Cyclic sulfonamide ribonucleotide reductase (RNR) inhibitors and uses thereof

Abstract

Provided herein are compounds and methods for treating cancer. The methods comprise administering to a subject in need thereof a therapeutically effective amount of a cyclic sulfonamide RNR inhibitor disclosed herein.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 375,495, filed on September 13, 2022, which is hereby incorporated by reference in its entirety. Technical Field

[0003] Compounds, methods for preparing such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds to inhibit ribonucleotide reductase (RNR) are described herein. Background Art

[0004] Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), consists of a heterooligomer of a large subunit M1 and a small subunit M2, and the expression of both subunits is required for enzyme activity. RNR is a highly regulated enzyme in the deoxyribonucleotide synthesis pathway, which is ubiquitous in humans, bacteria, yeast, and other organisms. RNR is responsible for the de novo conversion of ribonucleoside diphosphates into 2'-deoxyribonucleoside diphosphates, a process essential for DNA synthesis and repair. RNR is directly involved in DNA synthesis and repair, tumor growth, metastasis, and drug resistance. Overexpression of M2 and numerous associations with their prognosis have been reported in various types of solid tumors and hematological cancers. In addition, growth inhibition of cells and antitumor effects in vivo achieved by inhibiting RNR have been reported in cell lines derived from several cancer types and in non-clinical models.

[0005] Proliferation of cancer cells requires an excess of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. Therefore, an increase in RNR activity is necessary as it helps provide additional dNTPs for DNA replication in primary and metastatic cancer cells. Due to this key role in DNA synthesis, RNR represents an important cancer therapeutic target. However, existing chemotherapy targeting RNR is based on nucleoside analogs. Therefore, they are promiscuous, leading to non-specific binding to other nucleoside-binding proteins, which causes unwanted side effects. Thus, there is a need in the treatment of cancer for compositions and methods for specifically targeting and inhibiting RNR activity in neoplastic cells. Summary of the Invention

[0006] RNR inhibitors useful for treating cancer are described herein.

[0007] There is disclosed herein a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

[0008]

[0009] Formula (I) as defined herein.

[0010] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0011] Also disclosed herein is a method of treating cancer 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.

[0012] 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.

[0013] In some embodiments, inhibition of ribonucleotide reductase occurs in tumor cells in a subject in need thereof.

[0014] Also disclosed herein is a method for treating a tumor or tumor cells in a subject, the method 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 targeting therapeutic agent; wherein the tumor or tumor cells have an ecDNA signature; and wherein the growth or size of the tumor or the growth or number of tumor cells is reduced.

[0015] Also disclosed herein is a method of treating an ecDNA-related tumor or tumor cells, the method 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 the growth or size of the tumor or the growth or number of the tumor cells is reduced due to the treatment. In some embodiments, the method further comprises administering a cancer targeting therapeutic agent. In some embodiments, the cancer targeting therapeutic agent inhibits a gene or gene product contained on ecDNA in the tumor or tumor cells.

[0016] The present disclosure also provides a method for treating a tumor or tumor cells in a subject, the method comprising administering to the subject a compound or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof disclosed herein, 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 comprise ecDNA or have ecDNA characteristics; and wherein the growth or size of the tumor or the growth or number of tumor cells is reduced.

[0017] The present disclosure also provides a method for treating an ecDNA-related tumor or tumor cells, the method comprising administering to a subject a compound or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof disclosed herein, or a pharmaceutical composition disclosed herein, which is identified as having a tumor or tumor cells containing focal amplification of an oncogene, wherein the growth or size of the tumor or the growth or number of the tumor cells is reduced due to the treatment. In some embodiments, the method further comprises administering a cancer-targeted therapeutic agent, wherein the target of the therapeutic agent is a protein encoded by the oncogene. In some embodiments, the focal amplification is present on ecDNA.

[0018] Incorporated by reference

[0019] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference for the specific purposes identified herein. Detailed Description

[0020] Definitions

[0021] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, one skilled in the art will understand that the 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 requires otherwise, throughout the specification and the following claims, the word "comprise" and its variations, such as "comprises" and "comprising," are to be construed in an open, 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 claimed invention.

[0022] References to "some embodiments" or "an embodiment" throughout this specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" throughout this specification are not necessarily all referring to the same embodiment. Additionally, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its inclusive sense of "and / or" unless the context clearly dictates otherwise.

[0023] As used herein, unless otherwise specified, the following terms have the following meanings:

[0024] "Oxo group" means =O.

[0025] "Amine" means -NH2;

[0026] "Hydroxyl" means -OH;

[0027] "Carboxyl" means -COOH.

[0028] "Alkyl" means a straight-chain or branched-chain saturated hydrocarbon monovalent group having from one to about ten carbon atoms, more preferably from one to six 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, and longer alkyls such as heptyl, octyl, etc. Whenever a numerical range such as "C1-C6 alkyl" appears herein, it means that the alkyl can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is C1-C 10Alkyl. In 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 specifically stated otherwise in the specification, the alkyl may be optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups, etc. In some embodiments, the alkyl is optionally substituted by one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkyl is optionally substituted by one or more halogens, -CN, -OH or -OMe. In some embodiments, the alkyl is optionally substituted by a halogen.

[0029] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in the cis or trans or Z or E conformation with respect to one or more double bonds and should be understood to include all isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also covers the occurrence of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, the alkenyl may be optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups or heteroaryl groups, etc. In some embodiments, the alkenyl is optionally substituted by one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl is optionally substituted by one or more halogens, -CN, -OH or -OMe. In some embodiments, the alkenyl is optionally substituted by a halogen.

[0030] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrences of the term "alkynyl" where no numerical range is specified. Unless specifically stated otherwise in the specification, the alkynyl group can be optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, etc. In some embodiments, the alkynyl group is optionally substituted by one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted by one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted by a halogen.

[0031] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless specifically stated otherwise in the specification, the alkylene group can be optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, etc. In some embodiments, the alkylene group is optionally substituted by one or more oxo groups, halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene group is optionally substituted by one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted by a halogen.

[0032] "Alkoxy" refers to a group of the formula -Oalkyl, where alkyl is as defined above. Unless specifically stated otherwise in the specification, the alkoxy group can be optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, etc. In some embodiments, the alkoxy group is optionally substituted by one or more halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted by one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted by a halogen.

[0033] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl includes but is not limited to anthryl, naphthyl, phenanthryl, azulenyl, phenyl, yl, fluoranthenyl, fluorenyl, asym-indacenyl, sym-indacenyl, indanyl, indenyl, phenalenyl, phenanthryl, heptalenyl, pyrenyl and triphenylenyl. Unless otherwise specifically stated in the specification, the aryl can be optionally substituted, for example, by one or more halogens, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, etc. In some embodiments, the aryl is optionally substituted by one or more halogens, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the aryl is optionally substituted by one or more halogens, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl is optionally substituted by a halogen.

[0034] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), a spiro ring system and / or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include but are not limited to those having three to fifteen carbon atoms (such as C3-C 15 fully saturated cycloalkyl or C3-C 15 cycloalkenyl), three to ten carbon atoms (such as C3-C 10 fully saturated cycloalkyl or C3-C 10cycloalkyl having three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 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, decahydronaphthyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, 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]heptyl, 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 specifically stated in the specification, the cycloalkyl is optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, etc. In some embodiments, the cycloalkyl is optionally substituted by one or more oxo groups, halogens, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl is optionally substituted by one or more oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogens.

[0035] "Halogen group" or "halogen" refers to bromo group, chloro group, fluoro group, or iodo group. In some embodiments, the halogen is fluoro group or chloro group. In some embodiments, the halogen is fluoro group.

[0036] "Halogenated alkyl" means an alkyl group as defined above substituted with one or more halogenated groups as defined above, such as 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, etc.

[0037] "Halogenated alkoxy" means -O-halogenated alkyl, wherein the halogenated alkyl is as defined above.

[0038] "Hydroxyalkyl" means an alkyl group as defined above substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxy groups. 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-methylprop-1-yl, or 2,3-dihydroxypropyl.

[0039] "Aminoalkyl" means an alkyl group as defined above substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, CH2N(CH3)2, or CH(CH3)N(CH3)2. In some embodiments, the aminoalkyl is aminomethyl.

[0040] "Deuterated alkyl" means an alkyl group as defined above substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl is CD3.

[0041] "Heteroalkyl" means an alkyl group in which one or more of the skeletal atoms of the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group contains 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, and wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group contains 1 to 6 carbon atoms and 1 or 2 atoms selected from oxygen, nitrogen, and sulfur, and wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, --CH2C(CH3)2OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH(CH3)N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless specifically stated otherwise in the specification, the heteroalkyl group is optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, etc. In some embodiments, the heteroalkyl group is optionally substituted by one or more oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl group is optionally substituted by one or more oxo groups, halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl group is optionally substituted by a halogen.

[0042] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains one to three nitrogens. In some embodiments, the heterocycloalkyl contains one or two nitrogens. In some embodiments, the heterocycloalkyl contains one nitrogen. In some embodiments, the heterocycloalkyl contains one nitrogen and one oxygen. In some embodiments, the heterocycloalkyl contains one oxygen. Unless otherwise specifically stated in the specification, the heterocycloalkyl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), a spiro ring system, or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, those having two to fifteen carbon atoms (e.g., C2-C 15 fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), two to ten carbon atoms (e.g., C2-C 10 fully saturated heterocycloalkyl or C2-C 10heterocycloalkyl having from two to eight carbon atoms (such as C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (such as C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (such as C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (such as C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or from two to four carbon atoms (such as C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyls include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thieno[1,3]dithiacyclohexanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithiacyclohexanyl, 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, the heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) that make up the heterocycloalkyl, including heteroatoms. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless specifically stated otherwise in the specification, the heterocycloalkyl is optionally substituted, for example, by one or more oxo groups, halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc.In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo groups, halogens, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogens, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with a halogen.

[0043] "Heteroaryl" refers to a 5- to 14-membered ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains one to three heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl contains one to three heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl contains one to three nitrogens. In some embodiments, the heteroaryl contains one or two nitrogens. In some embodiments, the heteroaryl contains one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. In some embodiments, the heteroaryl is a 5-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur. Examples include but are not limited to azido group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxadiazolone, 2-oxoazido groups such as a base, oxazolyl, pyridin-1-yl oxide, pyrimidin-1-yl oxide, pyrazin-1-yl oxide, pyridazin-1-yl oxide, 1-phenyl-1H-pyrrolyl, phenazine, phenothiazine, phenoxazine, phthalazine, pteridine, purine, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically stated otherwise in the specification, the heteroaryl group is optionally substituted, for example, by one or more halogens, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic ester, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, etc. In some embodiments, the heteroaryl group is optionally substituted by one or more halogens, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted by one or more halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted by a halogen.

[0044] The term "optional" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes both the case where the event or situation occurs and the case where it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).

[0045] The term "one or more" when referring to an optional substituent means that the subject group is optionally substituted by one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted by one, two, or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents. In some embodiments, the subject group is optionally substituted by three substituents.

[0046] As used herein, the term "treat / treated / treatment / treating" refers to a therapeutic treatment in which the purpose is to slow down (alleviate) an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical outcome. For the purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; diminution of the degree of a condition, disorder or disease; stabilization (i.e., non-worsening) of the state of a condition, disorder or disease; delay in the onset or slowing of the progression of a condition, disorder or disease; improvement in the state of a condition, disorder or disease; and detectable or undetectable remission (whether partial or total), improvement or amelioration of a condition, disorder or disease. Treatment includes eliciting a clinically significant response without an excessive level of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. As used herein, the term "treat / treated / treatment / treating" and words derived therefrom do not necessarily mean 100% or complete treatment. Rather, there are varying degrees of treatment that are recognized by those of ordinary skill in the art as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount or level of treatment of a mammalian disorder. For example, a disorder, including its symptoms or conditions, can be alleviated by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%.

[0047] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound disclosed herein that is administered that will, to some extent, alleviate one or more symptoms of a disease or condition being treated, such as cancer or an inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is an amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction of the symptoms of a disease. In some embodiments, techniques such as dose escalation studies are used to determine the appropriate "effective" amount in any given case.

[0048] As used herein, the term "ecDNA signature" generally refers to one or more characteristics common to ecDNA+ (extrachromosomal DNA (ecDNA)-containing) tumors or tumor cells. In some cases, the ecDNA signature is selected from gene amplification; loss-of-function mutations in p53; loss of microsatellite instability (MSI-H); low levels of PD-L1 expression; low levels of tumor inflammation signature (TIS); low levels of tumor mutational burden (TMB); increased frequency of allelic substitutions, insertions, or deletions (insertion-deletion mutations (indel)); and any combination thereof. In some cases, the ecDNA signature includes the detection or identification of ecDNA using imaging techniques. In some cases, the ecDNA signature does not include any imaging or direct detection of ecDNA.

[0049] Compound

[0050] Described herein are cyclic sulfonamide RNR inhibitors useful for treating cancer.

[0051] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof:

[0052]

[0053] Wherein:

[0054] X 1 is N or CR 1 ;

[0055] X 2 is N or CR 2 ;

[0056] X 3 is N or CR 3 ;

[0057] X 4 is N or CR 4 ;

[0058] R 1 is 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 Rd 、 -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, heteroalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0059] R 2 is 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0060] R 3 is 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 , -NR c C(=O)NR d R b , -NR a C(=O)R b , -NR b C(=O)OR b , -NR 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0061] R 4 is 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 , -NR c R d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0062] Ring C is a 5- to 8-membered heterocycloalkyl containing one or two additional heteroatoms selected from -O-, -S-, -S(=O)-, -S(=O)2- and -NR 10 -;

[0063] R 10 is 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R 10a substituted;

[0064] Each R 10a is independently deuterium, halogen, -CN, -NO2, -OH, -ORa 、 -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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0065] or two R on the same carbon 10a together form an oxo group;

[0066] Each R 5 independently is 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0067] or two R on the same carbon 5 together form an oxo group;

[0068] or two R on the same carbon5 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R;

[0069] or two Rs on adjacent atoms 5 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted by one or more R;

[0070] or one R 5 and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more R;

[0071] p is 0 - 4;

[0072] Ring A is a 5 - membered heterocycloalkyl or 5 - membered heteroaryl;

[0073] Each R 6 independently is 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;

[0074] or two Rs on the same atom 6 together form an oxo group;

[0075] n is 0 - 3;

[0076] R 7 is hydrogen, deuterium, 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;

[0077] R 8 is hydrogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuterated alkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl or C1 - C6 heteroalkyl;

[0078] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0079] Each R 9Independently is 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 , -NR c C(=O)NR d , -NR b , -NR a , -NR b , -NR b , -NR b , -NR 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R 9a substituted;

[0080] or two R on the same atom 9 together form an oxo group;

[0081] Each R 9a independently is 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 , -NRb 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 said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R;

[0082] or two R on the same atom 9a together form an oxo group;

[0083] m is 0-5;

[0084] each R a independently is 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R;

[0085] each R b independently is hydrogen, 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R; and

[0086] each R c and R dindependently is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a C1-C6 heteroalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a C1-C6 alkylene(cycloalkyl), a C1-C6 alkylene(heterocycloalkyl), a C1-C6 alkylene(aryl) or a C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more R;

[0087] or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted by one or more R;

[0088] each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -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;

[0089] or two Rs on the same atom together form an oxo group.

[0090] In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, the compound has the following formula:

[0091]

[0092] In some embodiments of the compound of formula (I), ring C comprises one or two selected from -O-, -S- and -NR 10A 5- to 8-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having one or two additional heteroatoms selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom selected from -O-, -S- and -NR 10 A 5- to 8-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having one or two additional heteroatoms selected from -O- and -NR 10 A 5- to 8-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom selected from -O- and -NR 10 A 5- to 8-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom that is -O-. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom that is -NR 10 A 5- to 8-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom that is -S-. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom that is -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 5- to 8-membered heterocycloalkyl having an additional heteroatom that is -S(=O)-.

[0093] In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl having an additional heteroatom selected from -O-, -S- and -NR 10 A 5- to 7-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl having an additional heteroatom selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl having an additional heteroatom selected from -O- and -NR 10 A 5- to 7-membered heterocycloalkyl having an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl having an additional heteroatom that is -O-. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl having an additional heteroatom that is -NR 10A 5- to 7-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing an additional heteroatom of -S-. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing an additional heteroatom of -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 5- to 7-membered heterocycloalkyl containing an additional heteroatom of -S(=O)-.

[0094] In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom selected from -O-, -S- and -NR 10 - A 6- to 7-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom selected from -O- and -NR 10 - A 6- to 7-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom of -O-. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom of -NR 10 - A 6- to 7-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom of -S-. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom of -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom of -S(=O)-.

[0095] In some embodiments of the compounds of formula (I), ring C is a 6-membered heterocycloalkyl containing an additional heteroatom selected from -O-, -S- and -NR 10 - A 6-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6-membered heterocycloalkyl containing an additional heteroatom selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 6-membered heterocycloalkyl containing an additional heteroatom selected from -O- and -NR 10 - A 6-membered heterocycloalkyl with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6-membered heterocycloalkyl containing an additional heteroatom of -NR 10A 6-membered heteroalkyl group with an additional heteroatom of -. In some embodiments of the compounds of formula (I), ring C is a 6-membered heteroalkyl group containing an additional heteroatom of -O-. In some embodiments of the compounds of formula (I), ring C is a 6-membered heteroalkyl group containing an additional heteroatom of -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 6-membered heteroalkyl group containing an additional heteroatom of -S(=O)-. In some embodiments of the compounds of formula (I), ring C is a 6-membered heteroalkyl group containing an additional heteroatom of -S-.

[0096] In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom selected from -O-, -S- and -NR 10 -. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom selected from -S(=O)- and -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom selected from -O- and -NR 10 -. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -NR 10 -. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -O-. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -S-. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -S(=O)2-. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -S(=O)-. In some embodiments of the compounds of formula (I), ring C is a 7-membered heteroalkyl group containing an additional heteroatom of -S-.

[0097] In some embodiments of the compounds of formula (I), each R 5 is 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 heteroalkyl. In some embodiments of the compounds of formula (I), each R 5 is independently deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds of formula (I), each R 5independently is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I), each R 5 independently is C1-C6 alkyl.

[0098] In some embodiments of the compounds of formula (I), two Rs on the same carbon 5 together form an oxo group.

[0099] In some embodiments of the compounds of formula (I), two Rs on the same carbon 5 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more Rs.

[0100] In some embodiments of the compounds of formula (I), two Rs on adjacent atoms 5 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted by one or more Rs.

[0101] In some embodiments of the compounds of formula (I), one R 5 and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more Rs.

[0102] In some embodiments of the compounds of formula (I), p is 0-3. In some embodiments of the compounds of formula (I), p is 0-2. In some embodiments of the compounds of formula (I), p is 0 or 1. In some embodiments of the compounds of formula (I), p is 1 or 2. In some embodiments of the compounds of formula (I), p is 1-3. In some embodiments of the compounds of formula (I), p is 1. In some embodiments of the compounds of formula (I), p is 2. In some embodiments of the compounds of formula (I), p is 3.

[0103] In some embodiments of the compounds of formula (I), the compound of formula (I) has the formula (Ia):

[0104]

[0105] wherein:

[0106] X is -O-, -S-, -S(=O)-, -S(=O)2- or -NR 10 -;

[0107] each R 5’ independently is hydrogen or R 5 ;

[0108] or two Rs on the same carbon 5’ together form an oxo group;

[0109] or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more Rs;

[0110] or one R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more Rs.

[0111] In some embodiments of the compound of formula (Ia) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, the compound has the following formula:

[0112]

[0113] In some embodiments of the compound of formula (I), the compound of formula (I) has formula (Ib):

[0114]

[0115] wherein:

[0116] X is -O-, -S-, -S(=O)-, -S(=O)2- or -NR 10 -;

[0117] each R 5’ is independently hydrogen or R 5 ;

[0118] or two Rs on the same carbon 5’ together form an oxo group;

[0119] or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more Rs;

[0120] or two Rs on adjacent carbons 5’ together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more Rs;

[0121] or one R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more Rs.

[0122] In some embodiments of the compound of formula (Ib) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, the compound has the following formula:

[0123]

[0124] In some embodiments of the compounds of formula (I), the compounds of formula (I) have formula (Ic):

[0125]

[0126] wherein:

[0127] X is -O-, -S-, -S(=O)-, -S(=O)2- or -NR 10 -;

[0128] each R 5’ is independently hydrogen or R 5 ;

[0129] or two Rs on the same carbon 5’ together form an oxo group;

[0130] or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more Rs;

[0131] or one R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more Rs.

[0132] In some embodiments of the compounds of formula (Ic) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, the compound has the following formula:

[0133]

[0134] 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 the 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 -.

[0135] In some embodiments of the compounds of formula (Ia)-(Ic), each R 5’ is 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 the compounds of formulas (Ia)-(Ic), each R 5’ is independently hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds of formulas (Ia)-(Ic), each R 5’ is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I), each R 5 is independently hydrogen or C1-C6 alkyl.

[0136] In some embodiments of the compounds of formulas (Ia)-(Ic), two R's on the same carbon 5’ together form an oxo group.

[0137] In some embodiments of the compounds of formulas (Ia)-(Ic), two R's on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more R.

[0138] In some embodiments of the compounds of formulas (Ia)-(Ic), one R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more R.

[0139] In some embodiments of the 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R 10a .

[0140] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 10is 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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R 10a . In some embodiments of the 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 the alkyl is optionally and independently substituted by one or more R 10a . In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 10 is C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 10a is 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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 10a is 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 the compounds of formula (I) or (Ia)-(Ic), each R 10a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 10a is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 10a is independently halogen, -OH, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or heterocycloalkyl.

[0141] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing one to four heteroatoms selected from O, S and N. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing two to four heteroatoms selected from O, S and N. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heterocycloalkyl containing three to four heteroatoms selected from O, S and N. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing one to four heteroatoms selected from O, S and N. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing two to four heteroatoms selected from O, S and N.

[0142] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a 5-membered heteroaryl containing three to four heteroatoms selected from O, S and N. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a triazole or a tetrazole. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a triazole. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is a tetrazole. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), ring A is 2,3-dihydro-1,3,4-oxadiazole.

[0143] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 6 is independently deuterium, halogen, -CN, -OH, -OR a , -NR cR d 、 a C1-C6 alkyl, a C1-C6 haloalkyl or a C1-C6 deuterated alkyl; or two R's on the same atom 6 together form an oxo group. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 6 is independently deuterium, a halogen or a C1-C6 alkyl; or two R's on the same atom 6 together form an oxo group. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), two R's on the same atom 6 together form an oxo group.

[0144] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 0-3. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 0-2. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 2 or 3.

[0145] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 1-3. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 1. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 2. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), n is 3.

[0146] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), is wherein R 6’ is hydrogen or a C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), is

[0147] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 1 is CR 1 。 In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 1 is N.

[0148] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 1 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)ORb , -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 the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 1 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the 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 the alkyl is optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 1 is 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 the 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 the 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 the compounds of formula (I) or (Ia)-(Ic), R 1 is hydrogen.

[0149] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 2 is CR 2。In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 2 is N.

[0150] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 2 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 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 2 is 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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 2 is 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 the 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 the compounds of formula (I) or (Ia)-(Ic), R 2 is halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 2 is chloro.

[0151] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 3 is CR 3 。In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 3 is N.

[0152] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 3 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 , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 3 is 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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 3 is 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 the 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 the compounds of formula (I) or (Ia)-(Ic), R 3 is hydrogen.

[0153] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 4 is CR 4 . In some embodiments of the compounds of formula (I) or (Ia)-(Ic), X 4 is N.

[0154] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 4 is hydrogen, deuterium, halogen, -CN, -OH, -ORa 、 -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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), 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 、 C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), 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 、 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 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 the 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 the 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 d . In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 4 is hydrogen or -C(=O)R a . In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 4 is hydrogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 4 is -C(=O)R a .

[0155] In some embodiments of the 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 the 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 the compounds of formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 7 is C1-C6 alkyl. In some embodiments of the 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, heteroalkyl, aryl or heteroaryl. In some embodiments of the 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 heteroalkyl.

[0156] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 8is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), R 8 is hydrogen.

[0157] 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 pyridyl.

[0158] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 9 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ic), each R 9 is independently halogen or C1-C6 alkyl.

[0159] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), m is 0-2. 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 1-3. 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.

[0160] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), is

[0161] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R aindependently is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R a independently is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a independently is C1-C6 alkyl.

[0162] In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b independently is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b independently is C1-C6 alkyl.

[0163] In some embodiments of the compounds disclosed herein, each R c and R d independently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein each alkyl, alkylene, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R c and R dindependently is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R c and R d independently is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d independently is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d independently is C1-C6 alkyl.

[0164] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more Rs.

[0165] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, cycloalkyl or heterocycloalkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, cycloalkyl or heterocycloalkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cycloalkyl or heterocycloalkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl or C1-C3 haloalkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl or C1-C3 haloalkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl; or two Rs on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy.In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl.

[0166] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), the compounds are selected from the compounds in Table 1:

[0167] Table 1

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] An absolute configuration label (abs) is added to the chiral center to indicate that it is unambiguously a pure sample of the drawn stereoisomer.

[0193] In some embodiments of the compounds of formula (I) or (Ia)-(Ic), the compounds are selected from the compounds of Table 2:

[0194] Table 2

[0195]

[0196]

[0197] Other conformational isomers / stereoisomers of the compounds disclosed herein

[0198] In some embodiments, the compounds described herein exist in geometric isomer forms. In some embodiments, the compounds described herein have 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 cases, the compounds described herein have one or more chiral centers, and each center independently exists in the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimers forms and their corresponding mixtures. The compounds described herein include all rotational isomers and "atropisomers" and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion may be used in the applications described herein. In some embodiments, the compounds described herein are prepared into their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (such as melting point, boiling point, solubility, reactivity, etc.), and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer and the resolving agent are then recovered by any practical means that does not cause racemization.

[0199] Labeled compounds

[0200] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds described herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, l5 N, 18O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds described herein, and their pharmaceutically acceptable salts, solvates or stereoisomers containing the isotopes mentioned above and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, such as those incorporating radioactive isotopes such as 3 H and 14 C, can be used in drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium (i.e., 2 H) can result in 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 hydrogens in the compounds disclosed herein have been replaced with deuterium atoms. In some embodiments, one or more alkyl substituents in the compounds disclosed herein have been replaced with deuterated alkyl substituents.

[0201] 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.

[0202] Pharmaceutically acceptable salts

[0203] In some embodiments, the compounds described herein exist in their pharmaceutically acceptable salt forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0204] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt so formed.

[0205] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, and such salts include but are 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, caprate, digluconate, gluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-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, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propynoate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate and xylenesulfonate.

[0206] In addition, 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, said pharmaceutically acceptable inorganic or organic acids including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids such as oxalic acid, although not pharmaceutically acceptable per se, are used to prepare salts that are intermediates useful for obtaining the compounds, solvates or stereoisomers disclosed herein, and their pharmaceutically acceptable acid addition salts.

[0207] In some embodiments, those compounds described herein that contain a free acid group are reacted with a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts such as lithium salts, sodium salts, potassium salts, calcium salts, and magnesium salts, as well as aluminum salts, etc. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C1-C4 alkyl)4 hydroxide, etc.

[0208] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups contained therein. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0209] Solvate

[0210] In some embodiments, the compounds described herein exist in solvate form. The present invention provides methods of treating diseases by administering such solvates. The present disclosure also provides methods of treating diseases by administering such solvates in the form of pharmaceutical compositions.

[0211] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. 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 form as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered equivalent to unsolvated forms.

[0212] Tautomers

[0213] In some cases, compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, which is accompanied by the conversion of a single bond and one or more adjacent double bonds. In bonding arrangements where tautomerism is possible, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are considered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the tetrazoles disclosed herein exist in any of their tautomeric forms:

[0214]

[0215] Preparation of Compounds

[0216] The compounds used in the reactions described herein are prepared from commercially available chemicals and / or starting from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), 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, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, 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).

[0217] Suitable reference books and monographs that detail the synthesis of reactants useful for preparing the compounds described herein, or provide citations to articles describing the preparations, 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. Gilchrist, “Heterocyclic Chemistry”, 2nd ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th ed., Wiley-Interscience, New York, 1992. Other suitable reference books and monographs that detail the synthesis of reactants useful for preparing the compounds described herein, or provide citations to articles describing the preparations, 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, R.V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd ed. (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th ed. (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. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0218] Specific and analogous reactants are optionally determined by reference to the Index of Known Chemicals Prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and online. Known but non-commercially available chemicals in the catalog are optionally prepared by custom chemical synthesis facilities, many of which standard chemical suppliers (such as those listed above) offer custom synthesis services. One reference on the preparation and selection of pharmaceutical salts of the compounds described herein is P.H. Stahl and C.G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.

[0219] Pharmaceutical compositions

[0220] In certain embodiments, the compounds described herein are administered in the form of 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), which is selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0221] Accordingly, there is provided herein a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0222] In certain embodiments, the compounds provided herein are substantially pure, as they contain less than about 5% or less than about 1% or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthetic by-products generated, for example, in one or more steps of a synthetic method.

[0223] The pharmaceutical composition is administered in a manner suitable for the disease to be treated. The appropriate dosage, as well as the appropriate duration and frequency of administration, will be determined by factors such as the patient's medical condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen provide one or more compositions in an amount sufficient to provide a therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduction in symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. The optimal dosage depends on the patient's body mass, weight, or blood volume.

[0224] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intralung, intradermal, intrathecal, and epidural and intranasal administration. Parenteral administration includes 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 tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, solutions, emulsions, ointments, lotions, eye drops or ear drops. In some embodiments, the pharmaceutical composition is formulated as tablets.

[0225] Suitable dosages and dosage regimens are determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated at a lower dosage that is less than the optimal dosage of the compounds disclosed herein. Thereafter, the dosage is increased in small increments until the optimal effect in the circumstances is achieved. In some embodiments, the methods of the invention involve administering from about 0.1 μg to about 50 mg of at least one of the compounds described herein per kg of subject body weight. For a 70 kg patient, depending on the physiological response of the subject, a dosage of from about 10 μg to about 200 mg of the compounds disclosed herein will more typically be used.

[0226] By way of example only, the dosage of the compounds described herein for the methods of treating the diseases described herein is from about 0.001 to about 1 mg per kg of subject body weight per day, such as 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 dosage of the compounds described herein for the methods described is from about 1 to about 1000 mg per kg of subject body weight being treated per day, such as 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.

[0227] Method of treatment

[0228] The present disclosure provides methods for treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. The present disclosure provides methods for treating RNR-related cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0229] In some embodiments, the RNR-related cancer comprises a malignancy in which the incidence can be reduced, or the symptoms of which are in remission or alleviated and / or completely cured, by deletion or repression and / or inhibition of the function of RNR. The target malignancies are but not limited to head and neck cancer, gastrointestinal cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, cholangiocarcinoma, 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 tract cancer (renal cancer, bladder cancer, prostate cancer, testicular tumors, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumors, etc.

[0230] In some embodiments, the term cancer is used in accordance with its ordinary and common meaning as per the present disclosure and refers to all types of cancer, neoplasm, or malignancy found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumors, epithelial carcinomas, and sarcomas. Exemplary cancers treatable with the compounds or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, pharmaceutical compositions disclosed herein 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, 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 cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, 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., of the head, neck, or esophagus), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma. Additional examples include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, Hodgkin’s Disease, non-Hodgkin’s lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential 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 cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid epitheliocarcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget’s Disease of the Nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate 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.

[0231] Also disclosed herein is a method of inhibiting ribonucleotide reductase in a subject, comprising administering to the subject a compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof disclosed herein, or a pharmaceutical composition disclosed herein.

[0232] In some embodiments, the inhibition of ribonucleotide reductase occurs in tumor cells in a subject in need thereof.

[0233] Also disclosed herein is a method for treating a tumor or tumor cells in a subject, the method comprising administering a compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof disclosed herein, or a pharmaceutical composition disclosed herein, in an amount sufficient to induce replication stress in the tumor or tumor cells; and administering a cancer targeting therapeutic agent; wherein the tumor or tumor cells have an ecDNA signature; and wherein the growth or size of the tumor or the growth or number of the tumor cells is reduced.

[0234] Also disclosed herein is a method for treating an ecDNA-related tumor or tumor cells, the method comprising administering a compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof disclosed herein, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells containing ecDNA, wherein the growth or size of the tumor or the growth or number of the tumor cells is reduced due to the treatment. In some embodiments, the method further comprises administering a cancer targeting therapeutic agent. In some embodiments, the cancer targeting therapeutic agent inhibits a gene or gene product contained on ecDNA in the tumor or tumor cells.

[0235] Also disclosed herein is a method for treating a tumor or tumor cells in a subject, the method comprising administering a compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof disclosed herein, 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 wherein the growth or size of the tumor or the growth or number of the tumor cells is reduced.

[0236] The present disclosure also provides a method of treating ecDNA-related tumors or tumor cells, the method comprising administering a compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof disclosed herein, or a pharmaceutical composition disclosed herein, to a subject identified as having a tumor or tumor cells with focal amplification of an oncogene, wherein the growth or size of the tumor or the growth or number of the tumor cells is reduced due to the treatment. In some embodiments, the method further comprises administering a cancer-targeted therapeutic agent, wherein the target of the therapeutic agent is a protein encoded by the oncogene. In some embodiments, the focal amplification is present on ecDNA.

[0237] An important and clinically unique mechanism by which ecDNA mediates resistance to targeted therapies. One or more of the RNR inhibitors described herein present an immediate therapeutic opportunity as a single agent or in combination with other therapies. In some embodiments, one or more of the RNR inhibitors described herein can be used to treat ecDNA+ cancers, ecDNA+ tumors, or ecDNA+ tumor cells. One or more of the RNR inhibitors described herein can be used to treat tumors such as those having one or more amplified oncogenes (e.g., FGFR, EGFR, MET, KRAS, MDM2 amplifications), and in some cases, the one or more amplified oncogenes include non-mutated forms of the oncogene, and in some cases, the amplified oncogenes include mutated forms of the oncogene. In some cases, the tumor comprises one or more amplified oncogenes present on ecDNA, and one or more of the RNR inhibitors described herein are used in combination with a therapeutic agent that targets the one or more amplified oncogenes on the ecDNA (e.g., an inhibitor of the one or more amplified oncogenes) to treat the tumor. One or more of the RNR inhibitors described herein can be used to treat tumors for which there is no approved targeted therapy or for which there is a lack of highly effective therapy. One or more of the RNR inhibitors described herein can be used to treat tumors that have developed resistance to another therapy such as a targeted agent. In some cases, a tumor (or tumor cells) treated with one or more targeted agents develops resistance to the targeted agent, such as a targeted agent against an oncogene or a targeted agent that directly inhibits the activating mutant form of certain oncoproteins (e.g., KRAS, BRAF, EGFR), or develops resistance due to focal amplification such as ecDNA-based amplification of the target gene itself, and one or more of the RNR inhibitors described herein can be used alone or in combination with additional therapeutic agents to treat such tumors or tumor cells.

[0238] The present disclosure provides methods in which inhibition of RNR by one or more RNR inhibitors described herein exhibits synthetic lethality with a cancer targeting agent. In some embodiments, synthetic lethality is generated in the case of a combination of one or more RNR inhibitors described herein with a cancer targeting agent. In some cases, a tumor context is identified as highly sensitive to an RNR inhibitor and allows for a sufficient therapeutic index such that an effective tolerated dose can be achieved. In some embodiments, synthetic lethality is generated in the case of a combination of one or more RNR inhibitors described herein with a cancer targeting agent, wherein 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 against ecDNA+ cells. In some cases, the enhanced cytotoxicity is caused by a combination of RNR inhibition and inhibition of a cancer target such as an oncogene (e.g., an oncogene amplified on ecDNA).

[0239] In one aspect 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, the tumor or tumor cells are determined to have an ecDNA signature when the tumor or tumor cells have one or more characteristics associated with ecDNA+ tumors or tumor cells. By way of example, in some cases, the ecDNA signature is selected from gene amplification; loss-of-function mutations in p53; absence of microsatellite instability (MSI-H); low levels of PD-L1 expression; low levels of tumor inflammation signature (TIS); low levels of tumor mutational burden (TMB); increased frequency of allelic substitutions, insertions, or deletions (indel mutations); and any combination thereof.

[0240] In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein have favorable drug properties such as metabolic stability. In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein have a long half-life. In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein are stable in human hepatocytes. In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein have a low clearance rate in human hepatocytes. In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein have a hepatocyte clearance rate (Clhep) value of less than about 10 mL / min / kg. In some embodiments, the compounds or pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers thereof described herein have a Clhep value of less than about 20 mL / min / kg.

[0241] Combination therapy

[0242] In certain cases, the compounds or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof described herein are administered in combination with a second therapeutic agent or a cancer targeting agent.

[0243] In one aspect of the methods herein, the methods further comprise administering a cancer targeting therapeutic agent against the activity of the protein product of a target gene. In some cases, treatment with a cancer targeting therapeutic agent and an RNR inhibitor disclosed herein reduces the amplification or expression of the target gene in a tumor 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 concurrently with the RNR inhibitor.

[0244] In one aspect of the methods herein, the tumor or tumor cells have an ecDNA signature. In some cases, the tumor or tumor cells acquire an ecDNA signature after administration of the cancer targeting therapeutic agent. In some cases, the tumor or tumor cells have an ecDNA signature prior to treatment. In some cases, the methods prevent an increase in ecDNA in the tumor or tumor cells.

[0245] In some embodiments, the second therapeutic agent comprises an antimetabolite, a platinum drug, a plant alkaloid drug, and a molecular targeting drug.

[0246] In some embodiments, the antimetabolite comprises 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 (decitabine, guadecitabine, azacitidine, etc.).

[0247] In some embodiments, platinum drugs include cisplatin, oxaliplatin, carboplatin, and nedaplatin.

[0248] In some embodiments, plant alkaloid drugs include microtubule-inhibiting drugs such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase-inhibiting drugs such as irinotecan (or the active metabolite SN-38), nogitecan, and etoposide.

[0249] In some embodiments, the molecularly targeted drugs include ATR (ataxia telangiectasia and Rad3-related protein) inhibitors, Chk1 (checkpoint kinase 1) inhibitors, HSP (heat shock protein) 90 inhibitors, PARP (poly ADP-ribose polymerase) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, Her2 inhibitors, VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, MET inhibitors, AXL inhibitors, RET inhibitors, FLT3 (fms-related tyrosine kinase 3) inhibitors, KIT inhibitors, CSF1R (colony-stimulating factor 1 receptor) inhibitors, TIE2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) inhibitors, TRKB inhibitors, and CDK4 / 6 inhibitors. In some embodiments, the ATR inhibitors include AZD6738, berzosertib, BAY1895344, and VX-803. In some embodiments, the Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737. In some embodiments, the HSP90 inhibitors include luminespib, ganetespib, and onalespib. In some embodiments, the PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib. In some embodiments, the 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 inhibitors include small molecule inhibitors such as lapatinib, and anti-Her2 antibodies 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 includes small molecule inhibitors such as sunitinib, cabozantinib, midostaurin, sorafenib, vandetanib, pazopanib, lenvatinib, and axitinib, and anti-VEGFR antibodies 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, the CSF1R inhibitor includes sunitinib, BLZ-945, and ARRY-382. In some embodiments, the TIE2 inhibitor includes cabozantinib. In some embodiments, the TRKB inhibitor includes cabozantinib and entrectinib. In some embodiments, the CDK4 / 6 inhibitor includes palbociclib, ribociclib, and abemaciclib.

[0250] In some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein in combination with a second therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit.

[0251] In one specific embodiment, the compound described herein or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof is administered in combination with a second therapeutic agent, wherein the compound or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof and the second therapeutic agent described herein modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit compared to administering either therapeutic agent alone.

[0252] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is merely additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0253] In certain embodiments, when the compounds disclosed herein are administered in combination with a second therapeutic agent, different therapeutically effective doses of the compounds disclosed herein will be used to formulate the pharmaceutical composition and / or in the treatment regimen. The therapeutically effective doses of the drugs and other agents used in the combination treatment regimen are optionally determined by means similar to those described above for the active agent itself. In addition, the treatment methods described herein encompass the use of metronomic dosing, i.e., providing lower doses more frequently to minimize toxic side effects. In some embodiments, the combination treatment regimen encompasses the following treatment regimens: wherein the administration of the compounds or their pharmaceutically acceptable salts, solvates, tautomers or stereoisomers described herein is initiated before, during or after treatment with the second agent described herein and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes the following treatment: wherein the compounds or their pharmaceutically acceptable salts, solvates, tautomers or stereoisomers described herein and the second agent used in the combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. The combination treatment also includes cyclic treatment that starts and stops at various times to assist in the clinical management of the patient.

[0254] It should be understood that the dosage regimen for treating or ameliorating one or more conditions for which relief is sought is modified according to various factors (such as the disease, disorder or condition suffered by the subject; the age, weight, sex, diet and medical condition of the subject). Thus, in some cases, the dosage regimen actually employed will vary and, in some embodiments, deviate from the dosage regimen set forth herein.

[0255] For the combination therapies described herein, the doses of the compounds administered in combination vary depending on the type of co-drug employed, the specific drugs employed, the disease or condition being treated, etc. In additional embodiments, when administered in combination with a second therapeutic agent, the compounds provided herein are administered simultaneously with or sequentially to the second therapeutic agent.

[0256] In combination therapies, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If the administration is simultaneous, then by way of example only, the multiple therapeutic agents are provided in a single combined form or in multiple forms (e.g., in the form of a single pill or in the form of two separate pills).

[0257] The compounds described herein, or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof, and combination therapies are administered before, during or after the occurrence of a disease or condition, and the timing of administration of the composition containing the compound will vary. In another embodiment, the compound and composition are administered to a subject as soon as possible during or after the onset of symptoms. In a specific embodiment, the compounds described herein are administered as soon as practicable after the detection or suspicion of the onset of a disease or condition, and for the duration necessary to treat the disease. In some embodiments, the duration required for treatment will vary, and the treatment duration is adjusted to suit the specific needs of each subject. For example, in a specific embodiment, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, from about 1 month to about 5 years.

[0258] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof, are administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

[0259] Examples

[0260] Synthesis of common intermediate 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one I

[0261]

[0262] Step 1. Synthesis of 6-fluoro-2,3-dimethylbenzaldehyde

[0263] Place 2-bromo-6-fluoro-3-methylbenzaldehyde (50 g, 230 mmol, 1.0 equiv), methylboronic acid (23.4 g, 392 mmol, 1.7 equiv), K3PO4 (117.4 g, 553 mmol, 2.4 equiv), Pd(dppf)Cl2.CH2Cl2 (5.63 g, 6.91 mmol, 0.03 equiv), H2O (50 mL), and dioxane (450 mL) in a 1 L round-bottom flask purged and maintained with an inert nitrogen atmosphere. Stir the resulting solution at 110 °C for 2 h. Then quench the reaction by adding 200 mL of brine. Extract the resulting solution with 3 × 50 mL of ethyl acetate, and combine the organic layers. Apply the residue to a silica gel column using ethyl acetate / petroleum ether (1:3). This yielded 6-fluoro-2,3-dimethylbenzaldehyde (30 g, 85%) as a pale yellow oil.

[0264] Step 2.1-(6-Fluoro-2,3-dimethylphenyl)ethan-1-ol

[0265] At 0 °C, under a nitrogen atmosphere, in a 1 L three-necked round-bottom flask, bromo(methyl)magnesium (42.3 g, 355 mmol, 2 equivalents) was added dropwise to a mixture of 6-fluoro-2,3-dimethylbenzaldehyde (27 g, 177.4 mmol, 1 equivalent) in THF. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-(6-fluoro-2,3-dimethylphenyl)ethanol (27 g, 90.5%).

[0266] Step 3.2-(1-Bromoethyl)-1-fluoro-3,4-dimethylbenzene

[0267] At room temperature, 1-(6-fluoro-2,3-dimethylphenyl)ethanol (25 g, 148.6 mmol, 1.0 equivalent) and CHCl3 (250 mL) were added to a 500 mL three-necked round-bottom flask. At 0 °C, PBr3 (63.5 mL, 668.8 mmol, 4.5 equivalents) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for an additional 30 min. At 0 °C, the reaction was quenched by the addition of NaHCO3 (aqueous solution) (100 mL). The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (29 g, 84.4%).

[0268] Step 4.(2S)-2-Amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0269] At room temperature, under a nitrogen atmosphere, 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 to a mixture of Ni-(S)-BPB-Gly (5.39 g, 10.8 mmol, 0.5 equiv) in DMF (42.4 mL). At -15 °C, under a nitrogen atmosphere, KOH (6.07 g, 108.2 mmol, 5.0 equiv) was added portionwise to the resulting mixture, and the mixture was stirred at -15 °C for 1 h under a nitrogen atmosphere. At room temperature, the reaction was quenched by adding saturated NH4Cl (aqueous solution) (100 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (3 × 30 mL), 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). At room temperature, MeOH (42 mL) and HCl (50 mL) were added to the mixture. The resulting mixture was stirred at 80 °C for 1 h, and then purified by reverse-phase flash chromatography using the following conditions (water: ACN = 80:20) to give (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (3.05 g, 63%).

[0270] Step 5. (2S)-2-((tert-Butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0271] At room temperature, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (5 g, 22.2 mmol, 1.0 equiv), Et3N (6.74 g, 66.6 mmol, 3.0 equiv), H2O (25 mL), and dioxane (25 mL) were added to a 250 mL round-bottom flask. At 0 °C, di-tert-butyl dicarbonate (7.27 g, 33.3 mmol, 1.5 equiv) was added portionwise to the resulting mixture. The resulting mixture was stirred at room temperature for 2 h. 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)butyric acid (3.5 g, 48.5%).

[0272] Step 6: Synthesis of 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one hydrochloride

[0273] At room temperature, (2S)-2-[(tert-butoxycarbonyl)amino]-3-(6-fluoro-2,3-dimethylphenyl)butyric 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 to a 250 mL round-bottom flask, and the resulting mixture was stirred at room temperature for 30 min. At 0 °C, hydrazine (4.15 mL, 82.901 mmol, 3.0 equiv) was added dropwise to the mixture. The resulting mixture was stirred at 0 °C for 30 min. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, dioxane (60 mL) and CDI (11.2 g, 69.2 mmol, 2.5 equiv) were added to the crude mixture. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with PE / EtOAc (2:3) to afford 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%).

[0274] The product was dissolved in 2 mL of THF and treated with 2 mL of 4N HCl in THF. The reaction was left overnight at room temperature (RT) and concentrated in vacuo to afford 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one hydrochloride as an off-white solid (2.4 g, 100% yield).

[0275] Common Intermediate II: Synthesis of Methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0276]

[0277] At room temperature, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyric 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) were added to a 500 mL three-necked round-bottom flask. The resulting mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to afford methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (9.9 g, 72.8%).

[0278] Common Intermediate III: Synthesis of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0279]

[0280] At room temperature, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (15 g, 67 mmol, 1 equiv) and tert-butyl acetate (160 mL) were added to a 250 mL round-bottom flask. At 0 °C, HClO4 (21 mL, 366 mmol, 5.50 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. At room temperature, the reaction was quenched by the addition of HCl (1 M) (240 mL). 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), 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 afford tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (12 g, 68.6%).

[0281] Example 1: 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxido-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

[0282]

[0283] Step 1: Synthesis of 1-(benzylthio)-4-chloro-2-nitrobenzene

[0284] At room temperature, Cs2CO3 (17.2 g, 52.9 mmol, 5.0 equiv) and benzyl mercaptan (1.58 g, 12.7 mmol, 1.2 equiv) were added dropwise to a stirred solution / mixture of 1-bromo-4-chloro-2-nitrobenzene (2.5 g, 10.6 mmol, 1 equiv) and DMF (50 mL). The resulting mixture was stirred overnight at room temperature. 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), 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 afford 1-(benzylthio)-4-chloro-2-nitrobenzene (2 g, 67.6%).

[0285] Step 2: Synthesis of 4-chloro-2-nitrobenzenesulfonyl chloride

[0286] At room temperature, AcOH (1.47 mL, 25.7 mmol, 4.5 equiv) was added portionwise to a stirred solution of 1-(benzylthio)-4-chloro-2-nitrobenzene (1.6 g, 5.7 mmol, 1 equiv) and H2O (1 mL) in acetonitrile. At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.25 g, 11.4 mmol, 2 equiv) was added portionwise to the above mixture over 10 min. 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), 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 afford 4-chloro-2-nitrobenzenesulfonyl chloride (1.86 g).

[0287] 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

[0288] At 0 °C, 4-chloro-2-nitrobenzenesulfonyl chloride (1.83 g, 6.1 mmol, 1.2 eq) in DCM (5 mL) was added dropwise 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 eq) and pyridine (5 mL). The resulting mixture was stirred overnight at room temperature. 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 afford 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%).

[0289] 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

[0290] At room temperature, Fe (2225 mg, 39.8 mmol, 15 eq) was added 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 eq) in AcOH. 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 saturated NaHCO3. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 220 nm. This gave 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%).

[0291] Step 5: Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxido-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

[0292] At room temperature, 37% HCHO (1332 μL, 3.6 mmol, 12.9 eq) was added 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 eq) in 1 mL of MeOH. The resulting mixture was stirred overnight at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm. This gave 5-((1S)-1-(6-chloro-1,1-dioxido-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%).

[0293] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxido-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

[0294] At room temperature, AcOH (1.84 mL) was added dropwise to a stirred solution of 5-((1S)-1-(6-chloro-1,1-dioxido-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 eq) and (HCHO)n (59.1 mg, 1.97 mmol, 10 eq). The resulting mixture was stirred for 60 min at room temperature. NaBH3CN (37.2 mg, 0.59 mmol, 3 eq) was added portionwise to the above mixture 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 0% to 100% gradient in 15 min; detector, UV 220 nm. This gave 5-((1S)-1-(6-chloro-4-methyl-1,1-dioxido-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%).

[0295] The product (85 mg) was further purified by chiral preparative HPLC under the following conditions: column, XBridgePrep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (25% ACN to 52% ACN in 8 min); detector, UV 254 nm. This yielded 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-1λ6,2,4-benzothiadiazine-1,1-dione (3.6 mg, 4.24%).

[0296] LCMS: (ES, m / z): (M - H) = 479.1. 1 1H NMR (400 MHz, methanol-d4) δ 7.55 (d, J = 8.4 Hz, 1H), 6.99–6.96 (dd, J = 8.4, 5.7 Hz, 1H), 6.78–6.72 (dd, J = 8.5, 1.9 Hz, 1H), 6.72–6.67 (m, 2H), 5.48–5.41 (m, 1H), 5.35–5.32 (d, J = 14.5 Hz, 1H), 5.05–5.02 (d, J = 14.5 Hz, 2H), 3.92–3.86 (dtd, J = 13.0, 7.7, 6.2 Hz, 1H), 2.88 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H), 1.46–1.44 (dd, J = 7.0, 1.1 Hz, 3H).

[0297] Example 2: 5-((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0298]

[0299] Step 1: Synthesis of methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0300] At room temperature, methyl (2S)-2-(4-chloro-2-methoxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (490 mg, 1.1 mmol, 1 equiv) and DCM (5 mL) were added to a 50 mL round-bottom flask. At 0 °C, boron tribromide (14.4 mL, 14.3 mmol, 13 equiv) was added dropwise to the above mixture over 10 min. 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 afford methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (340 mg, 71.7%).

[0301] Step 2: Synthesis of methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0302] At room temperature, Cs2CO3 (773 mg, 2.37 mmol, 3 equiv) and 1,2-dibromoethane (68 μL, 0.79 mmol, 1 equiv) were added portionwise to a stirred mixture of methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (340 mg, 0.79 mmol, 1 equiv) and DMF (5 mL). 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 Na2SO4. 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 afford methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (290 mg, 80.4%). -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0303] Step 3: Synthesis of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0304] At room temperature, under an air atmosphere, to a stirred mixture of methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (290 mg, 0.64 mmol, 1 equiv) in MeOH (3 mL) was added dropwise NaOH (50.9 mg, 1.27 mmol, 2 equiv) and H2O (600 μL). The resulting mixture was stirred at 70 °C for 2 h. The mixture was neutralized to pH 5 with HCl (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (284 mg, 97.00%). To a stirred mixture of methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (290 mg, 0.64 mmol, 1 equiv) in MeOH (3 mL) was added dropwise NaOH (50.9 mg, 1.27 mmol, 2 equiv) and H2O (600 μL) 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 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (284 mg, 97.00%). (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0305] Step 4: Synthesis of tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyryl)hydrazine-1-carboxylate At room temperature, to a stirred mixture of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (284 mg, 0.64 mmol, 1 equiv) and DIEA (335 μL, 1.93 mmol, 3 equiv) in DCM (2 mL) was added portionwise HATU (367 mg, 0.97 mmol, 1.5 equiv) and tert-butyl carbazate (127 mg, 0.97 mmol, 1.5 equiv). 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 afford tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyryl)hydrazine-1-carboxylate (250 mg, 70%).

[0306] At room temperature, to a stirred mixture of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (284 mg, 0.64 mmol, 1 equiv) and DIEA (335 μL, 1.93 mmol, 3 equiv) in DCM (2 mL) was added portionwise HATU (367 mg, 0.97 mmol, 1.5 equiv) and tert-butyl carbazate (127 mg, 0.97 mmol, 1.5 equiv). 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 afford tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyryl)hydrazine-1-carboxylate (250 mg, 70%). tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyryl)hydrazine-1-carboxylate tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyryl)hydrazine-1-carboxylate (250 mg, 70%)

[0307] Step 5: (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid Synthesis of 6-fluoro-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butane hydrazide

[0308] In a 50 mL round-bottom flask, add 2-((2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylic acid tert-butyl ester (250mg, 0.45mmol, 1 eq) and DCM (3mL). At 0°C, 2,6-lutidine (1.05mL, 9.0mmol, 20 eq) and trimethylsilyl trifluoromethanesulfonate (469μL, 2.59mmol, 16 eq) were added dropwise to the above mixture. The resulting mixture was stirred for another 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water, 20% to 80% gradient in 20min; detector, UV 254nm. This produced (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (150 mg, 73.2%).

[0309] Step 6: 5-((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine Synthesis of 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0310] At room temperature, under air atmosphere, (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butane hydrazide (150 mg, 0.33 mmol, 1 eq) was added DIEA (143 μL, 0.82 mmol, 2.5 eq) and triphosgene (48.8 mg, 0.17 mmol, 0.5 eq) in a stirred mixture in THF (2 mL) in batches. The resulting mixture was stirred for 1 h at 80 ° C. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This produced 5-((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (150 mg, 94.6%).

[0311] The product (150 mg) was further purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; 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, 50% B; wavelength: 254 nm; RT1 (min): 7.45), to afford 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-5,1λ6,2-benzoxathiazine -1,1-dione (28.1 mg, 17.82%). LC-MS: (ES, m / z): M-H = 480.10. 1 H NMR (400 MHz, methanol-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.27–7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7.01–6.97 (dd, J = 8.4, 5.7 Hz, 1H), 6.75–6.70 (dd, J = 12.1, 8.4 Hz, 1H), 5.53–5.50 (dd, J = 11.6, 2.0 Hz, 1H), 4.64–4.58 (dt, J = 13.2, 5.4 Hz, 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, 1.1 Hz, 3H).

[0312] Example 3: 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxido-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

[0313]

[0314] Step 1: Synthesis of 3-(benzylthio)-6-chloro-2-fluoropyridine

[0315] At room temperature, 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), Pd2(dba)3 (218 mg, 0.24 mmol, 0.1 equiv), dioxane (5 mL) and benzyl mercaptan (325 mg, 2.61 mmol, 1.1 equiv) were added to a 20 mL round-bottom flask. The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The resulting mixture was filtered and the 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 afford 3-(benzylthio)-6-chloro-2-fluoropyridine (300 mg, 49.8%).

[0316] Step 2: Synthesis of 6-chloro-2-fluoropyridine-3-sulfonyl chloride

[0317] 3-(Benzylthio)-6-chloro-2-fluoropyridine (1 g, 3.9 mmol, 1 equiv), H2O (500 μl), AcOH (700 uL) and ACN (10 mL) were added to a 20 mL round-bottom flask. At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.55 g, 7.9 mmol, 2.0 equiv) was added to the mixture. The resulting mixture was stirred at 0 °C for 30 min 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 6-chloro-2-fluoropyridine-3-sulfonyl chloride (0.8 g, 88.2%).

[0318] 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

[0319] At room temperature, 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 to an 8 mL round-bottom flask. Then, at 0 °C, 6-chloropyridine-3-sulfonyl chloride (239 mg, 1.13 mmol, 1.5 equiv) in DCM (0.5 mL) was added. The resulting mixture was stirred at room temperature under an air atmosphere for 2 h. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 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%).

[0320] 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

[0321] At room temperature, 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 to a 40 mL round-bottom flask. The resulting mixture was stirred at room temperature under an air atmosphere overnight. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 254 nm, to afford 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%).

[0322] Step 5: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxido-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

[0323] At room temperature, 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) were added to a 40 mL round-bottom flask. 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 5% to 100% gradient in 30 min; detector, UV 220 nm. The crude product was purified by chiral preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (20% ACN up to 50% ACN in 8 min); detector, uv 220 nm to give 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-1λ6-pyrido[2,3-e][1,2,4]thiadiazine-1,1-dione (17.7 mg, 14.35%). LCMS: (ES, m / z): M-H: 480.10. 1 H NMR (400 MHz, methanol-d4) δ 7.88 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.4, 5.8 Hz, 1H), 6.78–6.67 (m, 2H), 5.47–5.27 (m, 2H), 5.13 (d, J = 14.8 Hz, 1H), 3.91 (dq, J = 13.5, 6.8 Hz, 1H), 3.02 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H).

[0324] Example 4: 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxido-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

[0325]

[0326] Step 1: Synthesis of 1-(benzylthio)-4-chloro-2-fluorobenzene

[0327] At room temperature, under a nitrogen atmosphere, 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 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). 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 afford 1-(benzylthio)-4-chloro-2-fluorobenzene (1 g, 82.9%).

[0328] Step 2: Synthesis of 4-chloro-2-fluorobenzenesulfonyl chloride

[0329] AcOH (0.8 mL) and H2O (0.8 mL) were added to a stirred mixture of 1-(benzylthio)-4-chloro-2-fluorobenzene (1.47 g, 5.8 mmol, 1 equiv) in ACN (15 mL). At 0 °C, under an air atmosphere, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.29 g, 11.6 mmol, 2 equiv) was added portionwise to the mixture. The resulting mixture was stirred for 30 min at 0 °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 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 afford 4-chloro-2-fluorobenzenesulfonyl chloride (1.14 g, 85.6%).

[0330] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0331] To a 250 mL round-bottom flask was added tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (III) (1.96 g, 6.96 mmol, 1 equiv), DCM (13.8 mL), and pyridine (1.9 mL, 24 mmol, 5 equiv). At 0 °C, 4-chloro-2-fluorobenzenesulfonyl chloride (1.10 g, 4.8 mmol, 1.0 equiv) was added to the mixture. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (6:1) to afford tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (1.78 g, 78.3%).

[0332] Step 4: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonylamino]-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0333] At room temperature, TEA (1.44 mL, 10.3 mmol, 14 equiv) and isopropylamine (888 μL, 10.3 mmol, 14 equiv) were added to a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (350 mg, 0.74 mmol, 1 equiv) in DMSO (4 mL). The resulting mixture was stirred overnight at 80 °C. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonylamino]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (370 mg, 97.6%).

[0334] Step 5: Synthesis of (2S)-2-(6-chloro-4-isopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0335] At room temperature, TsOH (124 mg, 0.72 mmol, 1 equiv) and 1,3,5-trioxane (650 mg, 7.21 mmol, 10 equiv) were added in portions to a stirred solution of tert-butyl (2S)-2-[4-chloro-2-(isopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (370 mg, 0.72 mmol, 1 equiv) in dioxane (14.8 mL). The resulting mixture was stirred at 110 °C for 24 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 254 nm. This gave ((2S)-2-(6-chloro-4-isopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (96 mg, 28.4%).

[0336] Step 6: Synthesis of 5-((1S)-1-(6-chloro-4-isopropyl-1,1-dioxido-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

[0337] A solution of ((2S)-2-(6-chloro-4-isopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric 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, and then N2H4·H2O (26.7 μL, 0.55 mmol, 3 equiv) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was extracted with EtOAc (2 × 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. CDI (148.7 mg, 0.92 mmol, 5 equiv) was added in portions to the above mixture at room temperature. The resulting mixture was stirred at room temperature for another 30 min. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0338] Step 7: Synthesis of 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxido-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

[0339] The crude product (90 mg) was purified by preparative HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; 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; RT1 (min): 7) to afford 5-((1S,2R)-1-(6-chloro-4-isopropyl-1,1-dioxido-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. 1 1H NMR (300 MHz, methanol-d4) δ 7.56–7.54 (d, J = 8.4 Hz, 1H), 7.01–6.93 (m, 2H), 6.78–6.68 (m, 2H), 5.43–5.39 (dd, J = 11.8, 1.8 Hz, 1H), 5.15 (s, 2H), 4.19–4.09 (hept, J = 6.8 Hz, 1H), 3.99–3.90 (dddd, J = 14.5, 12.9, 8.5, 6.7 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 1.53–1.38 (m, 6H), 1.27 (d, J = 6.6 Hz, 3H).

[0340] Example 5: 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxido-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

[0341]

[0342] Step 1: Synthesis of 2-(benzylthio)-5-chloro-3-fluoropyridine

[0343] At room temperature, 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 Pd2(dba)3 (239 mg, 0.26 mmol, 0.1 equiv), and dioxane (6 mL) were added to a 40 mL round-bottom flask. 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 afford 2-(benzylthio)-5-chloro-3-fluoropyridine (450 mg, 67.9%).

[0344] Step 2: Synthesis of 5-chloro-3-fluoropyridine-2-sulfonyl chloride

[0345] 2-(Benzylthio)-5-chloro-3-fluoropyridine (700 mg, 2.76 mmol, 1 equiv), AcOH (2.45 ml), H2O (1.75 ml), and ACN (7.00 mL) were added to a 20 mL round-bottom flask. At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1087 mg, 5.52 mmol, 2.0 equiv) was added to the mixture. The resulting mixture was stirred at 0 °C for 30 min 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-chloro-3-fluoropyridine-2-sulfonyl chloride as a pale yellow oil (500 mg, 78.8%).

[0346] Step 3: Synthesis of tert-butyl (2S)-2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0347] (2S)-tert-Butyl 2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (20 mg, 0.071 mmol, 1 equiv) and pyridine (10 mL) were added to a 20 mL round-bottom flask. At 0 °C, 5-chloro-3-fluoropyridine-2-sulfonyl chloride (1.23 g, 5.33 mmol, 1.5 equiv) in DCM (2 mL) was added to the mixture. The resulting mixture was stirred overnight at room temperature under an air atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm, to afford (2S)-tert-butyl 2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (700 mg, 41.5%) as a pale yellow oil.

[0348] Step 4: Synthesis of (2S)-2-[5-chloro-3-(methylamino)pyridine-2-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0349] (2S)-tert-Butyl 2-(5-chloro-3-fluoropyridine-2-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.42 mmol, 1 equiv), methylamine (2 M in THF) (130.8 mg, 4.21 mmol, 10 equiv), and TEA (426 mg, 4.21 mmol, 10 equiv) in DMSO were added to a 20 mL round-bottom flask at room temperature. The resulting mixture was stirred overnight at 65 °C under an air atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm, to afford (2S)-2-[5-chloro-3-(methylamino)pyridine-2-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (180 mg, 88%) as a pale yellow solid.

[0350] Step 5: Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0351] At room temperature, (2S)-tert-butyl 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) were added to a 20 mL round-bottom flask. The resulting mixture was stirred overnight at 100 °C under an air atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 254 nm, to afford (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid as a pale yellow oil (100 mg, 65.1%).

[0352] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4-methyl-1,1-dioxido-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

[0353] At room temperature, (2S)-2-(6-chloro-4-methyl-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (200 mg, 0.44 mmol, 1 equiv), CDI (142 mg, 0.88 mmol, 2.0 equiv) and THF (3 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature for 30 min. At 0 °C, hydrazine (42 mg, 1.32 mmol, 3.0 equiv) was added dropwise to the mixture. The resulting mixture was stirred at 0 °C for 30 min. 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. 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 min. 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. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm. The crude product was purified by chiral preparative HPLC using the following conditions: column, Xselect CSH F-Phenyl OBD column, 19*250 mm, 5 μm; mobile phase, water (0.05% FA) and ACN (44% ACN up to 53% ACN in 11 min); detector, UV 220, to afford 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxido-4H-1,3,4-oxadiazol-2-yl)propyl]-4-methyl-3H-1λ6-pyrido[3,2-e][1,2,4]thiadiazine-1,1-dione (53.5 mg, 25.2%). LCMS: (ES, m / z): [M+H]: 482.15. 11H NMR (300 MHz, methanol-d4) δ 7.91 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.00 (dd, J = 8.4, 5.7 Hz, 1H), 6.73 (dd, J = 12.1, 8.4 Hz, 1H), 5.53 (dd, J = 11.7, 1.8 Hz, 1H), 5.35 (d, J = 14.8 Hz, 1H), 5.05 (d, J = 14.7 Hz, 1H), 3.93 (dtd, J = 12.8, 7.6, 6.1 Hz, 1H), 2.90 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H), 1.46 (dd, J = 7.0, 1.1 Hz, 3H).

[0354] Example 6: 5-((1S,2R)-1-(6-chloro-4-cyclopropyl-1,1-dioxido-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

[0355]

[0356] Step 1: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(cyclopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0357] At room temperature, under an air atmosphere, TEA (3.20 mL, 23 mmol, 14 equiv) and aminocyclopropane (1.32 g, 23 mmol, 14 equiv) were added portionwise to a stirred mixture of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (see Example 4, Step 3) (10 mg, 0.021 mmol, 1 equiv) and DMSO (14 mL). 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 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)butyrate (713 mg, 84.8%).

[0358] Step 2: Synthesis of (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0359] At room temperature, add tert-butyl (2S)-2-[4-chloro-2-(cyclopropylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (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) to a 20 mL vial. Stir the resulting mixture at 100 °C overnight under an air atmosphere. Concentrate the resulting mixture under reduced pressure. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 70% to 72% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (92 mg, 55.9%).

[0360] Step 3: Synthesis of 5-((1S)-1-(6-chloro-4-cyclopropyl-1,1-dioxido-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

[0361] At room temperature, (2S)-2-(6-chloro-4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (80 mg, 0.17 mmol, 1 equiv), CDI (128 mg, 0.79 mmol, 4.6 equiv), and THF (1.6 mL) were added to a 50 mL round-bottom flask. At 0 °C, hydrazine hydrate (25.7 mg, 0.51 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 1 h at 0 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, a mixture of the above product and CDI (128 mg, 0.79 mmol, 4.6 equiv) in 1,4-dioxane was stirred overnight. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave 5-((1S)-1-(6-chloro-4-cyclopropyl-1,1-dioxido-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%).

[0362] The product was further purified by reverse-phase flash chromatography using the following conditions: column: XBridge ShieldRP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 9 min, 55% B; wavelength: 254 nm; RT1 (min): 7. This gave 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-1λ6,2,4-benzothiadiazine-1,1-dione (72.3 mg, 41.11%). LCMS: (ES, m / z): [M-H] + = 505.05. 11H NMR (300 MHz, methanol-d4) δ 7.57 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.99 (dd, J = 8.4, 5.7 Hz, 1H), 6.85 (dd, J = 8.4, 1.9 Hz, 1H), 6.72 (dd, J = 12.1, 8.4 Hz, 1H), 5.43 (dd, J = 11.8, 1.8 Hz, 1H), 5.26 (d, J = 14.4 Hz, 1H), 5.10 (d, J = 14.4 Hz, 1H), 4.00–3.83 (m, 1H), 2.44–2.36 (m, 4H), 2.22 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H), 1.08–0.85 (m, 2H), 0.85–0.64 (m, 2H).

[0363] Example 7: 5 - ((1S,2R)-1-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0364]

[0365] Step 1: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0366] At room temperature, methyl (2S)-2-(4-chloro-2-hydroxybenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (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 to a 40 mL vial. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This yielded methyl (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (470 mg, 53.2%).

[0367] Step 2: Synthesis of (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0368] At room temperature, methyl (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (470 mg, 1 mmol, 1 equiv), DCE (18 mL), and trimethyltin hydroxide (1923 mg, 10 mmol, 10 equiv) were added to a 100 mL round-bottom flask. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 70% to 75% gradient in 10 min; detector, UV 254 nm. This yielded (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (230 mg, 50.5%).

[0369] Step 3: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0370] At room temperature, under an air atmosphere, a solution of (2S)-2-(6-chloro-1,1-dioxobenzo[e][1,4,3]oxathiazin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (212 mg, 0.5 mmol, 1 equiv) and CDI (400 mg, 2.5 mmol, 5 equiv) in THF was stirred for 20 min. At 0 °C, hydrazine hydrate (124 mg, 2.5 mmol, 5 equiv) was added dropwise to the above mixture. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, the above crude product, dioxane (5 mL) and CDI (400 mg, 2.5 mmol, 5 equiv) were added to a 50 mL round-bottom flask. The resulting mixture was stirred at room temperature under an 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.

[0371] The residue was purified by reverse-phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 52% B in 8 min, 52% B; wavelength: 254 nm; RT1 (min): 7. This yielded 5-((1S,2R)-1-(6-chloro-1,1-dioxobenzo[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): [M-H] + = 485.15. 1 H NMR (300 MHz, methanol-d4) δ 7.63 (d, J = 8.6 Hz, 1H), 7.07 (dd, J = 8.6, 2.0 Hz, 1H), 6.99–6.84 (m, 2H), 6.64 (dd, J = 12.1, 8.4 Hz, 1H), 5.82 (q, J = 13.0 Hz, 2H), 5.50 (dd, J = 11.8, 1.7 Hz, 1H), 3.83 (ddt, J = 13.9, 7.0, 5.5 Hz, 1H), 2.29 (s, 3H), 2.13 (s, 3H), 1.35 (dd, J = 6.9, 1.1 Hz, 3H).

[0372] Example 8: 5-((1S,2R)-1-(6-chloro-1,1-dioxido-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

[0373]

[0374] Step 1: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxido-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0375] To a stirred solution of methyl (2S)-2-(2-amino-4-chlorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (12.7 g, 29.6 mmol, 1 equiv) in (diethoxymethoxy)ethane (250 mL). The resulting mixture was stirred overnight at 145 °C. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification.

[0376] Step 2: Synthesis of methyl (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0377] At room temperature, trimethyltin hydroxide (14.2 g, 78.2 mmol, 5 equiv) was added dropwise to a stirred solution of methyl (2S)-2-(6-chloro-1,1-dioxido-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (6.9 g, 2.27 mmol, 1 equiv) in DCE (15 mL). The resulting mixture was stirred at 65 °C for 2 days. The resulting mixture was filtered; the filter cake was washed with DCM (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave methyl (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (1.8 g, 26.9%).

[0378] Step 3: Synthesis of (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0379] At room temperature, trimethyltin hydroxide (14.2 g, 78.2 mmol, 5 eq) was added dropwise to a stirred solution of methyl (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (6.9 g, 2.27 mmol, 1 eq) in DCE (15 mL). The resulting mixture was stirred at 65 °C for 2 days. The resulting mixture was filtered; the filter cake was washed with DCM (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (1.8 g, 26.9%).

[0380] Step 4. Synthesis of tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0381] At room temperature, 2-(6-chloro-1,1-dioxido-3,4-dihydro-1λ6,2,4-benzothiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (1.8 g, 4.2 mmol, 1 eq) in DCM (20 mL) was added to a 50 mL round-bottom flask. At room temperature, HATU (1.92 g, 5 mmol, 1.2 eq), tert-butyl carbazate (0.84 g, 6.3 mmol, 1.5 eq), and DIEA (2.20 mL, 12.7 mmol, 3 eq) were added to the above mixture. 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 (8:1) to afford tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxido-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%).

[0382] Step 5: Synthesis of (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanohydrazide

[0383] At 0 °C, trimethylsilyl trifluoromethanesulfonate (10.7 mL, 58.8 mmol, 16 eq) and 2,6-lutidine (8.6 mL, 73.6 mmol, 20 eq) were added dropwise to a stirred solution of tert-butyl 2-((2S)-2-(6-chloro-1,1-dioxido-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 eq) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanohydrazide (1.4 g, 86.33%).

[0384] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxido-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 At room temperature, under an air atmosphere, DIEA (2.77 mL, 15.88 mmol, 2.5 equiv) and triphosgene (15.1 mg, 0.05 mmol, 0.5 equiv) were added portionwise to a stirred mixture of (2S)-2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanohydrazide (2.8 g, 6.35 mmol, 1 equiv) in THF (37 mL). The resulting mixture was stirred at 45 °C for 40 min. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 10% to 100% gradient in 15 min; detector, UV 254 nm. This yielded 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-1λ6,2,4-benzothiadiazine-1,1-dione (2.0171 g, 68.03%). LCMS: (ES, m / z): (M-H) 465.05. 1 1H NMR (300 MHz, methanol-d4) δ 7.51–7.48 (d, J = 8.5 Hz, 1H), 7.01–6.96 (dd, J = 8.4, 5.8 Hz, 1H), 6.74–6.63 (m, 3H), 5.43–5.39 (dt, J = 11.7, 1.2 Hz, 1H), 5.25–5.21 (d, J = 14.6 Hz, 1H), 5.09–5.04 (d, J = 14.6 Hz, 1H), 3.90–3.79 (m, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 1.51–1.46 (dd, J = 6.9, 1.1 Hz, 3H).

[0385] Example 9: 5-((1S,2R)-1-(6-chloro-4-(methyl-d3)-1,1-dioxido-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

[0386]

[0387] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-((methyl-d3)amino)phenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0388] At room temperature, TEA (2.9 mL, 21 mmol, 10 eq) and methyl-d3-amine hydrochloride (744 mg, 10.6 mmol, 5 eq) were added in portions to a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 4, Step 3) (1 g, 2.1 mmol, 1 eq) in DMSO (10 mL). The resulting mixture was stirred at 80 °C for 2 days. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-{4-chloro-2-[(D3)methylamino]benzenesulfonylamino}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 97.1%).

[0389] Step 2: Synthesis of (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0390] At room temperature, TsOH (176 mg, 1.03 mmol, 1 eq) and 1,3,5-trioxane (923 mg, 10.3 mmol, 10 eq) were added in portions to a stirred solution of tert-butyl (2S)-2-{4-chloro-2-[(D3)methylamino]benzenesulfonylamino}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 1.03 mmol, 1 eq) in dioxane (20 mL). The resulting mixture was stirred at 110 °C overnight. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 10% to 70% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (240 mg, 52.8%).

[0391] Step 2: Synthesis of 5-((1S)-1-(6-chloro-4-(methyl-d3)-1,1-dioxido-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

[0392] Add (2S)-2-(6-chloro-4-(methyl-d3)-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (230 mg, 0.52 mmol, 1 equiv) in THF (3 mL) to a 50 mL round-bottom flask. At room temperature, add CDI (126 mg, 0.78 mmol, 1.5 equiv) portionwise to the above mixture. Stir the resulting mixture at room temperature for an additional 30 min. At 0 °C, add N2H4.H2O (75.5 μL, 1.55 mmol, 3 equiv) dropwise to the above mixture. Stir the resulting mixture at 0 °C for an additional 30 min. Quench the reaction with water (5 ml) at 0 °C. Extract the resulting mixture with EtOAc (2 × 5 mL). Wash the combined organic layers with brine (1 × 10 mL), dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Charge the residue into a 50 mL round-bottom flask, add dioxane (3 mL). At room temperature, add CDI (210 mg, 1.3 mmol, 2.5 equiv) portionwise to the above mixture. Stir the resulting mixture at room temperature for an additional 30 min. Concentrate the resulting mixture in vacuo. Purify the crude product (200 mg) by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 22% B to 52% B in 9 min, 52% B; wavelength: 254 nm; RT1(min): 7,8 to give 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-1λ6,2,4-benzothiadiazine-1,1-dione (36.7 mg, 17.4%). LC:(ES,m / z):[M+H+17] + = 501.25. 11H NMR (400 MHz, methanol-d4) δ 7.58–7.56 (d, J = 8.4 Hz, 1H), 7.01–6.97 (dd, J = 8.4, 5.7 Hz, 1H), 6.80–6.77 (dd, J = 8.5, 1.9 Hz, 1H), 6.74–6.68 (m, 2H), 5.45–5.42 (d, J = 11.7 Hz, 1H), 5.38–5.32 (d, J = 14.6 Hz, 1H), 5.06–4.97 (d, J = 14.5 Hz, 1H), 3.93–3.85 (dq, J = 13.2, 6.8 Hz, 1H), 2.38 (s, 3H), 2.22 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H).

[0393] Example 10: 5-((1S,2R)-1-(6-chloro-1,1-dioxido-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

[0394]

[0395] According to Example 33, 5-((1S,2R)-1-(6-chloro-1,1-dioxido-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 starting from (2S)-2-[4-chloro-2-(propylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (285 mg, 0.019 mmol, 1 equiv) and propylamine (260 μL, 3.17 mmol, 5 equiv). The final product (180 mg) was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 62% B in 9 min, 62% B; wavelength: 254 nm; RT1 (min): 7) to afford 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxido-4H-1,3,4-oxadiazol-2-yl)propyl]-4-propyl-3H-1λ6,2,4-benzothiadiazine-1,1-dione (60.4 mg, 33.25%). LC-MS: (ES, m / z): [M-H] + = 507.10. 11H NMR (300 MHz, methanol-d4) δ 7.57–7.55 (d, J = 8.4 Hz, 1H), 7.01–6.96 (dd, J = 8.3, 5.8 Hz, 1H), 6.77–6.67 (m, 3H), 5.44–5.36 (dd, J = 13.2, 10.4 Hz, 2H), 5.11–5.06 (d, J = 14.6 Hz, 1H), 3.93–3.87 (dq, J = 13.3, 7.0 Hz, 1H), 3.46–3.36 (dt, J = 14.9, 7.4 Hz, 1H), 3.14–3.04 (dt, J = 15.5, 8H).

[0396] Example 11: 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxido-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

[0397]

[0398] Step 1: Synthesis of tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0399] To a 40 mL vial was added tert-butyl (2S)-2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (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 overnight at 65 °C. After evaporation, the residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This yielded tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (1.2 g, 78.2%).

[0400] Step 2: Synthesis of (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0401] At room temperature, add tert-butyl (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (1 g, 2.0 mmol, 1 equiv), DCM (5 mL), and TFA (3 mL) to a 40 mL vial. Stir the resulting mixture overnight at room temperature. Concentrate the resulting mixture in vacuo. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (800 mg, 90.5%).

[0402] Step 3: Synthesis of (2S)-2-(6-chloro-3,4-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0403] At room temperature, add (2S)-2-[4-chloro-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyric 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) to a 20 mL vial. Stir the resulting mixture at 45 °C for 3 h. Concentrate the resulting mixture in vacuo. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (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-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (200 mg, 18.9%).

[0404] Step 4: Synthesis of 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxido-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

[0405] At room temperature, (2S)-2-(6-chloro-3,4-dimethyl-1,1-dioxido-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 to an 8 mL vial. The resulting mixture was stirred at room temperature for 30 min. At 0 °C, NH2NH 2. H2O (33.0 mg, 0.66 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for another 30 min. 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. At room temperature, dioxane (0.5 mL) and CDI (92.7 mg, 0.57 mmol, 2.6 equiv) were added dropwise to the above mixture. The resulting mixture was stirred at room temperature for another 30 min. 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 was purified by chiral preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and preparative MeOH (20% preparative MeOH to 50% preparative MeOH in 8 min); detector, uv 254 nm. This gave 5-((1S,2R)-1-(6-chloro-3,4-dimethyl-1,1-dioxido-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%).

[0406] LCMS: (ES, m / z): [M + H]: 495.10. 11H NMR (300 MHz, methanol-d4) δ 7.60 (d, J = 8.4 Hz, 1H), 7.02 (dd, J = 8.4, 5.8 Hz, 1H), 6.83 (dd, J = 8.4, 1.9 Hz, 1H), 6.82–6.74 (m, 1H), 6.74–6.67 (m, 1H), 5.66 (dd, J = 11.8, 2.1 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 3.91 (tt, J = 13.1, 6.2 Hz, 1H), 2.87 (s, 3H), 2.41 (s, 3H), 2.25 (s, 3H), 1.78 (d, J = 6.8 Hz, 3H), 1.50 (dd, J = 6.9, 1.2 Hz, 3H).

[0407] Example 12: 5-((1S,2R)-1-(6-chloro-4,7-dimethyl-1,1-dioxido-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

[0408]

[0409] Step 1: Synthesis of 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene

[0410] At room temperature, Xantphos (2.59 g, 4.48 mmol, 0.2 equiv) and Pd2(dba)3 (2.0 g, 2.24 mmol, 0.1 equiv) were added portionwise 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. 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), 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 afford 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene (5.8 g, 97.2%).

[0411] Step 2: Synthesis of 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride

[0412] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.95 g, 15 mmol, 2 eq) was added portionwise to a stirred solution of 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene (2 g, 7.5 mmol, 1 eq) and H2O (1.22 mL, 67.5 mmol, 9 eq) in MeCN and AcOH (2.44 mL, 37.5 mmol, 5 eq). 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 Na2SO4. The resulting mixture was concentrated under reduced pressure. This gave 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, crude product).

[0413] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0414] At 0 °C, 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, 14.8 mmol, 1.5 eq), DCM (40 mL) were added dropwise to a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (2.5 g, 8.9 mmol, 0.9 eq) and pyridine (10 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous MgSO4. 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 afford tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (2.7 g, 56%).

[0415] Step 4: Synthesis of tert-butyl (2S)-2-[4-chloro-5-methyl-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0416] At room temperature, add tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (500 mg, 1 mmol, 1 equiv) in THF, methylamine (5.12 mL, 5.13 mmol, 5 equiv), and TEA (1.42 mL, 10 mmol, 10 equiv) to a 20 mL vial. Stir the resulting mixture overnight at 80 °C under an air atmosphere. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 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)butyrate (400 mg, 78.2%).

[0417] Step 5: Synthesis of (2S,3R)-2-(6-chloro-4,7-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0418] At room temperature, add tert-butyl (2S)-2-[4-chloro-5-methyl-2-(methylamino)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (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) to a 20 mL vial. Stir the resulting mixture overnight at 100 °C under an air atmosphere. Concentrate the resulting mixture under reduced pressure. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (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-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (228 mg, 71.5%).

[0419] Step 6: Synthesis of 5-((1S,2R)-1-(6-chloro-4,7-dimethyl-1,1-dioxido-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

[0420] At room temperature, (2S)-2-(6-chloro-4,7-dimethyl-1,1-dioxido-3H-1λ6,2,4-benzothiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (208 mg, 0.46 mmol, 1 equiv), THF (0.4 mL), and CDI (341 mg, 2.1 mmol, 4.6 equiv) were added to a 10 mL vial. The resulting mixture was stirred at room temperature for 20 min under an air atmosphere. At 0 °C, NH2NH 2. H2O (111 μL, 2.29 mmol, 5 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for an additional 30 min. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, the above crude product, dioxane (4 mL), and CDI (341 mg, 2.1 mmol, 4.6 equiv) were added to a 10 mL vial. The resulting mixture was stirred at room temperature for 0.5 h under an air atmosphere. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.

[0421] The crude product was purified by reverse-phase flash chromatography using the following conditions: column: XBridge Shield RP18 OBD column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 56% B in 9 min, 56% B; wavelength: 254 nm; RT1 (min): 7. This yielded 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxido-4H-1,3,4-oxadiazol-2-yl)propyl]-4,7-dimethyl-3H-1λ6,2,4-benzothiadiazine-1,1-dione (64.5 mg, 31.77%). LCMS: (ES, m / z): [M-H] + = 493.10. 11H NMR (300 MHz, methanol-d4) δ 7.43–7.37 (m, 1H), 6.87 (dd, J = 8.4, 5.7 Hz, 1H), 6.68–6.54 (m, 2H), 5.40–5.30 (m, 1H), 5.20 (d, J = 14.4 Hz, 1H), 4.89 (d, J = 14.4 Hz, 1H), 3.78 (dqd, J = 11.8, 6.9, 1.6 Hz, 1H), 2.74 (s, 3H), 2.28 (s, 3H), 2.14 (d, J = 15.4 Hz, 6H), 1.35 (dd, J = 6.9, 1.1 Hz, 3H).

[0422] Example 13: 5 - ((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one -2(3H)-one

[0423]

[0424] Step 1: Synthesis of tert-butyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0425] At 0 °C, 4-chloro-2-nitrobenzenesulfonyl chloride (prepared as described in Example 16) (5.8 g, 22.7 mmol, 1 equiv) in DCM was added dropwise to a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (5.10 g, 18.1 mmol, 0.8 equiv) and pyridine (18.3 mL, 226 mmol, 10 equiv) in DCM. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to afford tert-butyl (2S)-2-(4-chloro-2-nitrobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (6.2 g, 54.6%).

[0426] Step 2: Synthesis of (2S)-2-[N-(2-ethoxy-2-oxoethyl)-4-chloro-2-nitrobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0427] At room temperature, ethyl bromoacetate (398 μL, 3.59 mmol, 1 equiv) was added portionwise 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. 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), 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 afford tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)-4-chloro-2-nitrobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 63%).

[0428] Step 3: Synthesis of tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)-2-amino-4-chlorobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0429] At room temperature, Fe (1.24 g, 22.1 mmol, 10 equiv) was added portionwise 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). 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 cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 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%).

[0430] 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

[0431] At room temperature, lithium hydroxide (358 mg, 8.53 mmol, 5 eq) was added portionwise to a stirred solution of tert-butyl (2S)-2-[N-(2-ethoxy-2-oxoethyl)-2-amino-4-chlorobenzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (950 mg, 1.71 mmol, 1 eq) in THF and H2O (9.50 mL). The resulting mixture was stirred overnight at 65 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0432] Step 5: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0433] At room temperature, EDCI (319 mg, 1.67 mmol, 1.1 eq) was added portionwise to a stirred solution of {N-[(2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl]-2-amino-4-chlorobenzenesulfonamido}acetic acid (800 mg, 1.5 mmol, 1 eq) in DCM. At room temperature, DMAP (18.5 mg, 0.15 mmol, 0.1 eq) was added to the above mixture. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This yielded tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (430 mg, 55.6%).

[0434] Step 6: Synthesis of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0435] At 0 °C, sodium hydride (60%, in oil, 24 mg) was added to a solution of tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (200 mg, 0.39 mmol, 1 equiv) in DMF. The mixture was stirred for 15 min. CH3I (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), 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 (3:1) to afford tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (180 mg, 87.60%). At room temperature, BH3-THF (3 mL, 3 mmol, 5.3 equiv) was added dropwise to a stirred solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (300 mg, 0.57 mmol, 1 equiv) in THF (6 mL). The resulting mixture was stirred at 65 °C under a nitrogen atmosphere for 2 h. At room temperature, the reaction was quenched by the addition of MeOH (1 mL). The resulting mixture was stirred at 65 °C for 1 h. The resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (180 mg, 87.60%).

[0436] Step 7: Synthesis of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0437] At room temperature, sodium hydride (60%, in oil, 24 mg) was added to a solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (300 mg, 0.57 mmol, 1 equiv) in DMF. The mixture was stirred for 15 min. CH3I (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), 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 (3:1) to afford tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (180 mg, 87.60%). -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (180 mg, 87.60%).

[0438] Step 8: Synthesis of (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0439] At room temperature, trifluoroacetic acid (TFA, 4 mL) was added dropwise to a stirred solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (280 mg, 0.55 mmol, 1 equiv) in DCM (4 mL). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid. To a stirred solution of tert-butyl (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid. -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid.

[0440] Step 9: Synthesis of 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one -2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0441] At room temperature, carbonyldiimidazole (CDI, 97.5 mg, 0.6 mmol, 1.5 equiv) was added portionwise to a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (188 mg, 0.4 mmol, 1 equiv) in THF (3.8 mL). The resulting mixture was stirred for 30 min at room temperature. At 0 °C, hydrazine hydrate (58.5 μL, 1.2 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 10 min at 0 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL). At room temperature, carbonyldiimidazole (CDI, 106 mg, 1.204 mmol, 3.0 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was concentrated in vacuo. -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (188 mg, 0.4 mmol, 1 equiv) in THF (3.8 mL). The resulting mixture was stirred for 30 min at room temperature. At 0 °C, hydrazine hydrate (58.5 μL, 1.2 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 10 min at 0 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (4 mL). At room temperature, carbonyldiimidazole (CDI, 106 mg, 1.204 mmol, 3.0 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was concentrated in vacuo.

[0442] The crude product was purified by chiral preparative HPLC under the following conditions: column, XBridge Prep OBDC18 column, 19 * 250 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and preparative MeOH (57% preparative MeOH up to 70% preparative MeOH in 10 min); detector, UV 254 nm. This yielded 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- -2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (80 mg, 40%). LCMS: (ES, m / z) (M - H) = 493.1. 1 1H 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 = 11.7 Hz, 1H), 4.17–4.08 (m, 1H), 3.92–3.75 (m, 2H), 3.58–3.54 (m, 1H), 3.35 (d, J = 4.6 Hz, 2H), 2.88 (d, J = 1.6 Hz, 3H), 2.35 (s, 3H), 2.21 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H).

[0443] Example 14: 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol- -2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0444]

[0445] Step 1: Synthesis of (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol- -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0446] At room temperature, TFA (2 mL) was added to a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxido-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). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / 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-dioxido-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%).

[0447] Step 2: Synthesis of tert-butyl 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0448] At room temperature, DIEA (312 μL, 1.79 mmol, 3 equiv) was added to a stirred solution of (2S)-2-(7-chloro-5-methyl-1,1-dioxido-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). At room temperature, tert-butyl carbazate (118 mg, 0.9 mmol, 1.5 equiv) was added to the above mixture. 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 afford tert-butyl 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (305 mg, 87.60%).

[0449] Step 3: (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepine Synthesis of 2-(3H)-1-(6-fluoro-2,3-dimethylphenyl)butane hydrazide

[0450] At 0 ° C, 2-((2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepine To a stirred solution of tert-butyl-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (208 mg, 0.36 mmol, 1 eq.) in DCM (2 mL) was added 2,6-lutidine (831 μL, 7.14 mmol, 20 eq.) and trimethylsilyl trifluoromethanesulfonate (1033 μL, 5.71 mmol, 16 eq.) dropwise. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This yielded (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepine -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (96 mg, 55.7%).

[0451] Step 4: 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepine Synthesis of 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0452] At room temperature, (2S)-2-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepine -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanohydrazide (96 mg, 0.2 mmol, 1 equiv) and DIEA (86.6 μL, 0.5 mmol, 2.5 equiv) were added portionwise to a stirred solution of bis(trichloromethyl) carbonate (29.5 mg, 0.1 mmol, 0.5 equiv) in THF. The resulting mixture was stirred at 60 °C for 30 min. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 10% to 100% gradient in 10 min; detector, UV 254 nm. This yielded 5-((1S)-1-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol -2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (53 mg, 52.4%).

[0453] The product was further purified by preparative achiral SFC using the following conditions (column, Torus 2-PIC column, 4.6*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), to afford 5-((1S,2R)-1-(7-chloro-5-methyl-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol -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. 1 H NMR (300 MHz, methanol-d4) δ 7.80–7.74 (m, 2H), 7.53–7.50 (d, J = 8.6 Hz, 1H), 7.04–6.99 (t, J = 7.4 Hz, 1H), 6.81–6.74 (m, 1H), 5.58–5.54 (d, J = 11.8 Hz, 1H), 3.91–3.87 (d, J = 11.3 Hz, 1H), 3.81–3.77 (dd, J = 12.9, 6.6 Hz, 1H), 3.52–3.48 (d, J = 11.8 Hz, 1H), 3.37 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H), 1.40 (d, J = 6.9 Hz, 3H).

[0454] Example 15: 5 - ((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxido-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 -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0455]

[0456] Step 1: Synthesis of 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene

[0457] At room temperature, Xantphos (2.6 g, 4.5 mmol, 0.2 equiv) and Pd2(dba)3 (2.1 g, 2.24 mmol, 0.1 equiv) were added portionwise 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. 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), 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 afford 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene (5.8 g, 97.2%).

[0458] Step 2: Synthesis of 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride

[0459] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3 g, 15 mmol, 2 equiv) was added portionwise to a stirred solution of 1-(benzylthio)-4-chloro-2-fluoro-5-methylbenzene (2 g, 7.5 mmol, 1 equiv) and H2O (1.2 mL, 67.5 mmol, 9 equiv) in MeCN and AcOH (2.44 mL, 37.5 mmol, 5 equiv). 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), dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. This gave 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, crude product).

[0460] Step 3: Synthesis of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0461] At 0 °C, 4-chloro-2-fluoro-5-methylbenzenesulfonyl chloride (3.6 g, 14.8 mmol, 1.5 eq) and DCM (40 mL) were added dropwise to a stirred solution of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butyrate (2.5 g, 8.9 mmol, 1 eq) and pyridine (10 mL). The resulting mixture was stirred overnight at room temperature. 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 MgSO4. 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 afford tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (2.7 g, 56%).

[0462] Step 4: Synthesis of tert-butyl (2S)-2-(4-chloro-2-hydroxy-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0463] At 0 °C, NaH (246 mg, 6.15 mmol, 5 eq, 60%) was added portionwise to a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluoro-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (20 mg, 0.041 mmol, 1 eq) and 2-methanesulfonylethanol (458 mg, 3.69 mmol, 3 eq) in DMF. The resulting mixture was stirred overnight at 80 °C. 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-phase flash chromatography under the following conditions: column, C18 silica; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 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)butyrate (100 mg, 16.7%).

[0464] Step 5: Synthesis of tert-butyl ((2S)-2-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0465] At room temperature, dibromoethane (77.3 mg, 0.41 mmol, 1 equiv) was added portionwise to a stirred solution of tert-butyl (2S)-2-(4-chloro-2-hydroxy-5-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (200 mg, 0.41 mmol, 1 equiv) and Cs2CO3 (402 mg, 1.24 mmol, 3 equiv) in DMF. 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (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-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (130 mg, 61.7%).

[0466] Step 6: Synthesis of (2S)-2-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0467] At room temperature, trifluoroacetaldehyde (1 mL) was added to a stirred solution of tert-butyl ((2S)-2-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (115 mg, 0.23 mmol, 1 equiv) and DCM (0.92 mL). The resulting mixture was stirred at room temperature for 90 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 220 nm. This gave (2S)-2-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (80 mg, 78.12%).

[0468] Step 7: 5-((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin Synthesis of 2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0469] At room temperature, (2S)-2-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (75 mg, 0.16 mmol, 1 eq.) was added CDI (107 mg, 0.66 mmol, 4 eq.) in batches to a stirred solution in THF. The resulting mixture was stirred for 30 min at room temperature. NH2NH2.H2O (24 μL, 0.49 mmol, 3 eq.) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred for 30 min at room temperature. 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. CDI (107 mg, 0.66 mmol, 4 eq.) in dioxane (2 mL) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred for another 30 min at room temperature. The reaction was quenched with water at room temperature. The residue was purified by reverse phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B, 55% B in 9 min; wavelength: 254 nm; RT1 (min): 7. This produced 5-((1S,2R)-1-(7-chloro-8-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine -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. 11H NMR (300 MHz, methanol-d4) δ 7.66 - 7.26 (s, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.10 - 6.91 (t, J = 7.2 Hz, 1H), 6.75 - 6.68 (dd, J = 12.1, 8.4 Hz, 1H), 5.50 - 5.36 (d, J = 11.6 Hz, 1H), 4.55 - 4.51 (dd, J = 12.3, 5.6 Hz, 1H), 4.16–3.88 (m, 4H), 2.4 - 2.36 (dd, J = 9.0, 1.7 Hz, 6H), 2.33 - 2.16 (s, 3H), 1.44 - 1.24 (d, J = 7.0 Hz, 3H).

[0470] Example 16: 5 - ((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0471]

[0472] Step 1: Synthesis of 2-(benzylthio)-5-chloropyridin-3-ol

[0473] At 100 °C, 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 Pd2(dba)3 (2.6 g, 2.9 mmol, 0.1 equiv) were added to a 250 mL round-bottom flask. 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 afford 2-(benzylthio)-5-chloropyridin-3-ol (7 g, 96.6%).

[0474] Step 2: Synthesis of 2-(benzylthio)-5-chloropyridin-3-yl benzoate

[0475] At room temperature, 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 to a 20 mL vial. The resulting mixture was stirred at room temperature for 1 h to obtain Intermediate A. At 0 °C, 2-(benzylthio)-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 to another 8 mL vial. Intermediate A was added dropwise to the mixture at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm. This gave benzoic acid 2-(benzylthio)-5-chloropyridin-3-yl ester (89 mg, 63%).

[0476] Step 3: Synthesis of benzoic acid 5-chloro-2-(chlorosulfonyl)pyridin-3-yl ester

[0477] Benzoic acid 2-(benzylthio)-5-chloropyridin-3-yl ester (50 mg, 0.1 mmol, 1 equiv), CH3CN (5 ml), AcOH (14 μL, 0.25 mmol, 4.4 equiv), and H2O (10 μL, 0.560 mmol, 10 equiv) were added to a 20 mL vial. At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (22.2 mg, 0.11 mmol, 2 equiv) was added to the mixture. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave benzoic acid 5-chloro-2-(chlorosulfonyl)pyridin-3-yl ester as a pale yellow oil (13 mg, 27%).

[0478] Step 4: Synthesis of benzoic acid 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-yl ester

[0479] Add (2S)-tert-butyl 2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 1.07 mmol, 17 eq) and pyridine (3 mL) to a 20 mL vial. At 0 °C, add 5-chloro-2-(chlorosulfonyl)pyridin-3-yl benzoate (531 mg, 1.6 mmol, 1.5 eq) to the mixture. Stir the resulting mixture at room temperature for 1 h. Purify the residue by silica gel column chromatography eluting with PE / EtOAc (5:1) to afford tert-butyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-yl benzoate (228 mg, 37%).

[0480] Step 5: Synthesis of (2S)-2-((5-chloro-3-hydroxypyridin-2-yl)sulfamoyl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester

[0481] At room temperature, add tert-butyl 2-(N-((2S)-1-(tert-butoxy)-3-(6-fluoro-2,3-dimethylphenyl)-1-oxobutan-2-yl)sulfamoyl)-5-chloropyridin-3-yl benzoate (4.5 g, 7.8 mmol, 1 eq), THF (38 mL), H2O (12.5 mL) and NaOH (624 mg, 16 mmol, 2 eq) to a 100 mL round-bottom flask. Stir the resulting mixture at 50 °C for 1 h. Acidify the mixture to pH 6 with HCl (aqueous solution). Extract the resulting mixture with EtOAc (3 × 10 mL). Wash the combined organic layers with brine (3 × 10 mL), dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. Purify the residue by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-((5-chloro-3-hydroxypyridin-2-yl)sulfamoyl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester (2.5 g, 67.8%).

[0482] Step 6: Synthesis of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester

[0483] At room temperature, (2S)-2-((5-chloro-3-hydroxypyridin-2-yl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester (2.5 g, 5.29 mmol, 1 equiv), DMF (20 mL), 1,2-dibromoethane (709 μL, 7.93 mmol, 1.5 equiv), and Cs2CO3 (5.17 g, 15.9 mmol, 3 equiv) were added to a 100 mL round-bottom flask. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester (2.3 g, 87.20%).

[0484] Step 7: Synthesis of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0485] At room temperature, (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester (2.3 g, 4.6 mmol, 1 equiv), DCM (19 mL), and TFA (6.25 mL) were added to a 100 mL round-bottom flask. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.7 g, 83.3%).

[0486] Step 8: Synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0487] At room temperature, add (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (100 mg, 0.23 mmol, 1 equiv), THF (1 mL), and CDI (168 mg, 1.04 mmol, 4.6 equiv) to a 40 mL vial. Stir the resulting mixture at room temperature under an air atmosphere for 20 min. At 0 °C, add hydrazine hydrate (54.87 μL, 1.130 mmol, 5 equiv) dropwise to the above mixture. Stir the resulting mixture at 0 °C for an additional 1 h. Quench the resulting mixture with water and extract with EtOAc (2 × 5 mL). Wash the combined organic layers with brine (1 × 5 mL), dry over anhydrous Na2SO4. After filtration, concentrate the filtrate under reduced pressure. At room temperature, add the above crude product, dioxane (2 mL), and CDI (168 mg, 1.04 mmol, 4.6 equiv) to a 10 mL vial. Stir the resulting mixture at room temperature under an air atmosphere for 0.5 h. Purify the crude product by chiral preparative HPLC under the following conditions: column, XBridge Prep OBD C18 column, 19*250 mm, 5 μm; mobile phase, undetermined and undetermined (50% undetermined to 60% undetermined in 10 min); detector, UV 254 nm. This results in the synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[3,2-b][1,4,5]oxathiazin -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. 11H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.86 (s, 1H), 7.03 (t, J = 7.0 Hz, 1H), 6.83 (dd, J = 12.2, 8.3 Hz, 1H), 5.43 (d, J = 11.6 Hz, 1H), 4.59 (ddd, J = 13.1, 8.4, 3.8 Hz, 1H), 4.30 (d, J = 13.3 Hz, 1H), 3.83 (dp, J = 19.2, 6.2, 5.6 Hz, 3H), 2.30 (s, 3H), 2.18 (s, 3H), 2.08 (s, 1H), 1.34 (d, J = 6.9 Hz, 3H).

[0488] Example 17: 5 - ((1S,2R)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0489]

[0490] Step 1: Synthesis of 5-(benzylthio)-2-chloro-4-fluoropyridine

[0491] At room temperature, DIEA (2.5 mL, 14.3 mmol, 3 eq), Xantphos (550 mg, 0.95 mmol, 0.2 eq), Pd2(dba)3 (435 mg, 0.48 mmol, 0.1 eq), and benzyl mercaptan (669 μL, 5.7 mmol, 1.2 eq) were added to a stirred solution of 5-bromo-2-chloro-4-fluoropyridine (1 g, 4.75 mmol, 1 eq) and dioxane (10 mL). 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 220 nm. This gave 5-(benzylthio)-2-chloro-4-fluoropyridine (550 mg, 45.62%). Step 2: Synthesis of 6-chloro-4-fluoropyridine-3-sulfonyl chloride

[0492] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.08 g, 10.6 mmol, 2 equiv) was added portionwise to a stirred solution of 5-(benzylthio)-2-chloro-4-fluoropyridine (1.34 g, 5.28 mmol, 1 equiv), H2O (856 μl), and AcOH (1.5 mL, 26 mmol, 5 equiv) in MeCN. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0493] Step 3: Synthesis of methyl (2S)-2-((6-chloro-4-fluoropyridin-3-yl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0494] At 0 °C, 6-chloro-4-fluoropyridine-3-sulfonyl chloride (1.6 g, 7 mmol, 1 equiv), DCM (20 mL) was added dropwise 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). The resulting mixture was stirred overnight at room temperature. The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over anhydrous MgSO4. 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 afford methyl (2S)-2-((6-chloro-4-fluoropyridin-3-yl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.56 g, 51.8%).

[0495] Step 4: Synthesis of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridin-3-yl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0496] At 0 °C, NaH (197 mg, 4.92 mmol, 3 equiv, 60%) was added portionwise to a stirred solution of methyl (2S)-2-(6-chloro-4-fluoropyridine-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (710 mg, 1.64 mmol, 1 equiv) and 2-[(tert-butyldimethylsilyl)oxy]ethanol (650 μL, 3.28 mmol, 2.0 equiv) in DMF. 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 0% to 100% gradient 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)butyrate (190 mg, 24.4%).

[0497] Step 5: Synthesis of methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0498] At room temperature, CCl4 (137 μL, 1.42 mmol, 1.5 equiv) was added dropwise to a stirred solution of methyl (2S)-2-((6-chloro-4-(2-hydroxyethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (180 mg, 0.38 mmol, 1 equiv) and PPh3 (497 mg, 1.9 mmol, 2 equiv) in DCE (6 mL). 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 0% to 100% gradient in 30 min; detector, UV220 nm. This gave methyl (2S)-2-((6-chloro-4-(2-chloroethoxy)pyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (160 mg, 85.6%).

[0499] Step 6: Synthesis of methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0500] At room temperature, Cs2CO3 (343 mg, 1.05 mmol, 2 eq) was added to a stirred solution of methyl (2S)-2-[6-chloro-4-(2-chloroethoxy)pyridine-3-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butyrate (260 mg, 0.53 mmol, 1 eq) in DMF. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) was purified by preparative HPLC using the following conditions (PE:EtOAc 1:1) to afford methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (190 mg, 78.91%).

[0501] Step 7: Synthesis of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0502] At room temperature, LiOH·H2O (87 mg, 2.08 mmol, 5 eq) was added to a stirred solution of methyl (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (20 mg, 0.41 mmol, 1 eq) and H2O (1 mL) in THF. The resulting mixture was stirred at room temperature for 30 min. The mixture 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0503] Step 8: Synthesis of 5-((1S)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0504] At room temperature, to a stirred solution of (2S)-2-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (45 mg, 0.10 mmol, 1 equiv) and CDI (57.7 mg, 0.36 mmol, 3.5 equiv) in THF. The resulting mixture was stirred at room temperature for 30 min. At 0 °C, NH2NH2·H2O (14.8 μL, 0.31 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for another 30 min. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, CDI (57.7 mg, 0.36 mmol, 3.5 equiv), dioxane (1 mL) were added portionwise to the above mixture. The resulting mixture was stirred at room temperature for another 30 min. The reaction was quenched with water at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 52% B in 9 min, 52% B; wavelength: 220 nm; RT1 (min): 7. This gave 5-((1S)-1-(7-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-b][1,4,5]oxathiazin -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): [M-H] = 480.90. 11H 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 = 14.6 Hz, 1H), 3.87–3.79 (m, 1H), 3.63–3.55 (m, 1H), 2.4. - 2.35 (d, J = 14.8 Hz, 3H), 2.30 - 2.21 (d, J = 5.2 Hz, 3H), 1.60 - 1.50 (d, J = 7.0 Hz, 1H), 1.30 - 1.20 (d, J = 6.8 Hz, 2H).

[0505] Example 18: 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-carboxylic acid methyl ester 1,1-dioxide

[0506]

[0507] 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

[0508] At 0 °C, NaH (402 mg, 10.06 mmol, 2.5 equiv, 60%) was added portionwise 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-methylsulfonylethanol (749 mg, 6.03 mmol, 1.5 equiv) in DMF. The resulting mixture was stirred at room temperature for 1 h. At room temperature, the reaction was quenched by the addition of AcOH. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (10 mmol / L NH4HCO3), 0% to 100% gradient 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%).

[0509] 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

[0510] At room temperature, K2CO3 (358 mg, 2.59 mmol, 3 equiv) was added 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. The resulting mixture was stirred at 60 °C for 1 h. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 0% to 100% gradient 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%).

[0511] ​​Step 3: Synthesis of (2S)-2-(7-chloro-9-(methoxycarbonyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0512] At room temperature, TFA (1 mL) was added to a stirred solution of 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]oxathiazine -9-carboxylic acid methyl ester 1,1-dioxide (270 mg, 0.49 mmol, 1 equiv) in 1 mL of DCM. 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-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-9-(methoxycarbonyl)-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin -2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (230 mg, 94.75%).

[0513] Step 4: 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]oxathiazine -9-carboxylic acid methyl ester 1,1-dioxide

[0514] At room temperature, to a stirred solution of (2S)-2-[7-chloro-9-(methoxycarbonyl)-1,1-dioxido-3,4-dihydro-5,1λ6,2-benzoxathiazin -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. The resulting mixture was stirred at room temperature for 30 min. At 0 °C, NH2NH 2.H2O (10.21 μL, 0.210 mmol, 3 eq). The resulting mixture was stirred for an additional 30 min at 0 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, dioxane (1 mL) and CDI (28.38 mg, 0.175 mmol, 2.5 eq) were added portionwise to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. The reaction was quenched with water at room temperature. The residue was purified by reverse-phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; 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, 46% B; wavelength: 254 / 220 nm; RT1 (min): 6.88. This yielded 7-chloro-2-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-1,1-dioxido-3,4-dihydro-5,1λ6,2-benzoxathiazine -methyl 9-carboxylate (10 mg, 25.95%). LC-MS: (ES, m / z): [M-H] = 538.15. 1 H NMR (300 MHz, methanol-d4) δ 7.33 (d, J = 2.4 Hz, 1H), 7.19–7.13 (m, 1H), 7.03–6.67 (m, 2H), 5.4 - 5.45 (t, J = 11.5 Hz, 1H), 4.85 - 4.75 (d, J = 12.4 Hz, 1H), 4.46 - 4.42 (t, J = 13.5 Hz, 1H), 4.09–3.76 (m, 6H), 2.45 - 2.34 (d, J = 12.2 Hz, 3H), 2.30 - 2.21 (d, J = 6.0 Hz, 3H), 1.43 - 1.40 (d, J = 6.9 Hz, 2H), 1.25 - 1.23 (d, J = 7.0 Hz, 1H).

[0515] 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

[0516]

[0517] Step 1: Synthesis of methyl 2-(benzylthio)-5-chloro-3-fluorobenzoate

[0518] At room temperature, 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. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. At room temperature, the reaction was quenched by adding water. 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. The residue was purified by preparative TLC (PE / EtOAc 5:1) to afford methyl 2-(benzylthio)-5-chloro-3-fluorobenzoate (4.4 g, 80.6%).

[0519] Step 2: Synthesis of methyl 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoate

[0520] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.80 g, 19.3 mmol, 2 equiv) was added portionwise 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 H2O (1.57 mL, 86.9 mmol, 9 equiv) in MeCN. The resulting mixture was stirred at 0 °C for 30 min. 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 silica gel column chromatography eluting with PE / EtOAc (9:1) to afford methyl 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoate (2.45 g, 88.4%).

[0521] 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

[0522] At 0 °C, 5-chloro-2-(chlorosulfonyl)-3-fluorobenzoic acid methyl ester (2.46 g, 8.56 mmol, 1 equiv) in DCM (30 mL) was added dropwise 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. The resulting mixture was stirred overnight at room temperature. 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 MgSO4. 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 afford 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%).

[0523] 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

[0524] At room temperature, TEA (3.66 mL, 26.3 mmol, 10 equiv) and methylamine (6.58 mL, 13.2 mmol, 5 equiv) were added 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). The resulting mixture was stirred at room temperature for 6 h. 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 afford 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%).

[0525] Step 5: Synthesis of (2S)-2-(6-chloro-8-(methoxycarbonyl)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0526] At room temperature, TsOH (114 mg, 0.66 mmol, 1 equiv) and 1,3,5-trioxane (597 mg, 6.63 mmol, 10 equiv) were added in portions 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). The resulting mixture was stirred overnight at 110 °C. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (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-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (300 mg, 90.7%).

[0527] 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

[0528] To a 50 mL round-bottom flask was added (2S)-2-(6-chloro-8-(methoxycarbonyl)-4-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (387 mg, 0.78 mmol, 1 equiv) in THF (4 mL). At room temperature, CDI (189 mg, 1.16 mmol, 1.5 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. At 0 °C, N2H4.H2O (113 μL, 2.33 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 30 min at 0 °C. 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 (1 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product SM1. To a 50 mL round-bottom flask was added SM1 in dioxane (4 mL). At room temperature, CDI (314.42 mg, 1.940 mmol, 2.5 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 10% to 100% gradient 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%).

[0529] The product (60 mg) was further purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 9 min, 55% B; wavelength: 220 nm; RT1 (min): 7) to afford 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): [M-H] + = 537.15. 1 H NMR (300 MHz, methanol-d4) δ 6.98–6.92 (d, J = 19.9 Hz, 2H), 6.83 (s, 1H), 6.71 (s, 1H), 5.43–5.40 (d, J = 13.3 Hz, 2H), 5.09–5.04 (d, J = 15.1 Hz, 1H), 3.94–3.88 (d, J = 4.6 Hz, 4H), 2.93 (s, 3H), 2.37 (d, J = 4.0 Hz, 3H), 2.22 (d, J = 4.1 Hz, 3H), 1.43 (s, 3H).

[0530] Example 20: 5-((1S,2R)-1-(8-chloro-5,5-dioxido-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

[0531]

[0532] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-((4,4-diethoxybutyl)amino)phenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0533] At room temperature, (2S)-tert-butyl 2-(4-chloro-2-fluorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (see Example 4) (1 g, 2.1 mmol, 1 equiv), 4,4-diethoxybutan-1-amine (4.76 g, 29.5 mmol, 14 equiv), TEA (3 g, 29.5 mmol, 14 equiv) and DMSO (20 mL) were added to a 40 mL round-bottom flask. The resulting mixture was stirred overnight at 80 °C under an air atmosphere. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm, to afford (2S)-tert-butyl 2-((4-chloro-2-((4,4-diethoxybutyl)amino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 77%).

[0534] Step 2: Synthesis of (2S)-2-(8-chloro-5,5-dioxido-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

[0535] At room temperature, (2S)-tert-butyl 2-{4-chloro-2-[(4,4-diethoxybutyl)amino]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 0.33 mmol, 1 equiv), TFA (1 mL) and DCM (3 mL) were added to an 8 mL round-bottom flask. The resulting mixture was stirred overnight at room temperature under an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm, to afford (2S)-2-(8-chloro-5,5-dioxido-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 as a pale yellow oil (100 mg, 65.9%).

[0536] Step 3: Synthesis of 5-((1S,2R)-1-(8-chloro-5,5-dioxido-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

[0537] At room temperature, (2S)-2-(8-chloro-5,5-dioxido-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 to a 50 mL round-bottom flask, and the resulting mixture was stirred at room temperature for 30 min. At 0 °C, hydrazine (24.7 mg, 0.77 mmol, 3 equiv) was added dropwise to the mixture. The resulting mixture was stirred at 0 °C for 30 min. 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), 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 min and then poured into water and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (0.1% FA), 5% to 100% gradient in 30 min; detector, UV 220 nm. The product was further purified by chiral preparative HPLC using the following conditions: column, XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (35% ACN to 65% ACN in 8 min); detector, UV 220, to afford 5-((1S,2R)-1-(8-chloro-5,5-dioxido-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%). 11H NMR (300 MHz, methanol-d4) δ 7.55 (dd, J = 21.3, 8.5 Hz, 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 = 3.0 Hz, 1H), 4.44 (dd, J = 12.1, 6.9 Hz, 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 = 12.7 Hz, 1H), 2.03 (s, 1H), 1.50 (dd, J = 7.0, 1.3 Hz, 3H).

[0538] LCMS: (ES, m / z): [M+H]: 507.15.

[0539] Example 21: 5-((1S,2R)-1-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one -2(3H)-one

[0540]

[0541] Step 1: Synthesis of benzyl (4-chloro-2-nitrophenyl) sulfide

[0542] At room temperature, Cs2CO3 (207 g, 634 mmol, 3.00 equiv) and benzyl mercaptan (30 mL, 254 mmol, 1.2 equiv) were added dropwise to a stirred solution of 1-bromo-4-chloro-2-nitrobenzene (50 g, 211 mmol, 1 equiv) and DMF (500 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOEt (3 × 1000 mL). The combined organic layers were washed with brine (500 mL), 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 afford benzyl (4-chloro-2-nitrophenyl) sulfide (30 g, 50.7%).

[0543] Step 2: Synthesis of 4-chloro-2-nitrobenzenesulfonyl chloride

[0544] At room temperature, AcOH (28 mL) was added portionwise to a stirred solution of benzyl(4-chloro-2-nitrophenyl)sulfane (30 g, 107 mmol, 1 equiv) and H2O (20 mL) in acetonitrile. At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (42.3 g, 215 mmol, 2 equiv) was added portionwise to the above mixture over 10 min. 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 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 afford 4-chloro-2-nitrobenzenesulfonyl chloride (30 g, crude product).

[0545] Step 3: Synthesis of tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0546] At 0 °C, 4-chloro-2-nitrobenzenesulfonyl chloride (5.8 g, 22.7 mmol, 1 equiv) in DCM was added dropwise 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. 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 afford tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (6.2 g, 54.6%).

[0547] Step 4: Synthesis of tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0548] At room temperature, ethyl bromoacetate (400 μL, 3.6 mmol, 1 equiv) was added portionwise to a stirred solution of tert-butyl (2S)-2-((4-chloro-2-nitrophenyl)sulfonylamino)-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. 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), 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 afford tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 63.05%).

[0549] Step 5: Synthesis of tert-butyl (2S)-2-((2-amino-4-chloro-N-(2-ethoxy-2-oxoethyl)phenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0550] At room temperature, Fe (1.24 g, 22.1 mmol, 10 equiv) was added portionwise to a stirred solution of tert-butyl (2S)-2-((4-chloro-N-(2-ethoxy-2-oxoethyl)-2-nitrophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (970 mg, 2.1 mmol, 1 equiv) in AcOH (15 mL). 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 cake was washed with ethyl acetate (3 × 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 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)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (987 mg, 80.01%).

[0551] 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

[0552] At room temperature, lithium hydroxide (358 mg, 8.5 mmol, 5 eq) was added portionwise 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 eq) in THF and H2O (9.5 mL). The resulting mixture was stirred overnight at 65 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used directly in the next step without further purification.

[0553] Step 7: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0554] At room temperature, EDCI (319 mg, 1.66 mmol, 1.1 eq) was added portionwise 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 eq) in DCM. At room temperature, DMAP (18.5 mg, 0.15 mmol, 0.1 eq) was added to the above mixture. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This yielded tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazepin -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (430 mg, 55.6%).

[0555] Step 8: Synthesis of tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazepin -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0556] At room temperature, to a stirred solution of tert-butyl (2S)-2-(7-chloro-1,1-dioxido-4-oxo-4,5-dihydrobenzo[f][1,2,5]thiadiazol-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (500 mg, 0.95 mmol, 1 equiv) in THF (5 mL) was added dropwise BH3-THF (5 mL, 5 mmol, 5.25 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. 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. -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (500 mg, 0.95 mmol, 1 equiv) in THF (5 mL) was added dropwise BH3-THF (5 mL, 5 mmol, 5.25 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. 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.

[0557] Step 9: Synthesis of (2S)-2-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- 2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0558] At room temperature, to a stirred solution of (2S)-2-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- 2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (280 mg, 0.55 mmol, 1 equiv) in DCM (5 mL) was added TFA (5 mL). The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- 2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (255 mg, 57.3%).

[0559] Step 10: Synthesis of 5-((1S,2R)-1-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- 2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0560] At room temperature, to a stirred solution of (2S)-2-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2,5]thiadiazol- A stirred solution of -2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (235 mg, 0.53 mmol, 1 equiv) in THF (2.35 mL) was added portionwise with CDI (216 mg, 1.33 mmol, 2.5 equiv). The resulting mixture was stirred at room temperature for 30 min. At 0 °C, hydrazine hydrate (129.5 μL, 2.67 mmol, 5 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for another 30 min. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2.0 mL). At room temperature, CDI (259 mg, 1.6 mmol, 3 equiv) was added portionwise to the above mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was concentrated in vacuo.

[0561] The crude product (260 mg) was purified by chiral preparative HPLC under the following conditions: column, XBridgeShield RP18 OBD column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O) and ACN (26% ACN to 56% ACN in 8 min); detector, UV 254 nm. This gave 5-((1S,2R)-1-(7-chloro-1,1-dioxido-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. 1 H NMR (300 MHz, methanol-d4) δ 7.58 (d, J = 8.6 Hz, 1H), 7.00–6.95 (dd, J = 8.4, 5.7 Hz, 1H), 6.79–6.67 (m, 3H), 5.46–5.42 (dd, J = 11.7, 1.7 Hz, 1H), 4.06–3.96 (ddd, J = 14.9, 11.0, 4.2 Hz, 1H), 3.82–3.72 (ddd, J = 16.7, 9.5, 5.6 Hz, 2H), 3.62–3.55 (ddd, J = 13.0, 4.2, 2.2 Hz, 1H), 3.35 (dd, J = 5.7, 2.2 Hz, 4H), 2.34 (s, 3H), 2.21 (s, 3H), 1.44 (dd, J = 7.0, 1.1 Hz, 3H).

[0562] 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

[0563]

[0564] 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

[0565] At room temperature, LiOH.H2O (15.6 mg, 0.37 mmol, 2 equivalents) and H2O (0.5 mL) were added dropwise 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 equivalent) in THF (1.5 mL). The resulting mixture was stirred overnight at 65 °C. 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0566] 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

[0567] At room temperature, DIEA (95 μL, 0.54 mmol, 3 eq), HATU (103 mg, 0.27 mmol, 1.5 eq), and ammonium chloride (1.53 mg, 0.03 mmol, 1.5 eq) were added 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 eq) in DMF (1 mL). The resulting mixture was stirred at room temperature for 1 h. 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 by preparative HPLC under the following conditions (column: XSelect CSH Prep C18 OBD column, 19*250 mm, mobile phase A: water (0.1% FA), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: 20% B to 50% B in 8 min, 50% B; wavelength: 254 nm; RT1 (min): 7.45), to afford 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): [M-H] + = 522.05. 1 H NMR (300 MHz, methanol-d4) δ 7.01–6.96 (dd, J = 8.4, 5.7 Hz, 1H), 6.82–6.67 (m, 3H), 5.47–5.39 (m, 2H), 5.07–5.02 (d, J = 14.6 Hz, 1H), 3.94–3.83 (dd, J = 12.1, 7.2 Hz, 1H), 2.91 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H), 1.44 (dd, J = 7.0, 1.1 Hz, 3H).

[0568] 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]oxathiazine -9-carboxamide 1,1-dioxide

[0569]

[0570] Step 1: 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

[0571] At room temperature, 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-5,1λ6,2-benzoxathiazepine was added. To a stirred solution of methyl-9-formate (from Example 18) (80 mg, 0.15 mmol, 1 eq.) and lithium hydroxide (31 mg, 0.74 mmol, 5 eq.) in THF was added H2O (200 μL). The resulting mixture was stirred overnight at 60 °C. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0572] Step 2: 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 Synthesis of 9-formamide 1,1-dioxide

[0573] At room temperature, 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 was added to the mixture. -9-Carboxylic acid 1,1-dioxide (90 mg, 0.17 mmol, 1 equiv) and HATU (100 mg, 0.26 mmol, 1.5 equiv) were added portionwise to a stirred solution in DMF of ammonium chloride (11 mg, 0.21 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 30 min. The residue was purified by reverse-phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 23% B to 50% B in 8 min, 50% B; wavelength: 254 nm; RT1 (min): 7. This gave 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]oxathiazine -9-Carboxamide 1,1-dioxide (23.4 mg, 26%). LC-MS: (ES, m / z): [M-H] = 523.10. 1 1H NMR (300 MHz, methanol-d4) δ 7.25 - 7.24 (d, J = 2.1 Hz, 1H), 7.08 - 7.07 (d, J = 2.2 Hz, 1H), 6.98 - 6.95 (dd, J = 8.4, 5.7 Hz, 1H), 6.72 - 6.68 (dd, J = 12.0, 8.4 Hz, 1H), 5.55 - 5.51 (dd, J = 11.6, 1.8 Hz, 1H), 4.85 - 4.81 (s, 1H), 4.40 - 4.50 (d, J = 12.0 Hz, 1H), 4.01 - 3.98 (ddd, J = 15.9, 10.6, 5.7 Hz, 1H), 3.81 - 3.76 (t, J = 9.8 Hz, 2H), 2.35 - 2.40 (s, 3H), 2.39 - 2.21 (s, 3H), 1.44 - 1.42 (dd, J = 6.9, 1.1 Hz, 3H).

[0574] Example 24: 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0575]

[0576] Step 1: Synthesis of 2-Bromo-5-chloro-1-fluoro-3-methylbenzene

[0577] At room temperature, 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 to a 40 mL vial. At 0 °C, NaNO2 (2468 mg, 35.86 mmol, 2 equiv) in H2O (0.6 mL) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. At room temperature, CuCl (5313 mg, 53.6 mmol, 3 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 1 h at 60 °C. 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), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc 5:1) to afford 2-Bromo-5-chloro-1-fluoro-3-methylbenzene (3.2 g, 80.1%).

[0578] Step 2: Synthesis of Benzyl (4-chloro-2-fluoro-6-methylphenyl)sulfane

[0579] At room temperature, Xantphos (1036 mg, 1.79 mmol, 0.2 equiv) and Pd2(dba)3 (820 mg, 0.9 mmol, 0.1 equiv) were added 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. 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), 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 afford Benzyl (4-chloro-2-fluoro-6-methylphenyl)sulfane (1.45 g, 60.7%).

[0580] Step 3: Synthesis of 4-Chloro-2-fluoro-6-methylbenzenesulfonyl Chloride

[0581] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2142 mg, 10.9 mmol, 2 eq) was added portionwise to a stirred solution of benzyl (4-chloro-2-fluoro-6-methylphenyl)sulfane (1.45 g, 5.44 mmol, 1 eq), AcOH (1557 μL, 27 mmol, 5 eq), and H2O (881 μL) in MeCN. The resulting mixture was stirred at 0 °C for 30 min. 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), 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 afford 4-chloro-2-fluoro-6-methylbenzenesulfonyl chloride (930 mg, 70.4%).

[0582] Step 4: Synthesis of tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate At 0 °C, 4-chloro-2-fluoro-6-methylbenzenesulfonyl chloride (950 mg, 3.909 mmol, 1 eq) was added dropwise to a stirred mixture of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1100 mg, 3.91 mmol, 1 eq) and pyridine (15811 μL, 19.5 mmol, 5 eq) in DCM. 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 afford tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.33 g, 69.7%).

[0583] Step 5: Synthesis of tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0584] At 0 °C, NaH (123 mg, 3.08 mmol, 5 equiv, 60%) was added portionwise to a stirred solution of tert-butyl (2S)-2-((4-chloro-2-fluoro-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (300 mg, 0.62 mmol, 1 equiv) and 2-methanesulfonylethanol (229 mg, 1.85 mmol, 3 equiv) in DMF (3 mL). 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), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 3:1) to afford tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (177 mg, 59.2%).

[0585] Step 6: Synthesis of tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate At room temperature, Cs2CO3 (201 mg, 0.62 mmol, 3 equiv) and dibromoethane (17.7 μL, 0.21 mmol, 1 equiv) were added to a stirred solution of tert-butyl (2S)-2-((4-chloro-2-hydroxy-6-methylphenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (100 mg, 0.21 mmol, 1 equiv) in DMF (1 mL). The resulting mixture was stirred at 60 °C overnight. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / water (10 mmol / L NH4HCO3), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (70 mg, 39.08%).

[0586] Step 7: Synthesis of (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0587] ​​​

[0588] At room temperature, trifluoroacetic acid (TFA, 500 μL) was added to a stirred solution / mixture of tert-butyl (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (70 mg, 0.14 mmol, 1 equiv) in DCM (1 mL). The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient over 10 min; detector, UV 254 nm. This gave (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (60 mg, 96.3%).

[0589] Step 8: Synthesis of 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxido-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

[0590] To an 8 mL vial was added (2S)-2-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl) in THF (100 μL). ​​​-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (10 mg, 0.022 mmol, 1 equiv.). At room temperature, CDI (5.3 mg, 0.03 mmol, 1.5 equiv.) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. At 0 °C, N2H4.H2O (3.20 μL, 0.066 mmol, 3 equiv.) was added dropwise to the above mixture. The resulting mixture was stirred for an additional 30 min at 0 °C. 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 (1 × 2 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product SM1. SM1 in dioxane (100 μL) was added to an 8 mL vial. At room temperature, CDI (8.9 mg, 0.055 mmol, 2.5 equiv.) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), 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;), to afford 5-((1S,2R)-1-(7-chloro-9-methyl-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin -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): [M-H] + = 494.1. 11H NMR (300 MHz, methanol-d4) δ 7.12–7.08 (m, 1H), 6.98–6.96 (dd, J = 8.4, 5.8 Hz, 1H), 6.86–6.85 (d, J = 2.2 Hz, 1H), 6.75–6.72 (dd, J = 12.1, 8.4 Hz, 1H), 5.63–5.59 (dd, J = 11.7, 1.9 Hz, 1H), 4.46–4.37 (ddt, J = 16.5, 12.0, 5.3 Hz, 2H), 4.01–3.91 (ddd, J = 14.1, 10.6, 6.4 Hz, 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, 1.1 Hz, 3H).

[0591] Example 25: 5-((1S,2R)-1-(6-Acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0592]

[0593] Step 1: Synthesis of 1-(3-Bromo-6-chloro-2-fluorophenyl)ethan-1-ol

[0594] At 0 °C, CH3MgBr (3 M in Et2O) (17.6 mL, 52.6 mmol, 2.5 equivalents) was added dropwise to a stirred solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (5 g, 21 mmol, 1 equivalent) in THF under a nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under a nitrogen atmosphere. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0595] Step 2: Synthesis of 1-(3-Bromo-6-chloro-2-fluorophenyl)ethan-1-one

[0596] At room temperature, 1-(3-bromo-6-chloro-2-fluorophenyl)ethanol (5.1 g, 20 mmol, 1 equiv), DCM (100 mL), and MnO2 (17.5 g, 201 mmol, 10 equiv) were added to a 250 mL round-bottom flask. The resulting mixture was stirred overnight at 40 °C. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE to afford 1-(3-bromo-6-chloro-2-fluorophenyl)ethanone as a pale yellow oil (3.95 g, 78%).

[0597] Step 3: Synthesis of 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one

[0598] At room temperature, 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) were added to a 100 mL round-bottom flask. 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 afford 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one as a pale yellow solid (2.44 g, 93.7%).

[0599] Step 4: Synthesis of 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride

[0600] At 0 °C, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.26 g, 16.56 mmol, 2 eq) was added dropwise to a stirred solution of 1-(3-(benzylthio)-6-chloro-2-fluorophenyl)ethan-1-one (2.44 g, 8.28 mmol, 1 eq), H2O (0.8 mL), and AcOH (4 mL) in MeCN (20 mL). The resulting mixture was stirred at 0 °C for 30 min. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 20 mL), 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 (8:1) to afford 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride (1.8 g, 80.2%).

[0601] Step 5: Synthesis of tert-butyl (2S)-2-((3-acetyl-4-chloro-2-fluorophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0602] At 0 °C, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid tert-butyl ester (1.70 g, 6.04 mmol, 1 eq), DCM (15 mL), and pyridine (2.4 mL, 30 mmol, 5 eq) were added to a 100 mL round-bottom flask. At 0 °C, 3-acetyl-4-chloro-2-fluorobenzenesulfonyl chloride (1.8 g, 6.6 mmol, 1.1 eq) in DCM (15 mL) was added to the above mixture. The resulting mixture was stirred overnight at room temperature. The resulting mixture was washed with 1 × 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), 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 (7:1) to afford tert-butyl (2S)-2-((3-acetyl-4-chloro-2-fluorophenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.58 g, 82.8%).

[0603] Step 6: Synthesis of tert-butyl (2S)-2-((3-acetyl-4-chloro-2-hydroxyphenyl)sulfonylamino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0604] At 0 °C, sodium hydride (60%, in oil, 310 mg) was added 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. 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 under a nitrogen atmosphere for 2 h. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), 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 afford 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.

[0605] Step 7: Synthesis of tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0606] At room temperature, 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) were added to a 40 mL sealed tube. The resulting mixture was stirred at 65 °C overnight. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 20 mL), 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 afford tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 71.4%).

[0607] Step 8: Synthesis of (2S)-2-(6-acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0608] At room temperature, add tert-butyl (2S)-2-(6-acetyl-7-chloro-1,1-dioxido-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) to an 8 mL sealed tube. Stir the resulting mixture at room temperature for 1 h. Concentrate the resulting mixture in vacuo. The crude product is used directly in the next step without further purification.

[0609] Step 9: Synthesis of 5-((1S,2R)-1-(6-acetyl-7-chloro-1,1-dioxido-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

[0610] At room temperature, add (2S)-2-(6-acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepin-2-yl) to an 8 mL sealed tube. ​​​-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). The resulting mixture was stirred at room temperature for 40 min. At 0 °C, hydrazine hydrate (16.6 μL, 0.34 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred at 0 °C for an additional 30 min. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 1 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. At room temperature, dioxane (1 mL) and CDI (46.1 mg, 0.29 mmol, 2.5 equiv) were added to the above mixture. The resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated NH4Cl (aqueous solution) at room temperature. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4 and evaporated. The crude product was purified by chiral preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; 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, 50% B; wavelength: 254 nm; RT1 (min): 7.45, to afford 5-((1S,2R)-1-(6-acetyl-7-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazin -2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (14.6 mg, 23.6%).

[0611] LCMS: (ES, m / z): (M-H): 522.10. 11H NMR (300 MHz, methanol-d4) δ 7.82–7.79 (d, J = 8.6 Hz, 1H), 7.36–7.33 (d, J = 8.5 Hz, 1H), 6.99–6.97 (dd, J = 8.4, 5.7 Hz, 1H), 6.76–6.69 (dd, J = 12.1, 8.4 Hz, 1H), 5.55–5.51 (dd, J = 11.6, 2.2 Hz, 1H), 4.62 (dt, J = 12.2, 4.6 Hz, 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, 1.2 Hz, 3H).

[0612] Example 26: 5-((1S,2R)-1-(6-chloro-4,8-dimethyl-1,1-dioxido-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

[0613]

[0614] Step 1: Synthesis of tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate

[0615] At room temperature, TEA (855 μL, 6.15 mmol, 10 eq) and methylamine (1.54 mL, 3.1 mmol, 5 eq) were added to a stirred solution of tert-butyl (2S)-2-(4-chloro-2-fluoro-6-methylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (see Example 24) (300 mg, 0.62 mmol, 1 eq) in THF (3 mL). The resulting mixture was stirred overnight at 60 °C. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (9:1) to afford tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (285 mg, 92.9%).

[0616] Step 2: Synthesis of (2S)-2-(6-chloro-4,8-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid

[0617] At room temperature, TsOH (95 mg, 0.55 mmol, 1 equiv) and 1,3,5-trioxane (496 mg, 5.51 mmol, 10 equiv) were added to a stirred solution of tert-butyl (2S)-2-((4-chloro-2-methyl-6-(methylamino)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butyrate (285 mg, 0.55 mmol, 1 equiv) in dioxane (11 mL). The resulting mixture was stirred overnight at 110 °C. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN / H2O (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm. This gave (2S)-2-(6-chloro-4,8-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (47 mg, 18.8%).

[0618] Step 3: Synthesis of 5-((1S,2R)-1-(6-chloro-4,8-dimethyl-1,1-dioxido-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

[0619] (2S)-2-(6-Chloro-4,8-dimethyl-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butyric acid (60 mg, 0.13 mmol, 1 equiv) in THF (1 mL) was added to a 50 mL round-bottom flask. At room temperature, CDI (32.1 mg, 0.2 mmol, 1.5 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. At 0 °C, N2H4·H2O (19 μL, 0.4 mmol, 3 equiv) was added dropwise to the above mixture. The resulting mixture was stirred for 30 min at 0 °C. 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 (1 × 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product SM1. SM1 in dioxane (1 mL) was added to an 8 mL vial. At room temperature, CDI (53.5 mg, 0.33 mmol, 2.5 equiv) was added portionwise to the above mixture. The resulting mixture was stirred for an additional 30 min at room temperature. The crude product was used directly in the next step without further purification.

[0620] The crude product (60 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof: Wherein: X 1 is N or Cr 1 ; X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 4 is N or CR 4 ; R 1 is hydrogen, deuterium, a 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 、a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 deuterated alkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R; R 2 is hydrogen, deuterium, a 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 、a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 deuterated alkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R; R 3 is 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R; R 4 is hydrogen, deuterium, a 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 、a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 deuterated alkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, a heterocycloalkyl, an aryl or a heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R; Ring C is a 5- to 8-membered heterocycloalkyl containing one or two additional heteroatoms selected from -O-, -S-, -S(=O)-, -S(=O)2- and -NR 10 -; R 10 is 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R 10a substituents; Each R 10a is independently deuterium, a 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more Rs; or two Rs on the same carbon 10a together form an oxo group; Each R 5 is independently deuterium, a 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more Rs; or two Rs on the same carbon 5 together form an oxo group; or two Rs on the same carbon 5 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more Rs; or two Rs on adjacent atoms 5 together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; each of which is optionally substituted with one or more Rs; or an R 5 and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more R; p is 0-4; Ring A is a 5-membered heterocycloalkyl or 5-membered heteroaryl; Each R 6 is independently deuterium, a 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; or two Rs on the same atom 6 together form an oxo group; n is 0-3; R 7 is hydrogen, deuterium, a halogen, -CN, -NO2, -OH, -OR a , a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group; R 8 is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group; Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 9 is independently deuterium, a 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 -NR c R d 、-NR b -NR 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more R 9a substituted; or two Rs on the same atom 9 together form an oxo group; Each R 9a is independently deuterium, a 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 , -NR c R d , -NR b , -NR 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 the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted by one or more Rs; or two Rs on the same atom 9a together form an oxo group; m is 0-5; Each R a independently is 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted by one or more Rs; Each R b independently is hydrogen, 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; and Each R c and R d independently is hydrogen, 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, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, - S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1- C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -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; or two Rs on the same atom together form an oxo group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom selected from -O-, -S- and -NR 10 -.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein ring C is a 6- to 7-membered heterocycloalkyl containing an additional heteroatom selected from -O- and -NR 10 -.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein ring C is a 6-membered heterocycloalkyl containing an additional heteroatom selected from -O-, -S- and -NR 10 -.

5. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein ring C is a 6-membered heterocycloalkyl containing an additional heteroatom selected from -O- and -NR 10 -.

6. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein ring C is a 6-membered heterocycloalkyl containing an additional heteroatom which is -NR 10 -.

7. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein Ring C is a 6-membered heterocycloalkyl containing an additional heteroatom which is -O-.

8. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein Ring C is a 7-membered heterocycloalkyl containing an additional heteroatom selected from -O-, -S- and -NR 10 -.

9. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein Ring C is a 7-membered heterocycloalkyl containing an additional heteroatom selected from -O- and -NR 10 -.

10. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein Ring C is a 7-membered heterocycloalkyl containing an additional heteroatom which is -NR 10 -.

11. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein Ring C is a 7-membered heterocycloalkyl containing an additional heteroatom which is -O-.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein each R 5 is independently C1-C6 alkyl or C1-C6 haloalkyl.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein each R 5 is independently C1-C6 alkyl.

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

15. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the compound of formula (I) has the formula (Ia): Wherein: X is -O-, -S- or -NR 10 -; Each R 5’ is independently hydrogen or R 5 ; or two Rs on the same carbon 5’ together form an oxo group; or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more Rs; or an R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more Rs.

16. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the compound of formula (I) has formula (Ib): Wherein: X is -O-, -S- or -NR 10 -; Each R 5’ is independently hydrogen or R 5 ; or two Rs on the same carbon 5’ together form an oxo group; or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more Rs; or two Rs on adjacent carbons 5’ together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted by one or more Rs; or an R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted by one or more Rs.

17. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the compound of formula (I) has formula (Ic): Wherein: X is -O-, -S- or -NR 10 -; Each R 5’ is independently hydrogen or R 5 ; or two Rs on the same carbon 5’ together form an oxo group; or two Rs on the same carbon 5’ together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted by one or more Rs; or an R 5’ and R 10 together form a heterocycloalkyl or heteroaryl; each of which is optionally substituted with one or more Rs.

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

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

20. The compound according to any one of claims 1 - 10, 12 - 17 or 19, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein 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 the alkyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted by one or more R 10a substituents.

21. The compound according to any one of claims 1 - 10, 12 - 17 or 19, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 10is hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 deuterated alkyl group, a C1-C6 hydroxyalkyl group, a C1-C6 aminoalkyl group or a C1-C6 heteroalkyl group; wherein said alkyl group is optionally and independently substituted by one or more R 10a substituents.

22. The compound or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof according to any one of claims 1-10, 12-17 or 19, wherein R 10 is a C1-C6 alkyl group.

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

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

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

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

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

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

29. The compound or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof according to any one of claims 1-28, wherein each R 6 is independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C1-C6 deuterated alkyl group; or two R 6 on the same atom together form an oxo group.

30. The compound or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof according to any one of claims 1-29, wherein each R 6 is independently deuterium, halogen or a C1-C6 alkyl group; or two R 6 on the same atom together form an oxo group.

31. A compound as claimed in any one of claims 1 - 30, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein two Rs on the same atom 6 together form an oxo group.

32. A compound as claimed in any one of claims 1 - 31, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein n is 0 or 1.

33. A compound as claimed in any one of claims 1 - 31, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein n is 2 or 3.

34. A compound as claimed in any one of claims 1 - 22, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein is 35. A compound as claimed in any one of claims 1 - 34, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 1 is CR 1 .

36. A compound as claimed in any one of claims 1 - 35, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 1 is 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.

37. A compound as claimed in any one of claims 1 - 36, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 1 is hydrogen, deuterium, halogen, -C(=O)R a , C1 - C6 alkyl, C1 - C6 haloalkyl or C1 - C6 hydroxyalkyl.

38. A compound as claimed in any one of claims 1 - 37, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 1 is hydrogen, -C(=O)R a , C1 - C6 alkyl or C1 - C6 hydroxyalkyl.

39. A compound as claimed in any one of claims 1 - 38, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 1 is hydrogen.

40. The compound according to any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 1 is N.

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

42. The compound according to any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 2 is 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.

43. The compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 2 is hydrogen, deuterium, halogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl.

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

45. The compound according to any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 2 is N.

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

47. The compound according to any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 3 is 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.

48. A compound as claimed in any one of claims 1 - 47 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 3 is hydrogen, deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl or C1 - C6 hydroxyalkyl, C1 - C6 heteroalkyl.

49. A compound as claimed in any one of claims 1 - 48 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 3 is hydrogen.

50. A compound as claimed in any one of claims 1 - 45 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 3 is N.

51. A compound as claimed in any one of claims 1 - 50 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 4 is CR 4 .

52. A compound as claimed in any one of claims 1 - 51 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein 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 , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuterated alkyl, C1 - C6 hydroxyalkyl, C1 - C6 aminoalkyl, C1 - C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

53. A compound as claimed in any one of claims 1 - 52 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein 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.

54. A compound as claimed in any one of claims 1 - 50 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein X 4 is N.

55. The compound according to any one of claims 1 - 54, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein 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.

56. The compound according to any one of claims 1 - 55, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 7 is hydrogen, deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl or C1 - C6 deuterated alkyl.

57. The compound according to any one of claims 1 - 56, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 7 is C1 - C6 alkyl.

58. The compound according to any one of claims 1 - 57, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein R 8 is hydrogen or C1 - C6 alkyl.

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

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

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

62. The compound according to any one of claims 1 - 61, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein each R 9 is independently deuterium, halogen, C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuterated alkyl, cycloalkyl or heterocycloalkyl.

63. The compound according to any one of claims 1 - 62, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein each R 9 is independently halogen or C1 - C6 alkyl.

64. The compound according to any one of claims 1 - 63, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein m is 1 - 3.

65. A compound selected from the following: or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

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

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

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

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

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

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

72. The method according to claim 71, wherein the method further comprises administering a cancer - targeting therapeutic agent.

73. The method according to claim 72, wherein the cancer - targeting therapeutic agent inhibits a gene or gene product contained on ecDNA in the tumor or tumor cells.

74. A method for treating a tumor or tumor cells in a subject, the method comprising administering a compound according to any one of claims 1-65 or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, or a pharmaceutical composition according to 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 ecDNA characteristics; and wherein the growth or size of the tumor or the growth or number of tumor cells is reduced.

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

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

77. The method according to claim 75 or 76, wherein the focal amplification is present on ecDNA.

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