Cyclic sulfonamide ribonucleotide reductase (RNR) inhibitors and uses thereof

Abstract

Provided herein are compounds and methods for the treatment of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a cyclic sulfonamide RNR inhibitor disclosed herein.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 375,495, filed September 13, 2022, the entire contents of which are incorporated herein by reference.

[0002] Described herein are compounds for inhibiting ribonucleotide reductase (RNR), methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods for using such compounds. [Background technology]

[0003] Ribonucleotide reductase (RNR), also known as ribonucleotide diphosphate reductase (rNDP), is composed of a hetero-oligomer of a large subunit, M1, and a small subunit, M2, both of which must be expressed for enzymatic activity. RNR is a highly regulated enzyme in the deoxyribonucleotide synthesis pathway, present ubiquitously in humans, bacteria, yeast, and other organisms. RNR is involved in the de novo conversion of ribonucleotide diphosphates to 2'-deoxyribonucleotide diphosphates, a process essential for DNA synthesis and repair. RNR is directly involved in DNA synthesis and repair, tumor growth, metastasis, and drug resistance. Numerous correlations between M2 overexpression and their prognosis have been reported in various types of solid tumors and hematological cancers. Furthermore, cell growth inhibition due to inhibition of RNR and antitumor effects in vivo have been reported in cell lines derived from several cancer types and in preclinical models.

[0004] Cancer cell proliferation requires excess deoxyribonucleotide triphosphates (dNTPs) for DNA synthesis. Therefore, increased RNR activity is necessary to help provide extra dNTPs for DNA replication in primary and metastatic cancer cells. This important role in DNA synthesis makes RNR an important target for cancer therapy. However, existing chemotherapeutics targeting RNR are nucleoside-based analogs. Therefore, they are indiscriminate and result in nonspecific binding of other nucleoside-binding proteins, leading to undesirable side effects. Therefore, there is a need for compositions and methods for specifically targeting and inhibiting RNR activity in neoplastic cells in cancer treatment. Summary of the Invention

[0005] Described herein are RNR inhibitors useful in the treatment of cancer.

[0006] As used herein, the term "a compound of formula (I)" as defined herein refers to a compound of formula (I)

[0007] [ka] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0008] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0009] Also disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0010] Also disclosed herein is a method of inhibiting ribonucleotide reductase in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0011] In some embodiments, the inhibition of ribonucleotide reductase occurs in tumor cells of a subject in need thereof.

[0012] Also disclosed herein are methods of treating a tumor or tumor cells in a subject, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, in an amount sufficient to induce replication stress in the tumor or tumor cells, and administering a cancer targeted therapeutic agent, wherein the tumor or tumor cells have an ecDNA signature, and tumor growth or size, or tumor cell growth or number, is reduced.

[0013] Also disclosed herein are methods for treating ecDNA-associated tumors or tumor cells, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells containing ecDNA, wherein tumor growth or size, or tumor cell growth or number, is reduced as a result of treatment. In some embodiments, the method further comprises administering a targeted cancer therapy agent. In some embodiments, the targeted cancer therapy agent inhibits a gene or gene product contained in ecDNA in the tumor or tumor cells.

[0014] Also disclosed herein are methods of treating a tumor or tumor cells in a subject, said methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, in an amount sufficient to induce replication stress in the tumor or tumor cells, wherein the tumor or tumor cells contain ecDNA or have an ecDNA signature, and tumor growth or size, or tumor cell growth or number, is reduced.

[0015] Also disclosed herein are methods for treating ecDNA-associated tumors or tumor cells, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells with local amplification of an oncogene, wherein tumor growth or size, or tumor cell growth or number, is reduced as a result of treatment. In some embodiments, the method further comprises administering a cancer-targeting therapeutic agent, wherein the target of the therapeutic agent is a protein encoded by the oncogene. In some embodiments, the local amplification is present on ecDNA.

[0016] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the particular purposes identified herein. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition In the following description, specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the following specification and claims, the word "comprise" and variations thereof (e.g., "comprises" or "comprising") are intended to be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the subject invention.

[0018] References herein to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Similarly, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0019] As used herein, the following terms have the following meanings unless otherwise specified:

[0020] "Oxo" refers to =O.

[0021] "Amine" refers to -NH2.

[0022] "Hydroxy" refers to --OH.

[0023] "Carboxyl" refers to --COOH.

[0024] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical 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. Wherever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses appearances of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1-C6 alkyl. 10In some embodiments, the alkyl is a C1-C6 alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless otherwise specified herein, an alkyl group can be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0025] "Alkenyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans or Z or E configuration about the double bond, and should be understood to include all isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Wherever appearing herein, a numerical range such as "C-C alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also encompasses appearances of the term "alkenyl" where no numerical range is explicitly stated. Unless otherwise specified in the specification, an alkenyl group can be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0026] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" where no numerical range is explicitly stated. Unless otherwise specified in the specification, an alkynyl group can be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0027] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can be optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0028] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined above. Unless otherwise specified in the specification, an alkoxy group can be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0029] "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 fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless otherwise specified herein, an aryl can be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, an aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with a halogen.

[0030] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which can include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spirocyclic, and / or bridged ring systems. In some embodiments, a cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (e.g., C3-C4).15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (e.g., C-C fully saturated cycloalkyl or C-C cycloalkenyl). 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 to 6-membered fully saturated cycloalkyl or a 5 to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl. and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.Unless otherwise specified herein, cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In some embodiments, cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0031] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0032] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, bromomethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, 1-chloroethyl, and the like.

[0033] "Haloalkoxy" refers to an --O-haloalkyl, where haloalkyl is defined above.

[0034] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted by 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. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl. In some embodiments, the hydroxyalkyl is 1-hydroxyeth-1-yl, 2-hydroxy-prop-2-yl, 2-hydroxy-2-methylpropmethylprop-1-yl, or 2,3-dihydroxypropyl.

[0035] "Aminoalkyl" refers to an alkyl radical, as defined above, 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. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, CHN(CH), or CH(CH)N(CH). In some embodiments, the aminoalkyl is aminomethyl.

[0036] "Deuterated alkyl" refers to an alkyl radical, as defined above, substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuterated alkyls include, for example, CD3, CHD, CHD, CHCD, CDCD, CHDCD, CHCHD, or CHCHD. In some embodiments, the deuterated alkyl is CD3.

[0037] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CHOCH, -CHCHOCH, -CHCHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHC(CH)OCH, -CHNHCH, -CHN(CH), -CH(CH)N(CH), -CHCHNHCH, or -CHCHN(CH). 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, or heteroaryl. In some embodiments, heteroalkyls are optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0038] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl is C-bonded. In some embodiments, a heterocycloalkyl is N-bonded. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. In some embodiments, a heterocycloalkyl contains 1 oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spirocyclic, or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized; and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperazinyl, and 4-piperazinyl. Examples of heterocycloalkyl include lydonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, 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 cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specified herein, a heterocycloalkyl is optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0039] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. In some embodiments, a heteroaryl is C-linked. In some embodiments, a heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached by an aromatic ring atom) or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzo Thiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxadiazolonyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1 Examples of heteroaryl include H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified in the specification, heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl.In some embodiments, heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0040] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups can be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at levels ranging between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.).

[0041] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with one, two, three, or four or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0042] As used herein, the terms "treat," "treated," "treatment," or "treating" refer to therapeutic treatment, the purpose of which is to delay (lessen) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical result. For purposes described herein, a beneficial or desired clinical result includes, but is not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder, or condition, stabilization of the disease, disorder, or condition (i.e., not worsening), delay in the onset or slowing of progression of the disease, disorder, or condition, improvement of the disease, disorder, or disease state, and remission (whether partial or total), or enhancement or amelioration of the disease, disorder, or condition, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes prolonging survival compared to expected survival in the absence of treatment. The terms "treat," "treated," "treatment," or "treating," as well as words derived therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, the degree of treatment that one skilled in the art would recognize as potentially beneficial or therapeutically effective varies. In this regard, the disclosed methods can provide any level of treatment for a mammalian disorder in any amount. For example, a disorder, including its symptoms or conditions, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0043] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of a compound disclosed herein being administered that will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or amelioration of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the quantity of a composition comprising a compound as disclosed herein that is required to produce a clinically significant reduction in a disease symptom. In some embodiments, an appropriate "effective" amount in any individual case is determined using techniques, such as a dose escalation study.

[0044] The term "ecDNA signature," as used herein, generally refers to one or more features common to tumors or tumor cells that are ecDNA+ (including extrachromosomal DNA (ecDNA)). In some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutations, lack of microsatellite instability (MSI-H), low levels of PD-L1 expression, low levels of tumor inflammation signature (TIS), low levels of tumor mutation burden (TMB), increased frequency of allelic substitutions, insertions, or deletions (indels), and any combination thereof. In some cases, the ecDNA signature includes detection or identification of ecDNA using imaging techniques. In some cases, the ecDNA signature does not include any imaging or direct detection of ecDNA.

[0045] compound Described herein are cyclic sulfonamide RNR inhibitors useful for the treatment of cancer.

[0046] As used herein, the formula (I)

[0047] [ka] or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X1 is N or CR 1 and X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and R 1 are hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R 2 are hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)Ra , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R 3 are hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NRb C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R 4 are hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Ring C is -O-, -S-, -S(=O)-, -S(=O)2-, and -NR 10 -, and is a 5-8 membered heterocycloalkyl containing 1 or 2 additional heteroatoms selected from the group consisting of: R 10 are hydrogen, -OH, -OR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 10a is replaced by R 10a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR cR d , -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 , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same carbon 10a come together to form oxo, R 5 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same carbon 5 come together to form oxo, Alternatively, two R on the same carbon 5together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on adjacent atoms 5 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Or, one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R; p is 0 to 4; Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; R 6 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom 6 come together to form oxo, n is 0 to 3, R 7 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 8is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 9 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by Alternatively, two R on the same atom 9 come together to form oxo, R 9aare each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -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)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom 9a come together to form oxo, m is 0 to 5; R aare each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Alternatively, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; 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, -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, cycloalkyl, or heterocycloalkyl; Alternatively, two R on the same atom together form an oxo.

[0048] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound has the formula:

[0049] [ka] It is of the type.

[0050] In some embodiments of the compounds of Formula (I), ring C is selected from -O-, -S-, and -NR 10 In some embodiments of the compound of Formula (I), ring C is a 5- to 8-membered heterocycloalkyl containing one or two additional heteroatoms selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 5- to 8-membered heterocycloalkyl containing one or two additional heteroatoms selected from the group consisting of -O-, -S-, and -NR 10 In some embodiments of the compound of Formula (I), ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -O and -NR 10 In some embodiments of the compounds of Formula (I), ring C is a 5- to 8-membered heterocycloalkyl containing one or two additional heteroatoms selected from the group consisting of -O- and -NR 10 In some embodiments of the compounds of Formula (I), Ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom that is —O—. In some embodiments of the compounds of Formula (I), Ring C is —NR 10In some embodiments of a compound of Formula (I), Ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom that is -S-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 8-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-.

[0051] In some embodiments of the compounds of Formula (I), ring C is selected from -O-, -S-, and -NR 10 In some embodiments of the compound of Formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -O- and -NR 10 In some embodiments of the compounds of Formula (I), Ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom that is —O—. In some embodiments of the compounds of Formula (I), Ring C is —NR 10 In some embodiments of a compound of Formula (I), Ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (I), Ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-.

[0052] In some embodiments of the compounds of Formula (I), ring C is selected from -O-, -S-, and -NR 10 In some embodiments of the compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -O- and -NR 10 In some embodiments of the compounds of Formula (I), Ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom that is —O—. In some embodiments of the compounds of Formula (I), Ring C is —NR 10 In some embodiments of a compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S-. In some embodiments of a compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-.

[0053] In some embodiments of the compounds of Formula (I), ring C is selected from -O-, -S-, and -NR 10 In some embodiments of the compounds of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compounds of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compounds of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -O- and -NR 10 In some embodiments of the compounds of Formula (I), Ring C is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -NR10 In some embodiments of a compound of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom that is -O-. In some embodiments of a compound of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (I), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom that is -S-.

[0054] In some embodiments of the compounds of Formula (I), ring C is selected from -O-, -S-, and -NR 10 In some embodiments of the compounds of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compounds of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -S(=O)- and -S(=O)2-. In some embodiments of the compounds of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -O- and -NR 10 In some embodiments of the compounds of Formula (I), Ring C is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of -NR 10In some embodiments of a compound of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -O-. In some embodiments of a compound of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -S-. In some embodiments of a compound of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)2-. In some embodiments of a compound of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -S(=O)-. In some embodiments of a compound of Formula (I), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -S-.

[0055] In some embodiments of the compounds of Formula (I), R 5 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (I), R 5 are each independently deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I), R 5 are each independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 5 are each independently C1-C6 alkyl.

[0056] In some embodiments of the compounds of Formula (I), two R 5 come together to form oxo.

[0057] In some embodiments of the compounds of Formula (I), two R 5 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R.

[0058] In some embodiments of compounds of Formula (I), two R 5 together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R.

[0059] In some embodiments of the compounds of Formula (I), one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R.

[0060] In some embodiments of the compound of Formula (I), p is 0 to 3. In some embodiments of the compound of Formula (I), p is 0 to 2. In some embodiments of the compound of Formula (I), p is 0 or 1. In some embodiments of the compound of Formula (I), p is 1 or 2. In some embodiments of the compound of Formula (I), p is 1 to 3. In some embodiments of the compound of Formula (I), p is 1. In some embodiments of the compound of Formula (I), p is 2. In some embodiments of the compound of Formula (I), p is 3.

[0061] In some embodiments of the compound of Formula (I), the compound of Formula (I) has the formula (Ia):

[0062] [ka] wherein: X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR 10 - and R 5’ are each independently hydrogen or R5 and Alternatively, two R on the same carbon 5’ come together to form oxo, Alternatively, two R on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Or, one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R.

[0063] In some embodiments of the compound of Formula (Ia), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound has the formula:

[0064] [ka] It is of the type.

[0065] In some embodiments of the compound of Formula (I), the compound of Formula (I) has the formula (Ib):

[0066] [ka] wherein: X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR 10 - and R 5’ are each independently hydrogen or R 5 and Alternatively, two R on the same carbon 5’ come together to form oxo, Alternatively, two R on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on adjacent carbons 5’together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Or, one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R.

[0067] In some embodiments of the compound of Formula (Ib), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound has the formula:

[0068] [ka] It is of the type.

[0069] In some embodiments of the compound of Formula (I), the compound of Formula (I) has the formula (Ic):

[0070] [ka] wherein: X is -O-, -S-, -S(=O)-, -S(=O)2-, or -NR 10 - and R 5’ are each independently hydrogen or R 5 and Alternatively, two R on the same carbon 5’ come together to form oxo, Alternatively, two R on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Or, one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R.

[0071] In some embodiments of the compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, the compound has the formula:

[0072] [ka] It is of the type.

[0073] In some embodiments of the compounds of Formula (Ia)-(Ic), X is -S-, -S(=O)-, or -S(=O)2-. In some embodiments of the compounds of Formula (Ia)-(Ic), X is -O-, -S-, or -NR 10 In some embodiments of compounds of Formula (Ia)-(Ic), X is -O- or -NR 10 In some embodiments of the compounds of Formula (Ia)-(Ic), X is -O-. In some embodiments of the compounds of Formula (Ia)-(Ic), X is -NR 10 -It is.

[0074] In some embodiments of compounds of Formula (Ia)-(Ic), R 5’ are each independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulae (Ia)-(Ic), R 5’ are each independently hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formulae (Ia)-(Ic), R 5’ are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 5’ are each independently hydrogen or C1-C6 alkyl.

[0075] In some embodiments of compounds of Formula (Ia)-(Ic), two R 5’ come together to form oxo.

[0076] In some embodiments of compounds of Formula (Ia)-(Ic), two R 5’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R.

[0077] In some embodiments of compounds of Formula (Ia)-(Ic), one R 5 and R 10 together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R.

[0078] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen, -S(=O)R a , -S(=O)2R a , -S(=O)2NR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 10a is replaced by

[0079] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen, -S(=O)2R a, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently selected from one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein alkyl is optionally independently selected from one or more R 10a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10 is C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10a are each independently deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10a are each independently deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 10a are each independently a halogen, -OH, or -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or heterocycloalkyl.

[0080] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing 2 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing 3 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing 2 to 4 heteroatoms selected from the group consisting of O, S, and N.

[0081] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing 3 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is triazole or tetrazole. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is triazole. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is tetrazole. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), ring A is 2,3-dihydro-1,3,4-oxadiazole.

[0082] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 6are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl, or two R on the same atom 6 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 6 are each independently deuterium, halogen, or C1-C6 alkyl, or two R 6 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), two R on the same atom 6 come together to form oxo.

[0083] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 0 to 3. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 0 to 2. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 2 or 3.

[0084] In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 1 to 3. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 1. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 2. In some embodiments of the compound of Formula (I) or (Ia)-(Ic), n is 3.

[0085] In some embodiments of compounds of Formula (I) or (Ia)-(Ic),

[0086] [ka] teeth

[0087] [ka] and R 6’ is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic),

[0088] [ka] teeth

[0089] [ka] is.

[0090] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 1 is CR 1 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 1 is N.

[0091] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 are hydrogen, deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c Rd , -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 is hydrogen, deuterium, halogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, wherein alkyl is optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 is hydrogen, deuterium, halogen, -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 is hydrogen, -C(=O)R a , C1-C6 alkyl, or C1-C6 hydroxyalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 1 is hydrogen.

[0092] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 2 is CR 2 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 2 is N.

[0093] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 are hydrogen, deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 is hydrogen, deuterium, halogen, —OH, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 2 is halogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R2 is chloro.

[0094] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 3 is CR 3 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 3 is N.

[0095] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 3 are hydrogen, deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 3 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 3 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 hydroxyalkyl, C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 3 is hydrogen.

[0096] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 4 is CR 4 In some embodiments of compounds of Formula (I) or (Ia)-(Ic), X 4 is N.

[0097] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 are hydrogen, deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 are hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NRc R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally independently substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 are hydrogen, deuterium, halogen, -CN, -OH, -OR 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen, deuterium, halogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 heteroalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen, -C(=O)R a , -C(=O)OR b , or -C(=O)NR c R dIn some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen or -C(=O)R a In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is hydrogen. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 4 is -C(=O)R a is.

[0098] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is halogen, -CN, -NO2, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl.

[0099] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R8 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 8 is hydrogen.

[0100] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is aryl or heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is phenyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is 6-membered heteroaryl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), Ring B is pyridinyl.

[0101] In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 are each independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Ic), R 9 are each independently halogen or C1-C6 alkyl.

[0102] In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 0 to 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1 to 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 2 or 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic), m is 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ic),

[0103] [ka] teeth

[0104] [ka] is.

[0105] In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0106] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b Each is hydrogen. In some embodiments of the compounds disclosed herein, R b are each independently C1-C6 alkyl.

[0107] In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, heterocycloalkyl, C-C alkylene(cycloalkyl), or C-C alkylene(heterocycloalkyl), wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C deuterated alkyl, C-C hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each alkyl, 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 are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d are each hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1-C6 alkyl.

[0108] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0109] In some embodiments of the compounds disclosed herein, each R is independently halogen, —CN, —OH, —NH, —NHC-C alkyl, —N(C-C alkyl), —C(═O)C-C alkyl, —C(═O)OH, —C(═O)OC-C alkyl, —C(═O)NH, —C(═O)NHC-C alkyl, —C(═O)N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, cycloalkyl, or heterocycloalkyl; or two R on the same atom are joined together to form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, cycloalkyl, or heterocycloalkyl; or two R on the same atom are joined together to form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, or C-C haloalkoxy, or two R on the same atom are joined together to form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, or C-C haloalkyl, or two R on the same atom are joined together to form oxo.In some embodiments of the compounds disclosed herein, each R is independently halogen, C-C alkyl, or C-C haloalkyl, or two R on the same atom are joined together to form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen or C-C alkyl, or two R on the same atom are joined together to form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, C-C haloalkoxy, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, C-C alkoxy, C-C haloalkyl, or C-C haloalkoxy. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH, C-C alkyl, or C-C haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, C-C alkyl, or C-C haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen or C-C alkyl.

[0110] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), the compound is selected from the compounds of Table 1.

[0111] [Table 1-1]

[0112] [Table 1-2]

[0113] [Table 1-3]

[0114]

Table 1-4

[0115]

Table 1-5

[0116]

Table 1-6

[0117]

Table 1-7

[0118]

Table 1-8

[0119]

Table 1-9

[0120]

Table 1-10

[0121]

Table 1-11

[0122]

Table 1-12

[0123]

Table 1-13

[0124]

Table 1-14

[0125]

Table 1-15

[0126]

Table 1-16

[0127]

Table 1-17

[0128]

Table 1-18

[0129]

Table 1-19

[0130]

Table 1-20

[0131]

Table 1-21

[0132]

Table 1-22

[0133]

Table 1-23

[0134] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically depicted stereoisomer.

[0135] In some embodiments of a compound of Formula (I) or (Ia)-(Ic), the compound is selected from the compounds of Table 2.

[0136] [Table 2-1]

[0137] [Table 2-2]

[0138] 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 contain one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein contain one or more chiral centers, each of which independently exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. The compounds described herein include all rotamers and atropisomers, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived 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 individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0139] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds, such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers that are different from the atomic masses or mass numbers that are usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Isotopically labeled compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 The C isotope is particularly preferred because it is easy to prepare and detect. 2Substitution with heavy isotopes such as H provides certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms in the compounds disclosed herein are replaced by deuterium atoms. In some embodiments, one or more alkyl substituents in the compounds disclosed herein are replaced by deuterated alkyl substituents.

[0140] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0141] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0142] In some embodiments, the compounds described herein possess acidic or basic groups and therefore can be reacted with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0143] Examples of pharmaceutically acceptable salts include salts prepared by reacting a compound described herein with an inorganic, organic acid, or inorganic base, including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, Hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectin Acid salts, persulfate, phenyl 3-propionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0144] Additionally, 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, including, but not limited to, inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids including, but not limited to, 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) Examples of suitable pharmaceutically acceptable acids include benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-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 sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids that are not themselves pharmaceutically acceptable, such as oxalic acid, are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0145] In some embodiments, the compounds described herein containing free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates, or the like, of pharmaceutically acceptable metal cations, ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-C4 alkyl)4 hydroxides, etc.

[0146] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is noted that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0147] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0148] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0149] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert by migration of a hydrogen atom, accompanied by switching between a single bond and one or more adjacent double bonds. In bond structures that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the tetrazoles disclosed herein can be in the form of their tautomers.

[0150] [ka] It exists as either

[0151] Preparation of compounds The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" refers to Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; includes Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0152] Suitable references and articles detailing the synthesis of reactants useful in preparing the compounds described herein or referencing articles describing the preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions," 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif., 1972; T.L.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and articles detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4th Edition (1992)John Wiley & Sons,ISBN:0-471-60180-2;Otera, J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S. 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,TWG“Organic Chemistry”7th Edition (2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,JC,“Intermediate Organic Chemistry”2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 8 volumes of "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; 55 volumes of "Organic Reactions" (1942-2000) John Wiley & Sons; and 73 volumes of "Chemistry of Functional Groups" John Wiley & Sons.

[0153] Specific and similar reactants are optionally identified through an index of known chemicals prepared by the American Chemical Society's Chemical Abstract Service, available at most public and university libraries and online. Known but not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many standard drug supply companies (e.g., those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0154] Pharmaceutical Composition In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0155] Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0156] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, unreacted intermediates or synthetic by-products produced in one or more steps of the synthetic method.

[0157] Pharmaceutical compositions are administered in a manner appropriate for the disease to be treated.Appropriate dosage and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of active ingredient, and the method of administration.In general, appropriate dosage and treatment regimen provides the composition in an amount sufficient to bring about therapeutic and / or preventive benefits (for example, improved clinical results), such as more frequent complete or partial remission, or longer disease-free survival and / or overall survival, or reduced severity of symptoms.Optimal dosage is generally determined using experimental models and / or clinical trials.Optimal dosage varies depending on the patient's body type, weight, or blood volume.

[0158] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, epidural, and intranasal administration. Parenteral applications include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, intranasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, solution, emulsion, ointment, lotion, eye drop, or nasal spray. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0159] Appropriate dosages and administration regimens can be determined by conventional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with a small dosage that is less than the optimal dose of the compounds disclosed herein. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is achieved. In some embodiments, the method involves administering at least one compound described herein at a dosage of about 0.1 μg to about 50 mg per kg of subject body weight. For a 70 kg patient, a dosage of about 10 μg to about 200 mg of the compounds disclosed herein will generally be used, depending on the subject's physiological response.

[0160] By way of example only, the dose of a compound described herein for the methods of treating a disease described herein is about 0.001 to about 1 mg per kg of subject body weight per day, e.g., about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg per kg of body weight per day. In some embodiments, the dose of a compound described herein for the above methods is about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0161] Treatment method Disclosed herein are methods for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Disclosed herein are methods for treating RNR-associated cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0162] In some embodiments, RNR-associated cancers include malignant tumors whose incidence can be reduced, or whose symptoms can be alleviated, ameliorated, and / or completely cured by deleting, suppressing, and / or inhibiting the function of RNR. Malignant tumors of interest include, but are not limited to, head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumors, etc.

[0163] In some embodiments, the term cancer is used according to its ordinary and plain meaning in light of the present disclosure to refer to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, pharmaceutical compositions, include lymphoma (e.g., mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, Burkitt's lymphoma), sarcoma, bladder cancer, bone cancer, brain tumor, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistant, Herceptin (trastuzumab) resistant, HER2 positive, doxorubicin resistant, etc.). , tamoxifen-resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.Further examples include tumors of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasms, medullary thyroid cancer, medullary thyroid cancer, In some embodiments, the cancer is selected from ovarian cancer, prostate cancer, esophageal cancer, salivary gland cancer, breast cancer, liver cancer, pancreatic cancer, gastric cancer, lung cancer, bladder cancer, colon cancer, and uterine cancer. In some embodiments, the cancer is selected from muscle cancer, brain cancer, lymph node cancer, thyroid cancer, kidney cancer, and adrenal cancer.

[0164] Also disclosed herein is a method of inhibiting ribonucleotide reductase in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0165] In some embodiments, the inhibition of ribonucleotide reductase occurs in tumor cells of a subject in need thereof.

[0166] Also disclosed herein are methods of treating a tumor or tumor cells in a subject, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, in an amount sufficient to induce replication stress in the tumor or tumor cells, and administering a cancer targeted therapeutic agent, wherein the tumor or tumor cells have an ecDNA signature, and tumor growth or size, or tumor cell growth or number, is reduced.

[0167] Also disclosed herein are methods for treating ecDNA-associated tumors or tumor cells, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells containing ecDNA, wherein tumor growth or size, or tumor cell growth or number, is reduced as a result of treatment. In some embodiments, the method further comprises administering a targeted cancer therapy agent. In some embodiments, the targeted cancer therapy agent inhibits a gene or gene product contained in ecDNA in the tumor or tumor cells.

[0168] Also disclosed herein are methods of treating a tumor or tumor cells in a subject, said methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, in an amount sufficient to induce replication stress in the tumor or tumor cells, wherein the tumor or tumor cells contain ecDNA or have an ecDNA signature, and tumor growth or size, or tumor cell growth or number, is reduced.

[0169] Also disclosed herein are methods for treating ecDNA-associated tumors or tumor cells, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells with local amplification of an oncogene, wherein tumor growth or size, or tumor cell growth or number, is reduced as a result of treatment. In some embodiments, the method further comprises administering a cancer-targeting therapeutic agent, wherein the target of the therapeutic agent is a protein encoded by the oncogene. In some embodiments, the local amplification is present on ecDNA.

[0170] ecDNA mediates an important and clinically distinct mechanism of resistance to targeted therapies. Immediate therapeutic opportunities exist for the utility of one or more RNR inhibitors described herein, either as single agents or in combination with other therapies. In some embodiments, one or more RNR inhibitors described herein can be used to treat ecDNA+ cancers, ecDNA+ tumors, or ecDNA+ tumor cells. One or more RNR inhibitors described herein can be used to treat tumors with one or more amplified oncogenes (e.g., FGFR, EGFR, MET, KRAS, MDM2 amplification), etc., where in some cases the one or more amplified oncogenes include non-mutated oncogenes, and in some cases the amplified oncogenes include mutated oncogenes. In some cases, tumors contain one or more amplified oncogenes present on ecDNA, and one or more RNR inhibitors described herein are used to treat the tumor in combination with a therapeutic agent that targets (or inhibits) one or more amplified oncogenes on ecDNA. One or more RNR inhibitors described herein can be used to treat tumors for which there are no approved targeted therapies or few highly effective therapies. One or more RNR inhibitors described herein can be used to treat tumors that have developed resistance to another therapy, such as resistance to a targeted drug. In some cases, tumors (or tumor cells) treated with one or more targeted drugs develop resistance to the targeted drug, such as a targeted drug that targets an oncogene or that directly inhibits an activating mutant form of a particular oncoprotein (e.g., KRAS, BRAF, EGFR), or as a result of local amplification, such as ecDNA-based amplification, of the target gene itself, and one or more RNR inhibitors described herein can be used alone or in combination with an additional therapeutic agent to treat such tumors or tumor cells.

[0171] Provided herein are methods in which inhibition of RNRs by one or more RNR inhibitors described herein exhibits synthetic lethality with a cancer-targeted drug. In some embodiments, synthetic lethality occurs using one or more RNR inhibitors described herein in combination with a cancer-targeted drug. In some cases, a tumor background is identified as highly sensitive to the RNR inhibitor, allowing a sufficient therapeutic index to allow an effective tolerated dose. In some embodiments, synthetic lethality occurs using one or more RNR inhibitors described herein in combination with a cancer-targeted drug in which the tumor or tumor cells are ecDNA+. In some cases, RNR inhibition results in a decrease in ecDNA copy number. In some cases, RNR inhibition results in enhanced cytotoxicity in ecDNA+ cells. In some cases, enhanced cytotoxicity results from the combination of RNR inhibition and inhibition of a cancer target, such as an oncogene, e.g., an oncogene amplified on ecDNA. In some embodiments of the methods herein, the tumor or tumor cells to be treated are ecDNA+. In some cases, such tumors or tumor cells are determined to have an ecDNA signature. In some cases, if a tumor or tumor cell has one or more characteristics associated with ecDNA+ tumors or tumor cells, the tumor or tumor cell is determined to have an ecDNA signature. For example, in some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutation, lack of microsatellite instability (MSI-H), low levels of PD-L1 expression, low levels of tumor inflammation signature (TIS), low levels of tumor mutation burden (TMB), increased frequency of allelic substitutions, insertions, or deletions (indels), and any combination thereof.

[0172] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, have good drug properties, such as metabolic stability. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, have a long half-life. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, are stable in human hepatocytes. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, have low clearance in human hepatocytes. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, have a hepatocyte clearance (Clhep) value of less than about 10 mL / min / kg. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, have Cl hep values ​​that are less than about 20 mL / min / kg.

[0173] Combination therapy In certain instances, the compounds described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, are administered in combination with a second therapeutic agent or cancer-targeting agent.

[0174] In some embodiments of the methods herein, the method further comprises administering a cancer targeting therapeutic agent that targets the activity of the protein product of the target gene.In some cases, treatment with the cancer targeting therapeutic agent and the RNR inhibitor disclosed herein reduces the amplification or expression of the target gene in tumors or tumor cells.In some cases, the cancer targeting therapeutic agent is administered before the RNR inhibitor.In some cases, the cancer targeting therapeutic agent is administered simultaneously with the RNR inhibitor.

[0175] In some embodiments of the method herein, tumor or tumor cells have ecDNA signature.In some cases, tumor or tumor cells express ecDNA signature after administration of cancer targeting therapeutic agent.In some cases, tumor or tumor cells express ecDNA signature before treatment.In some cases, the method prevents the increase of ecDNA in tumor or tumor cells.

[0176] In some embodiments, the second therapeutic agent comprises antimetabolites, platinum drugs, plant alkaloid drugs, and molecularly targeted drugs.

[0177] In some embodiments, antimetabolites include 5-fluorouracil, 5-fluoro-2'-deoxyuridine, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil, pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride, fludarabine (or the active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors (such as decitabine, guadecitabine, azacitidine).

[0178] In some embodiments, platinum drugs include cisplatin, oxaliplatin, carboplatin, and nedaplatin.

[0179] In some embodiments, plant alkaloid drugs include microtubule inhibitors such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibitors such as irinotecan (or the active metabolite SN-38), nogitecan, and etoposide.

[0180] In some embodiments, the molecular targeted drug includes an ATR (ataxia telangiectasia and Rad3-related protein) inhibitor, a Chk1 (checkpoint kinase 1) inhibitor, an HSP (heat shock protein) 90 inhibitor, a PARP (poly ADP-ribose polymerase) inhibitor, an EGFR (epidermal growth factor receptor) inhibitor, a Her2 inhibitor, a VEGFR (vascular endothelial growth factor receptor) inhibitor, a PDGFR (platelet-derived growth factor receptor) inhibitor, a MET inhibitor, an AXL inhibitor, a RET inhibitor, an FLT3 (fms-related tyrosine kinase 3) inhibitor, a KIT inhibitor, a CSF1R (colony-stimulating factor 1 receptor) inhibitor, a TIE2 (intimal endothelial cell kinase 2) inhibitor, a TRKB inhibitor, and a CDK4 / 6 inhibitor. In some embodiments, the ATR inhibitor includes AZD6738, berzosertib, BAY1895344, and VX-803. In some embodiments, Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737. In some embodiments, HSP90 inhibitors include luminespib, ganetespib, and onalespib. In some embodiments, PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib. In some embodiments, EGFR inhibitors include small molecule inhibitors such as lapatinib, gefitinib, erlotinib, afatinib, and vandetanib, and anti-EGFR antibodies such as cetuximab and panitumumab. In some embodiments, the Her2 inhibitor comprises a small molecule inhibitor such as lapatinib, and an anti-Her2 antibody such as trastuzumab, pertuzumab, and trastuzumab emtansine. In some embodiments, the VEGFR inhibitor is an inhibitor of at least one of VEGFR1, VEGFR2, and VEGFR3, and comprises a small molecule inhibitor such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and an anti-VEGFR antibody such as ramucirumab.In some embodiments, the PDGFR inhibitor is a PDGFRα and / or PDGFRβ inhibitor, and includes sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. In some embodiments, the MET inhibitor includes cabozantinib, crizotinib, and tepotinib. In some embodiments, the AXL inhibitor includes cabozantinib and gilteritinib. In some embodiments, the RET inhibitor includes sunitinib, cabozantinib, sorafenib, lenvatinib, and vandetanib. In some embodiments, the FLT3 inhibitor includes sunitinib, cabozantinib, midostaurin, gilteritinib, and sorafenib. In some embodiments, the KIT inhibitor includes sunitinib, midostaurin, pazopanib, lenvatinib, and sorafenib. In some embodiments, CSF1R inhibitors include sunitinib, BLZ-945, and ARRY-382. In some embodiments, TIE2 inhibitors include cabozantinib. In some embodiments, TRKB inhibitors include cabozantinib and entrectinib. In some embodiments, CDK4 / 6 inhibitors include palbociclib, ribociclib, and abemaciclib.

[0181] In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (including a therapeutic regimen) that also has a therapeutic effect.

[0182] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing greater overall benefit than administration of either therapeutic agent alone.

[0183] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient is simply the addition of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0184] In certain embodiments, various therapeutically effective dosages of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. The therapeutically effective dosages of drugs and other agents used in combination therapy regimens are optionally determined by means similar to those specified above for the active ingredients themselves. Additionally, the treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination therapy regimens include treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is initiated before, during, or after treatment with a second agent described herein, and continues until any time during or after the end of treatment with the second agent. It further includes treatments in which a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a second agent used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination therapy also includes periodic treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0185] It will be understood that dosage regimens to treat or ameliorate the condition for which relief is sought will be modified to accommodate a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers, the subject's age, weight, sex, diet, and medical condition). Thus, in some instances, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0186] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In further embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0187] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form or in multiple forms (e.g., as a single pill or two separate pills).

[0188] The compounds described herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, as well as combination therapies, may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the duration necessary to treat the condition. In some embodiments, the duration of treatment required varies, and the treatment duration is tailored to the specific needs of each subject. For example, in certain embodiments, the compounds described herein, or formulations containing the compounds, are administered for at least two weeks, about one month, to about five years.

[0189] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic effect by itself, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). [Example]

[0190] Synthesis of the common intermediate 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one I

[0191] [ka]

[0192] Step 1. Synthesis of 6-fluoro-2,3-dimethylbenzaldehyde

[0193] A 1 L round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 2-bromo-6-fluoro-3-methylbenzaldehyde (50 g, 230 mmol, 1.0 equiv.), methylboronic acid (23.4 g, 392 mmol, 1.7 equiv.), KPO (117.4 g, 553 mmol, 2.4 equiv.), Pd(dppf)Cl.CHCl (5.63 g, 6.91 mmol, 0.03 equiv.), HO (50 mL), and dioxane (450 mL). The resulting solution was stirred at 110 °C for 2 h. The reaction was quenched by the addition of 200 mL of brine. The resulting solution was extracted with 3 × 50 mL of ethyl acetate, and the organic layers were combined. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:3). This gave 6-fluoro-2,3-dimethylbenzaldehyde (30 g, 85%) as a pale yellow oil.

[0194] Step 2. 1-(6-fluoro-2,3-dimethylphenyl)ethan-1-ol

[0195] In a 1 L three-neck round-bottom flask, to a mixture of 6-fluoro-2,3-dimethylbenzaldehyde (27 g, 177.4 mmol, 1 equiv.) in THF was added bromo(methyl)magnesium (42.3 g, 355 mmol, 2 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(6-fluoro-2,3-dimethylphenyl)ethanol (27 g, 90.5%).

[0196] Step 3. 2-(1-Bromoethyl)-1-fluoro-3,4-dimethylbenzene

[0197] To a 500 mL three-necked round-bottom flask, 1-(6-fluoro-2,3-dimethylphenyl)ethanol (25 g, 148.6 mmol, 1.0 equiv) and CHCl3 (250 mL) were added at room temperature. To the above mixture, PBr3 (63.5 mL, 668.8 mmol, 4.5 equiv) was added dropwise at 0 °C. The resulting mixture was stirred for an additional 30 min at 0 °C. The reaction was quenched by the addition of NaHCO3 (aq) (100 mL) at 0 °C. The resulting mixture was extracted with CHCl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (29 g, 84.4%).

[0198] Step 4: (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0199] To a mixture of Ni-(S)-BPB-Gly (5.39 g, 10.8 mmol, 0.5 equiv.) in DMF (42.4 mL) in a 500 mL three-necked round-bottom flask, 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (5 g, 21.6 mmol, 1.0 equiv.) was added dropwise at room temperature under a nitrogen atmosphere. To the resulting mixture, KOH (6.07 g, 108.2 mmol, 5.0 equiv.) was added portionwise at −15° C. under a nitrogen atmosphere and stirred for 1 h at −15° C. under a nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl(aq) (100 mL) at room temperature and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with PE / EtOAc (1:5). MeOH (42 mL) and HCl (50 mL) were added to the mixture at room temperature. The resulting mixture was stirred at 80° C. for 1 hour and then purified by reverse-phase flash chromatography under the following conditions (water:ACN=80:20) to give (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (3.05 g, 63%).

[0200] Step 5. (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid To a 250 mL round-bottom flask, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (5 g, 22.2 mmol, 1.0 equiv.), EtN (6.74 g, 66.6 mmol, 3.0 equiv.), HO (25 mL), and dioxane (25 mL) were added at room temperature. To the resulting mixture, di-tert-butyl dicarbonate (7.27 g, 33.3 mmol, 1.5 equiv.) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 2 hours. The crude product was purified by reverse-phase flash chromatography using the following conditions (water:ACN = 40:60) to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (3.5 g, 48.5%).

[0201] Step 6: Synthesis of 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one, HCl

[0202] To a 250 mL round-bottom flask, (2S)-2-[(tert-butoxycarbonyl)amino]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (9 g, 27.7 mmol, 1.0 equiv.), CDI (11.2 g, 69.2 mmol, 2.5 equiv.), and THF (60 mL) were added at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture, hydrazine (4.15 mL, 82.901 mmol, 3.0 equiv.) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the crude mixture, dioxane (60 mL) and CDI (11.2 g, 69.2 mmol, 2.5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to give tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]carbamate (3 g, 29.7%) as a pale yellow oil. The product was dissolved in 2 mL of THF and treated with 2 mL of 4N HCl in THF. The reaction was left at room temperature overnight and concentrated in vacuo to give 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one, HCl as an off-white solid (2.4 g, 100% yield).

[0203] Synthesis of common intermediate II: methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0204] [ka]

[0205] To a 500 mL three-necked round-bottom flask was added (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (12.8 g, 56.8 mmol, 1.00 equiv.), trimethylsilyldiazomethane (56.8 mL, 113.6 mmol, 2.0 equiv.), MeOH (130 mL), and THF (380 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (9.9 g, 72.8%).

[0206] Synthesis of common intermediate III: tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0207] [ka]

[0208] To a 250 mL round-bottom flask, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (15 g, 67 mmol, 1 equiv.) and tert-butyl acetate (160 mL) were added at room temperature. HClO4 (21 mL, 366 mmol, 5.50 equiv.) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 1 h. The reaction was quenched by the addition of HCl (1 M) (240 mL) at room temperature. The mixture was basified to pH 9 with Na2CO3 (solid) (300 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (12 g, 68.6%).

[0209] Example 1: 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0210] [ka]

[0211] Step 1: Synthesis of 1-(benzylsulfanyl)-4-chloro-2-nitrobenzene

[0212] To a stirred solution / mixture of 1-bromo-4-chloro-2-nitrobenzene (2.5 g, 10.6 mmol, 1 equiv.) and DMF (50 mL), Cs2CO3 (17.2 g, 52.9 mmol, 5.0 equiv.) benzyl mercaptan (1.58 g, 12.7 mmol, 1.2 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with brine (3 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from PE / ethyl acetate (10:1, 10 mL) to give 1-(benzylsulfanyl)-4-chloro-2-nitrobenzene (2 g, 67.6%).

[0213] Step 2: Synthesis of 4-chloro-2-nitrobenzenesulfonyl chloride

[0214] To a stirred solution of 1-(benzylsulfanyl)-4-chloro-2-nitrobenzene (1.6 g, 5.7 mmol, 1 equiv.) and HO (1 mL) in acetonitrile, AcOH (1.47 mL, 25.7 mmol, 4.5 equiv.) was added portionwise at room temperature. To the above mixture, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.25 g, 11.4 mmol, 2 equiv.) was added portionwise over 10 min at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with water / ice. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 4-chloro-2-nitrobenzenesulfonyl chloride (1.86 g).

[0215] Step 3: Synthesis of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-nitrobenzenesulfonamide

[0216] To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (1.86 g, 7.3 mmol, 1.0 equiv.) and pyridine (5 mL) was added 4-chloro-2-nitrobenzenesulfonyl chloride (1.83 g, 6.1 mmol, 1.2 equiv.) in DCM (5 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with 3 × 20 mL of HCl (1 M). The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8:1) to give 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-nitrobenzenesulfonamide (1.29 g, 43.9%).

[0217] Step 4: Synthesis of 2-amino-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide

[0218] To a stirred solution of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-nitrobenzenesulfonamide (1.29 g, 2.7 mmol, 1 equiv.) in AcOH was added Fe (2225 mg, 39.8 mmol, 15 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 30 min. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with 1 × 20 mL of NaHCO (saturated). The resulting mixture was concentrated in vacuo. The residue was purified under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L) in water; The residue was purified by reverse flash chromatography using HCl (NH4HCO3), a 0% to 100% gradient in 20 min, UV detector at 220 nm. This afforded 2-amino-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (400 mg, 33.1%).

[0219] Step 5: Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0220] To a stirred solution of 2-amino-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (128 mg, 0.28 mmol, 1 equiv.) in 1 mL of MeOH, 37% HCl (1332 μL, 3.6 mmol, 12.9 equiv.) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 20 min, detector, UV 254 nm. This gave 5-((1S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (95 mg, 72.3%).

[0221] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0222] To a stirred solution of 5-((1S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (92 mg, 0.2 mmol, 1 equiv.) and (HCHO)n (59.1 mg, 1.97 mmol, 10 equiv.) was added AcOH (1.84 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 60 minutes. To the above mixture was added NaBHCN (37.2 mg, 0.59 mmol, 3 equiv.) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 15 min; detector, UV 220 nm. This gave 5-((1S)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (85 mg, 89.7%).

[0223] The product (85 mg) was subjected to the following conditions: column, XBridge Prep OBD C18 column, 30 * Further purification was performed by chiral preparative HPLC using a 150 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and ACN (25% ACN to 52% in 8 min), UV detector at 254 nm, to give 6-chloro-2-[(1S,2S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-methyl-3H-1lambda 6,2,4-benzothiadiazine-1,1-dione (3.6 mg, 4.24%). LCMS: (ES, m / z): (M−H)=479.1. 1H NMR (400 MHz, methanol-d4) δ 7.55(d,J=8.4Hz,1H),6.99-6.96(dd,J=8.4,5.7Hz,1H),6.78-6.72(dd,J=8 .5,1.9Hz,1H),6.72-6.67(m,2H),5.48-5.41(m,1H),5.35-5.32(d,J=14.5H z,1H),5.05-5.02(d,J=14.5Hz,2H),3.92-3.86(dtd,J=13.0,7.7,6.2Hz,1H ),2.88(s,3H),2.37(s,3H),2.21(s,3H),1.46-1.44(dd,J=7.0,1.1Hz,3H).

[0224] Example 2: 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0225] [ka]

[0226] Step 1: Synthesis of methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0227] To a 50 mL round-bottom flask, methyl (2S)-2-(4-chloro-2-methoxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (490 mg, 1.1 mmol, 1 equiv.) and DCM (5 mL) were added at room temperature. To the above mixture, boron tribromide (14.4 mL, 14.3 mmol, 13 equiv.) was added dropwise over 10 minutes at 0 °C. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with DCM (1 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (77:23) to give methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (340 mg, 71.7%).

[0228] Step 2: Synthesis of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0229] To a stirred mixture of methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (340 mg, 0.79 mmol, 1 equiv.) and DMF (5 mL), CsCO (773 mg, 2.37 mmol, 3 equiv.) and dibromoethane (68 μL, 0.79 mmol, 1 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 60 °C overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (80:20) to give methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (290 mg, 80.4%).

[0230] Step 3: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0231] To a stirred mixture of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (290 mg, 0.64 mmol, 1 equiv.) in MeOH (3 mL), NaOH (50.9 mg, 1.27 mmol, 2 equiv.) and HO (600 μL) were added dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at 70° C. for 2 h. The mixture was neutralized to pH 5 with HCl (aq.). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (284 mg, 97.00%).

[0232] Step 4: Synthesis of tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0233] To a stirred mixture of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (284 mg, 0.64 mmol, 1 equiv.) and DIEA (335 μL, 1.93 mmol, 3 equiv.) in DCM (2 mL), HATU (367 mg, 0.97 mmol, 1.5 equiv.) and tert-butoxycarbohydrazide (127 mg, 0.97 mmol, 1.5 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (85:15) to give tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (250 mg, 70%).

[0234] Step 5: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide

[0235] In a 50 mL round-bottom flask, tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (250 mg, 0.45 mmol, 1 equiv.) and DCM (3 mL) were added at room temperature. 2,6-Lutidine (1.05 mL, 9.0 mmol, 20 equiv.) and trimethylsilyl triflate (469 μL, 2.59 mmol, 16 equiv.) were added dropwise to the above mixture at 0° C. The resulting mixture was stirred at room temperature for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water, gradient 20% to 80% over 20 min; detector: UV 254 nm. This afforded (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (150 mg, 73.2%).

[0236] Step 6: Synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0237] To a stirred mixture of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (150 mg, 0.33 mmol, 1 equiv.) in THF (2 mL), DIEA (143 μL, 0.82 mmol, 2.5 equiv.) and triphosgene (48.8 mg, 0.17 mmol, 0.5 equiv.) were added portionwise at room temperature under an air atmosphere. The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (150 mg, 94.6%). The product (150 mg) was purified using the following conditions: column: XBridge Prep OBD C18 column, 19 * Further purification by preparative HPLC using a 250 mm column, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeOH-HPLC, flow rate: 20 mL / min, gradient: 20% B to 50% B in 8 min, wavelength: 254 nm, RT (min): 7.45) gave 7-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-3,4-dihydro-5,1lambda 6,2-benzoxathiazepine-1,1-dione (28.1 mg, 17.82%). LC-MS: (ES, m / z): MH = 480.10. 1H NMR(400MHz, methanol-d4)δ 7.76(d,J=8.5Hz,1H),7.27-7.24(dd,J=8.5,2.0Hz,1H),7.12(d,J=2.1Hz,1H),7 .01-6.97(dd,J=8.4,5.7Hz,1H),6.75-6.70(dd,J=12.1,8.4Hz,1H),5.53-5.50( dd,J=11.6,2.0Hz,1H),4.64-4.58(dt,J=13.2,5.4Hz,1H),4.04-3.92(d,J=13.4 Hz,1H),3.88-3.83(m,3H),2.34(s,3H),2.21(s,3H),1.44(dd,J=6.9,1.1Hz,3H).

[0238] Example 3: 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0239] [ka]

[0240] Step 1: Synthesis of 3-(benzylsulfanyl)-6-chloro-2-fluoropyridine

[0241] To a 20 mL round-bottom flask was added 3-bromo-6-chloro-2-fluoropyridine (500 mg, 2.38 mmol, 1 equiv.), DIEA (921, 7.13 mmol, 3.0 equiv.), Xantphos (275 mg, 0.48 mmol, 0.2 equiv.), Pd(dba) (218 mg, 0.24 mmol, 0.1 equiv.), dioxane (5 mL), and benzyl mercaptan (325 mg, 2.61 mmol, 1.1 equiv.) at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give 3-(benzylsulfanyl)-6-chloro-2-fluoropyridine (300 mg, 49.8%).

[0242] Step 2: Synthesis of 6-chloro-2-fluoropyridine-3-sulfonyl

[0243] To a 20 mL round-bottom flask was added 3-(benzylsulfanyl)-6-chloro-2-fluoropyridine (1 g, 3.9 mmol, 1 equiv.), HO (500 μL), AcOH (700 μL), and ACN (10 mL). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (1.55 g, 7.9 mmol, 2.0 equiv.) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes under an air atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 6-chloro-2-fluoropyridine-3-sulfonyl chloride (0.8 g, 88.2%).

[0244] Step 3: Synthesis of 6-chloro-2-fluoro)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide

[0245] To an 8 mL round-bottom flask, 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (200 mg, 0.75 mmol, 1 equiv.) and pyridine (2 mL) were added at room temperature. Then, 6-chloropyridine-3-sulfonyl chloride (239 mg, 1.13 mmol, 1.5 equiv.) in DCM (0.5 mL) was added at 0 °C. The resulting mixture was stirred at room temperature under an air atmosphere for 2 hours. The resulting mixture was quenched with water and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (2 × 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 6-chloro-2-fluoro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide (300 mg, 86.7%).

[0246] Step 4: Synthesis of 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(methylamino)pyridine-3-sulfonamide

[0247] To a 40 mL round-bottom flask, 6-chloro-2-fluoro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide (800 mg, 1.74 mmol, 1 equiv.), methylamine hydrochloride (1.65 g, 24.4 mmol, 14 equiv.), TEA (2470 mg, 24.4 mmol, 14 equiv.), and DMSO (10 mL) were added at room temperature. The resulting mixture was stirred overnight at room temperature under an air atmosphere. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 5% to 100% in 30 min; detector (UV 254 nm) to give 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(methylamino)pyridine-3-sulfonamide (200 mg, 24.4%).

[0248] Step 5: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0249] To a 40 mL round-bottom flask was added 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(methylamino)pyridine-3-sulfonamide (120 mg, 0.26 mmol, 1 equiv.), TsOH (44 mg, 0.26 mmol, 1.0 equiv.), paraformaldehyde (230 mg, 2.6 mmol, 10 equiv.), and dioxane (2 mL) at room temperature. The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 5% to 100% gradient in 30 min; detector, UV 220 nm. The crude product was purified under the following conditions: column, XBridge Prep OBD C18 column, 30 * Purification by chiral preparative HPLC using a 150 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (20% ACN up to 50% in 8 min), UV detector at 220 nm, gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-methyl-3H-1lambda-6-pyrido[2,3-e][1,2,4]thiadiazine-1,1-dione (17.7 mg, 14.35%). LCMS: (ES, m / z): MH: 480.10. 1 H NMR(400MHz, methanol-d4)δ 7.88(d,J=8.0Hz,1H),7.00(dd,J=8.4,5.8Hz,1H),6.78-6.67(m,2H),5.47-5.27(m,2H),5.13(d,J=14 .8Hz,1H),3.91(dq,J=13.5,6.8Hz,1H),3.02(s,3H),2.38(s,3H),2.22(s,3H),1.45(d,J=6.9Hz,3H).

[0250] Example 4: 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0251] [ka]

[0252] Step 1: Synthesis of 1-(benzylsulfanyl)-4-chloro-2-fluorobenzene

[0253] To a stirred mixture of 1-bromo-4-chloro-2-fluorobenzene (1 g, 4.78 mmol, 1 equiv.) and DIEA (1.85 g, 14.3 mmol, 3 equiv.) in dioxane (10 mL), Xantphos (553 mg, 0.96 mmol, 0.2 equiv.), Pd2(dba)3 (437 mg, 0.48 mmol, 0.1 equiv.), and benzyl mercaptan (593 mg, 4.78 mmol, 1 equiv.) were added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give 1-(benzylsulfanyl)-4-chloro-2-fluorobenzene (1 g, 82.9%).

[0254] Step 2: Synthesis of 4-chloro-2-fluorobenzenesulfonyl chloride

[0255] To a stirred mixture of 1-(benzylsulfanyl)-4-chloro-2-fluorobenzene (1.47 g, 5.8 mmol, 1 equiv.) in ACN (15 mL) was added AcOH (0.8 mL) and HO (0.8 mL). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (2.29 g, 11.6 mmol, 2 equiv.) was added portionwise to the mixture at 0° C. under an air atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 4-chloro-2-fluorobenzenesulfonyl chloride (1.14 g, 85.6%).

[0256] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0257] To a 250 mL round-bottom flask was added tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenylbutanoate (III) (1.96 g, 6.96 mmol, 1 equiv), DCM (13.8 mL), and pyridine (1.9 mL, 24 mmol, 5 equiv). To the mixture was added 4-chloro-2-fluorobenzenesulfonyl chloride (1.10 g, 4.8 mmol, 1.0 equiv) at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (6:1) to give tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.78 g, 78.3%).

[0258] Step 4: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0259] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (350 mg, 0.74 mmol, 1 equiv.) in DMSO (4 mL), TEA (1.44 mL, 10.3 mmol, 14 equiv.) and isopropylamine (888 μL, 10.3 mmol, 14 equiv.) were added at room temperature. The resulting mixture was stirred at 80 °C overnight. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (370 mg, 97.6%).

[0260] Step 5: Synthesis of (2S)-2-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0261] To a stirred solution of tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (370 mg, 0.72 mmol, 1 equiv.) in dioxane (14.8 mL), TsOH (124 mg, 0.72 mmol, 1 equiv.) and 1,3,5-trioxane (650 μL, 7.21 mmol, 10 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 110 °C for 24 h. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 60% gradient in 10 min; detector, UV 254 nm. This gave ((2S)-2-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (96 mg, 28.4%).

[0262] Step 6: Synthesis of 5-((1S)-1-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0263] A solution of ((2S)-2-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (86 mg, 0.18 mmol, 1 equiv.) in THF (1 mL) was treated with CDI (89.2 mg, 0.55 mmol, 3 equiv.) at room temperature for 30 min, followed by the dropwise addition of N2H4.HO (26.7 μL, 0.55 mmol, 3 equiv.) at 0 °C. The resulting mixture The mixture was stirred at 0°C for 30 minutes. The resulting mixture was extracted with EtOAc (2 x 1 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) at room temperature. To the above mixture, CDI (148.7 mg, 0.92 mmol, 5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 30 minutes. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0264] Step 7: Synthesis of 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0265] The crude product (90 mg) was purified under the following conditions (column: Xselect CSH C18 OBD column 30 * Purification on a 150 mm 5 μm column (mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 10% B to 40% B in 8 min, 40% B, wavelength: 254 nm, RT (min): 7) gave 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (25.5 mg, 25.6%). LC-MS: (ES, m / z): [M+H] + =509.15. 1H NMR(300MHz, methanol-d4)δ 7.56-7.54(d,J=8.4Hz,1H),7.01-6.93(m,2H),6.78-6.68(m,2H),5.43-5.39(dd,J=11.8,1.8Hz,1H),5.15(s,2H),4.19-4.09 (hept,J=6.8Hz,1H),3.99-3.90(dddd,J=14.5,12.9,8.5,6.7Hz,1H),2.36(s,3H),2.21(s,3H),1.53-1.38(m,6H),1.27(d,J=6.6Hz,3H).

[0266] Example 5: 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0267] [ka]

[0268] Step 1: Synthesis of 2-(benzylsulfanyl)-5-chloro-3-fluoropyridine

[0269] To a 40 mL round-bottom flask was added 2-bromo-5-chloro-3-fluoropyridine (550 mg, 2.61 mmol, 1 equiv.), benzyl mercaptan (357 mg, 2.88 mmol, 1.1 equiv.), DIEA (1013 mg, 7.84 mmol, 3.0 equiv.), Xantphos (302 mg, 0.52 mmol, 0.2 equiv.), and Pd(dba) (239 mg, 0.26 mmol, 0.1 equiv.), and dioxane (6 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 2-(benzylsulfanyl)-5-chloro-3-fluoropyridine (450 mg, 67.9%).

[0270] Step 2: Synthesis of 5-chloro-3-fluoropyridine-3-sulfonyl chloride

[0271] To a 20 mL round-bottom flask were added 2-(benzylsulfanyl)-5-chloro-3-fluoropyridine (700 mg, 2.76 mmol, 1 equiv.), AcOH (2.45 mL), HO (1.75 mL), and ACN (7.00 mL). 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (1087 mg, 5.52 mmol, 2.0 equiv.) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes under an air atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 5-chloro-3-fluoropyridine-2-sulfonyl chloride (500 mg, 78.8%) as a pale yellow oil.

[0272] Step 3: Synthesis of tert-butyl (2S)-2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0273] To a 20 mL round-bottom flask was added tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenylbutanoate) (20 mg, 0.071 mmol, 1 equiv.) and pyridine (10 mL). To the mixture was added 5-chloro-3-fluoropyridine-2-sulfonyl chloride (1.23 g, 5.33 mmol, 1.5 equiv.) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature under an air atmosphere overnight. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 5% to 100% in 30 min; detector, UV 220 nm) to give tert-butyl (2S)-2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (700 mg, 41.5%) as a pale yellow oil.

[0274] Step 4: Synthesis of tert-butyl (2S)-2-[5-chloro-3-(methylamino)pyridine-2-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0275] In a 20 mL round-bottom flask, tert-butyl (2S)-2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.42 mmol, 1 equivalent), methylamine (2 M in THF) (130.8 mg, 4.21 mmol, 10 equivalents), and TEA (426 mg, 4.21 mmol, 10 equivalents) were added in DMSO at room temperature. The resulting mixture was stirred overnight at 65 °C under an air atmosphere. The residue was purified by reverse flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, gradient from 5% to 100% in 30 min; detector: UV 220 nm) to give tert-butyl (2S)-2-[5-chloro-3-(methylamino)pyridine-2-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 88%) as a pale yellow solid.

[0276] Step 5: Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0277] To a 20 mL round-bottom flask was added tert-butyl (2S)-2-[5-chloro-3-(methylamino)pyridine-2-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (150 mg, 0.31 mmol, 1 equiv.), paraformaldehyde (556 mg, 6.17 mmol, 10 equiv.), TsOH (159 mg, 0.93 mmol, 1.5 equiv.), and dioxane (3 mL) at room temperature. The resulting mixture was stirred overnight at 100° C. under an air atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 5% to 100% gradient in 30 min; detector, UV 254 nm) to give (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg, 65.1%) as a pale yellow oil.

[0278] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0279] To a 50 mL round-bottom flask was added (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (200 mg, 0.44 mmol, 1 equiv.), CDI (142 mg, 0.88 mmol, 2.0 equiv.), and THF (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, and hydrazine (42 mg, 1.32 mmol, 3.0 equiv.) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and dioxane (5 mL) and CDI (185 mg, 1.14 mmol, 2.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 5% to 100% gradient in 30 minutes, detector, UV 220 nm. The crude product was purified by reverse flash chromatography under the following conditions: column, Xselect CSH F-phenyl OBD column, 19 * Purification by chiral preparative HPLC using a 250 mm column, 5 μm column, mobile phase: water (0.05% FA) and ACN (44% ACN up to 53% in 11 minutes), detector: UV220, gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-methyl-3H-)lambda 6-pyrido[3,2-e][1,2,4]thiadiazine-1,1-dione (53.5 mg, 25.2%). LCMS: (ES, m / z): [M+H]: 482.15. 1H NMR(300MHz, methanol-d4)δ 7.91(d,J=1.9Hz,1H),7.28(d,J=1.9Hz,1H),7.00(dd,J=8.4,5.7Hz,1H),6.73(dd,J=12.1,8.4Hz,1H),5.53(dd,J=11.7,1.8Hz,1H),5.35(d, J=14.8Hz,1H),5.05(d,J=14.7Hz,1H),3.93(dtd,J=12.8,7.6,6.1Hz,1H),2.90(s,3H),2.39(s,3H),2.23(s,3H),1.46(dd,J=7.0,1.1Hz,3H).

[0280] Example 6: 5-((1S,2R)-1-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0281] [ka]

[0282] Step 1: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(cyclopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0283] To a stirred mixture of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 4, Step 3) (10 mg, 0.021 mmol, 1 eq.) and DMSO (14 mL), TEA (3.20 mL, 23 mmol, 14 eq.) and aminocyclopropane (1.32 g, 23 mmol, 14 eq.) were added portionwise at room temperature under an air atmosphere. The resulting mixture was stirred overnight at 80° C. under an air atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-[4-chloro-2-(cyclopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (713 mg, 84.8%).

[0284] Step 2: Synthesis of (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0285] To a 20 mL vial, tert-butyl (2S)-2-[4-chloro-2-(cyclopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 0.35 mmol, 1 equiv.), dioxane (3.6 mL), 1,3,5-trioxane (317 mg, 3.52 mmol, 10 equiv.), and TsOH (61 mg, 0.35 mmol, 1 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 70% to 72% in 10 min, detector, UV 254 nm. This gave (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (92 mg, 55.9%).

[0286] Step 3: Synthesis of 5-((1S)-1-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0287] To a 50 mL round-bottom flask, (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (80 mg, 0.17 mmol, 1 equiv.), CDI (128 mg, 0.79 mmol, 4.6 equiv.), and THF (1.6 mL) were added at room temperature. To the above mixture, hydrazine hydrate (25.7 mg, 0.51 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 1 h. The resulting mixture was quenched with water and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. A mixture of the above product and CDI (128 mg, 0.79 mmol, 4.6 equiv.) in 1,4-dioxane was stirred overnight at room temperature under air. The residue was purified by reverse flash chromatography using the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, 10% to 50% FA gradient in 10 min; detector: UV 254 nm. This afforded 5-((1S)-1-(6-chloro-4-cyclopropyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (80 mg, 92.1%).

[0288] The product was purified under the following conditions: Column: XBridge Shield RP18 OBD column, 30 *Further purification was achieved by reverse flash chromatography using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B to 55% B in 9 min, wavelength: 254 nm, RT1 (min): 7. This afforded 6-chloro-4-cyclopropyl-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-3H-1lambda 6,2,4-benzothiadiazine-1,1-dione (72.3 mg, 41.11%). LCMS: (ES, m / z): [MH] + =505.05. 1 H NMR (300 MHz, methanol-d4) δ 7.57(d,J=8.4Hz,1H),7.21(d,J=1.9Hz,1H),6.99(dd,J=8.4,5.7Hz,1H),6.85( dd,J=8.4,1.9Hz,1H),6.72(dd,J=12.1,8.4Hz,1H),5.43(dd,J=11.8,1.8Hz,1H) ,5.26(d,J=14.4Hz,1H),5.10(d,J=14.4Hz,1H),4.00-3.83(m,1H),2.44-2.36( m,4H),2.22(s,3H),1.45(d,J=6.9Hz,3H),1.08-0.85(m,2H),0.85-0.64(m,2H).

[0289] Example 7: 5-((1S,2R)-1-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0290] [ka]

[0291] Step 1: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0292] To a 40 mL vial, methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 2) (860 mg, 2 mmol, 1 equiv.), dioxane (34.4 mL), trioxane (2.70 g, 30.0 mmol, 15 equiv.), and TsOH (344 mg, 2 mmol, 1 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave methyl (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (470 mg, 53.2%).

[0293] Step 2: Synthesis of (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0294] To a 100 mL round-bottom flask was added methyl (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (470 mg, 1 mmol, 1 equiv.), DCE (18 mL), and trimethyltin hydroxide (1923 mg, 10 mmol, 10 equiv.) at room temperature. The resulting mixture was stirred overnight at 60 °C under an air atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 70% to 75% gradient in 10 min; detector, UV 254 nm. This afforded (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (230 mg, 50.5%).

[0295] Step 3: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0296] A solution of (2S)-2-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (212 mg, 0.5 mmol, 1 equiv.) and CDI (400 mg, 2.5 mmol, 5 equiv.) in THF was stirred at room temperature under air atmosphere for 20 minutes. To the above mixture, hydrazine hydrate (124 mg, 2.5 mmol, 5 equiv.) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for an additional 1 hour. The resulting mixture was quenched with water and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To a 50 mL round-bottom flask, the above crude product, dioxane (5 mL), and CDI (400 mg, 2.5 mmol, 5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 0.5 h. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by reverse flash chromatography using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B to 52% B in 8 min, wavelength: 254 nm, RT1 (min): 7. This gave 5-((1S,2R)-1-(6-chloro-1,1-dioxidobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (35.9 mg, 16.2%). LCMS: (ES, m / z): [MH] + =485.15. 1H NMR(300MHz, methanol-d4)δ 7.63(d,J=8.6Hz,1H),7.07(dd,J=8.6,2.0Hz,1H),6.99-6.84(m,2H),6.64(dd,J=12.1,8.4Hz,1H),5.82(q,J=13.0Hz,2H ),5.50(dd,J=11.8,1.7Hz,1H),3.83(ddt,J=13.9,7.0,5.5Hz,1H),2.29(s,3H),2.13(s,3H),1.35(dd,J=6.9,1.1Hz,3H).

[0297] Example 8: 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0298] [ka]

[0299] Step 1: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxide-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0300] To a stirred solution of methyl (2S)-2-(2-amino-4-chlorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (12.7 g, 29.6 mmol, 1 equiv.) in (diethoxymethoxy)ethane (250 mL). The resulting mixture was stirred at 145° C. overnight. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0301] Step 2: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0302] To a stirred solution of methyl (2S)-2-(6-chloro-1,1-dioxide-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (6.9 g, 2.27 mmol, 1 equiv.) in DCE (15 mL) was added trimethyltin hydroxide (14.2 g, 78.2 mmol, 5 equiv.) dropwise at room temperature. The resulting mixture was stirred at 65 °C for 2 days. The resulting mixture was filtered, and the filter cake was washed with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min; detector, UV 254 nm. This gave methyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.8 g, 26.9%).

[0303] Step 3: Synthesis of (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0304] To a stirred solution of methyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (6.9 g, 2.27 mmol, 1 equiv.) in DCE (15 mL) was added trimethyltin hydroxide (14.2 g, 78.2 mmol, 5 equiv.) dropwise at room temperature. The resulting mixture was stirred at 65 °C for 2 days. The resulting mixture was filtered, and the filter cake was washed with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.8 g, 26.9%).

[0305] Step 4: Synthesis of tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0306] To a 50 mL round-bottom flask, 2-(6-chloro-1,1-dioxo-3,4-dihydro-1 lambda 6,2,4-benzothiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.8 g, 4.2 mmol, 1 equiv.) in DCM (20 mL) was added at room temperature. HATU (1.92 g, 5 mmol, 1.2 equiv.), tert-butoxycarbohydrazide (0.84 g, 6.3 mmol, 1.5 equiv.), and DIEA (2.20 mL, 12.7 mmol, 3 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (2 g, 87.2%).

[0307] Step 5: Synthesis of (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide

[0308] To a stirred solution of tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (1.99 g, 3.7 mmol, 1 equiv.) in DCM (30 mL) was added trimethylsilyl triflate (10.7 mL, 58.8 mmol, 16 equiv.) and 2,6-lutidine (8.6 mL, 73.6 mmol, 20 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (1.4 g, 86.33%).

[0309] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0310] To a stirred mixture of (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (2.8 g, 6.35 mmol, 1 equiv.) in THF (37 mL), DIEA (2.77 mL, 15.88 mmol, 2.5 equiv.) and triphosgene (15.1 mg, 0.05 mmol, 0.5 equiv.) were added portionwise at room temperature under an air atmosphere. The resulting mixture was stirred at 45 °C for 40 min. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 100% gradient in 15 min; detector, UV 254 nm. This gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)]propyl]-3,4-dihydro-1lambda 6,2,4-benzothiadiazine-1,1-dione (2.0171 g, 68.03%). LCMS: (ES, m / z): (MH) 465.05. 1 H NMR (300 MHz, methanol-d4) δ 7.51-7.48 (d, J = 8.5 Hz, 1H), 7.01 * 6.96(dd,J=8.4,5.8Hz,1H),6.74-6.63(m,3H),5.43-5.39(dt,J=11.7,1.2Hz,1H),5.25-5.21(d,J=14.6Hz,1H ),5.09-5.04(d,J=14.6Hz,1H),3.90-3.79(m,1H),2.36(s,3H),2.21(s,3H),1.51-1.46(dd,J=6.9,1.1Hz,3H).

[0311] Example 9: 5-((1S,2R)-1-(6-chloro-4-(methyl-d3)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0312] [ka]

[0313] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-((methyl-d3)amino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0314] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 4, Step 3) (1 g, 2.1 mmol, 1 equiv.) in DMSO (10 mL), TEA (2.9 mL, 21 mmol, 10 equiv.) and methyl-d3-amine hydrochloride (744 mg, 10.6 mmol, 5 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 80 °C for 2 days. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-{4-chloro-2-[(D3)methylamino]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 97.1%).

[0315] Step 2: Synthesis of (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0316] To a stirred solution of tert-butyl (2S)-2-{4-chloro-2-[(D3)methylamino]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 1.03 mmol, 1 equiv.) in dioxane (20 mL), TsOH (176 mg, 1.03 mmol, 1 equiv.) and 1,3,5-trioxane (923 mg, 10.3 mmol, 10 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 110 °C overnight. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 70% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (240 mg, 52.8%).

[0317] Step 2: Synthesis of 5-((1S)-1-(6-chloro-4-(methyl-d3)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0318] To a 50 mL round-bottom flask was added (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (230 mg, 0.52 mmol, 1 equiv.) in THF (3 mL). To the above mixture was added CDI (126 mg, 0.78 mmol, 1.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. To the above mixture was added N2H4.HO (75.5 μL, 1.55 mmol, 3 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The reaction was quenched with water (5 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was loaded into a 50 mL round-bottom flask and dioxane (3 mL) was added. To the above mixture, CDI (210 mg, 1.3 mmol, 2.5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 30 minutes. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 22% B to 52% B in 9 min, wavelength: 254 nm, RT1 (min: 7, 8) gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-(2H3)methyl-3H-1lambda 6,2,4-benzothiadiazine-1,1-dione (36.7 mg, 17.4%). LC: (ES, m / z): [M+H+17] + =501.25. 1H NMR(400MHz, methanol-d4)δ 7.58-7.56(d,J=8.4Hz,1H),7.01-6.97(dd,J=8.4,5.7Hz,1H),6.80-6.7 7(dd,J=8.5,1.9Hz,1H),6.74-6.68(m,2H),5.45-5.42(d,J=11.7Hz,1H) ,5.38-5.32(d,J=14.6Hz,1H),5.06-4.97(d,J=14.5Hz,1H),3.93-3.85( dq,J=13.2,6.8Hz,1H),2.38(s,3H),2.22(s,3H),1.45(d,J=6.9Hz,3H).

[0319] Example 10: 5-((1S,2R)-1-(6-chloro-1,1-dioxide-4-propyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0320] [ka]

[0321] 5-((1S,2R)-1-(6-chloro-1,1-dioxide-4-propyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one was prepared according to Example 33 starting from (2S)-2-[4-chloro-2-(propylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (285 mg, 0.019 mmol, 1 equiv.) and propylamine (260 μL, 3.17 mmol, 5 equiv.). The final product (180 mg) was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 *Purification at 150 mm, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 32% B to 62% B in 9 min, wavelength: 254 nm, RT1 (min): 7) gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-propyl-3H-1lambda 6,2,4-benzothiadiazine-1,1-dione (60.4 mg, 33.25%). LC-MS: (ES, m / z): [MH] + =507.10. 1 H NMR(300MHz, methanol-d4)δ 7.57-7.55(d,J=8.4Hz,1H),7.01-6.96(dd,J=8.3,5.8Hz,1H),6.77-6.67(m,3H),5.44-5.36(dd,J=13.2,10.4Hz,2H),5.11 -5.06(d,J=14.6Hz,1H),3.93-3.87(dq,J=13.3,7.0Hz,1H),3.46-3.36(dt,J=14.9,7.4Hz,1H),3.14-3.04(dt,J=15.5,8H).

[0322] Example 11: 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0323] [ka]

[0324] Step 1: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0325] To a 40 mL vial was added tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenylbutanoate (1.5 g, 3.17 mmol, 1 equiv.) in DMSO, methylamine (2 M in THF) (15.8 mL, 31.7 mmol, 10 equiv.), and TEA (4.4 mL, 31.7 mmol, 10 equiv.). The resulting mixture was stirred at 65 °C overnight. After evaporation, the residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), gradient: 10% to 50% in 10 min; detector: UV 254 nm. This gave tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.2 g, 78.2%).

[0326] Step 2: Synthesis of (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0327] To a 40 mL vial, tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 2.0 mmol, 1 equiv.), DCM (5 mL), and TFA (3 mL) were added at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 10 min, detector, UV 254 nm. This afforded (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (800 mg, 90.5%).

[0328] Step 3: Synthesis of (2S)-2-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0329] To a 20 mL vial, (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1 g, 2.33 mmol, 1 equiv.), MeCN (10 mL), acetaldehyde (3081 mg, 70 mmol, 30 equiv.), and DL-camphorsulfonic acid (541 mg, 2.33 mmol, 1 equiv.) were added at room temperature. The resulting mixture was stirred at 45 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min, detector, UV 254 nm. This gave (2S)-2-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (200 mg, 18.9%).

[0330] Step 4: Synthesis of 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0331] To an 8 mL vial, (2S)-2-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg, 0.22 mmol, 1 equiv.), THF (0.5 mL), and CDI (71.3 mg, 0.44 mmol, 2 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, NH2NH2.HO (33.0 mg, 0.66 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the above mixture, dioxane (0.5 mL) and CDI (92.7 mg, 0.57 mmol, 2.6 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at room temperature for another 30 minutes. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified under the following conditions: column, XBridge Shield RP18 OBD column, 30 * Purification by chiral preparative HPLC using a 150 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and MeOH prep (20% MeOH prep, up to 50% in 8 min), UV detector at 254 nm, afforded 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (23.3 mg, 19.8%). LCMS: (ES, m / z): [M+H]: 495.10. 1H NMR(300MHz, methanol-d4)δ 7.60(d,J=8.4Hz,1H),7.02(dd,J=8.4,5.8Hz,1H),6.83(dd,J=8.4,1.9Hz,1H),6.82-6.74(m,1H),6.74-6.67(m,1H),5.66(dd,J=11.8,2.1Hz,1H ),5.27(q,J=6.7Hz,1H),3.91(tt,J=13.1,6.2Hz,1H),2.87(s,3H),2.41 (s,3H),2.25(s,3H),1.78(d,J=6.8Hz,3H),1.50(dd,J=6.9,1.2Hz,3H).

[0332] Example 12: 5-((1S,2R)-1-(6-chloro-4,7-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0333] [ka]

[0334] Step 1: Synthesis of 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene

[0335] To a stirred solution of 1-bromo-4-chloro-2-fluoro-5-methylbenzene (5 g, 22.3 mmol, 1 equiv.) and DIEA (11.7 mL, 67.1 mmol, 3 equiv.) in dioxane, Xantphos (2.59 g, 4.48 mmol, 0.2 equiv.) Pd2(dba)3 (2.0 g, 2.24 mmol, 0.1 equiv.) was added portionwise at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene (5.8 g, 97.2%).

[0336] Step 2: Synthesis of 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride

[0337] To a stirred solution of 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene (2 g, 7.5 mmol, 1 equiv.) and HO (1.22 mL, 67.5 mmol, 9 equiv.) in MeCN and AcOH (2.44 mL, 37.5 mmol, 5 equiv.), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.95 g, 15 mmol, 2 equiv.) was added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. This afforded 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, crude).

[0338] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0339] To a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.5 g, 8.9 mmol, 0.9 equiv.) and pyridine (10 mL) was added 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, 14.8 mmol, 1.5 equiv.) in DCM (40 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.7 g, 56%).

[0340] Step 4: Synthesis of tert-butyl (2S)-2-[4-chloro-5-methyl-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenylbutanoate

[0341] To a 20 mL vial, tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 1 mmol, 1 equiv.), methylamine (5.12 mL, 5.13 mmol, 5 equiv.), and TEA (1.42 mL, 10 mmol, 10 equiv.) were added in THF at room temperature. The resulting mixture was stirred overnight at 80 °C under an air atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 100% gradient in 10 min, detector, UV 254 nm. This gave tert-butyl (2S)-2-[4-chloro-5-methyl-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (400 mg, 78.2%).

[0342] Step 5: Synthesis of (2S,3R)-2-(6-chloro-4,7-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0343] To a 20 mL vial, tert-butyl (2S)-2-[4-chloro-5-methyl-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (350 mg, 0.7 mmol, 1 equiv.), dioxane (7 mL), trioxane (632 mg, 7.0 mmol, 10 equiv.), and TsOH (121 mg, 0.70 mmol, 1 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min, detector, UV 254 nm. This gave (2S)-2-(6-chloro-4,7-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (228 mg, 71.5%).

[0344] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4,7-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0345] To a 10 mL vial, (2S)-2-(6-chloro-4,7-dimethyl-1,1-dioxo-3H-lambda 6,2,4-benzothiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (208 mg, 0.46 mmol, 1 equiv.), THF (0.4 mL), and CDI (341 mg, 2.1 mmol, 4.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 20 minutes. NH2NH2.HO (111 μL, 2.29 mmol, 5 equiv.) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The resulting mixture was quenched with water and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To a 10 mL vial, the above crude product, dioxane (4 mL), and CDI (341 mg, 2.1 mmol, 4.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 0.5 hours. The resulting mixture was quenched with water and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.

[0346] The residue was purified under the following conditions: Column: XBridge Shield RP18 OBD column, 30 * Purification by reverse flash chromatography (150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 26% B to 56% B in 9 min, wavelength: 254 nm, RT (min): 7) afforded 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4,7-dimethyl-3H-1lambda 6,2,4-benzothiadiazine-1,1-dione (64.5 mg, 31.77%). LCMS: (ES, m / z): [MH] + =493.10. 1H NMR(300MHz, methanol-d4)δ 7.43-7.37(m,1H),6.87(dd,J=8.4,5.7Hz,1H),6.68-6.54(m,2H),5.40-5.30(m,1H),5.20(d,J=14.4Hz,1H),4.89(d,J=14. 4Hz,1H),3.78(dqd,J=11.8,6.9,1.6Hz,1H),2.74(s,3H),2.28(s,3H),2.14(d,J=15.4Hz,6H),1.35(dd,J=6.9,1.1Hz,3H).

[0347] Example 13: 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0348] [ka]

[0349] Step 1: Synthesis of tert-butyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0350] To a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (5.10 g, 18.1 mmol, 0.8 equiv.) and pyridine (18.3 mL, 226 mmol, 10 equiv.) in DCM, 4-chloro-2-nitrobenzenesulfonyl chloride (prepared as described in Example 16) (5.8 g, 22.7 mmol, 1 equiv.) in DCM was added dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give tert-butyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (6.2 g, 54.6%).

[0351] Step 2: Synthesis of (2S)-2-[N-(2-ethoxy-2-oxoethyl)4-chloro-2-nitrobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0352] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.8 g, 3.59 mmol, 1 equiv.) and K2CO3 (1 g, 7.19 mmol, 2 equiv.) in DMF, ethyl bromoacetate (398 μL, 3.59 mmol, 1 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60 °C for 60 min. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)4-chloro-2-nitrobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 63%).

[0353] Step 3: Synthesis of tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)2-amino-4-chlorobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0354] To a stirred solution of methyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 2.1 mmol, 1 equiv.) in AcOH (15 mL) was added Fe (1.24 g, 22.1 mmol, 10 equiv.) portionwise at room temperature. The resulting mixture was stirred at 70 °C for 15 min. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 20 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)2-amino-4-chlorobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (987 mg, 80%).

[0355] Step 4: Synthesis of N-((2-amino-4-chlorophenyl)sulfonyl)-N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)glycine

[0356] To a stirred solution of tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)2-amino-4-chlorobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (950 mg, 1.71 mmol, 1 equiv.) in THF and HO (9.50 mL) was added lithium hydride (358 mg, 8.53 mmol, 5 equiv.) portionwise at room temperature. The resulting mixture was stirred at 65° C. overnight. The mixture was acidified to pH 5 with HCl (2 M). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0357] Step 5: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0358] To a stirred solution of {N-[(2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl]2-amino-4-chlorobenzenesulfonamide}acetic acid (800 mg, 1.5 mmol, 1 equiv.) in DCM, EDCI (319 mg, 1.67 mmol, 1.1 equiv.) was added portionwise at room temperature. To the above mixture, DMAP (18.5 mg, 0.15 mmol, 0.1 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min, detector, UV 254 nm. This gave tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (430 mg, 55.6%).

[0359] Step 6: Synthesis of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0360] To a solution of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.39 mmol, 1 equiv.) in DMF was added sodium hydride (60% in oil, 24 mg) at 0 °C. The mixture was stirred for 15 min. CHI (48.7 μL, 0.78 mmol, 2 equiv.) was added, and the mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 87.60%).

[0361] Step 7: Synthesis of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0362] To a stirred solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 0.57 mmol, 1 equiv.) in THF (6 mL) was added BH3-THF (3 mL, 3 mmol, 5.3 equiv.) dropwise at room temperature. The resulting mixture was stirred at 65° C. under a nitrogen atmosphere for 2 hours. The reaction was quenched at room temperature by the addition of MeOH (1 mL). The resulting mixture was stirred at 65° C. for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0363] Step 8: Synthesis of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0364] To a stirred solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (280 mg, 0.55 mmol, 1 equiv.) in DCM (4 mL) was added dropwise TFA (4 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid.

[0365] Step 9: Synthesis of 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0366] To a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (188 mg, 0.4 mmol, 1 equiv.) in THF (3.8 mL) was added CDI (97.5 mg, 0.6 mmol, 1.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, hydrazine hydrate (58.5 μL, 1.2 mmol, 3 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 10 minutes. The reaction was quenched with water / ice at 0° C. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL). To the above mixture, CDI (106 mg, 1.204 mmol, 3.0 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 1 hour. The resulting mixture was concentrated under vacuum.

[0367] The crude product was purified under the following conditions: Column, XBridge Prep OBD C18 column, 19 *Purification by chiral preparative HPLC using a 250 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO) and MeOH prep (57% MeOH prep, up to 70% in 10 min), UV detector at 254 nm. This gave 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (80 mg, 40%). LCMS: (ES, m / z)(MH) = 493.1. 1 H NMR (300 MHz, methanol-d4) δ 7.73-7.70 (dd, J = 8.5, 1.6 Hz, 1H), 6.98-6.95 (t, J = 7.1 Hz, 1H), 6.90-6.87 (dd, J = 8.5, 2.0 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 6.74-6.67 (dd, J = 12.1, 8.4 Hz, 1H), 5.53-5.49 ( d,J=11.7Hz,1H),4.17-4.08(m,1H),3.92-3.75(m,2H),3.58-3.54(m,1H),3.35(d,J =4.6Hz,2H),2.88(d,J=1.6Hz,3H),2.35(s,3H),2.21(s,3H),1.44(d,J=6.9Hz,3H).

[0368] Example 14: 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0369] [ka]

[0370] Step 1: Synthesis of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0371] To a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (400 mg, 0.76 mmol, 1 equiv.) in DCM (4 mL) was added TFA (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (290 mg, 81.18%).

[0372] Step 2: Synthesis of tert-butyl 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanonyl)hydrazine-1-carboxylate

[0373] To a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (28 mg, 0.6 mmol, 1 equiv.) and HATU (272 mg, 0.72 mmol, 1.2 equiv.) in DCM (3 mL) was added DIEA (312 μL, 1.79 mmol, 3 equiv.) at room temperature. To the above mixture was added tert-butoxycarbohydrazide (118 mg, 0.9 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for an additional 30 min. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (3:1) to give tert-butyl 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanonyl)hydrazine-1-carboxylate (305 mg, 87.60%).

[0374] Step 3: Synthesis of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide

[0375] To a stirred solution of tert-butyl 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanonyl)hydrazine-1-carboxylate (208 mg, 0.36 mmol, 1 equiv.) in DCM (2 mL) was added 2,6-lutidine (831 μL, 7.14 mmol, 20 equiv.) and trimethylsilyl triflate (1033 μL, 5.71 mmol, 16 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This afforded (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (96 mg, 55.7%).

[0376] Step 4: Synthesis of 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0377] To a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (96 mg, 0.2 mmol, 1 equiv.) and DIEA (86.6 μL, 0.5 mmol, 2.5 equiv.) in THF, ditrichloromethyl carbonate (29.5 mg, 0.1 mmol, 0.5 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60 °C for 30 min. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (53 mg, 52.4%).

[0378] The product was purified under the following conditions (column: Torus 2-PIC column, 4.6 * Further purification by Prep-Achiral-SFC (100 mm, 5 μm, mobile phase B: ACN:MeOH = 80:20 (1% 2M NH3-MeOH), flow rate: 4 mL / min, gradient: isocratic 10% B, wavelength: 220 nm) gave 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (29.1 mg, 57.97%). LC-MS: (ES, m / z): [M+H] + =509.05. 1H NMR(300MHz, methanol-d4)δ 7.80-7.74(m,2H),7.53-7.50(d,J=8.6Hz,1H),7.04-6.99(t,J=7.4Hz,1H),6.81-6.74(m,1H),5.58-5.54(d,J=11.8Hz,1H),3.91-3.87(d,J =11.3Hz,1H),3.81-3.77(dd,J=12.9,6.6Hz,1H),3.52-3.48(d,J=11.8Hz,1H),3.37(s,3H),2.26(s,3H),2.20(s,3H),1.40(d,J=6.9Hz,3H).

[0379] Example 15: 5-((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0380] [ka]

[0381] Step 1: Synthesis of 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene

[0382] To a stirred solution of 1-bromo-4-chloro-2-fluoro-5-methylbenzene (5 g, 22.4 mmol, 1 equiv.) and DIEA (11.7 mL, 67.1 mmol, 3 equiv.) in dioxane, Xantphos (2.6 g, 4.5 mmol, 0.2 equiv.) Pd2(dba)3 (2.1 g, 2.24 mmol, 0.1 equiv.) was added portionwise at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene (5.8 g, 97.2%).

[0383] Step 2: Synthesis of 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride

[0384] To a stirred solution of 1-(benzylsulfanyl)-4-chloro-2-fluoro-5-methylbenzene (2 g, 7.5 mmol, 1 equiv.) and HO (1.2 mL, 67.5 mmol, 9 equiv.) in MeCN and AcOH (2.44 mL, 37.5 mmol, 5 equiv.) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3 g, 15 mmol, 2 equiv.) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. The resulting mixture was concentrated under reduced pressure. This afforded 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, crude).

[0385] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0386] To a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.5 g, 8.9 mmol, 1 equiv.) and pyridine (10 mL) was added 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, 14.8 mmol, 1.5 equiv.) in DCM (40 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous MgSO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.7 g, 56%).

[0387] Step 4: Synthesis of (2S)-2-(4-chloro-2-hydroxy-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0388] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (20 mg, 0.041 mmol, 1 equiv.) and 2-methanesulfonylethanol (458 mg, 3.69 mmol, 3 equiv.) in DMF at 0° C., NaH (246 mg, 6.15 mmol, 5 equiv., 60%) was added portionwise. The resulting mixture was stirred at 80° C. overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-(4-chloro-2-hydroxy-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg, 16.7%).

[0389] Step 5: Synthesis of tert-butyl ((2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0390] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-hydroxy-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.41 mmol, 1 equiv.) and CsCO (402 mg, 1.24 mmol, 3 equiv.) in DMF, dibromoethane (77.3 mg, 0.41 mmol, 1 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The reaction was quenched with water at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl ((2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (130 mg, 61.7%).

[0391] Step 6: Synthesis of (2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0392] To a stirred solution of tert-butyl ((2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (115 mg, 0.23 mmol, 1 equiv.) and DCM (0.92 mL) was added trifluoroacetaldehyde (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 90 minutes. The resulting mixture was concentrated under reduced pressure. The residue The residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector: UV 220 nm. This afforded (2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (80 mg, 78.12%).

[0393] Step 7: Synthesis of 5-((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one)

[0394] To a stirred solution of (2S)-2-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (75 mg, 0.16 mmol, 1 equiv.) in THF was added CDI (107 mg, 0.66 mmol, 4 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, NH2NH2.HO (24 μL, 0.49 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the above mixture, CDI (107 mg, 0.66 mmol, 4 equiv.) in dioxane (2 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water at room temperature. The residue was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by reverse flash chromatography using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B to 55% B in 9 min, wavelength: 254 nm, RT (min): 7. This afforded 5-((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (34.6 mg, 41.7%). LC-MS: (ES, m / z): [MH] = 494.15. 1H NMR(300MHz, methanol-d4)δ 7.66-7.26(s,1H),7.11(d,J=1.7Hz,1H),7.10-6.91(t,J=7.2Hz,1H),6.75-6.68(dd,J=12.1,8.4Hz,1H),5.50-5.36(d,J=11.6Hz,1H), 4.55-4.51(dd,J=12.3,5.6Hz,1H),4.16-3.88(m,4H),2.4-2.36(dd,J=9.0,1.7Hz,6H),2.33-2.16(s,3H),1.44-1.24(d,J=7.0Hz,3H).

[0395] Example 16: 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0396] [ka]

[0397] Step 1: Synthesis of 2-(benzylsulfanyl)-5-chloropyridin-3-ol

[0398] To a 250 mL round-bottom flask was added 2-bromo-5-chloropyridin-3-ol (6 g, 28.8 mmol, 1 equiv.), dioxane (120 mL), DIEA (15 mL, 86.4 mmol, 3 equiv.), Xantphos (3.33 g, 5.8 mmol, 0.2 equiv.), benzyl mercaptan (3.4 mL, 28.8 mmol, 1 equiv.), and Pd(dba) (2.6 g, 2.9 mmol, 0.1 equiv.) at 100 °C. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 2-(benzylsulfanyl)-5-chloropyridin-3-ol (7 g, 96.6%).

[0399] Step 2: Synthesis of 2-(benzylthio)-5-chloropyridin-3-yl benzoate

[0400] To a 20 mL vial, benzoic acid (97 mg, 0.79 mmol, 2 equiv.), DCM (2 mL), SOCl2 (37.5 μL, 0.52 mmol, 1.3 equiv.), and DMF (1 drop) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour to give Intermediate A. To another 8 mL vial, 2-(benzylsulfanyl)-5-chloropyridin-3-ol (100 mg, 0.4 mmol, 1 equiv.), DCM (2 mL), and pyridine (35.4 μL, 0.44 mmol, 1.1 equiv.) were added at 0 °C. Intermediate A was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. The residue was purified by reverse flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, gradient 0% to 100% in 10 min; detector: UV 254 nm. This gave 2-(benzylthio)-5-chloropyridin-3-ylbenzoate (89 mg, 63%).

[0401] Step 3: Synthesis of 5-chloro-2-(chlorosulfonyl)pyridin-3-ylbenzoate

[0402] To a 20 mL vial, 2-(benzylthio)-5-chloropyridin-3-ylbenzoate (50 mg, 0.1 mmol, 1 equiv.), CHCN (5 mL), AcOH (14 μL, 0.25 mmol, 4.4 equiv.), and HO (10 μL, 0.560 mmol, 10 equiv.) were added. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (22.2 mg, 0.11 mmol, 2 equiv.) was added to the mixture at 0° C. The resulting mixture was quenched with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 5-chloro-2-(chlorosulfonyl)pyridin-3-ylbenzoate (13 mg, 27%) as a pale yellow oil.

[0403] Step 4: Synthesis of 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-yl benzoate

[0404] To a 20 mL vial was added tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 1.07 mmol, 17 equivalents) and pyridine (3 mL). 5-Chloro-2-(chlorosulfonyl)pyridin-3-ylbenzoate (531 mg, 1.6 mmol, 1.5 equivalents) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (5:1) to give 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-ylbenzoate (228 mg, 37%).

[0405] Step 5: Synthesis of tert-butyl (2S)-2-((5-chloro-3-hydroxypyridine)-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0406] To a 100 mL round-bottom flask was added 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-ylbenzoate (4.5 g, 7.8 mmol, 1 equiv.), THF (38 mL), HO (12.5 mL), and NaOH (624 mg, 16 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The mixture was acidified to pH 6 with HCl (aq.). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm. This resulted in the synthesis of tert-butyl (2S)-2-((5-chloro-3-hydroxypyridine)-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.5 g, 67.8%).

[0407] Step 6: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0408] To a 100 mL round-bottom flask was added tert-butyl (2S)-2-((5-chloro-3-hydroxypyridine)-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.5 g, 5.29 mmol, 1 equiv.), DMF (20 mL), 1,2-dibromoethane (709 μL, 7.93 mmol, 1.5 equiv.), and CsCO (5.17 g, 15.9 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred overnight at 60° C. under a nitrogen atmosphere. The resulting mixture was quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 20 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.3 g, 87.20%).

[0409] Step 7: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0410] A 100 mL round-bottom flask was charged with tert-butyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.3 g, 4.6 mmol, 1 equiv.), DCM (19 mL), and TFA (6.25 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 0% to 100% in 20 min, detector, UV 254 nm. This gave (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.7 g, 83.3%).

[0411] Step 8: 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0412] To a 40 mL vial, (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg, 0.23 mmol, 1 equiv.), THF (1 mL), and CDI (168 mg, 1.04 mmol, 4.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 20 minutes. To the above mixture, hydrazine hydrate (54.87 μL, 1.130 mmol, 5 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 1 hour. The resulting mixture was quenched with water and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product, dioxane (2 mL), and CDI (168 mg, 1.04 mmol, 4.6 equivalents) were added to a 10 mL vial at room temperature. The resulting mixture was stirred at room temperature under an air atmosphere for 0.5 hours. The crude product was purified under the following conditions: column, XBridge Prep OBD C18 column, 19 * Purification by chiral preparative HPLC using a 250 mm column, 5 μm column, undefined and undefined mobile phase (50% undefined in 10 minutes up to 60%), UV detector at 254 nm gave 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (13.8 mg, 12.3%). LCMS: (ES, m / z): [M+H]: 483.10. 1H NMR(400MHz,DMSO-d6)δ 8.50(s,1H),7.86(s,1H),7.03(t,J=7.0Hz,1H),6.83(dd,J=12.2,8.3Hz,1H),5.43(d,J=11.6Hz,1H),4.59(ddd,J=13.1,8.4,3. 8Hz,1H),4.30(d,J=13.3Hz,1H),3.83(dp,J=19.2,6.2,5.6Hz,3H),2.30(s,3H),2.18(s,3H),2.08(s,1H),1.34(d,J=6.9Hz,3H).

[0413] Example 17: 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0414] [ka]

[0415] Step 1: Synthesis of 5-(benzylthio)-2-chloro-4-fluoropyridine

[0416] To a stirred solution of 5-bromo-2-chloro-4-fluoropyridine (1 g, 4.75 mmol, 1 equiv.) and dioxane (10 mL), DIEA (2.5 mL, 14.3 mmol, 3 equiv.), Xantphos (550 mg, 0.95 mmol, 0.2 equiv.), Pd2(dba)3 (435 mg, 0.48 mmol, 0.1 equiv.), and benzyl mercaptan (669 μL, 5.7 mmol, 1.2 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 20 min; detector, UV 220 nm. This gave 5-(benzylthio)-2-chloro-4-fluoropyridine (550 mg, 45.62%).

[0417] Step 2: Synthesis of 6-chloro-4-fluoropyridine-3-sulfonyl chloride

[0418] To a stirred solution of 5-(benzylthio)-2-chloro-4-fluoropyridine (1.34 g, 5.28 mmol, 1 equiv.) and HO (856 μL), AcOH (1.5 mL, 26 mmol, 5 equiv.) in MeCN, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.08 g, 10.6 mmol, 2 equiv.) was added portionwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0419] Step 3: Synthesis of methyl (2S)-2-((6-chloro-4-fluoropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0420] To a stirred solution of methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.7 g, 7 mmol, 1 equiv.) and pyridine (2.8 mL, 35 mmol, 5 equiv.) was added 6-chloro-4-fluoropyridine-3-sulfonyl chloride (1.6 g, 7 mmol, 1 equiv.) in DCM (20 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous MgSO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give methyl (2S)-2-((6-chloro-4-fluoropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.56 g, 51.8%).

[0421] Step 4: Synthesis of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0422] To a stirred solution of methyl(2S)-2-(6-chloro-4-fluoropyridine-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl) (710 mg, 1.64 mmol, 1 equiv.) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (650 μL, 3.28 mmol, 2.0 equiv.) in DMF at 0 °C was added NaH (197 mg, 4.92 mmol, 3 equiv., 60%) in portions. The resulting mixture was stirred at room temperature for 3 h. The reaction was allowed to stand for 3 h. The mixture was quenched with water at room temperature. The residue was purified by reverse flash chromatography using the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min; detector: UV 220 nm. This afforded methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (190 mg, 24.4%).

[0423] Step 5: Synthesis of methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0424] To a stirred solution of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 0.38 mmol, 1 equiv.) and PPh3 (497 mg, 1.9 mmol, 2 equiv.) in DCE (6 mL), CCl4 (137 μL, 1.42 mmol, 1.5 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 30 min; detector, UV 220 nm. This gave methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (160 mg, 85.6%).

[0425] Step 6: Synthesis of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0426] To a stirred solution of methyl (2S)-2-[6-chloro-4-(2-chloroethoxy)pyridine-3-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (260 mg, 0.53 mmol, 1 equiv.) in DMF was added CS2CO3 (343 mg, 1.05 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 60 °C for 1 hour. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC under the following conditions (PE: EtOAc 1:1) to give methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (190 mg, 78.91%).

[0427] Step 7: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0428] To a stirred solution of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (20 mg, 0.41 mmol, 1 equiv.) and HO (1 mL) in THF was added LiOH.HO (87 mg, 2.08 mmol, 5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The mixture was acidified to pH 6 with concentrated concentrated HCl. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0429] Step 8: Synthesis of 5-((1S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0430] (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (45 mg, 0.10 mmol, 1 equiv.) and CDI (57.7 mg, 0.36 mmol, 3.5 equiv.) in THF at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, NH2NH2.HO (14.8 μL, 0.31 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for another 30 minutes. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the above mixture, CDI (57.7 mg, 0.36 mmol, 3.5 equiv.) in dioxane (1 mL) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water at room temperature. The residue was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by reverse flash chromatography using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 24% B to 52% B in 9 min, wavelength: 220 nm, RT (min): 7. This afforded 5-((1S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (8.3 mg, 16.7%). LCMS: (ES, m / z): [MH] = 480.90. 1H NMR (300 MHz, methanol-d4) δ 8.67-8.42 (m, 1H), 7.08-6.97 (m, 2H), 6.87-6.44 (ddd, J = 75.1, 12.0, 9.2 Hz, 1H), 5.57-5.51 (dd, J = 11.7, 6.5 Hz, 1H), 4.66-4.62 (q, J = 6.3, 5.3 Hz, 1H), 4.48-4.46 (m, 1H), 4.03-3. .95(d,J=14.6Hz,1H),3.87-3.79(m,1H),3.63-3.55(m,1H),2.4.-2.35(d,J=14.8Hz,3H ),2.30-2.21(d,J=5.2Hz,3H),1.60-1.50(d,J=7.0Hz,1H),1.30-1.20(d,J=6.8Hz,2H).

[0431] Example 18: Methyl 7-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylate 1,1-dioxide

[0432] [ka]

[0433] Step 1: Synthesis of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-hydroxybenzoate

[0434] To a stirred solution of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-fluorobenzoate (2.14 g, 4.02 mmol, 1 equiv) (see Example 19) and 2-methanesulfonylethanol (749 mg, 6.03 mmol, 1.5 equiv) in DMF, NaH (402 mg, 10.06 mmol, 2.5 equiv, 60%) was added portionwise at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched by the addition of AcOH at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 40 min; detector, UV 220 nm. This gave methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-hydroxybenzoate (470 mg, 22.1%).

[0435] Step 2: Synthesis of methyl 2-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)-7-chloro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylate 1,1-dioxide

[0436] To a stirred solution of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-hydroxybenzoate (458 mg, 0.86 mmol, 1 equiv.) and dibromoethane (74.5 μL, 0.86 mmol, 1 equiv.) in DMF, KCO (358 mg, 2.59 mmol, 3 equiv.) was added at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 0% to 100% in 30 min; detector, UV 220 nm. This gave methyl 2-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)-7-chloro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylate 1,1-dioxide (290 mg, 60.4%).

[0437] Step 3: Synthesis of (2S)-2-(7-chloro-9-(methoxycarbonyl)-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0438] To a stirred solution of methyl 2-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)-7-chloro-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylate 1,1-dioxide (270 mg, 0.49 mmol, 1 equiv.) in 1 mL of DCM, TFA (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 0% to 100% in 20 min, detector, UV 254 nm. This gave (2S)-2-(7-chloro-9-(methoxycarbonyl)-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (230 mg, 94.75%).

[0439] Step 4: Synthesis of methyl 7-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylate 1,1-dioxide

[0440] To a stirred solution of (2S)-2-[7-chloro-9-(methoxycarbonyl)-1,1-dioxo-3,4-dihydro-5,1 lambda 6,2-benzoxathiazepin-2-yl]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (35 mg, 0.070 mmol, 1 equiv.) and CDI (17.03 mg, 0.105 mmol, 1.5 equiv.) in THF at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture, NH2NH2.HO (10.21 μL, 0.210 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the above mixture, dioxane (1 mL) and CDI (28.38 mg, 0.175 mmol, 2.5 equivalents) were added portionwise at room temperature. The resulting mixture was stirred at room temperature for another hour. The reaction was quenched with water at room temperature. The residue was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by reverse flash chromatography (150 mm, 5 μm column, mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3H2O, mobile phase B: ACN, flow rate: 60 mL / min, gradient: 20% B to 46% B in 12 min, wavelength: 254 / 220 nm, RT (min): 6.88) afforded methyl 7-chloro-2-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-1,1-dioxo-3,4-dihydro-5,1 lambda 6,2-benzoxathiazepine-9-carboxylate (10 mg, 25.95%). LC-MS: (ES, m / z): [MH] = 538.15. 1H NMR(300MHz, methanol-d4)δ 7.33(d,J=2.4Hz,1H),7.19-7.13(m,1H),7.03-6.67(m,2H),5.4-5.45 (t,J=11.5Hz,1H),4.85-4.75(d,J=12.4Hz,1H),4.46-4.42(t,J=13.5H z,1H),4.09-3.76(m,6H),2.45-2.34(d,J=12.2Hz,3H),2.30-2.21(d,J=6.0Hz,3H),1.43-1.40(d,J=6.9Hz,2H),1.25-1.23(d,J=7.0Hz,1H).

[0441] Example 19: Methyl 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylate 1,1-dioxide

[0442] [ka]

[0443] Step 1: Synthesis of methyl 2-(benzylthio)-5-chloro-3-fluorobenzoate

[0444] Methyl 2-bromo-5-chloro-3-fluorobenzoate (4.7 g, 17.5 mmol, 1 equiv.) and dioxane (50 mL) were added to a 250 mL round-bottom flask at room temperature. DIEA (9.2 mL, 52.7 mmol, 3 equiv.), Xantphos (43.3 mg, 0.075 mmol, 0.2 equiv.), Pd2(dba)3 (34.2 mg, 0.037 mmol, 0.1 equiv.), and benzyl mercaptan (50.5 μL, 0.430 mmol, 1.15 equiv.) were added dropwise to the above mixture at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched by the addition of water at room temperature. The resulting mixture was filtered. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc 5:1) to give methyl 2-(benzylthio)-5-chloro-3-fluorobenzoate (4.4 g, 80.6%).

[0445] Step 2: Synthesis of methyl 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoate

[0446] To a stirred mixture of methyl 2-(benzylthio)-5-chloro-3-fluorobenzoate (3 g, 9.6 mmol, 1 equiv.), AcOH (2.77 mL, 48.3 mmol, 5 equiv.), and HO (1.57 mL, 86.9 mmol, 9 equiv.) in MeCN, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.80 g, 19.3 mmol, 2 equiv.) was added portionwise at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1) to give methyl 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoate (2.45 g, 88.4%).

[0447] Step 3: Synthesis of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-fluorobenzoate

[0448] To a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.41 g, 8.562 mmol, 1 equiv.) and pyridine (3.46 mL, 42.8 mmol, 5 equiv.) in DCM was added methyl 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoate (2.46 g, 8.56 mmol, 1 equiv.) in DCM (30 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (2 × 30 mL) and dried over anhydrous MgSO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1) to give methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-fluorobenzoate (3.45 g, 75.7%).

[0449] Step 4: Synthesis of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-(methylamino)benzoate

[0450] To a stirred solution of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-fluorobenzoate (1.4 g, 2.63 mmol, 1 equiv.) in THF (15 mL) was added TEA (3.66 mL, 26.3 mmol, 10 equiv.) and methylamine (6.58 mL, 13.2 mmol, 5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 6 hours. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-(methylamino)benzoate (495 mg, 34.6%).

[0451] Step 5: Synthesis of (2S)-2-(6-chloro-8-(methoxycarbonyl)-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0452] To a stirred mixture of methyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloro-3-(methylamino)benzoate (360 mg, 0.66 mmol, 1 equiv.) in dioxane (14 mL), TsOH (114 mg, 0.66 mmol, 1 equiv.) and 1,3,5-trioxane (597 mg, 6.63 mmol, 10 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 110 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 80% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-8-(methoxycarbonyl)-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg, 90.7%).

[0453] Step 6: Synthesis of methyl 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylate 1,1-dioxide

[0454] To a 50 mL round-bottom flask was added (2S)-2-(6-chloro-8-(methoxycarbonyl)-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (387 mg, 0.78 mmol, 1 equiv.) in THF (4 mL). To the above mixture was added CDI (189 mg, 1.16 mmol, 1.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. To the above mixture was added N2H4.HO (113 μL, 2.33 mmol, 3 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product SM1. To a 50 mL round-bottom flask, SM1 in dioxane (4 mL) was added. To the above mixture, CDI (314.42 mg, 1.940 mmol, 2.5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min, detector, UV 254 nm. This gave methyl 6-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylate 1,1-dioxide (360 mg, 86.1%).

[0455] The product (60 mg) was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 *Further purification using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B to 55% B in 9 min, wavelength: 220 nm, RT1 (min): 7) gave methyl 6-chloro-2-methyl 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylate 1,1-dioxide (20.6 mg, 33.9%). LC-MS: (ES, m / z): [MH] + =537.15. 1 H NMR(300MHz, methanol-d4)δ 6.98-6.92(d,J=19.9Hz,2H),6.83(s,1H),6.71(s,1H),5.43-5.40(d,J=13.3Hz,2H),5.09-5.04(d,J=15.1 Hz,1H),3.94-3.88(d,J=4.6Hz,4H),2.93(s,3H),2.37(d,J=4.0Hz,3H),2.22(d,J=4.1Hz,3H),1.43(s,3H).

[0456] Example 20: 5-((1S,2R)-1-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0457] [ka]

[0458] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-((4,4-diethoxybutyl)amino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0459] In a 40 mL round-bottom flask, tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 4) (1 g, 2.1 mmol, 1 equivalent), 4,4-diethoxy-butylamine (4.76 g, 29.5 mmol, 14 equivalents), TEA (3 g, 29.5 mmol, 14 equivalents), and DMSO (20 mL) were added at room temperature. The resulting mixture was stirred overnight at 80 °C under an air atmosphere. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 5% to 100% gradient in 30 min; detector, UV 220 nm) to give tert-butyl (2S)-2-((4-chloro-2-((4,4-diethoxybutyl)amino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 77%).

[0460] Step 2: Synthesis of (2S)-2-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0461] To an 8 mL round-bottom flask was added tert-butyl (2S)-2-{4-chloro-2-[(4,4-diethoxybutyl)amino]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.33 mmol, 1 equivalent), TFA (1 mL), and DCM (3 mL) at room temperature. The resulting mixture was stirred overnight under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, 5% to 100% gradient in 30 min; detector, UV 220 nm) to give (2S)-2-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (100 mg, 65.9%) as a pale yellow oil.

[0462] Step 3: Synthesis of 5-((1S,2R)-1-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0463] To a 50 mL round-bottom flask, (2S)-2-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (200 mg, 0.44 mmol, 1 equiv.), CDI (108 mg, 0.67 mmol, 2.6 equiv.), and THF (2 mL) were added at room temperature, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture, hydrazine (24.7 mg, 0.77 mmol, 3 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and dioxane (2 mL) and CDI (108 mg, 0.67 mmol, 2.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes, then poured into water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), 5% to 100% gradient in 30 minutes, detector, UV 220 nm. The product was purified under the following conditions: column, XBridge Prep OBD C18 column, 30 * Purification by chiral preparative HPLC using a 150 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (35% ACN up to 65% in 8 min), detector: UV220) gave 5-((1S,2R)-1-(8-chloro-5,5-dioxide-1,2,3,3a-tetrahydro-4H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazin-4-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (14 mg, 10.6%). 1H NMR(300MHz, methanol-d4)δ 7.55(dd,J=21.3,8.5Hz,1H),7.01-6.91(m,1H),6.80-6.66(m,2H),6.61-6.43(m,1H),5. 97-5.64(m,1H),4.92(d,J=3.0Hz,1H),4.44(dd,J=12.1,6.9Hz,1H),3.56-3.31(m,2H),3. 07(s,1H),2.70-2.36(m,2H),2.33(s,1H),2.27(s,2H),2.21(s,1H),2.18(s,2H),2.11(d ,J=12.7Hz,1H),2.03(s,1H),1.50(dd,J=7.0,1.3Hz,3H).LCMS:(ES,m / z):[M+H]:507.15.

[0464] Example 21: 5-((1S,2R)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0465] [ka]

[0466] Step 1: Synthesis of benzyl(4-chloro-2-nitrophenyl)sulfane

[0467] To a stirred solution of 1-bromo-4-chloro-2-nitrobenzene (50 g, 211 mmol, 1 equiv.) and DMF (500 mL), Cs2CO3 (207 g, 634 mmol, 3.00 equiv.) and benzyl mercaptan (30 mL, 254 mmol, 1.2 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOEt (3 x 1000 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from PE / ethyl acetate (10:1) to give benzyl (4-chloro-2-nitrophenyl) sulfane (30 g, 50.7%).

[0468] Step 2: Synthesis of 4-chloro-2-nitrobenzenesulfonyl chloride

[0469] To a stirred solution of benzyl(4-chloro-2-nitrophenyl)sulfane (30 g, 107 mmol, 1 equiv.) and HO (20 mL) in acetonitrile, AcOH (28 mL) was added portionwise at room temperature. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (42.3 g, 215 mmol, 2 equiv.) was added portionwise over 10 min at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. The reaction was quenched with water / ice. The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (1 × 500 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1), to give 4-chloro-2-nitrobenzenesulfonyl chloride (30 g, crude).

[0470] Step 3: Synthesis of tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0471] To a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (5.10 g, 18.1 mmol, 0.8 equiv.) and pyridine (18.3 mL, 227 mmol, 10 equiv.) in DCM was added 4-chloro-2-nitrobenzenesulfonyl chloride (5.8 g, 22.7 mmol, 1 equiv.) in DCM dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (6.2 g, 54.6%).

[0472] Step 4: Synthesis of tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0473] To a stirred solution of tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.8 g, 3.6 mmol, 1 equiv.) and K2CO3 (1 g, 7.2 mmol, 2 equiv.) in DMF, ethyl bromoacetate (400 μL, 3.6 mmol, 1 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60 °C for 60 min. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 63.05%).

[0474] Step 5: Synthesis of tert-butyl (2S)-2-((2-amino-4-chloro-N-(2-ethoxy-2-oxoethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0475] To a stirred solution of methyl (tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (970 mg, 2.1 mmol, 1 equiv.) in AcOH (15 mL), Fe (1.24 g, 22.1 mmol, 10 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 70° C. for 15 min. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was separated into ethyl acetate (3×30 mL). ) and washed with hexane. The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, 10% to 100% gradient in 20 min, detector, UV 254 nm. This gave tert-butyl (2S)-2-((2-amino-4-chloro-N-(2-ethoxy-2-oxoethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (987 mg, 80.01%).

[0476] Step 6: Synthesis of N-((2-amino-4-chlorophenyl)sulfonyl)-N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)glycine

[0477] To a stirred solution of tert-butyl (2S)-2-((2-amino-4-chloro-N-(2-ethoxy-2-oxoethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (950 mg, 1.71 mmol, 1 equiv.) in THF and HO (9.5 mL) was added lithium hydroxide (358 mg, 8.5 mmol, 5 equiv.) portionwise at room temperature. The resulting mixture was stirred at 65° C. overnight. The mixture was acidified to pH 5 with HCl (2 M). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0478] Step 7: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0479] To a stirred solution of N-((2-amino-4-chlorophenyl)sulfonyl)-N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)glycine (800 mg, 1.51 mmol, 1 equiv.) in DCM, EDCI (319 mg, 1.66 mmol, 1.1 equiv.) was added portionwise at room temperature. To the above mixture, DMAP (18.5 mg, 0.15 mmol, 0.1 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (430 mg, 55.6%).

[0480] Step 8: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0481] To a stirred solution of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 0.95 mmol, 1 equiv.) in THF (5 mL) was added BH3-THF (5 mL, 5 mmol, 5.25 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was quenched with MeOH at room temperature. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0482] Step 9: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0483] To a stirred solution of tert-butyl (2S)-2-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (280 mg, 0.55 mmol, 1 equiv.) in DCM (5 mL) was added dropwise TFA (5 mL) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (255 mg, 57.3%).

[0484] Step 10: Synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0485] To a stirred solution of (2S)-2-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (235 mg, 0.53 mmol, 1 equiv.) in THF (2.35 mL) was added CDI (216 mg, 1.33 mmol, 2.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. To the above mixture was added hydrazine hydrate (129.5 μL, 2.67 mmol, 5 equiv.) dropwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 30 minutes. The reaction was quenched with water / ice at 0° C. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2.0 mL). To the above mixture, CDI (259 mg, 1.6 mmol, 3 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 1 hour. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum.

[0486] The crude product (260 mg) was purified under the following conditions: column, XBridge Shield RP18 OBD column, 30 * Purification was performed by chiral preparative HPLC using a 150 mm column, 5 μm column, mobile phase: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (from 26% ACN to a maximum of 56% in 8 min), UV detector at 254 nm. This gave 5-((1S,2R)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2,5]thiadiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (152 mg, 58.4%). LCMS: ES, m / z (M−H) = 478.9. 1H NMR (300 MHz, methanol-d4) δ 7.58(d,J=8.6Hz,1H),7.00-6.95(dd,J=8.4,5.7Hz,1H),6.79-6.67(m,3H),5.4 6-5.42(dd,J=11.7,1.7Hz,1H),4.06-3.96(ddd,J=14.9,11.0,4.2Hz,1H),3.82- 3.72(ddd,J=16.7,9.5,5.6Hz,2H),3.62-3.55(ddd,J=13.0,4.2,2.2Hz,1H),3. 35(dd,J=5.7,2.2Hz,4H),2.34(s,3H),2.21(s,3H),1.44(dd,J=7.0,1.1Hz,3H).

[0487] Example 22: 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxamide 1,1-dioxide

[0488] [ka]

[0489] Step 1: Synthesis of 6-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylic acid 1,1-dioxide

[0490] To a stirred solution of methyl 6-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylate 1,1-dioxide (from Example 19 (100 mg, 0.19 mmol, 1 equiv.)) in THF (1.5 mL) was added LiOH.HO (15.6 mg, 0.37 mmol, 2 equiv.) and HO (0.5 mL) dropwise at room temperature. The resulting mixture was stirred at 65 °C overnight. The mixture was acidified to pH 5 with citric acid. The resulting mixture was extracted with EtOAc (1 × 20 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification.

[0491] Step 2: Synthesis of 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxamide 1,1-dioxide

[0492] To a stirred solution of 6-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxylic acid 1,1-dioxide (95 mg, 0.18 mmol, 1 equiv.) in DMF (1 mL) was added DIEA (95 μL, 0.54 mmol, 3 equiv.), HATU (103 mg, 0.27 mmol, 1.5 equiv.), and ammonium chloride (1.53 mg, 0.03 mmol, 1.5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (90 mg) was purified under the following conditions (column: XSelect CSH Prep C18 OBD column, 19 * 250mm, 5I 1 / 4 Purification by preparative HPLC using a mixture of water (0.1% FA), MeOH (MeOH)-HPLC, flow rate: 20 mL / min, gradient: 20% B to 50% B in 8 min, wavelength: 254 nm, RT1 (min): 7.45 gave 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-methyl-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-8-carboxamide 1,1-dioxide (12.2 mg, 13%). LC-MS: (ES, m / z): [MH] + =522.05. 1 H NMR(300MHz, methanol-d4)δ 7.01-6.96(dd,J=8.4,5.7Hz,1H),6.82-6.67(m,3H),5.47-5.39(m,2H),5.07-5.02(d,J=14.6Hz,1H), 3.94-3.83(dd,J=12.1,7.2Hz,1H),2.91(s,3H),2.38(s,3H),2.22(s,3H),1.44(dd,J=7.0,1.1Hz,3H).

[0493] Example 23: 7-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxamide 1,1-dioxide

[0494] [ka]

[0495] Step 1: Synthesis of 7-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylic acid 1,1-dioxide

[0496] To a stirred solution of methyl 7-chloro-2-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-1,1-dioxo-3,4-dihydro-5,1lambda 6,2-benzoxathiazepine-9-carboxylate (from Example 18) (80 mg, 0.15 mmol, 1 equiv.) and lithiumol hydrate (31 mg, 0.74 mmol, 5 equiv.) in THF, HO (200 μL) was added at room temperature. The resulting mixture was stirred at 60° C. overnight. The mixture was acidified to pH 6 with AcOH. The resulting mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0497] Step 2: Synthesis of 7-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxamide 1,1-dioxide

[0498] To a stirred solution of 7-chloro-2-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxylic acid 1,1-dioxide (90 mg, 0.17 mmol, 1 equiv.) and HATU (100 mg, 0.26 mmol, 1.5 equiv.) in DMF, ammonium chloride (11 mg, 0.21 mmol, 1.2 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The residue was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification by reverse flash chromatography using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 23% B to 50% B in 8 min, wavelength: 254 nm, RT (min): 7. This afforded 7-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-9-carboxamide 1,1-dioxide (23.4 mg, 26%). LC-MS: (ES, m / z): [MH] = 523.10. 1H NMR (300 MHz, methanol-d4) δ 7.25-7.24(d,J=2.1Hz,1H),7.08-7.07(d,J=2.2Hz,1H),6.98-6.95(dd,J=8 .4,5.7Hz,1H),6.72-6.68(dd,J=12.0,8.4Hz,1H),5.55-5.51(dd,J=11.6,1. 8Hz,1H),4.85-4.81(s,1H),4.40-4.50(d,J=12.0Hz,1H),4.01-3.98(ddd,J= 15.9,10.6,5.7Hz,1H),3.81-3.76(t,J=9.8Hz,2H),2.35-2.40(s,3H),2.39- 2.21(s,3H),1.44-1.42(dd,J=6.9,1.1Hz,3H).

[0499] Example 24: 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0500] [ka]

[0501] Step 1: Synthesis of 2-bromo-5-chloro-1-fluoro-3-methylbenzene

[0502] To a 40 mL vial, 4-bromo-3-fluoro-5-methylaniline (3.65 g, 17.9 mmol, 1 equiv.) and HCl (36.5 mL, 1201 mmol, 67 equiv.) were added at room temperature. To the above mixture, NaNO (2468 mg, 35.86 mmol, 2 equiv.) in HO (0.6 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 30 minutes. To the above mixture, CuCl (5313 mg, 53.6 mmol, 3 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60 °C for an additional hour. The mixture was cooled to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (1 × 20 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 5:1) to give 2-bromo-5-chloro-1-fluoro-3-methylbenzene (3.2 g, 80.1%).

[0503] Step 2: Synthesis of benzyl(4-chloro-2-fluoro-6-methylphenyl)sulfane

[0504] To a stirred solution of 2-bromo-5-chloro-1-fluoro-3-methylbenzene (2 g, 8.95 mmol, 1 equiv.) and DIEA (4676 μL, 26.9 mmol, 3 equiv.) in dioxane, Xantphos (1036 mg, 1.79 mmol, 0.2 equiv.) and Pd2(dba)3 (820 mg, 0.9 mmol, 0.1 equiv.) were added portionwise at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 10:1) to give benzyl (4-chloro-2-fluoro-6-methylphenyl)sulfane (1.45 g, 60.7%).

[0505] Step 3: Synthesis of 4-chloro-2-fluoro-6-methylbenzenesulfonyl chloride

[0506] To a stirred solution of benzyl(4-chloro-2-fluoro-6-methylphenyl)sulfane (1.45 g, 5.44 mmol, 1 equiv.) and AcOH (1557 μL, 27 mmol, 5 equiv.) in MeCN and HO (881 μL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2142 mg, 10.9 mmol, 2 equiv.) portionwise at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (12:1) to give 4-chloro-2-fluoro-6-methylbenzenesulfonyl chloride (930 mg, 70.4%).

[0507] Step 4: Synthesis of tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate To a stirred mixture of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1100 mg, 3.91 mmol, 1 equiv.) and pyridine (15811 μL, 19.5 mmol, 5 equiv.) in DCM, 4-chloro-2-fluoro-6-methylbenzenesulfonyl chloride (950 mg, 3.909 mmol, 1 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 69.7%).

[0508] Step 5: Synthesis of tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0509] To a stirred solution of tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 0.62 mmol, 1 equiv) and 2-methanesulfonylethanol (229 mg, 1.85 mmol, 3 equiv) in DMF (3 mL) was added NaH (123 mg, 3.08 mmol, 5 equiv, 60%) in portions at 0 °C. The resulting mixture was stirred at 60 °C for 2 days. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3:1) to give tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (177 mg, 59.2%).

[0510] Step 6: Synthesis of tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0511] To a stirred solution of tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg, 0.21 mmol, 1 equiv.) in DMF (1 mL) was added CsCO (201 mg, 0.62 mmol, 3 equiv.) and dibromoethane (17.7 μL, 0.21 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred at 65 °C overnight. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NHHCO) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (70 mg, 39.08%).

[0512] Step 7: Synthesis of (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0513] To a stirred solution / mixture of tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (70 mg, 0.14 mmol, 1 equiv.) in DCM (1 mL) was added TFA (500 μL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min, detector, UV 254 nm. This gave (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (60 mg, 96.3%).

[0514] Step 8: Synthesis of 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one)

[0515] To an 8 mL vial was added (2S)-2-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (10 mg, 0.022 mmol, 1 equiv.) in THF (100 mL). To the above mixture was added CDI (5.3 mg, 0.03 mmol, 1.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. To the above mixture was added N2H4.HO (3.20 μL, 0.066 mmol, 3 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 minutes. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (2 × 1 mL). The combined organic layers were washed with brine (1x2 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product SM1. To an 8 mL vial, SM1 in dioxane (100 μL) was added. To the above mixture, CDI (8.9 mg, 0.055 mmol, 2.5 equiv) was added portionwise at room temperature. The resulting mixture was stirred at room temperature for another 30 min. The crude product (60 mg) was purified under the following conditions: Column: YMC-Actus Triart C18 ExRS, 30 * Purification by preparative HPLC using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 20% B to 50% B in 8 min, 50% B, wavelength: 254 nm, RT1 (min): 7) gave 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (12.3 mg, 20.21%). LCMS: (ES, m / z): [MH] + =485.15. 1H NMR(300MHz, methanol-d4)δ 7.12-7.08(m,1H),6.98-6.96(dd,J=8.4,5.8Hz,1H),6.86-6.85(d,J=2.2Hz,1H) ,6.75-6.72(dd,J=12.1,8.4Hz,1H),5.63-5.59(dd,J=11.7,1.9Hz,1H),4.46-4.3 7(ddt,J=16.5,12.0,5.3Hz,2H),4.01-3.91(ddd,J=14.1,10.6,6.4Hz,1H),3.85 -3.71(m,2H),2.65(s,3H),2.36(s,3H),2.22(s,3H),1.44(dd,J=7.0,1.1Hz,3H).

[0516] Example 25: 5-((1S,2R)-1-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0517] [ka]

[0518] Step 1: Synthesis of 1-(3-bromo-6-chloro-2-fluorophenyl)ethan-1-ol

[0519] To a stirred solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (5 g, 21 mmol, 1 equiv.) in THF was added CHMgBr (3 M in EtO) (17.6 mL, 52.6 mmol, 2.5 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was quenched with saturated NHCl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0520] Step 2: Synthesis of 1-(3-bromo-6-chloro-2-fluorophenyl)ethan-1-one

[0521] To a 250 mL round-bottom flask, 1-(3-bromo-6-chloro-2-fluorophenyl)ethanol (5.1 g, 20 mmol, 1 equiv.), DCM (100 mL), and MnO (17.5 g, 201 mmol, 10 equiv.) were added at room temperature. The resulting mixture was stirred at 40 °C overnight. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE, to give 1-(3-bromo-6-chloro-2-fluorophenyl)ethanone (3.95 g, 78%) as a pale yellow oil.

[0522] Step 3: Synthesis of 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one

[0523] To a 100 mL round-bottom flask was added 1-(3-bromo-6-chloro-2-fluorophenyl)ethanone (2 g, 7.95 mmol, 1 equiv.), dioxane (35 mL), benzyl mercaptan (1.13 mL, 9.5 mmol, 1.2 equiv.), DIEA (4.16 mL, 23.8 mmol, 3 equiv.), Xantphos (920 mg, 1.59 mmol, 0.2 equiv.), and Pd2(dba)3 (728 mg, 0.8 mmol, 0.1 equiv.) at room temperature. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one (2.44 g, 93.7%) as a pale yellow solid.

[0524] Step 4: Synthesis of 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride

[0525] To a stirred solution of 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one (2.44 g, 8.28 mmol, 1 equiv.), HO (0.8 mL), and AcOH (4 mL) in MeCN (20 mL) was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.26 g, 16.56 mmol, 2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with saturated NH Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (8:1) to give 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride (1.8 g, 80.2%).

[0526] Step 5: Synthesis of tert-butyl (2S)-2-((3-acetyl-4-chloro-2-fluorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0527] To a 100 mL round-bottom flask was added tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenylbutanoate (1.70 g, 6.04 mmol, 1 equiv.), DCM (15 mL), and pyridine (2.4 mL, 30 mmol, 5 equiv.) at 0° C. To the above mixture was added 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride (1.8 g, 6.6 mmol, 1.1 equiv.) in DCM (15 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with 1× The mixture was washed with 20 mL of water. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (7:1) to give tert-butyl (2S)-2-((3-acetyl-4-chloro-2-fluorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.58 g, 82.8%).

[0528] Step 6: Synthesis of tert-butyl (2S)-2-((3-acetyl-4-chloro-2-hydroxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0529] To a solution of tert-butyl (2S)-2-((3-acetyl-4-chloro-2-fluorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 1.94 mmol, 1 equiv.) in DMF was added sodium hydride (60% in oil, 310 mg) at 0° C. The mixture was stirred for 15 min. 2-Methanesulfonylethanol (481 mg, 3.88 mmol, 2 equiv.) was added, and the mixture was warmed to room temperature and stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give tert-butyl (2S)-2-((3-acetyl-4-chloro-2-hydroxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (410 mg, 41.2%) as a brown semi-solid.

[0530] Step 7: Synthesis of tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0531] To a 40 mL sealed tube was added tert-butyl (2S)-2-((3-acetyl-4-chloro-2-hydroxyphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (400 mg, 0.78 mmol, 1 equiv.), DMF (8 mL), dibromoethane (100 μL, 1.17 mmol, 1.5 equiv.), and K2CO3 (323 mg, 2.33 mmol, 3 equiv.) at room temperature. The resulting mixture was stirred at 65 °C overnight. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 71.4%).

[0532] Step 8: Synthesis of (2S)-2-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0533] To an 8 mL sealed tube was added tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 0.56 mmol, 1 equiv.), DCM (1.5 mL), and TFA (1.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0534] Step 9: Synthesis of 5-((1S,2R)-1-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0535] To an 8 mL sealed tube, (2S)-2-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (55 mg, 0.11 mmol, 1 equiv.), THF (1 mL), and CDI (46.1 mg, 0.29 mmol, 2.5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 40 minutes. To the above mixture, hydrazine hydrate (16.6 μL, 0.34 mmol, 3 equiv.) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for an additional 30 minutes. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 × 1 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To the above mixture, dioxane (1 mL) and CDI (46.1 mg, 0.29 mmol, 2.5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4, and evaporated. The crude product was purified under the following conditions: Column: XBridge Prep OBD C18 column, 19 *Purification by chiral preparative HPLC using a 250 mm column, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: MeOH-HPLC, flow rate: 20 mL / min, gradient: 20% B to 50% B in 8 min, wavelength: 254 nm, RT1 (min): 7.45 gave 5-((1S,2R)-1-(6-acetyl-7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (14.6 mg, 23.6%).

[0536] LCMS: (ES, m / z): (M-H): 522.10. 1 H NMR(300MHz, methanol-d4)δ 7.82-7.79(d,J=8.6Hz,1H),7.36-7.33(d,J=8.5Hz,1H),6.99-6.97(dd,J=8.4,5.7Hz,1H),6.76-6.69(dd,J=12.1,8.4Hz,1H),5.55-5.51(dd,J= 11.6,2.2Hz,1H),4.62(dt,J=12.2,4.6Hz,1H),3.96-3.93(m,4H),2.44( s,3H),2.33(s,3H),2.21-2.03(s,3H),1.45-1.42(dd,J=7.0,1.2Hz,3H).

[0537] Example 26: 5-((1S,2R)-1-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0538] [ka]

[0539] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0540] To a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluoro-6-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 24) (300 mg, 0.62 mmol, 1 equiv.) in THF (3 mL), TEA (855 μL, 6.15 mmol, 10 equiv.) and methylamine (1.54 mL, 3.1 mmol, 5 equiv.) were added at room temperature. The resulting mixture was stirred at 60° C. overnight. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (285 mg, 92.9%).

[0541] Step 2: Synthesis of (2S)-2-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0542] To a stirred solution of tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (285 mg, 0.55 mmol, 1 equiv.) in dioxane (11 mL), TsOH (95 mg, 0.55 mmol, 1 equiv.) and 1,3,5-trioxane (496 mg, 5.51 mmol, 10 equiv.) were added at room temperature. The resulting mixture was stirred at 110 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), gradient 10% to 100% in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (47 mg, 18.8%).

[0543] Step 3: Synthesis of 5-((1S,2R)-1-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0544] To a 50 mL round-bottom flask was added (2S)-2-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (60 mg, 0.13 mmol, 1 equiv.) in THF (1 mL). To the above mixture was added CDI (32.1 mg, 0.2 mmol, 1.5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 30 minutes. To the above mixture was added N2H4.HO (19 μL, 0.4 mmol, 3 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product SM1. To an 8 mL vial was added SM1 in dioxane (1 mL). To the above mixture was added CDI (53.5 mg, 0.33 mmol, 2.5 equiv) portionwise at room temperature. The resulting mixture was stirred at room temperature for another 30 minutes. The crude product was used directly in the next step without further purification.

[0545] The crude product (60 mg) was purified under the following conditions: Column: XBridge Prep OBD C18 column, 30 * Purification using a 150 mm, 5 μm column, mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 25% B to 55% B in 9 min, wavelength: 220 nm, RT1 (min): 7) gave 5-((1S,2R)-1-(6-chloro-4,8-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (10.3 mg, 17.13%). LCMS: (ES, m / z): [MH] + =493.05. 1H NMR(300MHz, methanol-d4)δ 6.99(s,1H),6.75-6.65(m,2H),6.54(d,J=2.5Hz,1H),5.59-5.55(m,1H),5.27-5.22(d,J=13.8Hz,1 H),4.96(s,1H),3.90(s,1H),2.84(s,3H),2.59(s,3H),2.39(s,3H),2.23(s,3H),1.45-1.43(m,3H).

[0546] Example 27: -((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0547] [ka]

[0548] Step 1: Synthesis of 5-(benzylthio)-2-chloro-4-fluoropyridine

[0549] To a stirred solution of 5-bromo-2-chloro-4-fluoropyridine (1 g, 4.75 mmol, 1 equiv.) and dioxane (10 mL), DIEA (2.48 mL, 14.2 mmol, 3 equiv.), Xantphos (550 mg, 0.95 mmol, 0.2 equiv.), Pd2(dba)3 (435 mg, 0.48 mmol, 0.1 equiv.), and benzyl mercaptan (669 μL, 5.7 mmol, 1.2 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 4 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, 10% to 50% gradient in 20 min; detector, UV 220 nm. This gave 5-(benzylsulfanyl)-2-chloro-4-fluoropyridine (550 mg, 45.6%).

[0550] Step 2: Synthesis of 6-chloro-4-fluoropyridine-3-sulfonyl chloride

[0551] To a stirred solution of 5-(benzylsulfanyl)-2-chloro-4-fluoropyridine (1.34 g, 5.28 mmol, 1 equiv.) and HO (900 μL), AcOH (1.51 mL, 26 mmol, 5 equiv.) in MeCN, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.08 g, 10.6 mmol, 2 equiv.) was added portionwise at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0552] Step 3: Synthesis of methyl (2S)-2-((6-chloro-4-fluoropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0553] To a stirred solution of methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.66 g, 6.94 mmol, 1.00 equiv.) and pyridine (2.81 mL, 34.8 mmol, 5 equiv.) was added 6-chloro-4-fluoropyridine-3-sulfonyl chloride (1.6 g, 7 mmol, 1.00 equiv.) in DCM (20 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous MgSO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to give methyl (2S)-2-((6-chloro-4-fluoropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.56 g, 51.8%).

[0554] Step 4: Synthesis of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0555] To a stirred solution of methyl (2S)-2-((6-chloro-4-fluoropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenylbutanoate (710 mg, 1.64 mmol, 1 equiv.) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (650 μL, 3.28 mmol, 2.0 equiv.) in DMF, NaH (200 mg, 4.92 mmol, 3 equiv., 60%) was added portionwise at 0° C. The resulting mixture was stirred at room temperature for 3 h. The reaction was quenched with water at room temperature. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% FA) in water, gradient 0% to 100% in 30 min, detector, UV 220 nm. This gave methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (190 mg, 24.4%).

[0556] Step 5: Synthesis of methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0557] To a stirred solution of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 0.38 mmol, 1 equiv.) and PPh3 (497 mg, 1.9 mmol, 2 equiv.) in DCE (6 mL), CCl4 (137 μL, 1.42 mmol, 1.5 equiv.) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (10 mmol / L NH4HCO3) in water, gradient 0% to 100% in 30 min; detector, UV 220 nm. This gave methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (160 mg, 85.6%).

[0558] Step 6: Synthesis of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0559] To a stirred solution of methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (260 mg, 0.53 mmol, 1 equiv.) in DMF was added CS2CO3 (343 mg, 1.05 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions (PE: EtOAc 1:1) to give methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (190 mg, 78.91%).

[0560] Step 7: Synthesis of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0561] To a stirred solution of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (5 mg, 0.011 mmol, 1 equiv.) and HO (1 mL) in THF was added LiOH.HO (87 mg, 2.08 mmol, 5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The mixture / residue was acidified to pH 6 with concentrated HCl. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product / residue was used directly in the next step without further purification.

[0562] Step 8: Synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]ox...

Claims

1. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, X １ is N or CR １ and X ２ is N or CR ２ and X ３ is N or CR ３ and X ４ is N or CR ４ and R １ are hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R ２ are hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R ３ are hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; R ４ are hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Ring C is —O—, —S—, —S(═O)—, —S(═O) ２ - and -NR １０ - is a 5-8 membered heterocycloalkyl containing 1 or 2 additional heteroatoms selected from the group consisting of: R １０ is hydrogen, -OH, -OR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R １０ａ is replaced by R １０ａ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same carbon １０ａ come together to form oxo, R ５ are each independently deuterium, halogen, —CN, —OH, or —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same carbon ５ come together to form oxo, Alternatively, two R on the same carbon ５ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on adjacent atoms ５ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Or, one R ５ and R １０ together form a heterocycloalkyl or heteroaryl, each optionally substituted with one or more R; p is 0 to 4; Ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; R ６ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Alternatively, two R on the same atom ６ come together to form oxo, n is 0 to 3; R ７ represents hydrogen, deuterium, halogen, -CN, -NO ２ , —OH, —OR ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ８ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ９ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ９ａ is replaced by Alternatively, two R on the same atom ９ come together to form oxo, R ９ａ are each independently deuterium, halogen, —CN, or —NO ２ , —OH, —OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -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 , -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 Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently substituted with one or more R; Alternatively, two R on the same atom ９ａ come together to form oxo, m is 0 to 5; R ａ are each independently １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; and R ｃ and R ｄ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, 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, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, or —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 , -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, cycloalkyl, or heterocycloalkyl; Alternatively, two R on the same atom are joined together to form oxo, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

2. Ring C is —O—, —S—, or —NR １０ -, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

3. Ring C is —O— and —NR １０ -, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

4. Ring C is —O—, —S—, or —NR １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of:

5. Ring C is —O— and —NR １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of:

6. Ring C is —NR １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the aryl group is a 6-membered heterocycloalkyl containing one additional heteroatom that is -.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring C is a 6-membered heterocycloalkyl containing one additional heteroatom that is -O-.

8. Ring C is —O—, —S—, or —NR １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of:

9. Ring C is —O— and —NR １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of:

10. Ring C is —NR １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein the compound is a 7-membered heterocycloalkyl containing one additional heteroatom that is -.

11. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring C is a 7-membered heterocycloalkyl containing one additional heteroatom that is -O-.

12. R ５ are each independently １ -C ６ Alkyl, or C １ -C ６ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is haloalkyl.

13. R ５ are each independently １ -C ６ 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is alkyl.

14. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein p is 0 or 1.

15. The compound of formula (I) has the formula (Ia) 【Chemistry 2】 It is of During the ceremony, X is —O—, —S—, or —NR １０ - and R ５’ are each independently hydrogen or R ５ and Alternatively, two R on the same carbon ５’ come together to form oxo, Alternatively, two R on the same carbon ５’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Or, one R ５ and R １０ and R are substituted with R. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is substituted with R.

16. The compound of formula (I) may be a compound of formula (Ib) 【Chemistry 3】 It is of During the ceremony, X is —O—, —S—, or —NR １０ - and R ５’ are each independently hydrogen or R ５ and Alternatively, two R on the same carbon ５’ come together to form oxo, Alternatively, two R on the same carbon ５’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Alternatively, two R on adjacent carbons ５’ together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R; Or, one R ５ and R １０ and R are substituted with R. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is substituted with R.

17. The compound of formula (I) has the formula (Ic) 【Chemistry 4】 It is of During the ceremony, X is —O—, —S—, or —NR １０ - and R ５’ are each independently hydrogen or R ５ and Alternatively, two R on the same carbon ５’ come together to form oxo, Alternatively, two R on the same carbon ５’ together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R; Or, one R ５ and R １０ and R are substituted with R. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is substituted with R.

18. 18. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein X is -O-.

19. X is -NR １０ 18. The compound of any one of claims 15 to 17, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

20. R １０ is hydrogen, -S(=O) ２ R ａ , -C(=O)R ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally independently selected from one or more R １０ａ 20. The compound of any one of claims 1-10, 12-17, or 19, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, substituted with:

21. R １０ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ heteroalkyl, wherein the alkyl is optionally independently selected from one or more R １０ａ 20. The compound of any one of claims 1-10, 12-17, or 19, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, substituted with:

22. R １０ is C １ -C ６ 20. The compound of any one of claims 1-10, 12-17, or 19, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

23. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is a 5-membered heterocycloalkyl.

24. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is 2,3-dihydro-1,3,4-oxadiazole.

25. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is a 5-membered heteroaryl.

26. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is triazole or tetrazole.

27. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is triazole.

28. 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring A is tetrazole.

29. R ６ are each independently deuterium, halogen, —CN, —OH, or —OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ deuterated alkyl, or two R ６ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

30. R ６ are each independently deuterium, halogen, or C １ -C ６ alkyl, or two R on the same atom ６ 30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

31. Two R on the same atom ６ 31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

32. 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein n is 0 or 1.

33. 32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein n is 2 or 3.

34. 【Chemical 5】 teeth, 【Chemistry 6】 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

35. X １ is CR １ 35. The compound of any one of claims 1 to 34, wherein:

36. R １ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

37. R １ is hydrogen, deuterium, halogen, -C(=O)R ａ , C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ 37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is hydroxyalkyl.

38. R １ is hydrogen, -C(=O)R ａ , C １ -C ６ Alkyl, or C １ -C ６ 38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is hydroxyalkyl.

39. R １ 39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein is hydrogen.

40. X １ is N, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

41. X ２ is CR ２ 41. The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

42. R ２ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl.

43. R ２ are hydrogen, deuterium, halogen, -OH, C １ -C ６ Alkyl, or C １ -C ６ 43. The compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is haloalkyl.

44. R ２ 44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein is halogen.

45. X ２ is N, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

46. X ３ is CR ３ 46. ​​The compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

47. R ３ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

48. R ３ are hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ Hydroxyalkyl, C １ -C ６ 48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl.

49. R ３ 49. The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein is hydrogen.

50. X ３ is N, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

51. X ４ is CR ４ 51. The compound of any one of claims 1 to 50, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:

52. R ４ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -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 Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ 52. The compound of any one of claims 1 to 51, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl, cycloalkyl, or heterocycloalkyl.

53. R ４ is hydrogen, deuterium, halogen, -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 Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ 53. The compound of any one of claims 1 to 52, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is heteroalkyl.

54. X ４ is N, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

55. R ７ is halogen, -CN, -NO ２ , —OH, —OR ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Deuterated alkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ 55. The compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

56. R ７ are hydrogen, deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ haloalkyl, or C １ -C ６ 56. The compound of any one of claims 1 to 55, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is a deuterated alkyl.

57. R ７ is C １ -C ６ 57. The compound of any one of claims 1 to 56, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein: R is alkyl.

58. R ８ is hydrogen or C １ -C ６ 58. The compound of any one of claims 1 to 57, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is alkyl.

59. R ８ 59. The compound of any one of claims 1 to 58, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein is hydrogen.

60. 60. The compound of any one of claims 1 to 59, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is aryl or heteroaryl.

61. 61. The compound of any one of claims 1 to 60, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein Ring B is phenyl.

62. R ９ are each independently deuterium, halogen, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ 62. The compound of any one of claims 1 to 61, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is a deuterated alkyl, cycloalkyl, or heterocycloalkyl.

63. R ９ are each independently a halogen or C １ -C ６ 63. The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R is alkyl.

64. 64. The compound of any one of claims 1 to 63, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein m is 1 to 3. 【Request 65】 【Chemical 7-1】 【Chemistry 7-2】 【Chemistry 7-3】 【Chemistry 7-4】 【Chemistry 7-5】 【Chemistry 7-6】 【7-7】 【7-8】 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

66. 66. A pharmaceutical composition comprising a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

67. 67. A method of treating cancer in a subject, comprising administering to the subject a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition of claim 66.

68. 67. A method of inhibiting ribonucleotide reductase in a subject, comprising administering to the subject a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition of claim 66.

69. 69. The method of claim 68, wherein the inhibition of ribonucleotide reductase occurs in tumor cells of the subject in need thereof.

70. 67. A method of treating a tumor or tumor cells in a subject, the method comprising administering a compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of claim 66, in an amount sufficient to induce replication stress in the tumor or tumor cells, and administering a cancer targeted therapeutic agent, wherein the tumor or tumor cells have an ecDNA signature, and the growth or size of the tumor, or the growth or number of tumor cells, is reduced.

71. 67. A method of treating an ecDNA-associated tumor or tumor cells, the method comprising administering a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition of claim 66, to a subject identified as having a tumor or tumor cells that have ecDNA, wherein the growth or size of the tumor, or the growth or number of the tumor cells, is reduced as a result of the treatment.

72. 72. The method of claim 71, wherein the method further comprises administering a targeted cancer therapy.

73. 73. The method of claim 72, wherein the cancer targeted therapy inhibits a gene or gene product contained in ecDNA in the tumor or tumor cells.

74. 67. A method of treating a tumor or tumor cells in a subject, the method comprising administering a compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of claim 66, in an amount sufficient to induce replication stress in the tumor or tumor cells, wherein the tumor or tumor cells contain ecDNA or have an ecDNA signature, and wherein the growth or size of the tumor, or the growth or number of tumor cells, is reduced.

75. 67. A method of treating an ecDNA-associated tumor or tumor cells, the method comprising administering a compound of any one of claims 1 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or the pharmaceutical composition of claim 66, to a subject identified as having a tumor or tumor cells with localized amplification of an oncogene, wherein the growth or size of the tumor, or the growth or number of the tumor cells, is reduced as a result of the treatment.

76. 76. The method of claim 75, further comprising administering a targeted cancer therapy agent, wherein the target of the targeted cancer therapy agent is a protein encoded by the oncogene.

77. 77. The method of claim 75 or 76, wherein the local amplification is present on ecDNA.

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