.53 - 2.51 (m, 3H), 2.11 - 2.01 (m, 2H), 1.63 - 1.47 (m, 2H).

[0434] Intermediate B51 [ka]

[0435] To a solution of B01-01 (500 mg, 2.50 mmol) in DMF (10 mL), 3-bromo-4-fluorobenzene-1-carbonitrile (749 mg, 3.74 mmol) and K2CO3 (1.04 g, 7.49 mmol) were added. The mixture was stirred at 100°C for 2.5 hours. The reaction mixture was diluted with water (20 mL) and extracted with siRNA (15 mL x 3). The organic phase was separated, washed with brine (10 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 7% EA / petroleum ether gradient at 25 mL / min) to obtain B51-01 (1.00 g, 98.0% yield). LCMS: MS m / z (ESI) [Mt-Bu+H] + = 324.2.

[0436] To a solution of B51-01 (100 mg, 0.263 mmol) and cyclopropylboranediol (45.2 mg, 0.526 mmol) in toluene (6 mL), H2O (3 mL), K3PO4 (168 mg, 0.789 mmol), and cataCXium A Pd G3 (19.2 mg, 26.0 μmol) were added. The mixture was stirred at 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 6% siRNA / petroleum ether gradient at 18 mL / min) to obtain B51-02 (90 mg, 90.2% yield). LCMS: MS m / z (ESI) [M+H] + = 342.2

[0437] Compound B51-02 (90.0 mg, 0.264 mmol) was dissolved in HCl / dioxane (4 M, 5 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain crude product B51 (80 mg, 98.4% yield). LCMS: MS m / z (ESI) [M+H] + = 242.2.

[0438] Intermediate B52 [ka]

[0439] The title compound was prepared from 3,4-difluorobenzonitrile using the same procedure as described for the synthesis of B01. LCMS: MS m / z (ESI) [M+1] + = 219.9;

[0440] Intermediate B53 [ka]

[0441] The title compound was prepared from iodobenzene using a procedure similar to that described for the synthesis of B12. LCMS: MS m / z (ESI) [M+H]+ = 176.9.

[0442] Intermediate B54 [ka]

[0443] To a solution of B51-01 (600 mg, 1.58 mmol) in H2O (2 mL) and dioxane (10 mL), Pd(dppf)Cl2 (115 mg, 0.158 mmol), Cs2CO3 (1.03 g, 3.16 mmol), and 4,4,5,5-tetramethyl-2-(propa-1-en-2-yl)-1,3,2-dioxaborolane (398 mg, 2.37 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL), extracted with siRNA (20 mL x 3), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / siRNA = 8 / 1) to obtain B54-01 (258 mg, 47.9% yield). LCMS: MS m / z (ESI) [M+H] + = 341.9.

[0444] To a solution of B54-01 (50 mg, 0.146 mmol) in  (1 mL), 10% Pd / C (5 mg, 0.0470 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours under an H2 atmosphere (15 psi). The mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain B54-02 (35.0 mg, 69.6% yield). LCMS: MS m / z (ESI) [M+H] + = 344.0; 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 1.6 Hz, 1H), 7.48 (dd, J = 8.4, 1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 4.75 - 4.60 (m, 1H), 3.33 - 3.20 (m, 4H), 3.02 - 2.91 (m, 1H), 2.79 (s, 3H), 2.17 - 2.05 (m, 2H), 1.41 (s, 9H), 1.15 (d, J = 5.6 Hz, 6H).

[0445] A solution of B54-02 (35.0 mg, 0.102 mmol) dissolved in HCl / dioxane (4 M, 2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain B54 (23 mg, 92.7% yield). LCMS: MS m / z (ESI) [M+H] + = 243.9.

[0446] Intermediate B55 [ka]

[0447] To a solution of B51-01 (400 mg, 1.05 mmol) in TEA (10 mL), Pd(PPh3)2Cl2 (81.8 mg, 0.105 mmol), CuI (20.0 mg, 0.105 mmol), and ethinyl[tri(propa-2-yl)]silane (192 mg, 1.052 mmol) were added, and the mixture was stirred at 80°C for 16 hours under N2 protection. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 20% → 40% THF / petroleum ether gradient at 50 mL / min) to obtain B55-01 (400 mg, 78.9% yield). LCMS: MS m / z (ESI) [M+H] + = 482.3;

[0448] A mixture of B55-01 (370 mg, 0.768 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B55 (320 mg, 99.7% yield). LCMS: MS m / z (ESI) [M+H] + = 382.3.

[0449] Intermediate B56 [ka]

[0450] To a solution of 4-fluoro-3-formylbenzonitrile (500 mg, 3.35 mmol) in DMSO (10 mL), B01-01 (672 mg, 3.35 mmol) and K2CO3 (1.39 g, 10.1 mmol) were added. The mixture was stirred at 100°C for 16 hours. The reaction solution was diluted with H2O (50 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 40% → 50% THF / petroleum ether gradient at 100 mL / min) to obtain B56-01 (1.06 g, 96.0% yield). LCMS: MS m / z (ESI) [M+H] + = 330.2.

[0451] To a solution of B56-01 (500 mg, 1.52 mmol) in DCM (10 mL), DAST (2.45 mg, 15.2 mmol) was slowly added, and the resulting mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched by adding H2O (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (100 mL / min with 30% THF / petroleum ether eluent) to obtain B56-02 (521 mg, 97.6% yield). LCMS: MS m / z (ESI) [M+H] += 352.2.

[0452] A mixture of B56-02 (750 mg, 2.13 mmol) in HCl / dioxane (4 M, 18 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B56 (500 mg, 81.4% yield). LCMS: MS m / z (ESI) [M+H] + = 252.1.

[0453] Intermediate B57 [ka]

[0454] To a solution of B49-02 (200 mg, 0.664 mmol) in DMF (4 mL), NaH (159 mg, 3.98 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 30 minutes, after which MeI (565 mg, 3.98 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was quenched with NH4Cl (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica column chromatography (petroleum ether / RINKAN = 100 / 0 → 1 / 1) to obtain B57-01 (200 mg, 87.7% yield). LCMS: MS m / z (ESI) [M+1] + = 344.2; 1 H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 8.8 Hz, 2H), 7.69 (d, J= 8.8 Hz, 2H), 4.91 - 4.38 (m, 1H), 4.29 - 4.08 (m, 1H), 3.82 - 3.61 (m, 1H), 2.86 - 2.52 (m, 3H), 1.48 (s, 9H), 1.31 (s, 3H), 1.18 (s, 3H).

[0455] A solution of B57-01 (200 mg, 0.634 mmol) in HCl / dioxane (3 mL) was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to obtain B57 (92.0 mg, 64.9%). LCMS: MS m / z (ESI) [M+H] + = 244.1.

[0456] Intermediate B58 [ka]

[0457] To a solution of B58-01 (210 mg, 1.04 mmol) in DCM (4 mL), TEA (0.29 mL, 2.08 mmol) was added, followed by the addition of benzyl chloromethanoate (0.19 mL, 1.35 mmol) at 0°C. The reaction solution was warmed to 25°C and stirred for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (12 g silica flash column, 30 mL / min eluent of 0% → 37% THF / petroleum ether gradient) to obtain B58-02 (340 mg, 97.4% yield). LCMS: MS m / z (ESI) [M+H-Boc] + = 237.1; 1 H NMR (400MHz, CDCl3) δ 7.44 - 7.28 (m, 5H), 5.19 - 5.07 (m, 2H), 5.07 - 4.96 (m, 1H), 4.39 - 4.27 (m, 1H), 4.25 - 4.09 (m, 1H), 3.92 - 3.78 (m, 1H), 3.66 - 3.48 (m, 2H), 3.31 - 3.11 (m, 1H), 1.46 (s, 9H).

[0458] To a solution of B58-02 (310 mg, 0.922 mmol) and CH3I (392 mg, 2.76 mmol) in DMF (6 mL), NaH (147 mg, 3.69 mmol) was added. The reaction solution was stirred at 25°C for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with siRNA (15 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (12 g silica flash column, 0% → 20% THF / petroleum ether gradient eluent at 30 mL / min) to obtain B58-03 (260 mg, 77.4% yield). LCMS: MS m / z (ESI) [M-Boc+H] + = 265.3; 1 H NMR (400MHz, CDCl3) δ 7.42 - 7.29 (m, 5H), 5.23 - 5.08 (m, 2H), 4.78 - 4.39 (m, 1H), 4.03 - 3.87 (m, 1H), 3.72 - 3.54 (m, 3H), 3.53 - 3.47 (m, 1H), 3.34 (s, 3H), 2.91 (s, 3H), 1.48 (s, 9H).

[0459] To a solution of B58-03 (230 mg, 0.631 mmol) in MeOH (5 mL), Pd / C (336 mg, 0.316 mmol) was added. The suspension was stirred at 25°C for 16 hours under H2 (50 psi). The reaction mixture was concentrated under reduced pressure to obtain B58-04 (140 mg, 96.3% yield). 1 H NMR (400MHz, CDCl3) δ 4.84 - 4.34 (m, 1H), 4.00 - 3.76 (m, 1H), 3.35 - 3.28 (m, 3H), 3.13 - 3.02 (m, 2H), 2.97 - 2.93 (m, 1H), 2.93 - 2.84 (m, 3H), 2.79 - 2.54 (m, 1H), 1.48 (s, 9H).

[0460] To a solution of B58-04 (120 mg, 0.521 mmol) in THF (2.5 mL), 4-iodobenzene-1-carbonitrile (143 mg, 0.625 mmol), Cs2CO3 (509 mg, 1.56 mmol), and RuPhos Pd G3 (7.30 mg, 9.00 μmol) were added under an N2 atmosphere. The reaction mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction solution was diluted with H2O (10 mL) and extracted with RINKAN (8 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel chromatography (4 g silica flash column, eluent of 0% → 12% ethyl acetate / petroleum ether gradient at 18 mL / min) to obtain B58-05 (140 mg, 81.1% yield). LCMS: MS m / z (ESI) [M+H] + = 331.9; 1 H NMR (400MHz, CDCl3) δ 7.51 (d, J = 8.8 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 5.00 - 4.57 (m, 1H), 4.19 - 4.05 (m, 1H), 3.63 - 3.50 (m, 3H), 3.45 - 3.38 (m, 1H), 3.41 (s, 3H), 2.95 (s, 3H), 1.52 (s, 9H).

[0461] Compound B58-05 (120 mg, 0.362 mmol) was dissolved in HCl / dioxane (4 M, 1.2 mL). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain B58 (110 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 231.9.

[0462] Intermediate B59 [ka]

[0463] To a solution of B59-01 (170 mg, 0.840 mmol) in THF (4 mL), 4-iodobenzene-1-carbonitrile (231 mg, 1.01 mmol), Cs2CO3 (821 mg, 2.521 mmol), and RuPhos Pd G3 (12.4 mg, 15.0 μmol) were added. The mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 45% THF / petroleum ether gradient at 100 mL / min) to obtain B59-02 (90.0 mg, 35.3% yield). LCMS: MS m / z (ESI) [M+H] + = 304.4.

[0464] To a solution of B59-02 (40.0 mg, 0.132 mmol) in DMF (1 mL), NaH (26.4 mg, 0.659 mmol) and CH3I (93.5 mg, 0.659 mmol) were added. The reaction solution was stirred at 25°C for 16 hours. The resulting mixture was poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL x 2), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B59-03 (40.0 mg, crude product). LCMS: MS m / z (ESI) [M+H] + = 332.2.

[0465] A solution of B59-03 (40.0 mg, 0.121 mmol) in HCl / dioxane (4 M, 2 mL) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B59 (32.0 mg, crude product). LCMS: MS m / z (ESI) [M+H] + = 232.2.

[0466] Intermediate B60 [ka]

[0467] A solution of B47-01 (3.00 g, 10.4 mmol) in HCl / dioxane (4 M, 30 mL) was stirred at 20°C for 1 hour. The reaction mixture was filtered, and the filter cake was dried under high vacuum to obtain B60-01 (1.4 g, 60.0% yield).

[0468] To a solution of B60-01 (200 mg, 0.894 mmol) in methanol (4 mL), TEA (0.37 mL, 2.68 mmol), oxetane-3-carbaldehyde (100 mg, 1.16 mmol), and sodium cyanoboranoid (168 mg, 2.68 mmol) were added, and the mixture was stirred at 20°C for 16 hours. The reaction product was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 20% → 40% THF / petroleum ether gradient at 50 mL / min) to obtain B60 (159 mg, 69.1% yield). LCMS: MS m / z (ESI) [M+H] + = 258.2.

[0469] Intermediate B61 [ka]

[0470] To a solution of B60-01 (500 mg, 2.24 mmol) in DMF (6 mL), 3-(bromomethyl)-1,1-difluorocyclobutane (496 mg, 2.68 mmol), potassium iodide (371 mg, 2.24 mmol), and DIPEA (1.85 mL, 11.2 mmol) were added. The mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 40% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain B61 (600 mg, 92.2% yield). LCMS: MS m / z (ESI) [M+H] + = 292.2.

[0471] Intermediate B62 [ka]

[0472] The title compound was prepared from 4-(bromomethyl)tetrahydro-2H-pyran using a procedure similar to that described for the synthesis of B61. LCMS: MS m / z (ESI) [M+H] + = 286.1.

[0473] Intermediate B63 [ka]

[0474] The title compound was prepared from 4,4-difluorocyclohexane-1-carbaldehyde using a procedure similar to that described for the synthesis of B60. LCMS: MS m / z (ESI) [M+H] + = 320.1; 1 H NMR (400MHz, DMSO-d6) δ 7.51 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 8.8 Hz, 2H), 3.51 - 3.42 (m, 1H), 3.42 - 3.20 (m, 3H), 3.11 - 3.00 (m, 1H), 2.49 - 2.39 (m, 2H), 2.15 - 1.90 (m, 4H), 1.88 - 1.66 (m, 4H), 1.57 - 1.40 (m, 1H), 1.22 - 1.07 (m, 2H).

[0475] Intermediate B64 [ka]

[0476] The title compound was prepared from 3,3-difluorocyclobutan-1-amine using a procedure similar to that described for the synthesis of B46. LCMS: MS m / z (ESI) [M+H] + = 277.9.

[0477] Intermediate B65 [ka]

[0478] The title compound was prepared from tetrahydro-2H-pyran-4-amine using a procedure similar to that described for the synthesis of B46. LCMS: MS m / z (ESI) [M+H] + = 272.1.

[0479] Intermediate B66 [ka]

[0480] The title compound was prepared from 4,4-difluorocyclohexane-1-one using a procedure similar to that described for the synthesis of B60. LCMS: MS m / z (ESI) [M+H] + = 306.1.

[0481] Intermediate B67 [ka]

[0482] The title compound was prepared from bicyclo[1.1.1]pentane-1-amine hydrochloride using a procedure similar to that described for the synthesis of B46. LCMS: MS m / z (ESI) [M+H] + = 254.1.

[0483] Intermediate B68 [ka]

[0484] The title compound was prepared from (iodomethyl)cyclohexane using a procedure similar to that described for the synthesis of B61. LCMS: MS m / z (ESI) [M+H] + = 284.2.

[0485] Intermediate B69 [ka]

[0486] To a solution of B69-01 (800 mg, 7.14 mmol) in THF (16 mL), LiAlH4 (3.43 mL, 8.56 mmol) was slowly added at 0°C under a N2 atmosphere. The reaction mixture was stirred at 0°C for 1 hour. The combined mixture was slowly quenched at 0°C with water (0.33 mL), 15% NaOH (0.99 mL), and water (0.33 mL). The mixture was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain B69-02 (6.52 mmol, 91.4% yield). 1 1H NMR (400 MHz, CDCl) 3) δ 3.54 (s, 2H), 2.55 (s, 1H), 1.75 (s, 6H).

[0487] To a solution of B69-02 (640 mg, 6.52 mmol) in DCM (10 mL), TEA (3.62 mL, 26.1 mmol) and methanesulfonic anhydride (3.63 g, 20.9 mmol) were slowly added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was then quenched with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried through anhydrous Na2SO4, filtered, concentrated, and the residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 11 / 1) to obtain B69-03 (888 mg, 77.2% yield). 1 H NMR (400 MHz, CDCl3) δ 4.14 (s, 2H), 3.01 (s, 3H), 2.57 (s, 1H), 1.84 (s, 6H).

[0488] B69 was prepared from B69-03 using the same procedure as that described for the synthesis of B47. 1H NMR (400 MHz, DMSO-d6) δ 9.52 - 9.06 (m, 2H), 7.58 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.98 - 3.86 (m, 1H), 3.72 - 3.49 (m, 4H), 3.07 (t, J = 5.6 Hz, 2H), 2.51 (s, 1H), 2.42 - 2.27 (m, 2H), 1.86 (s, 6H).

[0489] Intermediate B70 [ka]

[0490] To a solution of B47-01 (1.00 g, 3.48 mmol) in DMF (10.0 mL), NaH (0.800 g, 20.9 mmol) was slowly added at 0°C under an N2 atmosphere. After stirring the reaction mixture for 15 minutes, 2,2-dimethyloxirane (2.50 g, 34.8 mmol) was slowly added at 0°C. The reaction mixture was then warmed to room temperature and stirred for 12 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried through Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2 / 1) to obtain B70-01 (300 mg, 30.2% yield). LCMS: MS m / z (ESI) [M+H] + = 285.9.

[0491] To a solution of B70-01 (300 mg, 1.05 mmol) in EtOH (2.0 mL), 4 M NaOH (1.31 mL, 5.26 mmol) was added, and the reaction mixture was stirred at 65°C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with SiO2 (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 2 / 1) to obtain B70 (70.0 mg, 25.7% yield). LCMS: MS m / z (ESI) [M+H] + = 259.9.

[0492] Intermediate B71 [ka]

[0493] To a solution of B46-02 (1.00 g, 5.31 mmol) in DMSO (10 mL), TEA (5.89 mL, 42.5 mmol) and pyridine sulfur trioxide (4.23 g, 26.6 mmol) were added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched by adding H2O (50 mL). Then, it was extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (30 mL), dried via Na2SO4, and the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 40% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain B71-01 (300 mg, 30.3% yield). LCMS: MS m / z (ESI) [M+H] + = 187.1.

[0494] To a solution of B71-01 (240 mg, 1.29 mmol) in MeOH (5 mL), (aminocyclopropyl)methanol hydrochloride (239 mg, 1.93 mmol), TEA (0.27 mL, 1.93 mmol), and NaBH3CN (243 mg, 3.87 mmol) were added. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 30% ethyl acetate / petroleum ether gradient at 100 mL / min) to obtain B71 (300 mg, 90.5% yield). LCMS: MS m / z (ESI) [M-56+H] + = 258.2.

[0495] Intermediate B72 [ka]

[0496] The title compound was prepared from 3,4-difluorobenzonitrile and 2,2-difluoroethyltrifluoromethanesulfonate using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+1] + = 270.0.

[0497] Intermediate B73 [ka]

[0498] The title compound was prepared from 1-fluoro-2-iodobenzene using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 195.2.

[0499] Intermediate B74 [ka]

[0500] The title compound was prepared from 2-bromo-1,3-difluorobenzene using a procedure similar to that described for the synthesis of B19. LCMS: MS m / z (ESI) [M+H] + = 213.4.

[0501] Intermediate B75 [ka]

[0502] The title compound was prepared from (bromomethyl)cyclopropane using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 260.3.

[0503] Intermediate B76 [ka]

[0504] To a solution of B76-01 (2.00 g, 19.2 mmol) in THF (20 mL), LiAlH4 (2.5 mol / L in THF, 8.45 mL, 21.1 mmol) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The reaction product was quenched at 0°C by adding Na2SO4·10H2O (5.00 g), filtered, and concentrated under reduced pressure to obtain B76-02 (1.00 g, 57.8% yield). 1 H NMR (400MHz, CDCl3) δ 3.82 (d, J = 22.0 Hz, 2H), 2.17 (s, 1H), 1.15 - 1.01 (m, 2H), 0.74 - 0.63 (m, 2H).

[0505] To a solution of B76-02 (955 mg, 10.599 mmol) in DCM (20 mL), TEA (4.41 mL, 31.8 mmol) was added, followed by the slow addition of methanesulfonic anhydride (2.77 g, 15.9 mmol). The mixture was stirred at 20°C for 2 hours. The resulting mixture was quenched with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B76-03 (1.70 g, 95.4% yield). 1 H NMR (400MHz, CDCl3) δ 4.40 (d, J = 22.0 Hz, 2H), 3.03 (s, 3H), 1.27 - 1.16 (m, 2H), 0.89 - 0.81 (m, 2H).

[0506] To a solution of B76-04 (800 mg, 3.31 mmol) in DMF (20 mL), DIPEA (2.74 mL, 16.5 mmol) and KI (589 mg, 3.31 mmol) were added, followed by B76-03 (668 mg, 3.97 mmol). The mixture was stirred at 80°C for 16 hours. The reaction product was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 20% → 40% THF / petroleum ether gradient at 50 mL / min) to obtain B76 (500 mg, 54.5% yield). LCMS: MS m / z (ESI) [M+H] + = 278.2.

[0507] Intermediate B77 [ka]

[0508] To a solution of B39-01 (1.00 g, 5.37 mmol) and 2-fluoro-1-iodobenzene (1.20 g, 5.37 mmol) in THF (10.0 mL), Cs2CO3 (5.20 g, 16.1 mmol) and RuPhos Pd G3 (45.2 mg, 0.054 mmol) were added. The reaction mixture was stirred at 80°C for 12 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 3 / 1) to obtain B77-01 (300 mg, 19.9% ​​yield). LCMS: MS m / z (ESI) [M+H] + = 281.1.

[0509] To a solution of B77-01 (200 mg, 0.714 mmol) in DMF (2.00 mL), NaH (114 mg, 2.85 mmol) was slowly added at 0°C. After 15 minutes, B77-02a (125 mg, 0.714 mmol) was added at 0°C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 4 / 1) to obtain B77-02 (120 mg, 46.8% yield). LCMS: MS m / z (ESI) [M+H] + = 360.0.

[0510] To a solution of B77-02 (120 mg, 0.334 mmol) in dioxane (0.5 mL), HCl / dioxane (4 M, 1.0 mL) was added. The resulting mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain B77 (100 mg, crude product).

[0511] Intermediate B78 [ka]

[0512] To a solution of B39-01 (300 mg, 1.61 mmol) in DMF (5 mL), 3-chloro-4-fluorobenzene-1-carbonitrile (251 mg, 1.61 mmol) and K2CO3 (668 mg, 4.83 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to remove the DMF. The residue was purified by column chromatography (SiO2, MeOH / DCM = 3 / 100) to obtain B78-01 (410 mg, 79.1% yield). LCMS: MS m / z (ESI) [M+H] + = 322.0.

[0513] A solution of B78-01 (410 mg, 1.27 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain B78-02 (320 mg, 97.3%). LC-MS: MS m / z (ESI) [M+1] + = 222.0.

[0514] To a solution of B78-02 (320 mg, 1.24 mmol) in DMF (5 mL), (bromomethyl)cyclopropane (209 mg, 1.55 mmol), K2CO3 (1.07 g, 7.75 mmol), and potassium iodide (257 mg, 1.55 mmol) were added. The reaction mixture was stirred at 90°C for 18 hours. The residue was diluted with H2O (10 mL) and extracted with RINKAN (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 0 → 100 / 3) to obtain B78 (240 mg, 70.2% yield). LCMS: MS m / z (ESI) [M+1] + = 276.1.

[0515] Intermediate B79 [ka]

[0516] To a solution of B79-01 (3.50 g, 11.5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.00 g, 9.61 mmol) in DMSO (20.0 mL), Cs2CO3 (9.40 g, 28.8 mmol), KOAc (0.900 g, 9.61 mmol), and Pd(dppf)Cl2 (0.700 g, 0.961 mmol) were added. The reaction mixture was stirred at 80°C for 1 hour under an N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with siRNA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF=3 / 1) to obtain B79-02 (2.20 g, 89.7% yield). LCMS: MS m / z (ESI) [M+H] + = 254.8.

[0517] B79 was prepared from B79-02 using the same procedure as described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 314.9.

[0518] Intermediate B80 [ka]

[0519] The title compound was prepared from 2,4-difluoro-1-iodobenzene using a procedure similar to that described for the synthesis of B77. LCMS: MS m / z (ESI) [M+H] + = 253.2.

[0520] Intermediate B81 [ka]

[0521] The title compound was prepared from (bromomethyl)cyclopropane using a procedure similar to that described for the synthesis of B77. LCMS: MS m / z (ESI) [M+H] + = 235.2.

[0522] Intermediate B82 [ka]

[0523] The title compound was prepared from 2-bromo-1,3-difluorobenzene using a procedure similar to that described for the synthesis of B77. LCMS: MS m / z (ESI) [M+H] + = 253.1;

[0524] Intermediate B83 [ka]

[0525] A mixture of B76-04 (780 mg, 3.23 mmol) and 1-bromobuta-2-yne (429 mg, 3.23 mmol) in DMF (10 mL) was mixed with DIPEA (2.67 mL, 16.1 mmol) and KI (574 mg, 3.23 mmol). The mixture was stirred at 80°C for 16 hours. The reaction product was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 20% → 50% THF / petroleum ether gradient at 50 mL / min) to obtain B83 (410 mg, 49.4% yield). LCMS: MS m / z (ESI) [M+H] + = 258.2.

[0526] Intermediate B84 [ka]

[0527] The title compound was prepared from (bromomethyl)cyclobutane using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 274.1.

[0528] Intermediate B85 [ka]

[0529] The title compound was prepared from B76-04 and 1-iodo-2-methylpropane using a procedure similar to that described for the synthesis of B83. LCMS: MS m / z (ESI) [M+H] + = 262.2.

[0530] Intermediate B86 [ka]

[0531] The title compound was prepared from pyrimidine-2-carbaldehyde using a procedure similar to that described for the synthesis of B60. LCMS: MS m / z (ESI) [M+H] + = 273.2.

[0532] Intermediate B87 [ka]

[0533] The title compound was prepared from 2,3,5-trifluoropyridine using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 254.3.

[0534] Intermediate B88 [ka]

[0535] The title compound was prepared from 2,3-difluoropyridine using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 236.1.

[0536] Intermediate B89 [ka]

[0537] The title compound was prepared from 3-chloro-2-fluoropyridine using a procedure similar to that described for the synthesis of B01. 1 H NMR (400 MHz, DMSO-d6) δ 9.75 - 9.38 (m, 2H), 8.10 (d, J = 3.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 6.82 (dd, J = 7.6, 4.8 Hz, 1H), 3.97 - 3.66 (m, 5H), 2.58 (s, 3H), 2.35 - 2.24 (m, 1H), 2.23 - 2.12 (m, 1H).

[0538] Intermediate B90 [ka]

[0539] To a solution of B58-01 (316 mg, 1.56 mmol) in DMF (5 mL), 2,3-difluoropyridine (180 mg, 1.56 mmol) and DIPEA (0.78 mL, 4.69 mmol) were added, and the mixture was stirred at 70°C for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B90-01 (80.0 mg, 79.1% yield). LCMS: MS m / z (ESI) [M+H] + = 298.1.

[0540] To a solution of B90-01 (400 mg, 1.35 mmol) in DMF (4 mL), imidazole (229 mg, 3.36 mmol) and TBSCl (243 mg, 1.62 mmol) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (50 mL / min with 20% THF / petroleum ether eluent) to obtain B90-02 (410 mg, 74.0% yield). LCMS: MS m / z (ESI) [M+H] + = 412.2.

[0541] To a solution of B90-02 (400 mg, 0.972 mmol) in DMF (10 mL), NaH (58.3 mg, 1.46 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, and then CH3I (414 mg, 2.92 mmol) was added. The mixture was stirred at 20°C for 16 hours. The resulting mixture was poured into saturated NH4Cl aqueous solution (20 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (20 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: 20% THF / petroleum ether gradient at 100 mL / min) to obtain B90-03 (260 mg, 62.9% yield). LCMS: MS m / z (ESI) [M+H] + = 426.3.

[0542] A solution of B90-03 (240 mg, 0.564 mmol) in MeOH (2 mL) was mixed with HCl / dioxane (4 mol / L, 5 mL), and the mixture was stirred at 20°C for 3 hours. The resulting mixture was concentrated under reduced pressure to obtain B90 (200 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 326.2.

[0543] Intermediate B91 [ka]

[0544] A solution of 2,3-difluoropyridine (142 mg, 1.23 mmol) and B59-01 (250 mg, 1.23 mmol) in DMF (4 mL) was mixed with DIPEA (0.20 mL, 1.23 mmol). The mixture was stirred at 70°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (2 mL), extracted with RINKAN (10 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 1 / 1) to obtain B91-01 (340 mg, 92.5% yield). LCMS: MS m / z (ESI) [M+H]+ = 297.9; 1 H NMR (400 MHz, CD3OD) δ 7.83 (dt, J = 4.8, 1.2 Hz, 1H), 7.29 (ddd, J = 13.6, 7.6, 1.2 Hz, 1H), 6.59 (ddd, J = 8.0, 4.8, 3.2 Hz, 1H), 4.23 - 4.18 (m, 1H), 4.02 - 3.91 (m, 2H), 3.91 - 3.83 (m, 1H), 3.58 - 3.48 (m, 2H), 1.45 (s, 9H).

[0545] To a solution of B91-01 (277 mg, 0.932 mmol) in DMF (3 mL), TBSCl (168 mg, 1.12 mmol) and imidazole (159 mg, 2.33 mmol) were added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (2 mL), extracted with HCl (10 mL x 3), and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / HCl = 100 / 1 → 90 / 10) to obtain B91-02 (380 mg, 99.1% yield). LCMS: MS m / z (ESI) [M+H] + = 412.2.

[0546] To a solution of B91-02 (372 mg, 0.904 mmol) in DMF (4 mL), NaH (54.2 mg, 1.36 mmol) was added at 0°C. The mixture was stirred at 0°C for 30 minutes, after which CH3I (384 mg, 2.71 mmol) was slowly added. The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction mixture was quenched with H2O (3 mL) and extracted with RINKAN (10 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried via Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 1 → 10 / 1) to obtain B91-03 (320 mg, 83.2% yield). LCMS: MS m / z (ESI) [M+H] + = 426.3; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 4.4 Hz, 1H), 7.17 (dd, J = 12.8, 8.0 Hz, 1H), 6.62 - 6.52 (m, 1H), 4.55 - 4.39 (m, 2H), 3.99 - 3.90 (m, 1H), 3.90 - 3.80 (m, 1H), 3.73 - 3.61 (m, 1H), 3.49 - 3.39 (m, 1H), 2.85 (s, 3H), 1.48 (s, 9H), 0.89 (s, 9H), 0.09 (s, 6H).

[0547] To a solution of B91-03 (281 mg, 0.660 mmol) in MeOH (2 mL), HCl / dioxane (4 M, 4 mL) was added. The mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated to obtain B91 (130 mg, 93.2% yield). LCMS: MS m / z (ESI) [M+H] + = 212.0.

[0548] Intermediate B92 [ka]

[0549] To a solution of B92-01 (2 g, 13.6 mmol) in acetone (40 mL), K2CO3 (3.7 g, 27.1 mmol) and CH3I (5.8 g, 40.7 mmol) were added at 0°C. The mixture was then heated to 40°C and stirred for 12 hours. The reaction solution was diluted with H2O (50 mL) and extracted with siRNA (30 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B92-02 (1.80 g, 82.1% yield). LCMS: MS m / z (ESI) [M+H] + = 162.2; 1 H NMR (400MHz, CDCl3) δ 7.92 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 9.2, 2.4 Hz, 1H), 3.87 (s, 3H).

[0550] To a solution of B92-02 (500 mg, 3.09 mmol) in dioxane (10 mL), B01-01 (744 mg, 3.71 mmol), RuPhos Pd G3 (129 mg, 0.15 mmol), and Cs2CO3 (2.02 g, 6.19 mmol) were added. The reaction mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was concentrated. The residue was purified by silica gel chromatography (SiO2, petroleum ether / siRNA = 100 / 0 → 4 / 1) to obtain B92-03 (900 mg, 89.4% yield). LCMS: MS m / z (ESI) [M+H] + = 326.3; 1 H NMR (400MHz, CDCl3) δ 7.70 (d, J = 2.4 Hz, 1H), 6.93 (dd, J = 13.6, 2.4 Hz, 1H), 5.00 -4.62 (m, 1H), 3.78 (s, 3H), 3.76 - 3.59 (m, 2H), 3.55 - 3.45 (m, 2H), 2.83 (s, 3H), 2.18 - 1.94 (m, 2H), 1.47 (s, 9H).

[0551] A solution of B92-03 (300 mg, 0.922 mmol) in HCl / dioxane (4 M, 8 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain crude product B92 (200 mg, 96.3%). LC-MS: MS m / z (ESI) [M+H] + = 226.2.

[0552] Intermediate B93 [ka]

[0553] The title compound was prepared from 5-bromo-1-methylpyridine-2(1H)-one using a procedure similar to that described for the synthesis of B12.

[0554] Intermediate B94 [ka]

[0555] The title compound was prepared from 4-bromo-1-methylpyridine-2(1H)-one using a procedure similar to that described for the synthesis of B13. 1 H NMR (400 MHz, DMSO-d6) δ 9.73 - 9.40 (m, 2H), 7.83 (d, J = 7.6 Hz, 1H), 6.37 - 6.31 (m, 1H), 5.87 (s, 1H), 3.92 - 3.84 (m, 1H), 3.74 - 3.67 (m, 1H), 3.65 - 3.58 (m, 2H), 3.53 (s, 3H), 3.46 - 3.39 (m, 1H), 2.61 - 2.57 (m, 3H), 2.37 - 2.27 (m, 2H).

[0556] Intermediate B95 [ka]

[0557] The title compound was prepared from 6-bromo-1-methylpyridine-2(1H)-one using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 207.9.

[0558] Intermediate B96 [ka]

[0559] The title compound was prepared from 3-bromo-1-methylpyridine-2(1H)-one using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 207.9.

[0560] Intermediate B97 [ka]

[0561] To a mixture of B97-01 (1.50 g, 4.64 mmol) and 4-bromo-2-methylbenzene-1-carbonitrile (0.910 g, 4.64 mmol) in dioxane (15 mL) and H2O (3 mL), Pd(dppf)Cl2 (340 mg, 0.464 mmol) and K2CO3 (1.92 g, 13.9 mmol) were added. The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction product was filtered, and the filtrate was concentrated to obtain the residue. The residue was diluted with H2O (20 mL) and extracted with siRNA (5 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (using a 0% to 5% siRNA / petroleum ether gradient at 50 mL / min) to obtain the desired product B97-02 (1.0 g, 68.98% yield). LCMS: MS m / z (ESI) [Mt-Bu+H] + = 257.0.

[0562] To a mixture of B97-02 (500 mg, 1.60 mmol) in MeCN (5 mL), NaH (115 mg, 4.80 mmol) was added at 0°C and the mixture was stirred at 0°C for 1 hour. Then, MeI (341 mg, 2.40 mmol) was added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with H2O (10 mL) and extracted with siRNA (5 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (SiO2, 40 mL / min, eluent of 0% → 6% siRNA / petroleum ether gradient) to obtain the desired product B97-03 (500 mg, 95.7% yield). LCMS: MS m / z (ESI) [Mt-Bu+H] + = 271.0; 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J = 8.0, 1,2 Hz, 1H), 6.34 - 6.26 (m, 1H), 4.20 - 3.94 (m, 1H), 2.72 (s, 3H), 2.62 - 2.52 (m, 2H), 2.47 (s, 3H), 2.38 - 2.15 (m, 2H), 1.89 - 1.70 (m, 2H), 1.41 (s, 9H).

[0563] A mixture of B97-03 (450 mg, 1.379 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 25°C for 1 hour. The solvent was then removed under reduced pressure to obtain B97 (390 mg, crude product). LC-MS: MS m / z (ESI) [M+1] + = 227.1.

[0564] Intermediate B98 [ka]

[0565] The title compound was prepared from 4-bromo-1-methyl-1H-pyrazole using a procedure similar to that described for the synthesis of B97. LCMS:MS m / z (ESI) [M+1] + = 192.1.

[0566] Intermediate B99 [ka]

[0567] The title compound was prepared from 4-bromobenzonitrile and ethyl iodide using a procedure similar to that described for the synthesis of B97.

[0568] Intermediate B100 [ka]

[0569] To a mixture of B97-01 (1 g, 3.10 mmol) in THF (20 mL), 60% NaH (0.370 g, 15.5 mmol) was slowly added at 0°C, and the mixture was stirred at 0°C for 10 minutes. Then, MeI (0.880 g, 6.19 mmol) was added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (10 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (eluent: 0% → 7% siRNA / petroleum ether gradient at 60 mL / min) to obtain the desired product B100-01 (580 mg, 55.6% yield). 1 H NMR: (400 MHz, DMSO-d6) δ 6.47 - 6.35 (m, 1H), 4.21 - 3.76 (m, 1H), 2.66 (s, 3H), 2.29 - 2.00 (m, 4H), 1.62 - 1.52 (m, 2H), 1.39 (s, 9H), 1.20 (s, 12H).

[0570] A mixture of B100-01 (580 mg, 1.72 mmol) and 2-bromo-1,3-thiazole-4-carbonitrile (325 mg, 1.72 mmol) in dioxane (10 mL) and H2O (2 mL) was mixed with K2CO3 (713 mg, 5.16 mmol) and Pd(PPh3)4 (199 mg, 0.172 mmol). The mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was filtered and concentrated. The residue was diluted with H2O (10 mL) and extracted with siRNA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (eluent of 0% → 10% siRNA / petroleum ether gradient at 50 mL / min) to obtain the desired product B100-02 (210 mg, 38.2%). LCMS: MS m / z (ESI) [M+1] + = 220.1; 1H NMR: (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 6.83 - 6.67 (m, 1H), 4.17 - 3.95 (m, 1H), 2.71 (s, 3H), 2.62 - 2.51 (m, 2H), 2.44 - 2.20 (m, 2H), 1.90 - 1.90 (m, 2H), 1.40 (s, 9H).

[0571] Compound B100-02 (210 mg, 0.657 mmol) was dissolved in 4 M HCl / dioxane (2 mL), and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain B100 (140 mg, 97.1%, HCl salt).

[0572] Intermediate B101 [ka]

[0573] To a solution of bromobenzene (3.36 mL, 31.8 mmol) in DMSO (50 mL), B101-01 (3.10 g, 38.2 mmol), Na2CO3 (10.1 g, 95.5 mmol), XPHOS (1.50 g, 3.19 mmol), t-Bu3PBF4 (1.80 g, 6.37 mmol), and Pd(PPh3)2Cl2 (1.20 g, 1.59 mmol) were added. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using a 0% to 40% THF / petroleum ether gradient eluent at 100 mL / min) to obtain B101-02 (1.50 g, 29.8% yield).

[0574] To a solution of B101-02 (1.30 g, 8.22 mmol) in ethanol (20 mL), trichlorocerium(III) (2.03 g, 8.217 mmol) and NaBH4 (373 mg, 9.86 mmol) were added at 0°C, and the mixture was stirred at 20°C for 3 hours. The resulting mixture was quenched at 0°C by adding 1 mol / L HCl (3 mL), diluted with H2O (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B101-03 (1.30 g, crude product). LCMS: MS m / z (ESI) [M+H] + = 161.2.

[0575] To a solution of B101-03 (1.20 g, 7.49 mmol) in DCM (20 mL), TEA (3.12 mL, 22.5 mmol) was added, followed by the slow addition of methanesulfonic anhydride (1.96 g, 11.2 mmol). The mixture was stirred at 20°C for 2 hours. The resulting mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B101-04 (1.70 g, crude product).

[0576] A solution of B101-04 (1.60 g, 6.71 mmol) in methylamine (15.0 g, 145 mmol, 30% in ethanol) was stirred at 20°C for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using a 60% → 80% THF / PE eluent at 20 mL / min) to obtain B101 (300 mg, 33.3% yield). LCMS: MS m / z (ESI) [M+H] + = 174.2.

[0577] Intermediate B102 [ka]

[0578] To a solution of PPh3 (23.5 g, 89.7 mmol) in DCM (200 mL), Br2 (4.62 mL, 84.1 mmol) was added at 0°C, and the reaction mixture was stirred at the same temperature for 15 minutes. A solution of TEA (13.6 mL, 98.0 mmol) and B102-01 (8.00 g, 81.5 mmol) in DCM (100 mL) was added. The mixture was stirred at 20°C for 16 hours. The reaction product was concentrated. The residue was purified by flash silica gel chromatography (100 mL / min with 30% THF / petroleum ether eluent) to obtain B102-02 (1.50 g, 11.4% yield). 1 H NMR (400MHz, DMSO-d6) δ 6.58 (t, J = 1.6 Hz, 1H), 3.02 - 2.94 (m, 2H), 2.50 - 2.46 (m, 2H).

[0579] To a solution of B102-02 (2.00 g, 12.4 mmol) in dioxane (20 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.80 g, 14.9 mmol), KOAc (2.40 g, 24.8 mmol), and Pd(dppf)Cl2 (0.90 g, 1.24 mmol) were added. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain B102-03 (2.56 g, crude product).

[0580] To a solution of 2-bromo-3-fluoropyridine (2.15 g, 12.3 mmol) in dioxane (40 mL) and H2O (10 mL), K3PO4 (5.22 g, 24.6 mmol), B102-03 (2.56 g, 12.3 mmol), and Pd(dppf)Cl2 (899 mg, 1.23 mmol) were added, and the reaction mixture was stirred at 80°C for 16 hours under an N2 atmosphere. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (50 mL / min with 20% THF / petroleum ether eluent) to obtain B102-04 (3.00 g, 96.4% yield). LCMS: MS m / z (ESI) [M+H] + = 178.1.

[0581] To a solution of B102-04 (3.00 g, 16.9 mmol) in ethanol (50 mL), trichlorocerium(III) (4.17 g, 16.9 mmol) was added, followed by the addition of NaBH4 (768 mg, 20.3 mmol) at 0°C. The mixture was stirred at 20°C for 3 hours. The reaction product was poured into ice-cold saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (100 mL / min with 30% THF / petroleum ether eluent) to obtain B102-05 (1.50 g, 49.4% yield). LCMS: MS m / z (ESI) [M+H] + = 180.1.

[0582] To a solution of B102-05 (1.00 g, 5.58 mmol) in THF (20 mL), DPPA (1.84 g, 6.70 mmol) and DBU (1.02 mg, 6.70 mmol) were added, and the mixture was stirred at 20°C for 16 hours under an N2 atmosphere. The resulting mixture was diluted with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (100 mL / min with 30% THF / petroleum ether eluent) to obtain B102-06 (1.08 g, 94.8% yield). LCMS: MS m / z (ESI) [M+H] + = 205.1.

[0583] To a solution of B102-06 (1.00 mg, 4.90 mmol) in THF (20 mL) and H2O (2 mL), PPh3 (1.41 mg, 5.39 mmol) was added. The mixture was stirred at 70°C for 1 hour under an N2 atmosphere, then cooled to 20°C. (Boc)2O (2.25 mL, 9.79 mmol) and TEA (2.04 mL, 14.7 mmol) were added, and the mixture was stirred at 50°C for 0.5 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (100 mL / min with 20% THF / petroleum ether eluent) to obtain B102-07 (700 mg, 51.4% yield). LCMS: MS m / z (ESI) [M+H] + = 279.2.

[0584] To a solution of B102-07 (700 mg, 2.52 mmol) in DMF (14 mL), NaH (201 mg, 5.03 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. CH3I (1.07 mg, 7.55 mmol) was added. The mixture was stirred at 30°C for 2 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain B102-08 (700 mg, 95.2% yield). LCMS: MS m / z (ESI) [M+H] + = 293.1.

[0585] A mixture of B102-08 (700 mg, 2.39 mmol) in HCl / dioxane (4 mol / L, 10 mL) was stirred at 20°C for 1 hour. The resulting mixture was concentrated under reduced pressure to obtain B102 (540 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 193.1.

[0586] Intermediate B103 [ka]

[0587] To a solution of B103-01 (5.00 g, 44.603 mmol) in DCM (150 mL), DIPEA (8.87 mL, 53.524 mmol) was added, and then trifluoromethanesulfonic acid anhydride (13.8 g, 49.063 mmol) was added dropwise at -70°C, and the mixture was stirred at -70°C for 2 hours. The resulting mixture was quenched with H2O (200 mL) and extracted with DCM (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (using 0% → 10% THF / petroleum ether eluent at 100 mL / min) to obtain B103-02 (5.40 g, 49.6% yield). 1H NMR (400MHz, CDCl3) δ 2.96 - 2.83 (m, 2H), 2.70 - 2.58 (m, 2H), 1.77 (t, J = 2.0 Hz, 3H).

[0588] B103 was prepared from B103-02 using the same procedure as described for the synthesis of B102. LCMS: MS m / z (ESI) [M+H] + = 207.1; 1 H NMR (400MHz, DMSO-d6) δ 9.65 - 9.15 (m, 2H), 8.58 - 8.48 (m, 1H), 7.93 - 7.82 (m, 1H), 7.58 - 7.48 (m, 1H), 4.39 - 4.27 (m, 1H), 2.95 - 2.83 (m, 1H), 2.82 - 2.72 (m, 1H), 2.50 - 2.46 (m, 3H), 2.38 - 2.25 (m, 1H), 2.09 - 1.98 (m, 1H), 1.84 (s, 3H).

[0589] Intermediate B104 [ka]

[0590] To a solution of B101-01 (2.00 g, 24.4 mmol) in DCM (60 mL), 2-methylpropan-2-ylaminomethanoate (2.90 g, 24.4 mmol) and bismuth nitrate (11.5 g, 29.2 mmol) were added, and the reaction mixture was stirred at 25°C for 5 hours. The reaction suspension was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether / siRNA = 10 / 1 → 3 / 1) to obtain B104-01 (700 mg, 14.4%). 1H NMR (400MHz, CDCl3) δ 4.63 (brs, 1H), 4.22 (brs, 1H), 2.68 - 2.55 (m, 1H), 2.43 - 2.29 (m, 2H), 2.27 - 2.17 (m, 1H), 2.16 - 2.06 (m, 1H), 1.88 - 1.79 (m, 1H), 1.44 (s, 9H).

[0591] To a mixture of B104-01 (700 mg, 3.51 mmol) in THF (7 mL), 2-(methoxymethyl)oxiran-1-ium (7.02 mL, 7.03 mmol) was added at -78°C, and after stirring for 30 minutes, N-[dioxo(trifluoromethyl)-λ 6 -Sulfanyl]-1,1,1-trifluoro-N-phenylmethanesulfonamide (2.13 g, 5.97 mmol) was slowly added. The reaction mixture was stirred at 0°C for 10 minutes under an N2 atmosphere. The reaction suspension was quenched with water (10 mL) and extracted with RINKAN (10 mL × 3). The combined organic layers were washed with brine (5 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether / RINKAN = 10 / 1 → 3 / 1) to obtain a mixture of B104-02a and B104-02b (1.00 g, 85.9% yield).

[0592] To a solution of B104-02a and B104-02b (1.00 g, 3.02 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (920 mg, 3.62 mmol), Pd(dppf)Cl2 (221 mg, 0.302 mmol), and KOAc (592.2 mg, 6.04 mmol) were added. The reaction suspension was then stirred at 80°C for 14 hours under an N2 atmosphere. The reaction suspension was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column chromatography (petroleum ether / siRNA = 10 / 1 → 1 / 1) to obtain a mixture of B104-03 and B102-07 (730 mg, 78.2% yield).

[0593] To a solution of B104-03a and B104-03b (738 mg, 2.39 mmol) in dioxane (6 mL) and H2O (1 mL), 2-bromo-3-fluoropyridine (350 mg, 1.99 mmol), K3PO4 (844.4 mg, 3.98 mmol), and Pd(dppf)Cl2 (146 mg, 0.199 mmol) were added, and the reaction suspension was stirred at 90°C for 2 hours. The reaction suspension was diluted with water (5 mL) and extracted with siRNA (4 mL × 3). The combined organic layer was washed with brine (2 mL), dried through anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica column (petroleum ether / siRNA = 10 / 1 → 1 / 1) to obtain a mixture of B104-04 and B102-07 (370 mg, 66.9% yield). LCMS: MS m / z (ESI) [M+H] + = 279.2.

[0594] To a solution of B104-04 and B102-07 (370 mg, 1.33 mmol) in DMF (3 mL), NaH (160 mg, 3.99 mmol) was added, and the reaction mixture was stirred at 0°C for 30 minutes. CH3I (566 mg, 3.99 mmol) was added to the mixture, and the mixture was stirred at 25°C for 2 hours. The reaction suspension was quenched with water (5 mL) and extracted with RINKAN (5 mL x 3). The combined organic layers were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a mixture of B104-05 and B102-08 (350 mg, 90.0% yield). LCMS: MS m / z (ESI) [M+H] + = 293.2.

[0595] Solutions of B104-05 and B102-08 (350 mg, 1.20 mmol) in HCl / dioxane (4 M, 2.5 mL) were stirred at 25°C for 1 hour. The reaction suspension was concentrated under reduced pressure to obtain a crude mixture of B104 and B102 (273 mg, crude), which was used directly in the next step. LCMS: MS m / z (ESI) [M+H] + = 193.3.

[0596] Intermediate B105 [ka]

[0597] A mixture of B01-01 (567 mg, 2.83 mmol) and 6-bromo-3-methylbenzo[d]isoxazole (500 mg, 2.36 mmol) in dioxane (10 mL) was mixed with Cs2CO3 (2.30 g, 7.07 mmol) and Pd-PEPPSI-IheptCl (229 mg, 0.236 mmol). The mixture was stirred at 100°C for 18 hours under an N2 atmosphere. The resulting mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 24% THF / petroleum ether gradient at 50 mL / min) to obtain B105-01 (400 mg, 51.2% yield). LCMS: MS m / z (ESI) [M+H] + = 332.2; 1 H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 8.4 Hz, 1H), 6.69 (dd, J = 8.8, 2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 4.87 - 4.66 (m, 1H), 3.52 - 3.42 (m, 2H), 3.32 - 3.23 (m, 2H), 2.76 (s, 3H), 2.43 (s, 3H), 2.21 - 2.06 (m, 2H), 1.43 (s, 9H).

[0598] A mixture of B105-01 (100 mg, 0.302 mmol) in 4 M HCl / dioxane (1 mL) was stirred at 25°C for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain B105. LCMS: MS m / z (ESI) [M+H] + = 232.1.

[0599] Intermediate B106 [ka]

[0600] The title compound was prepared from B01-01 and 4-fluoro-2-methoxybenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 232.2; 1 H NMR: (400 MHz, DMSO-d6) δ 9.50 (brs, 2H), 7.42 (d, J = 8.8 Hz, 1H), 6.23 (dd, J = 8.4, 1.6 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 3.88 (s, 3H), 3.93 - 3.83 (m, 1H), 3.70 - 3.63 (m, 1H), 3.62 - 3.50 (m, 2H), 3.44 - 3.32 (m, 1H), 2.60 (t, J = 5.2 Hz, 3H), 2.41 - 2.30 (m, 1H), 2.29 - 2.18 (m, 1H).

[0601] Intermediate B107 [ka]

[0602] The title compound was prepared from B107-01 and 5-fluoropicolinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 217.1.

[0603] Intermediate B108 [ka]

[0604] The title compound was prepared from B107-01 and 6-fluoronicotinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 217.2.

[0605] Intermediate B109 [ka]

[0606] The title compound was prepared from B01-01 and 4-bromo-2-(fluoromethoxy)benzonitrile using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 250.1.

[0607] Intermediate B110 [ka]

[0608] The title compound was prepared from B01-01 and 5-bromo-2-methylisoindoline-1,3-dione using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + =260.1; 1 H NMR (400 MHz, CD3OD) δ 7.67 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 4.09 - 3.98 (m, 1H), 3.87 - 3.78 (m, 1H), 3.74 - 3.64 (m, 2H), 3.61 - 3.52 (m, 1H), 3.07 (s, 3H), 2.82 (s, 3H), 2.64 - 2.51 (m, 1H), 2.38 - 2.26 (m, 1H).

[0609] Intermediate B111 [ka]

[0610] To a solution of B111-01 (1.14 g, 8.43 mmol) in DMF (20 ml), NBS (1.5 g, 8.43 mmol) was added at 0°C. The mixture was stirred at 25°C for 2.5 hours. The mixture was diluted with water (30 mL), the solid was filtered, and the mixture was concentrated under vacuum to obtain B111-02 (1.6 g, 89% yield). LCMS: MS m / z (ESI) [M+H] + = 213.9; 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 5.10 (d, J = 2.0 Hz, 2H), 5.07 (d, J = 2.0 Hz, 2H), 3.54 (brs, 2H).

[0611] To a solution of B111-02 (1.5 g, 7.01 mmol) in DMF (2 ml), Zn(CN)2 (1.23 g, 10.5 mmol) and Pd(Ph3P)4 (0.81 g, 0.70 mmol) were added. The resulting mixture was stirred at 120°C for 4 hours under an N2 atmosphere. After cooling to room temperature, the mixture was diluted with water and extracted with SiO2 (50 ml x 3). The organic layers were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel with elution using (petroleum ether / THF = 20 / 1 → 2 / 1) to obtain B111-03 (800 mg, 71.3% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.4 Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.20 (s, 2H), 5.04 (d, J = 2.0 Hz, 2H), 4.87 (d, J = 2.0 Hz, 2H).

[0612] To a solution of B111-03 (770 mg, 4.81 mmol) in water (4 ml), concentrated HCl (2.20 ml, 26.4 mmol) was added at 0°C, followed by the dropwise addition of sodium nitrite (348 mg, 5.05 mmol) in water (2 ml) at 0°C. The mixture was stirred at 0°C for 15 minutes, after which potassium iodide (838 mg, 5.05 mmol) in water (2 ml) was slowly added. The resulting mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with SiO2 (20 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain B111-04 (1200 mg, 92% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 5.33 (s, 2H), 4.97 (s, 2H).

[0613] B111 was prepared from B01-01 and B114-04 using the same procedure as described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 244.1.

[0614] Intermediate B112 [ka]

[0615] To a solution of B01-01 (5.00 g, 25.0 mmol) in DCM (200 mL), (4-bromophenyl)boronic acid (7.52 g, 37.4 mmol), TEA (17.4 ml, 125 mmol), Cu(OAc)2 (6.80 g, 37.4 mmol), and a 4 Å molecular sieve (1.00 g, 25.0 mmol) were added, and the reaction solution was stirred at 25°C for 12 hours under an O2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 3% THF / petroleum ether gradient at 100 mL / min) to obtain B112-01 (5.26 g, 59.3% yield). LCMS: MS m / z (ESI) [M+H] + = 355.0; 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 8.8 Hz, 2H), 5.05 - 4.77 (m, 1H), 3.49 - 3.37 (m, 2H), 3.30 - 3.15 (m, 2H), 2.81 (s, 3H), 2.26 - 2.17 (m, 1H), 2.16 - 2.05 (m, 1H), 1.49 (s, 9H).

[0616] To a solution of B112-01 (300 mg, 0.844 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (181 mg, 0.929 mmol) in dioxane (2 ml) and H2O (0.4 ml), K2CO3 (350 mg, 2.53 mmol) and Pd(dppf)Cl2 (61.8 mg, 0.084 mmol) were added. The reaction mixture was degassed three times and purged with N2, and then the mixture was stirred at 100°C for 1 hour under an N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with siRNA (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried via Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF 10 / 1) to obtain compound B112-02 (200 mg, 69.0% yield). LCMS: MS m / z (ESI) [M+H] + = 344.2 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 9.03 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 4.87 - 4.64 (m, 1H), 3.49 - 3.36 (m, 2H), 3.28 - 3.17 (m, 2H), 2.74 (s, 3H), 2.18 - 2.03 (m, 2H), 1.42 (s, 9H).

[0617] To a solution of B112-02 (200 mg, 0.582 mmol) in dioxane (1 ml), HCl / dioxane (5 ml) was added, and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and dried in vacuum to obtain compound B112 (150 mg, 92.0% yield). LCMS: MS m / z (ESI) [M+H] + = 244.2; 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.17 (brs, 2H), 9.05 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.92 - 3.84 (m, 1H), 3.58 - 3.52 (m, 1H), 3.52 - 3.41 (m, 2H), 3.32 - 3.22 (m, 1H), 2.62 (t, J = 5.6 Hz, 3H), 2.40 - 2.32 (m, 1H), 2.25 - 2.13 (m, 1H).

[0618] Intermediate B113 [ka]

[0619] The title compound was prepared from B01-01 and 3-(4-bromophenyl)isoxazole using a procedure similar to that described for the synthesis of B13. LCMS: MS m / z (ESI) [M+H] + = 244.1.

[0620] Intermediate B114 [ka]

[0621] The title compound was prepared from B107-01 and 4-fluoro-2-methoxybenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 246.1.

[0622] Intermediate B115 [ka]

[0623] The title compound was prepared from B01-01 and 2-(difluoromethyl)-4-fluorobenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 252.0.

[0624] Intermediate B116 [ka]

[0625] The title compound was prepared from B01-01 and 5-fluoro-4-methylpicolinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 217.2.

[0626] Intermediate B117 [ka]

[0627] The title compound was prepared from B107-01 and 4-fluoro-3-methylbenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 230.2.

[0628] Intermediate B118 [ka]

[0629] To a solution of B01-01 (500 mg, 2.50 mmol) in 1,4-dioxane (5 mL), Cs2CO3 (2.44 g, 7.49 mmol), 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (657 mg, 2.75 mmol), and Ruphos Pd G3 (209 mg, 0.25 mmol) were added. The mixture was stirred at 100°C for 16 hours under an N2 atmosphere. The mixture was filtered and extracted with siRNA (20 mL × 3) and water (5 mL). The organic layers were combined, washed with brine, and dried over anhydrous Na2O4. The crude product was purified by column chromatography on silica gel with elution using (petroleum ether / THF 20:1 → 3:1) to obtain B118-01 (880 mg, 98% yield). LCMS: MS m / z (ESI) [M+H] + = 359.1; 1 H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 8.8 Hz, 2H), 4.95 - 4.85 (m, 1H), 3.63 - 3.46 (m, 2H), 3.40 - 3.33 (m, 2H), 2.83 (s, 3H), 2.56 (s, 3H), 2.26 - 2.15 (m, 2H), 1.49 (s, 9H).

[0630] A solution of B118-01 (200 mg, 0.56 mmol) in HCl / dioxane (2 M, 2 mL, 4.00 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to obtain B118 (164 mg, crude). LCMS: MS m / z (ESI) [M+H] + = 259.1. 1H NMR (400 MHz, DMSO-d6) δ 9.50 (brs, 2H), 7.79 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 3.94 - 3.83 (m, 1H), 3.72 - 3.62 (m, 1H), 3.60 - 3.51 (m, 2H), 3.43 - 3.32 (m, 1H), 2.60 (t, J = 5.2 Hz, 3H), 2.53 (s, 3H), 2.43 - 2.21 (m, 2H).

[0631] Intermediate B119 [ka]

[0632] The title compound was prepared from B107-01 and 5-fluoro-4-methylpicolinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 231.2.

[0633] Intermediate B120 [ka]

[0634] The title compound was prepared from B01-01 and 2-chloro-4-fluorobenzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 236.1.

[0635] Intermediate B121 [ka]

[0636] The title compound was prepared from B01-01 and 5-fluoro-6-methylpicolinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + =217.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.83 - 9.55 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.84 - 3.69 (m, 2H), 3.68 - 3.63 (m, 2H), 3.43 - 3.35 (m, 1H), 2.58 (s, 3H), 2.57 (t, J = 5.2 Hz, 3H), 2.35 - 2.17 (m, 2H).

[0637] Intermediate B122 [ka]

[0638] The title compound was prepared from B107-01 and 5-fluoro-6-methylpicolinonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + =231.1; 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (brs, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.90 - 3.79 (m, 1H), 3.75 - 3.64 (m, 3H), 3.46 - 3.35 (m, 1H), 3.08 - 2.94 (m, 2H), 2.58 (s, 3H), 2.36 - 2.19 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0639] Intermediate B123 [ka]

[0640] The title compound was prepared from 2,3-difluoropyridine and B123-01 using a procedure similar to that described for the synthesis of B47. LCMS: MS m / z (ESI) [M+H] + = 222.2.

[0641] Intermediate B124 [ka]

[0642] To a solution of B124-01 (2g, 9.13 mmol) in SiO2 (20 ml), T4P (16.45 g, 22.83 mmol), DIPEA (4.78 ml, 27.4 mmol), and acethydrazide (0.744 g, 10.05 mmol) were added. The mixture was stirred at 80°C for 12 hours under N2. The reaction mixture was diluted with H2O (20 mL) and extracted with SiO2 (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 30 / 1) to obtain B124-02 (700 mg, 29.8% yield). LCMS: MS m / z (ESI) [M+H] + = 256.9; 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (t, J = 8.0 Hz, 1H), 7.89 (dd, J = 10.4, 1.6 Hz, 1H), 7.66 (dd, J = 8.4, 1.6 Hz, 1H), 2.60 (s, 3H).

[0643] To a solution of B01-01 (500 mg, 2.50 mmol) in dioxane (10 ml), B124-02 (642 mg, 2.50 mmol), Cs2CO3 (1.63 g, 4.99 mmol), and Ruphos Pd G3 (209 mg, 0.250 mmol) were added. The mixture was stirred at 100°C for 3 hours under N2. The reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried through Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / THF = 100 / 0 → 20 / 1) to obtain B124-03 (940 mg, 100% yield). LCMS: MS m / z (ESI) [M+H] + = 377.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.69 (m, 1H), 6.59 - 6.50 (m, 2H), 4.86 - 4.67 (m, 1H), 3.53 - 3.45 (m, 2H), 3.37 - 3.23 (m, 2H), 2.75 (s, 3H), 2.53 (s, 3H), 2.16 - 2.06 (m, 2H), 1.42 (s, 9H).

[0644] A solution of B124-03 (990 mg, 2.63 mmol) in 2 M HCl / dioxane (20 ml) was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain B124 (820 mg, crude). LCMS: MS m / z (ESI) [M+H] + =277.0; 1H NMR (400 MHz, DMSO-d6) δ 9.45 (brs, 2H), 7.82 - 7.72 (m, 1H), 6.61 - 6.53 (m, 2H), 3.95 - 3.83 (m, 1H), 3.71 - 3.62 (m, 1H), 3.60 - 3.50 (m, 2H), 3.44 - 3.34 (m, 1H), 2.60 (br t, J = 5.2 Hz, 3H), 2.54 (s, 3H), 2.40 - 2.31 (m, 1H), 2.30 - 2.22 (m, 1H).

[0645] Intermediate B125 [ka]

[0646] The title compound was prepared from B01-01 and 4-fluoro-2-(trifluoromethyl)benzonitrile using a procedure similar to that described for the synthesis of B01. LCMS: MS m / z (ESI) [M+H] + = 270.1.

[0647] Intermediate B126 [ka]

[0648] The title compound was prepared from B123-01 and 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole using a procedure similar to that described for the synthesis of B118. LCMS: MS m / z (ESI) [M+H] + = 285.1; 1H NMR (400 MHz, DMSO-d6) δ = 9.38 - 8.91 (m, 2H), 7.79 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 9.2 Hz, 2H), 3.89 - 3.81 (m, 1H), 3.80 - 3.70 (m, 2H), 3.52 - 3.45 (m, 1H), 3.12 - 3.00 (m, 1H), 2.60 - 2.54 (m, 3H), 2.53 (s, 3H), 1.43 - 1.35 (m, 1H), 0.93 - 0.79 (m, 2H), 0.77 - 0.68 (m, 1H).

[0649] Intermediate B127 [ka]

[0650] The title compound was prepared from B127-01 and B01-01 using the same procedure as described for the synthesis of B124. LCMS: MS m / z (ESI) [M+H] + = 273.1.

[0651] Intermediate B128 [ka]

[0652] The title compound was prepared from B112-01 and (1-methyl-1H-pyrazole-5-yl)boronic acid using a procedure similar to that described for the synthesis of B112. LCMS: MS m / z (ESI) [M+H] + = 257.1; 1H NMR (400 MHz, DMSO-d6) δ 9.75 - 9.55 (m, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 6.69 (d, J = 8.8 Hz, 2H), 6.37 (d, J = 2.0 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.86 (s, 3H), 3.68 - 3.60 (m, 1H), 3.56 - 3.50 (m, 2H), 3.41 - 3.29 (m, 1H), 2.60 (t, J = 5.2 Hz, 3H), 2.43 - 2.23 (m, 2H).

[0653] Intermediate B129 [ka]

[0654] To a solution of B01-01 (5g, 25.0 mmol) in DCM (50 ml), (4-bromo-3-fluorophenyl)boronic acid (13.7g, 62.4 mmol), Cu(OAc)2 (9.07g, 49.9 mmol), TEA (10.4 ml, 74.9 mmol), and a 4 Å molecular sieve (5.00 g, 25.0 mmol) were added, and the reaction solution was stirred at 25°C for 12 hours under an O2 atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (eluent: 0% → 7% THF / petroleum ether gradient at 80 mL / min) to obtain B129-01 (3.90 g, 10.5 mmol, 41.9% yield). LCMS: MS m / z (ESI) [M+H] + = 373.0; 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J = 8.4 Hz, 1H), 6.31 (dd, J = 11.6, 2.8 Hz, 1H), 6.22 (dd, J = 8.8, 2.8 Hz, 1H), 5.03 - 4.82 (m, 1H), 3.47 - 3.37 (m, 2H), 3.30 - 3.14 (m, 2H), 2.81 (s, 3H), 2....

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, Ring A is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocycloalkyl, Each R １ , ｃ , １ , ｂ , １ , ２ , ６ , ６ , ｄ , ６ , ２ , ６ , ｂ , ２ , ａ , １ , １ , ａ , ６ , ２ , ６ , ｂ , ６ is independently halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ )R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S(=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -P(=O)(R ｂ ) ２ , C １ ~C ６ alkyl, C １ ~C<000004一]]haloalkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ aminoalkyl, C １ ~C ６ heteroalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R ４ａ It is arbitrarily replaced with, or Two R atoms on the same atom ４ They combine to form an oxo, or, Two R atoms on the same atom ４ They come together, each with one or more R ４ｂ This forms a cycloalkyl or heterocycloalkyl group with arbitrary substitutions. Each R ４ａ is, independently, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ), R ｂ , -NR ｃ R ｄ , -NR ｂ , -NR ｃ C(=O)NR ｄ R ｂ , -NR ａ C(=O)R ｂ , -NR ｂ C(=O)OR ｂ , -NR ２ S(=O) ａ R ｂ ), ２ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , -P(=O)(R ｂ ), ２ , C １ ~C ６ alkyl, C １ ~C<00_{00096}haloalkyl, C １ ~C ６ hydroxyalkyl, C １ ~C ６ aminoalkyl, C １ [[ID=Q2]]~C ６ heteroalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ４ａ They come together to form an oxo, Each R ４ｂ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ４ｂ They come together to form an oxo, n is 1, 2, 3, 4, 5, or 6. R ５ is -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R ５ａ It is arbitrarily replaced with, Each R ５ａ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ５ａ They come together to form an oxo, W is N or CR Ｗ And, R Ｗ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. U is N or CR Ｕ And, R Ｕ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. T is N or CR Ｔ And, R Ｔ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. X is C, and Y is C, or X is C, and Y is N, or X is N and Y is C, Z １ O, S, N, NR １ａ CR １ｂ , or C(R １ｃ ) ２ And, Z ２ O, S, N, NR ２ａ CR ２ｂ , or C(R ２ｃ ) ２ And, Z ３ O, S, N, NR ３ａ CR ３ｂ , or C(R ３ｃ ) ２ And, Each R １ａ , R ２ａ , and R ３ａ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. Each R １ｂ , R ２ｂ , and R ３ｂ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. Each R １ｃ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R １ｃ They come together to form an oxo, Each R ２ｃ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R ２ｃ They come together to form an oxo, Each R ３ｃ These are independently hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R ３ｃ They come together to form an oxo, Each R ａ Independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. Each R ｂ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are independently substituted with one or more R groups. R ｃ and R ｄ Each of them is independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or R ｃ and R ｄ These, together with the atoms to which they are bonded, form a heterocycloalkyl group optionally substituted with one or more R atoms. L is either nonexistent or C is arbitrarily replaced by one or more R's. １ ~C ４ It is alkylene, and also Each R is independently halogen, -CN, -OH, -SF ５ , -SH, -S(=O)C １ ~C ３ Alkyl, -S (=O) ２ C １ ~C ３ Alkyl, -S (=O) ２ NH ２ , -S (=O) ２ NHC １ ~C ３ Alkyl, -S (=O) ２ N(C) １ ~C ３ Alkyl) ２ , -S(=O)(=NC １ ~C ３ (Alkyl) (C １ ~C ３ Alkyl), -NH ２ , - NHC １ ~C ３ Alkyl, -N(C) １ ~C ３ Alkyl) ２ , -N=S(=O)(C １ ~C ３ Alkyl) ２ , -O-C １ ~C ４ Alkylene-OH,-O-C １ ~C ４ Alkylene-NH ２ , -C(=O)C １ ~C ３ Alkyl, -C(=O)OH, -C(=O)OC １ ~C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ ~C ３ Alkyl, -C(=O)N(C １ ~C ３ Alkyl) ２ , -P(=O)(C １ ~C ３ Alkyl) ２ , C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Heteroalkyl, C ３ ~C ６ A cycloalkyl group, or a 3- to 6-membered heterocycloalkyl group, or Compounds of which (two R atoms on the same atom form an oxo) or pharmaceutically acceptable salts or stereoisomers thereof.

2. The compound of formula (I) is of formula (Ia): 【Chemistry 2】 (In the formula, Ring B is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring. Each R ６ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ６ They come together to form an oxo, m is 0, 1, 2, 3, 4, 5, or 6. Each R ７ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ７ They come together to form an oxo, p is 0, 1, 2, 3, 4, or 5, and, L is either nonexistent or C is arbitrarily replaced by one or more R's. １ ~C ４ The compound according to claim 1, which is an alkylene compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. Each R ６ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C (=O) OR ｂ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ A compound according to claim 1 or 2, wherein each alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently optionally substituted with one or more R groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. ring 【Transformation 3】 teeth, 【Chemistry 4】 The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 5】 【Chemistry 5】 teeth, 【Transformation 6】 The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof. [Request Item 6] [Chemistry 7] teeth, 【Transformation 8】 The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 7】 【Chemistry 9】 teeth, 【Chemistry 10】 The compound according to claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

8. The compound of formula (I) is of formula (Ib): 【Chemistry 11】 (In the formula, Ring C is cycloalkyl or heterocycloalkyl, Each R ６ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ６ They come together to form an oxo, m is 0, 1, 2, 3, 4, 5, or 6. Each R ７ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SF ５ -SH, -SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ｃ R ｄ , -S(=O)(=NR ｂ ) R ｂ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C (=O) OR ｂ , -NR ｂ S (=O) ２ R ａ , -N=S(=O)(R ｂ ) ２ , -C(=O)R ａ , -C (=O) OR ｂ , -C(=O)NR ｃ R ｄ , -P (=O) (R ｂ ) ２ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more R groups, or Two R atoms on the same atom ７ They come together to form an oxo, The compound according to claim 1, wherein q is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt or stereoisomer thereof.

9. The compound according to any one of claims 1 to 8, wherein ring A is a 4- to 6-membered cycloalkyl group, or a pharmaceutically acceptable salt or stereoisomer thereof.

10. The compound according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered fully saturated cycloalkyl group.

11. The compound according to claim 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered partially saturated cycloalkyl group.

12. Ring A is, 【Chemistry 12】 The compound according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 13】 【Chemistry 13】 teeth, 【Chemistry 14】 The compound according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The compound according to any one of claims 1 to 8, wherein ring A is a 4- to 6-membered heterocycloalkyl group, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The compound according to claim 14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered fully saturated heterocycloalkyl group.

16. Ring A is, 【Chemistry 15】 The compound according to claim 15, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 17】 【Chemistry 16】 teeth, 【Chemistry 17】 The compound according to claim 15, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound according to claim 14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 4- to 6-membered partially saturated heterocycloalkyl group.

19. Each R ７ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ A compound according to any one of claims 2 to 18, which is a heteroalkyl compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

20. Two R atoms on the same atom ７ The compounds according to any one of claims 2 to 18, or pharmaceutically acceptable salts or stereoisomers thereof, which together form an oxo.

21. R ５ C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more R ５ａ A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, which is optionally substituted with .

22. L is a bond or -CH ２ - The compound according to claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

23. R ５ は、CH ３ 、㼣㼨㼦 ２ 、㼣㼦 ３ 、㼣㼨 ２ CH ３ 、㼣㼨 ２ CH(CH ３ ) ２ 、㼣㼨 ２ CHF ２ 、㼣㼨 ２ CF ３ 、 [Chemistry 18] The compound according to claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof.

24. Each R ５ａ These are, independently, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ A compound according to any one of claims 1 to 23, wherein the heteroalkyl group is independently substituted with one or more R groups, or a pharmaceutically acceptable salt or stereoisomer thereof.

25. W is CR Ｗ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or stereoisomer thereof.

26. R Ｗ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ The compound according to claim 25, which is a heteroalkyl compound, wherein the alkyl is optionally substituted with one or more R atoms, or a pharmaceutically acceptable salt or stereoisomer thereof.

27. U is CR Ｕ The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof.

28. R Ｕ These are hydrogen, halogen, -CN, and -NO ２ -OH, -OR ａ , -SF ５ -SH, -SR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ The compound according to claim 27, which is a heteroalkyl compound, wherein the alkyl is optionally substituted with one or more R atoms, or a pharmaceutically acceptable salt or stereoisomer thereof.

29. T is CR Ｔ The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt or stereoisomer thereof.

30. R Ｔ is hydrogen, halogen, -C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or C ２ Or C ３ The compound according to claim 29, which is an alkynyl, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 31】 【Chemistry 19】 teeth, 【Chemistry 20】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 32】 【Chemistry 21】 teeth, 【Chemistry 22】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 33】 【Chemistry 23】 teeth, 【Chemistry 24】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof. 【Request Item 34】 【Chemistry 25】 teeth, 【Chemistry 26】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof.

35. The compound is a compound according to claim 1, selected from Tables 1 and 2, or a pharmaceutically acceptable salt or stereoisomer thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.

37. A method for treating a disease or condition, comprising administering to a subject in need of treatment a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 36, wherein the disease or condition is related to the overexpression of PRMT5.

38. The method according to claim 37, wherein the disease or condition is cancer.

39. A method for treating cancer, comprising administering to a subject in need of treatment a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition according to claim 37.

40. The method according to claim 38 or 39, wherein the cancer is selected from pancreatic cancer, colorectal cancer, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, cervical cancer, testicular germ cell carcinoma, and non-small cell lung cancer, and multiple myeloma, diffuse large B-cell lymphoma, rhabdomyosarcoma, and cutaneous squamous cell carcinoma.

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