Cyclic sulfonamide ribonucleotide reductase (RNR) inhibitors and uses thereof

Abstract

Compounds and methods for the treatment of cancer are provided herein. The methods include administering a therapeutically effective amount of the cyclic sulfonamide RNR inhibitors disclosed herein to a subject in need of treatment.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 245,718, filed September 17, 2021, the entirety of which is incorporated herein by reference.

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

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

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

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

[0006] As used herein, the formula (I)

[0007] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, X 1 is N or CR 1 and X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and R 1 , R 2 , R 3 , and R 4 are independently 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; Ring C is a 4-8 membered heterocycloalkyl optionally containing 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, two R on the same carbon 5 come together to form oxo, p is 0 to 4; Ring A is a 5-membered ring containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N; R 6are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 6 come together to form oxo, n is 0 to 3; R 7 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 9 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c 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, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by Or, two R on the same atom 9 come together to form oxo, R 9a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a, -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from deuterium, halogen, -CN, -NO2, -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; Alternatively, two R on the same atom 9a come together to form oxo, m is 0 to 5; R aare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and heteroaryl is independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R bare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); aryl, and heteroaryl are each independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R c and R dare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, and heteroaryl are each independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl.

[0008] As used herein, the formula (Ia)

[0009] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0010] As used herein, the formula (Ib)

[0011] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, R 6’ is hydrogen or C1-C6 alkyl; R 5’ are each independently hydrogen or R 5 It is.

[0012] As used herein, the formula (Ic)

[0013] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0014] As used herein, the formula (Id)

[0015] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0016] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0017] Also disclosed herein is a method of treating cancer in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0018] Also disclosed herein is a method of inhibiting ribonucleotide reductase in a subject, the method comprising administering to the subject a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0019] In some embodiments, inhibition of ribonucleotide reductase occurs in tumor cells of a subject in need thereof.

[0020] Also disclosed herein is a method of treating a tumor or tumor cells in a subject, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in the tumor or tumor cells, and administering a cancer targeted therapeutic agent, wherein the tumor or tumor cells have an ecDNA signature, and tumor growth or size, or tumor cell growth or number is reduced.

[0021] Also disclosed herein is a method of treating an ecDNA-associated tumor or tumor cells, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, to a subject identified as having a tumor or tumor cells having ecDNA, wherein the growth or size of the tumor, or the growth or number of tumor cells, is reduced as a result of the treatment.

[0022] In some embodiments, the method further comprises administering a cancer targeted therapy.

[0023] In some embodiments, the cancer targeted therapeutic agent inhibits a gene or gene product contained in ecDNA in a tumor or tumor cells.

[0024] Also disclosed herein is a method of treating a tumor or tumor cells in a subject, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in an amount sufficient to induce replication stress in the tumor or tumor cells, wherein the tumor or tumor cells contain ecDNA or have an ecDNA signature, and tumor growth or size, or tumor cell growth or number, is reduced.

[0025] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] definition As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "an agent" includes a plurality of such agents, a reference to "a cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges relating to physical properties, such as molecular weight, or chemical properties, such as formulas, are used herein, all combinations and subcombinations of the ranges, and specific embodiments within the ranges, are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is an approximation within experimental variation (or within statistical experimental error), and thus the number or range of numbers may vary, in some cases, by 1% to 15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other specific embodiments, such as, for example, any composition of matter, composition, method, or process described herein "consist of" or "consist essentially of" the described features.

[0027] As used in this specification and the appended claims, unless otherwise defined, the following terms have the meanings indicated below.

[0028] "Oxo" refers to =O.

[0029] "Alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Wherever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the definition also encompasses occurrences of the term "alkyl" when no numerical range is specified. In some embodiments, alkyl is any of the C1-C6 alkyl groups. 10Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specified herein, alkyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen. In some embodiments, alkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0030] "Alkenyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" appears herein, it means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses the appearance of the term "alkenyl" when no numerical range is explicitly stated. In some embodiments, alkenyl is any of the C2-C6 alkenyls. 10alkenyl, C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless otherwise specified herein, an alkenyl group is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen. In some embodiments, the alkenyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0031] "Alkynyl" refers to an optionally substituted straight chain or an optionally substituted branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition includes C2-C6 alkynyl. 10It also encompasses alkynyl that is alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless otherwise specified herein, alkynyl groups are optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen. In some embodiments, the alkynyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0032] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen. In some embodiments, an alkylene is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0033] "Alkoxy" refers to a radical of the formula -Oalkyl, where alkyl is as defined. Unless otherwise specified in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen. In some embodiments, an alkoxy is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0034] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0035] "Aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is 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. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, the aryl is phenyl. Unless otherwise specified herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen. In some embodiments, an aryl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0036] "Cycloalkyl" refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl), 3 to 10 carbon atoms (C3-C 10cycloalkyl), cycloalkyl having 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3-membered to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5-membered to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen. In some embodiments, cycloalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0037] "Deuteroalkyl" refers to an alkyl radical, as defined above, substituted by one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuteroalkyls include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0038] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, or 3 halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

[0039] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro. In some embodiments, the halogen is chloro. In some embodiments, the halogen is bromo. In some embodiments, the halogen is iodo.

[0040] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, or -CH(CH)OCH. Unless otherwise specified herein, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen. In some embodiments, heteroalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0041] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0042] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated, not fully aromatic ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl contains 1 or 2 heteroatoms selected from nitrogen and oxygen. Unless otherwise specified in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached by a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocyclic rings containing 2-15 carbon atoms (C2-C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C31, C32, C33, C34, C35, C35, C46, ​​C47, C48, C49, C51, C52, C53, C54, C55, C56, C67, C68, C69, C70, C71, C72, C73, C74, C75, C75, C76, C77, C78, ​​C79, C81, C82, C83, C84, C85, C86, C87, C88, C91, C92, C93, C94, C95, C96, C97, C98, C99, C100, C111, C122, C131, C141, C15 15 Heterocycloalkyl, 2 to 10 carbon atoms (C2-C 10Heterocycloalkyl includes heterocycloalkyls having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, and 4-piperidonyl. , pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in the specification, heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen. In some embodiments, heterocycloalkyl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0043] "Heteroaryl" refers to a radical of a 5-14 membered ring system containing a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring containing at least one heteroatom. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofurano ... Nonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl ( indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl ), 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated in the specification, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen. In some embodiments, the heteroaryl is optionally substituted with -COOH, -COOMe, -CONH2, -CONHMe, or -CONMe2.

[0044] The term "one or more" when referring to any substituent means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0045] The terms "treat", "treated", "treatment", or "treating" as used herein refer to therapeutic treatment, the purpose of which is to prevent or delay (lessen) an undesirable physiological disease, disorder, or condition, or to obtain a beneficial or desired clinical outcome. For purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, disorder, or disease, stabilization (i.e., not worsening) of the disease, disorder, or disease state, delay in onset or slowing of progression of the disease, disorder, or disease, improvement of the disease, disorder, or disease state, and remission (whether partial or total), or enhancement or amelioration of the disease, disorder, or disease, whether detectable or undetectable. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment further includes extending survival time as compared to the expected survival time in the absence of treatment. The terms "treat", "treated", "treatment", or "treating", as well as the words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that those skilled in the art will recognize as potentially beneficial or therapeutic. In this regard, the disclosed methods can provide any level of treatment of a mammalian disorder in any amount. For example, a disorder, including its symptoms or conditions, can be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0046] The term "effective amount" or "therapeutically effective amount", as used herein, refers to a sufficient amount of a compound disclosed herein being administered that relieves to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or amelioration of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to clinically significantly reduce a disease symptom. In some embodiments, the appropriate "effective" amount in a particular case is determined using techniques such as a dose escalation study.

[0047] The term "ecDNA signature" as used herein generally refers to one or more features common to tumors or tumor cells that are ecDNA+ (including extrachromosomal DNA (ecDNA)). In some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutations, lack of microsatellite instability (MSI-H), low levels of PD-L1 expression, low levels of tumor inflammation signature (TIS), low levels of tumor mutation burden (TMB), increased frequency of allelic substitutions, insertions, or deletions (indels), and any combination thereof. In some cases, the ecDNA signature includes detection or identification of ecDNA using imaging techniques. In some cases, the ecDNA signature does not include any imaging or direct detection of ecDNA.

[0048] compound Described herein are cyclic sulfonamide RNR inhibitors useful for the treatment of cancer.

[0049] As used herein, the formula (I)

[0050] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, During the ceremony, X 1 is N or CR 1 and X 2 is N or CR 2 and X 3 is N or CR 3 and X 4 is N or CR 4 and R 1 , R 2 , R 3 , and R 4 are independently 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; Ring C is a 4-8 membered heterocycloalkyl optionally containing 1 or 2 additional heteroatoms selected from the group consisting of O, S, and N; R 5 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl; Or, two R on the same carbon 5 come together to form oxo, p is 0 to 4; Ring A is a 5-membered ring containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N; R 6 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom 6 come together to form oxo, n is 0 to 3; R 7 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 9 are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by Or, two R on the same atom 9 come together to form oxo, R 9a are each independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NRc 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, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from deuterium, halogen, -CN, -NO2, -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; Alternatively, two R on the same atom 9a come together to form oxo, m is 0 to 5; R aare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, each aryl, and heteroaryl is independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R bare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); aryl, and heteroaryl are each independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R c and R dare each independently 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl); alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl , aryl, and heteroaryl are each independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents that are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0051] In some embodiments of the compound of formula (I), the compound has the formula

[0052] [ka] It is of the following.

[0053] In the present specification, the formula (I-1)

[0054] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0055] In some embodiments of the compound of formula (I-1), the compound has the formula

[0056] [ka] It is of the following.

[0057] In the present specification, the formula (I-2)

[0058] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0059] In some embodiments of the compound of formula (I-2), the compound has the formula

[0060] [ka] It is of the following.

[0061] In the present specification, the formula (I-3)

[0062] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0063] In some embodiments of the compound of formula (I-3), the compound has the formula

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

[0065] In the present specification, the formula (I-4)

[0066] [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0067] In some embodiments of the compound of formula (I-4), the compound has the formula

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

[0069] In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing one or two heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing two or three heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing two to four heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing one to three heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing three or four heteroatoms selected from the group consisting of O, S, and N.

[0070] In some embodiments of the compounds of Formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing one heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing two heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing three heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing four heteroatoms selected from the group consisting of O, S, and N.

[0071] In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing one or two heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing two or three heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing two to four heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing one to three heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered ring containing three or four heteroatoms selected from the group consisting of O and N.

[0072] In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is a 5-membered ring containing one heteroatom selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is a 5-membered ring containing two heteroatoms selected from the group consisting of O and N.

[0073] In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is a five-membered ring containing three heteroatoms selected from the group consisting of O and N. In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is a five-membered ring containing four heteroatoms selected from the group consisting of O and N.

[0074] In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heterocycloalkyl or a 5-membered heteroaryl. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heterocycloalkyl. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heterocycloalkyl containing 2 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heterocycloalkyl containing 3 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heteroaryl. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heteroaryl containing 2 to 4 heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), ring A is a 5-membered heteroaryl containing 3 to 4 heteroatoms selected from the group consisting of O, S, and N.

[0075] In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is triazole or tetrazole. In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is triazole. In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is tetrazole. In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), ring A is 2,3-dihydro-1,3,4-oxadiazole.

[0076] In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), R 6 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl; or two R 6 In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), R 6 are each independently deuterium, halogen, or C1-C6 alkyl; or two R 6 In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), R 6 are each independently C1-C6 alkyl, or two R 6 In some embodiments of the compounds of Formula (I) or (I-1) through (I-4), R 6 are each independently C1-C6 alkyl.

[0077] In some embodiments of the compounds of Formula (I) or (I-1) to (I-4), two R 6 come together to form oxo.

[0078] In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 0 to 2. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 0 or 1. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 1 or 2. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 2 or 3. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 0. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 1. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 2. In some embodiments of the compounds of formula (I) or (I-1) to (I-4), n is 3.

[0079] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0080] [ka] The During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0081] In some embodiments of the compound of Formula (Ia), the compound has the formula

[0082] [ka] It is of the following.

[0083] In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 1 is N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 1 is CR 1 It is.

[0084] In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 2 is N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 2 is CR 2 It is.

[0085] In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 3 is N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 3 is CR 3 It is.

[0086] In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 4 is N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), X 4 is CR 4 It is.

[0087] In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is a 5- to 7-membered heterocycloalkyl optionally containing one or two additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is a 6- to 7-membered heterocycloalkyl optionally containing one or two additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is a 5- to 6-membered heterocycloalkyl optionally containing one or two additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1) through (I-4), Ring C is a 5-membered heterocycloalkyl optionally containing one or two additional heteroatoms selected from the group consisting of O, S, and N. In some embodiments of a compound of Formula (I), (Ia), or (I-1) through (I-4), Ring C is a 6-membered heterocycloalkyl optionally containing one or two additional heteroatoms selected from the group consisting of O, S, and N.

[0088] In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 6- to 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5- to 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is a 6-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is a 7-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N. In some embodiments of the compounds of Formula (I), (Ia), or (I-1) through (I-4), ring C is an 8-membered heterocycloalkyl containing one additional heteroatom selected from the group consisting of O, S, and N.

[0089] In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5- to 7-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 6- to 7-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5- to 6-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 5-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 6-membered heterocycloalkyl. In some embodiments of the compounds of formula (I), (Ia), or (I-1) to (I-4), ring C is a 7-membered heterocycloalkyl.

[0090] In some embodiments of the compound of Formula (I) or (Ia), the compound has the formula (Ib):

[0091] [ka] The During the ceremony, R 6’ is hydrogen or C1-C6 alkyl; R 5’ are each independently hydrogen or R 5 It is.

[0092] In some embodiments of the compound of Formula (Ib), the compound has the formula

[0093] [ka] It is of the following.

[0094] In some embodiments of the compounds of Formula (Ib), R 5’ are each independently hydrogen, deuterium, halogen, -OH, -OR a , -NR c Rd , C1-C6 alkyl, or C1-C6 haloalkyl, or two R 5 In some embodiments of the compounds of formula (Ib), R 5’ are each independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (Ib), R 5’ are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (Ib), R 5’ Each is hydrogen. In some embodiments of the compound of Formula (Ib), R 5’ are each independently hydrogen or deuterium.

[0095] In some embodiments of the compound of Formula (I) or (Ia), the compound has the formula (Ic):

[0096] [ka] The During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0097] In some embodiments of the compound of Formula (Ic), the compound has the formula

[0098] [ka] It is of the following.

[0099] In some embodiments of the compound of Formula (I) or (Ia), the compound has the formula (Id):

[0100] [ka] The During the ceremony, R 6’ is hydrogen or C1-C6 alkyl.

[0101] In some embodiments of the compound of Formula (Id), the compound has the formula

[0102] [ka] It is of the following.

[0103] In some embodiments of the compounds of Formula (Ia)-(Id), R 6’ is hydrogen.

[0104] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 5 are each independently deuterium, halogen, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl, or two R 5 In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 5 are each independently deuterium, halogen, or C-C alkyl; in some embodiments of compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 5 are each independently deuterium. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 5 are each independently C1-C6 alkyl.

[0105] In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 0 or 1. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 1 or 2. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 0. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 1. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 2. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), p is 3.

[0106] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 , R 2 , R 3 , and R 4 are 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, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 , R 2 , R 3 , and R 4 are independently hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 , R 2 , R 3 , and R 4 are independently hydrogen or halogen, -OR a It is.

[0107] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 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, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen, 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), (Ia)-(Id), or (I-1)-(I-4), R1 is hydrogen, halogen, -OH, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is hydrogen, halogen, or -OR a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 1 is a halogen.

[0108] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), 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, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, 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), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, halogen, -OH, -OR a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is hydrogen, halogen, or -OR a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 2 is a halogen.

[0109] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), 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, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, 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), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, halogen, -OH, -OR a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is hydrogen, halogen, or -OR a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 3 is a halogen.

[0110] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), 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, or C1-C6 heteroalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, 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), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, halogen, -OH, -OR a, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is hydrogen, halogen, or -OR a In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 4 is a halogen.

[0111] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 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. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), 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), (Ia)-(Id), or (I-1)-(I-4), R 7 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 7 is methyl.

[0112] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 8 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 8 is hydrogen.

[0113] In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), ring B is aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), ring B is phenyl. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), ring B is aryl or heteroaryl. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), ring B is 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), ring B is 5-membered heteroaryl. In some embodiments of compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), Ring B is a 6-membered heteroaryl.

[0114] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 9 are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a or two R on the same atom 9 come together to form oxo.

[0115] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 9are each independently deuterium, halogen, -CN, -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 9a is replaced by.

[0116] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 9 are each independently halogen or C1-C6 alkyl.

[0117] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 9a are each independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from deuterium, halogen, -CN, -NO2, -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.

[0118] In some embodiments of the compounds of Formula (I), (Ia)-(Id), or (I-1)-(I-4), R 9a are each independently deuterium, halogen, -OR a , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, where alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally independently selected from deuterium, halogen, -CN, -NO2, -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.

[0119] In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 1 to 3. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 0 or 1. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 1 to 3. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 0 to 2. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 1 to 3. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 1 or 2. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 0 to 3. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 1. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 2. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 3. In some embodiments of the compounds of formula (I), (Ia) to (Id), or (I-1) to (I-4), m is 4.

[0120] In some embodiments of the compounds disclosed herein, R aare each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents that are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl.

[0121] In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b Each is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R a are hydrogen.

[0122] In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more substituents which are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d Each is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R dare hydrogen.

[0123] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents that are oxo, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl. 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 substituents that are oxo, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, or C1-C6 aminoalkyl.

[0124] In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d , and R c and R d When taken together, the heterocycloalkyl formed is each independently substituted with one, two, three, or four substituents as defined herein. In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d, and R c and R d taken together form a heterocycloalkyl, which is independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, which is independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, which is independently substituted with one substituent as defined herein. In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, which is independently substituted with two substituents as defined herein. In some embodiments of the compounds disclosed herein, R 9 , R 9a , R a , R b , R c , R d , and R c and R d taken together form a heterocycloalkyl, which is independently substituted with three substituents as defined herein.

[0125] In some embodiments of the compound of Formula (I) or (Ia)-(Id), the compound is selected from the compounds of Table 1.

[0126] [Table 1-1]

[0127] [Table 1-2]

[0128] [Table 1-3]

[0129] [Table 1-4]

[0130] [Table 1-5]

[0131] [Table 1-6]

[0132] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically depicted stereoisomer.

[0133] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, each of which exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered with the resolving agent.

[0134] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds, such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates, tautomers, or stereoisomers, respectively, include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included among the isotopes are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Isotopically labeled compounds, in which a radioactive isotope such as C is incorporated, are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 The C isotope is particularly preferred because it is easy to prepare and detect. In addition, deuterium, i.e. 2Substitution with heavy isotopes, such as H, offers certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically-labeled compounds, or pharma- ceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, are prepared by any suitable method.

[0135] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0136] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts.In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0137] 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, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0138] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of a mineral, organic acid, or inorganic base with the compounds described herein, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, or the like. acid salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Examples of suitable salts include metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0139] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids including, but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) These include benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0140] In some embodiments, the compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxide, carbonate, bicarbonate, or sulfate, of a pharma- ceutically acceptable metal cation, with ammonia, or with a pharma-ceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts of tetrazoles.

[0141] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is noted that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0142] solvate In some embodiments, the compounds described herein exist as solvates.The present disclosure provides a method for treating disease by administering such solvates.The present disclosure further provides a method for treating disease by administering such solvates as pharmaceutical compositions.

[0143] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. The solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0144] Tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom, accompanied by switching of a single bond and an adjacent double bond. In bond structures where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. In some embodiments, the tetrazoles disclosed herein can be in their tautomeric form.

[0145] [ka] It exists as either:

[0146] Preparation of compounds The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in the art, beginning with commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" refers to Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI; includes Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0147] Suitable references and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or referencing articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. 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. Additional suitable references and articles detailing the synthesis of reactants useful in the preparation of the compounds described herein or referring to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure” 4th Edition(1992)John Wiley & Sons,ISBN:0-471-60180-2; Otera, J.(editor)“Modern Carbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1; Patai,S. “Patai's 1992 Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9; Solomons,TWG“Organic Chemistry” 7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0; Stowell,JC,“Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; 8 volumes of "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; 55 volumes of "Organic Reactions" (1942-2000) John Wiley & Sons, and 73 volumes of "Chemistry of Functional Groups" John Wiley & Sons.

[0148] Specific and similar reactants are optionally identified through indexes of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available at most public and university libraries and through online databases. Chemical products that are known but not sold in catalogs are optionally prepared by custom chemical synthesis houses, and many of the standard drug supply companies (e.g., those listed above) offer custom synthesis services. For the preparation and selection of pharmaceutical salts of the compounds described herein, see PH Stahl & CG Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0149] Pharmaceutical Compositions In certain embodiments, the compounds as described herein are administered as pure chemicals. In some embodiments, the compounds as described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as pharma- ceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), which is selected based on the selected route of administration and standard pharmaceutical practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0150] Accordingly, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0151] In certain embodiments, the compounds provided herein are substantially pure, in that they contain less than about 5%, or less than about 1%, or less than about 0.1%, of other small organic molecules, e.g., unreacted intermediates or synthetic by-products produced in one or more steps of a synthetic method.

[0152] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's disease, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition in an amount sufficient to provide a therapeutic and / or preventive benefit (e.g., improved clinical outcome), such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduced severity of symptoms. Optimal doses are generally determined using experimental models and / or clinical trials. Optimal doses vary depending on the patient's body type, weight, or blood volume.

[0153] In some embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, pulmonary, intradermal, intrathecal, and epidural, and intranasal administration. Parenteral applications include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated as a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, suspension, gel, colloid, dispersion, solution, emulsion, ointment, lotion, eye drop, or nasal drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0154] The appropriate dose and administration regimen is determined by conventional distance measuring techniques known to those skilled in the art. Generally, treatment is initiated with a small dosage that is less than the optimal dose of the compounds described herein. The dosage is then increased by small increments until the optimal effect under such circumstances is achieved. In some embodiments, the method includes administration of about 0.1 μg to about 50 mg of at least one compound described herein per kg of subject body weight. For a 70 kg patient, a dosage of about 10 μg to about 200 mg of the compounds disclosed herein will generally be used, depending on the physiological response of the subject.

[0155] By way of example only, doses of the compounds described herein for the methods of treating the diseases described herein are from about 0.001 to about 1 mg per kg of subject body weight per day, e.g., about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg per kg of body weight per day. In some embodiments, the dose of a compound described herein for the above methods is about 1 to about 1000 mg per kg of body weight of the subject being treated per day, e.g., about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0156] Treatment Disclosed herein is a method for treating cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof. Disclosed herein is a method for treating RNR-associated cancer in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof.

[0157] In some embodiments, RNR-associated cancers include malignant tumors whose incidence can be reduced or whose symptoms can be ameliorated, alleviated, and / or completely cured by deleting, suppressing, and / or inhibiting the function of RNR. Malignant tumors of interest include, but are not limited to, head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer, cervical cancer, endometrial cancer, etc.), urinary cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumor (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumor, skin cancer, brain tumor, etc.

[0158] In some embodiments, the term cancer is used according to its ordinary and plain meaning in light of this disclosure to refer to all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that may be treated with the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, tautomers, or stereoisomers, pharmaceutical compositions include lymphomas (e.g., mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, Burkitt's lymphoma), sarcomas, bladder cancer, bone cancer, brain tumors, 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 carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia (e.g., lymphoblastic leukemia, chronic lymphocytic leukemia, hairy cell leukemia), acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.Further examples include tumors of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, pancreatic endocrine or exocrine neoplasms, medullary thyroid cancer, medullary thyroid cancer, carcinoma), melanoma, colon cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the papilla, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell cancer, hepatic stellate cell cancer, or prostate cancer. In embodiments, the cancer is selected from ovarian cancer, prostate cancer, esophageal cancer, salivary gland cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, lung cancer, bladder cancer, colon cancer, and uterine cancer. In embodiments, the cancer is selected from muscle cancer, brain cancer, lymph node cancer, thyroid cancer, kidney cancer, and adrenal cancer.

[0159] ecDNA mediates an important and clinically distinct mechanism of resistance to targeted therapies. There is an immediate therapeutic opportunity for the utility of one or more RNR inhibitors described herein, either as single agents or in combination with other therapies. In some embodiments, one or more RNR inhibitors described herein can be used to treat ecDNA+ cancers, ecDNA+ tumors, or ecDNA+ tumor cells. One or more RNR inhibitors described herein can be used to treat tumors with one or more amplified cancer genes (e.g., FGFR, EGFR, MET, KRAS, MDM2 amplified), etc., and in some cases, the one or more amplified cancer genes include non-mutated cancer genes, and in some cases, the amplified cancer genes include mutated cancer genes. In some cases, the tumor includes one or more amplified cancer genes present on ecDNA, and one or more RNR inhibitors described herein are used to treat the tumor in combination with (an inhibitor of) a therapeutic agent that targets one or more amplified cancer genes on ecDNA. One or more RNR inhibitors described herein can be used to treat tumors for which there are no approved targeted therapies or few highly effective therapies. One or more RNR inhibitors described herein can be used to treat tumors that have developed resistance to another therapy, such as resistance to a targeted agent. In some cases, tumors (or tumor cells) treated with one or more targeted agents develop resistance to targeted agents, such as targeted agents that target cancer genes or that directly inhibit activating mutant forms of certain cancer proteins (e.g., KRAS, BRAF, EGFR), or as a result of local amplification, such as ecDNA-based amplification, of the target gene itself, and one or more RNR inhibitors described herein can be used to treat such tumors or tumor cells, either alone or in combination with additional therapeutic agents.

[0160] Provided herein is a method 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 occurs with one or more RNR inhibitors described herein in combination with a cancer targeting agent. In some cases, a tumor background is identified as being highly sensitive to an RNR inhibitor, allowing a sufficient therapeutic index to allow an effective resistant dose. In some embodiments, synthetic lethality occurs with one or more RNR inhibitors described herein in combination with a cancer targeting agent, where the tumor or tumor cells are ecDNA+. In some cases, RNR inhibition results in a reduction in ecDNA copy number. In some cases, RNR inhibition results in enhanced cytotoxicity in ecDNA+ cells. In some cases, enhanced cytotoxicity results from a combination of RNR inhibition and inhibition of a cancer target, such as a cancer gene, e.g., a cancer gene amplified on ecDNA.

[0161] In some embodiments of the method herein, the tumor or tumor cell treated is ecDNA+. In some cases, such tumor or tumor cell is determined to have ecDNA signature. In some cases, if the tumor or tumor cell has one or more features associated with ecDNA+ tumor or tumor cell, the tumor or tumor cell is determined to have ecDNA signature. For example, in some cases, the ecDNA signature is selected from the group consisting of gene amplification, p53 loss-of-function mutation, lack of microsatellite instability (MSI-H), low level of PD-L1 expression, low level of tumor inflammation signature (TIS), low level of tumor mutation burden (TMB), increased frequency of allelic substitution, insertion, or deletion (indel), and any combination thereof.

[0162] Combination therapy In certain instances, the compounds described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, are administered in combination with a second therapeutic agent or cancer targeting agent.

[0163] In some embodiments of the method herein, the method further comprises administering a cancer targeting agent that targets the activity of the protein product of the target gene.In some cases, the treatment with the cancer targeting agent and the RNR inhibitor disclosed herein reduces the amplification or expression of the target gene in tumor or tumor cell.In some cases, the cancer targeting agent is administered before the RNR inhibitor.In some cases, the cancer targeting agent is administered simultaneously with the RNR inhibitor.

[0164] In some embodiments of the method herein, tumor or tumor cell has ecDNA signature.In some cases, tumor or tumor cell expresses ecDNA signature after administration of cancer targeting therapeutic agent.In some cases, tumor or tumor cell expresses ecDNA signature before treatment.In some cases, the method prevents the increase of ecDNA in tumor or tumor cell.

[0165] In some embodiments, the second therapeutic agent comprises antimetabolites, platinum drugs, plant alkaloid drugs, and molecular targeted drugs.

[0166] In some embodiments, antimetabolites include 5-fluorouracil, 5-fluoro-2'-deoxyuridine, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil, pemetrexed, trifluridine, trifluridine-tipiracil hydrochloride, fludarabine (or the active metabolite fludarabine nucleoside), cytarabine, gemcitabine, capecitabine, nelarabine, clofarabine, and DNA methylation inhibitors such as decitabine, guadecitabine, azacitidine.

[0167] In some embodiments, the platinum agents include cisplatin, oxaliplatin, carboplatin, and nedaplatin.

[0168] In some embodiments, plant alkaloid drugs include microtubule inhibitors such as paclitaxel, docetaxel, vinblastine, vincristine, vindesine, vinorelbine, and eribulin, and topoisomerase inhibitors such as irinotecan (or the active metabolite SN-38), topotecan, and etoposide.

[0169] In some embodiments, the molecular targeting drug comprises ATR (ataxia telangiectasia and Rad3-related protein) inhibitor, Chk1 (checkpoint kinase 1) inhibitor, HSP (heat shock protein) 90 inhibitor, PARP (poly ADP-ribose polymerase) inhibitor, EGFR (epidermal growth factor receptor) inhibitor, Her2 inhibitor, VEGFR (vascular endothelial growth factor receptor) inhibitor, PDGFR (platelet-derived growth factor receptor) inhibitor, MET inhibitor, AXL inhibitor, RET inhibitor, FLT3 (fms-related tyrosine kinase 3) inhibitor, KIT inhibitor, CSF1R (colony-stimulating factor 1 receptor) inhibitor, TIE2 (intimal endothelial cell kinase 2) inhibitor, TRKB inhibitor, and CDK4 / 6 inhibitor. In some embodiments, the ATR inhibitor comprises AZD6738, berzosertib, BAY1895344, and VX-803. In some embodiments, Chk1 inhibitors include prexasertib, SCH900776, GDC-0575, and CCT245737. In some embodiments, HSP90 inhibitors include luminespib, ganetespib, and onalespib. In some embodiments, PARP inhibitors include olaparib, rucaparib, niraparib, veliparib, and talazoparib. In some embodiments, EGFR inhibitors include small molecule inhibitors such as lapatinib, gefitinib, erlotinib, afatinib, and vandetanib, and anti-EGFR antibodies such as cetuximab and panitumumab. In some embodiments, the Her2 inhibitors include small molecule inhibitors such as lapatinib, and anti-Her2 antibodies such as trastuzumab, pertuzumab, and trastuzumab emtansine. In some embodiments, the VEGFR inhibitors are inhibitors of at least one of VEGFR1, VEGFR2, and VEGFR3, and include 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 inhibitors include sunitinib, BLZ-945, and ARRY-382. In some embodiments, the TIE2 inhibitors include cabozantinib. In some embodiments, the TRKB inhibitors include cabozantinib and entrectinib. In some embodiments, the CDK4 / 6 inhibitors include palbociclib, ribociclib, and abemaciclib.

[0170] In some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein in conjunction with a second therapeutic agent (including a therapeutic regimen) that also has a therapeutic effect.

[0171] In a specific embodiment, a compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, is co-administered with a second therapeutic agent, where the compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0172] In all cases, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient will be simply the addition of the two therapeutic agents or the patient will experience a synergistic benefit.

[0173] In certain embodiments, various therapeutically effective dosages of the compounds disclosed herein are utilized in the formulation of pharmaceutical compositions and / or treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. The therapeutically effective dosages of drugs and other agents used in combination therapy regimens are optionally determined by means similar to those specified above for the active ingredients themselves. In addition, the prevention / treatment methods described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination therapy regimens include treatment regimens in which administration of the compounds described herein, or pharma- ceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, is initiated before, during, or after treatment with a second agent described herein, and continues until any time during or after the end of treatment with the second agent. It further includes treatments in which the compound described herein, or a pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and the second agent used in combination are administered simultaneously or at different times, and / or at decreasing or increasing intervals during the treatment period. Combination therapy also includes periodic treatments that are started and stopped at different times to aid in the clinical management of the patient.

[0174] It will be understood that the dosage regimen to treat, prevent, or ameliorate the condition for which relief is sought will be modified to suit a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers, the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0175] With respect to the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In further embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously or sequentially with the second therapeutic agent.

[0176] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms (e.g., as a single pill, or as two separate pills), by way of example only.

[0177] The compounds described herein, or pharma- ceutically acceptable salts, solvates, tautomers, or stereoisomers thereof, as well as combination therapies, are administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactics and are administered continuously to subjects prone to a disease or condition to prevent the onset of a disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the period of time required to treat the condition. In some embodiments, the period of time required for treatment varies, and the treatment period is tailored to the particular needs of each subject. For example, in certain embodiments, the compounds described herein or formulations containing the compounds are administered for at least 2 weeks, about 1 month to about 5 years.

[0178] In some embodiments, the compound disclosed herein, or its pharma- ceutically acceptable salt, solvate, tautomer, or stereoisomer, is administered in combination with an adjuvant.In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant has minimal therapeutic benefit by itself, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). EXAMPLES

[0179] Synthesis of common intermediate I: 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenylpropyl)-1,3,4-oxadiazol-2(3H)-one

[0180] [ka]

[0181] Step 1. Synthesis of 6-fluoro-2,3-dimethylbenzaldehyde A 1 L round bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 2-bromo-6-fluoro-3-methylbenzaldehyde (50 g, 230 mmol, 1.0 equiv), methylboronic acid (23.4 g, 392 mmol, 1.7 equiv), 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). The resulting solution was stirred at 110 °C for 2 h. The reaction was quenched by the addition of 200 mL of brine. The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers were combined. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). This gave 6-fluoro-2,3-dimethylbenzaldehyde (30 g, 85%).

[0182] Step 2. 1-(6-fluoro-2,3-dimethylphenyl)ethan-1-ol In a 1 L 3-neck round bottom flask, to a mixture of 6-fluoro-2,3-dimethylbenzaldehyde (27 g, 177.4 mmol, 1 equiv.) in THF was added bromo(methyl)magnesium (42.3 g, 355 mmol, 2 equiv.) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl(aq.) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(6-fluoro-2,3-dimethylphenyl)ethanol (27 g, 90.5%).

[0183] Step 3. 2-(1-Bromoethyl)-1-fluoro-3,4-dimethylbenzene In a 500 mL 3-neck round bottom flask, 1-(6-fluoro-2,3-dimethylphenyl)ethanol (25 g, 148.6 mmol, 1.0 equiv) and CHCl3 (250 mL) were added at room temperature. To the above mixture, PBr3 (63.5 mL, 668.8 mmol, 4.5 equiv) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 30 min. The reaction was quenched by the addition of NaHCO3(aq) (100 mL) at 0° C. The resulting mixture was extracted with CHCl2 (3×50 mL). The combined organic layers were washed with brine (1×30 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (29 g, 84.4%).

[0184] Step 4: (2S)-2-Amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid In a 500 mL 3-neck round bottom flask, to a mixture of Ni-(S)-BPB-Gly (5.39 g, 10.8 mmol, 0.5 equiv.) in DMF (42.4 mL) was added 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (5 g, 21.6 mmol, 1.0 equiv.) dropwise at room temperature under nitrogen atmosphere. To the resulting mixture was added KOH (6.07 g, 108.2 mmol, 5.0 equiv.) portionwise at −15° C. under nitrogen atmosphere and stirred at −15° C. for 1 h under nitrogen atmosphere. The reaction was quenched by adding saturated NH4Cl(aq) (100 mL) at room temperature and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. To the mixture was added MeOH (42 mL) and HCl (50 mL) at room temperature. The resulting mixture was stirred at 80° C. for 1 h and then purified by reverse phase flash to give (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (3.05 g, 63%).

[0185] Step 5. (2S)-2-((tert-butoxycarbonyl)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid In a 250 mL round bottom flask, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (5 g, 22.2 mmol, 1.0 equiv), EtN (6.74 g, 66.6 mmol, 3.0 equiv), HO (25 mL), and dioxane (25 mL) were added at room temperature. To the resulting mixture, di-tert-butyl dicarbonate (7.27 g, 33.3 mmol, 1.5 equiv) was added in portions at 0° C. The resulting mixture was stirred at room temperature for 2 h. The crude product was purified by reverse phase flash chromatography to give (2S)-2-[(tert-butoxycarbonyl)amino]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (3.5 g, 48.5%).

[0186] Step 6: Synthesis of 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one, HCl In a 250 mL round bottom flask, (2S)-2-[(tert-butoxycarbonyl)amino]-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (9 g, 27.7 mmol, 1.0 equiv), CDI (11.2 g, 69.2 mmol, 2.5 equiv), and THF (60 mL) were added at room temperature, and the resulting mixture was stirred at room temperature for 30 min. To the mixture, hydrazine (4.15 mL, 82.901 mmol, 3.0 equiv) was added dropwise at 0° C. The resulting mixture was stirred at 0° C. for 30 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. To the crude mixture was added dioxane (60 mL) and CDI (11.2 g, 69.2 mmol, 2.5 equiv.) 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. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]carbamate (3 g, 29.7%).

[0187] The product was dissolved in 2 ml of THF and treated with 2 ml of 4N HCl in THF. The reaction was left at room temperature overnight and concentrated in vacuo to give 5-((1S)-1-amino-2-(6-fluoro-2,3-dimethylphenylpropyl)-1,3,4-oxadiazol-2(3H)-one, HCl (2.4 g, 100% yield).

[0188] Common intermediate II: Synthesis of methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0189] [ka]

[0190] To a 500 mL 3-neck round bottom flask was added (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (12.8 g, 56.8 mmol, 1.00 equiv), trimethylsilyldiazomethane (56.8 mL, 113.6 mmol, 2.0 equiv), MeOH (130 mL), and THF (380 mL) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was concentrated to give methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (9.9 g, 72.8%).

[0191] Common intermediate III: Synthesis of tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0192] [ka]

[0193] To a 250 mL round bottom flask, (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (15 g, 67 mmol, 1 equiv.) and tert-butyl acetate (160 mL) were added at room temperature. To the above mixture, HClO4 (21 mL, 366 mmol, 5.50 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional hour. The reaction was quenched by the addition of HCl (1M) (240 mL) at room temperature. The mixture was basified to pH 9 with Na2CO3 (solid) (300 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (1×300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (12 g, 68.6%).

[0194] Examples 1 and 2: 5-((1S,2R)-1-(5-chloro-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2S)-1-(5-chloro-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0195] Step 1. Methyl 2-(benzylsulfanyl)-5-chlorobenzoate

[0196] [ka]

[0197] To a 100 mL round bottom flask was added methyl 2-bromo-5-chlorobenzoate (1 g, 4.01 mmol, 1.00 equiv) in dioxane (10 mL) at room temperature. To the above mixture was added Pd2(dba)3 (367.0 mg, 0.40 mmol, 0.1 equiv), Xantphos (463 mg, 0.80 mmol, 0.2 equiv), DIEA (1.99 mL, 12.0 mmol, 3 equiv), and benzyl mercaptan (564.6 uL, 4.81 mmol, 1.2 equiv). The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(benzylsulfanyl)-5-chlorobenzoate (1.08 g, 92.03%).

[0198] Step 2. Methyl 5-chloro-2-(chlorosulfonyl)benzoate

[0199] [ka]

[0200] To a 50 mL 3-neck round bottom flask was added methyl 2-(benzylsulfanyl)-5-chlorobenzoate (500 mg, 1.708 mmol, 1.00 equiv), CH3CN (0.3 mL). This was followed by dropwise addition of HO (0.3 mL), AcOH (5 mL, 87.258 mmol, 51.09 equiv), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (672.93 mg, 3.416 mmol, 2 equiv) at 0°C. The resulting mixture was stirred at 0°C for 30 min under nitrogen atmosphere. The reaction was quenched with water. 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. This gave methyl 5-chloro-2-(chlorosulfonyl)benzoate (400 mg, 87%).

[0201] Step 3. Methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate

[0202] [ka]

[0203] To a 50 mL round bottom flask was added 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (168.21 mg, 0.557 mmol, 1 equiv) in Py (3 mL). To the mixture was added methyl 5-chloro-2-(chlorosulfonyl)benzoate (150 mg, 0.557 mmol, 1.00 equiv) in DCM dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water. The resulting mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (150 mg, 54%).

[0204] Step 4. 5-Chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid

[0205] [ka]

[0206] To an 8 mL vial was added 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (50 mg, 0.100 mmol, 1 equiv.), THF (3 mL), and LiOH.HO (16.85 mg, 0.400 mmol, 4 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 7 with HCl (aq.). The resulting mixture was concentrated under vacuum. This gave 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoic acid (40 mg, 82%).

[0207] Step 5. 5-((1S,2R)-1-(5-chloro-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0208] [ka]

[0209] To a 20 mL vial was added 5-((1S,2R)-1-(5-chloro-1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (300 mg, 0.620 mmol, 1.00 equiv), DCM (6 mL), EDCI (118.85 mg, 0.620 mmol, 1 equiv), and DMAP (227.22 mg, 1.860 mmol, 3 equiv). The resulting mixture was stirred at 45° C. for 2 h. The residue was purified by reverse phase flash chromatography. The crude product was purified by chiral preparative HPLC.

[0210] First isomer: (20.4 mg, 7%). LC-MS: (ES, m / z): [M+H]: 466.00. 1 H NMR(300MHz,DMSO-d6)δ12.48-12.35(m,1H),8.46(d,J=8.3Hz,1H),8.33-8.14(m,2H),7.11(dd,J=8.4,5.9Hz,1H),6.94(dd ,J=12.2,8.4Hz,1H),5.79(d,J=11.6Hz,1H),4.48(dd,J=12.0,7.0Hz,1H),2.32(s,3H),2.23(s,3H),1.31(d,J=6.9Hz,3H).

[0211] Second isomer: (7.9 mg, 2.7%). LC-MS (ES, m / z): [M+H]: 466.00. 1 H NMR(300MHz,DMSO-d6)δ12.62(s,1H),8.28(d,J=8.3Hz,1H),8.18-8.05(m,2H),7.00(dd,J=8.4,5.8Hz,1H),6. 83(dd,J=12.0,8.3Hz,1H),5.72(d,J=11.4Hz,1H),4.49(s,1H),2.18(d,J=26.8Hz,6H),1.43(d,J=6.9Hz,3H).

[0212] Examples 3 and 4: 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2S)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0213] Step 1. Methyl 2-amino-5-chloro-3-methoxybenzoate

[0214] [ka]

[0215] To a 100 mL round bottom flask was added methyl 2-amino-3-methoxybenzoate (2 g, 11.038 mmol, 1.00 equiv) and N-chlorosuccinimide (1.62 g, 12.142 mmol, 1.1 equiv) in DMF (20 mL) at room temperature. The resulting mixture was stirred at 50° C. for 2 h. The resulting mixture was extracted with EtOAc (3×15 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. The residue was purified by silica gel column chromatography to give methyl 2-amino-5-chloro-3-methoxybenzoate (2 g, 84%).

[0216] Step 2. Methyl 2-bromo-5-chloro-3-methoxybenzoate

[0217] [ka]

[0218] To a 100 mL round bottom flask, methyl 2-amino-5-chloro-3-methoxybenzoate (1 g, 4.638 mmol, 1.00 equiv), CuBr2 (2.07 g, 9.276 mmol, 2.0 equiv), and CH3CN (10.00 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 20 min. Then, tert-butyl nitrite (0.86 g, 8.348 mmol, 1.8 equiv) was added. The resulting mixture was stirred at 60 °C overnight. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography to give methyl 2-bromo-5-chloro-3-methoxybenzoate (0.8 g, 61.72%).

[0219] Step 3. Methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate

[0220] [ka]

[0221] A 100 mL round bottom flask was charged with methyl 2-bromo-5-chloro-3-methoxybenzoate (1.6 g, 5.724 mmol, 1.00 equiv), benzyl mercaptan (0.85 g, 6.869 mmol, 1.2 equiv), DIEA (2.22 g, 17.172 mmol, 3.0 equiv), Xantphos (0.66 g, 1.145 mmol, 0.2 equiv), Pd2(dba)3 (0.52 g, 0.572 mmol, 0.1 equiv), and dioxane (15 mL). The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was 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 to obtain methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate (1.2 g, 64%).

[0222] Step 4. Methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate

[0223] [ka]

[0224] In a 250 mL round bottom flask, to a mixture of methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate (1.3 g, 4.027 mmol, 1.00 equiv) in MeCN, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.59 g, 8.054 mmol, 2.0 equiv), AcOH (0.90 mL, 15.705 mmol, 3.90 equiv), and H2O (0.70 mL, 38.861 mmol, 9.65 equiv) were added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate (1 g, 83.01%).

[0225] Step 5. Methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate

[0226] [ka]

[0227] To a mixture of 5-[(1S,2R)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (200 mg, 0.664 mmol, 1.00 equiv) in C5H5N (5 mL) in a 100 mL round bottom flask, methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate (397.50 mg, 1.328 mmol, 2.0 equiv) was added dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EtOAc (3×10 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. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate (100 mg, 28%).

[0228] Step 6. 5-Chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoic acid

[0229] [ka]

[0230] To an 8 mL round bottom flask was added 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate (100 mg, 0.189 mmol, 1.00 equiv.) in THF (3 mL), water (1 mL), and LiOH.HO (15.90 mg, 0.378 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 60° C. for 2 h. The mixture was acidified to pH 5. The residue was purified by reverse phase flash chromatography to give 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoic acid (70 mg, 71.91%).

[0231] Step 7. 5-((1S,2S)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0232] [ka]

[0233] In a 20 mL round bottom flask, 5-chloro-2-{[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl}-3-methoxybenzoic acid (120 mg, 0.233 mmol, 1.00 equiv), EDCI (89.52 mg, 0.466 mmol, 2.0 equiv), DMAP (2.85 mg, 0.023 mmol, 0.1 equiv), and DCM (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with CHCl (3x10 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. The crude product was purified by chiral preparative HPLC to give:

[0234] First isomer (9.4 mg, 8%). LC-MS-(ES, m / z): [M+H]: 496.10. 1 H NMR (300MHz, methanol-d4) δ7.79-7.67(m,2H),7.15-7.04(m,1H),6.83(dd,J=12.1,8.4Hz,1H),6.01-5 .89(m,1H),4.61(dd,J=12.1,6.9Hz,1H),4.12(s,3H),2.34(d,J=36.4Hz,6H),1.38(d,J=7.0Hz,3H).

[0235] Second isomer: (1.1 mg, 5.7%). LC-MS: (ES, m / z): [M+H]: 496.10. 1 H NMR (300MHz, methanol-d4) δ7.73(d,J=4.7Hz,2H),7.13-7.02(m,1H),6.83(dd,J=12.0,8.5Hz,1H),5 .95(d,J=11.7Hz,1H),4.61(s,1H),4.12(s,3H),2.40(s,3H),2.28(s,3H),1.37(d,J=6.9Hz,3H).

[0236] Examples 5 and 6: 5-((1S,2S)-1-(5-chloro-7-methoxy-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(H)-one

[0237] Step 1. 4-Chloro-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-2-(hydroxymethyl)-6-methoxybenzenesulfonamide

[0238] [ka]

[0239] To a 50 mL round bottom flask was added 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate (200 mg, 0.379 mmol, 1.00 equiv), THF (3 mL), and 2 M LiBH4 in THF (284.12 uL, 0.569 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The residue was purified by reverse phase flash chromatography. This gave 4-chloro-(N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(hydroxymethyl)-6-methoxybenzenesulfonamide (50 mg, 26.40%).

[0240] Step 2. 5-Chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzyl methanesulfonate

[0241] [ka]

[0242] To an 8 mL vial was added 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(hydroxymethyl)-6-methoxybenzenesulfonamide (100 mg, 0.200 mmol, 1.00 equiv), DCM (3 mL), and TEA (83.41 uL, 0.600 mmol, 3 equiv). This was followed by the dropwise addition of MsCl (600.07 uL, 0.600 mmol, 3 equiv) at 0° C. The resulting mixture was stirred at room temperature overnight. The residue was purified by preparative TLC to give 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzyl methanesulfonate (50 mg, 43.25%).

[0243] Step 3. 5-((1S,2S)-1-(5-chloro-7-methoxy-1,1-dioxidebenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxidebenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0244] [ka]

[0245] To a 25 mL round bottom flask was added 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzyl methanesulfonate (50 mg, 0.087 mmol, 1.00 equiv) and DMF (2 mL). This was followed by dropwise addition of NaH (11 mg, 0.46 mmol, 5.30 equiv) at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched with water. 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. The residue was purified by preparative TLC. The crude product was purified by chiral preparative HPLC. This gave:

[0246] First isomer: (2.7 mg, 6.5%). LC-MS: (ES, m / z): [MH]: 480.05. 1 H NMR (300MHz, methanol-d4) δ7.15-6.94(m,3H),6.81(dd,J=12.0,8.4Hz,1H),5.37(d,J=11.4Hz,1H),4.70(d,J=14.7H) z,1H),4.13(d,J=14.6Hz,1H),3.92(d,J=9.3Hz,4H),3.79(s,1H),2.40(s,3H),2.26(s,3H),1.35(d,J=6.9Hz,3H).

[0247] Second isomer: (9.1 mg, 21.8%). LC-MS: (ES, m / z): [M+H]: 482.10. 1 H NMR (300MHz, methanol-d4) δ7.24(d,J=3.9Hz,2H),7.06(dd,J=8.4,5.8Hz,1H),6.83(dd,J=12.1,8.4Hz,1H),5. 29(d,J=11.6Hz,1H),4.83-4.69(m,2H),4.03(s,4H),2.34(s,3H),2.25(s,3H),1.44(dd,J=7.0,1.2Hz,3H).

[0248] Examples 7 and 8: Synthesis of 5-((1S,2S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0249] Step 1. Methyl 2-[(diphenylmethylidene)amino]acetate

[0250] [ka]

[0251] To a stirred mixture of methyl 2-aminoacetate hydrochloride (12.6 g, 100.358 mmol, 1 equiv.) in toluene was added benzophenone (36.58 g, 200.716 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 120° C. for 30 min. DIPEA (25.94 g, 200.716 mmol, 2 equiv.) was added dropwise to the above mixture at 120° C. over 3 h. The resulting mixture was further stirred at 120° C. for 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-[(diphenylmethylidene)amino]acetate (8 g, 31.47%).

[0252] Step 2. Methyl 2-((diphenylmethylene)amino)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0253] [ka]

[0254] To a stirred mixture of methyl 2-[(diphenylmethylidene)amino]acetate (8 g, 31.583 mmol, 1 equiv) in DMSO was added KOH (5.32 g, 94.821 mmol, 3.00 equiv) in portions at 25° C. The resulting mixture was stirred at 25° C. for 5 min. To the above mixture was added 2-(1-bromoethyl)-1-fluoro-3,4-dimethylbenzene (7.30 g, 31.587 mmol, 1.00 equiv) dropwise at 25° C. The resulting mixture was stirred at room temperature for another 2 h. The mixture was acidified to pH 7 with HCl (2 M). The resulting mixture was extracted with EtOAc (3×100 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 crude product was used directly in the next step without further purification.

[0255] Step 3. Methyl 2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate, formic acid

[0256] [ka]

[0257] To a stirred mixture of methyl 2-[(diphenylmethylidene)amino]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (8 g, 19.827 mmol, 1 equiv.) in THF was added hydrogen chloride (5 mL, 137.137 mmol, 6.92 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature for 10 min. The mixture was basified to pH 7 with NaOH (1N). The resulting mixture was extracted with EtOAc (3x25 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave formic acid, methyl 2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.5 g, 44.19%).

[0258] Step 4. tert-Butyl 2-(2-bromo-5-chlorophenyl)acetate

[0259] [ka]

[0260] To a 250 mL round bottom flask, (2-bromo-5-chlorophenyl)acetic acid (5 g, 20.041 mmol, 1.00 equiv) and t-BuOH (50 mL) were added at room temperature. To the mixture was added (Boc)2O (25 g, 114.6 mmol, 5.72 equiv). The resulting mixture was stirred at 90 °C overnight. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 2-(2-bromo-5-chlorophenyl)acetate (5 g, 81.64%).

[0261] Step 5. tert-Butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate

[0262] [ka]

[0263] To a 40 mL vial was added tert-butyl 2-(2-bromo-5-chlorophenyl)acetate (2 g, 6.545 mmol, 1.00 equiv) and dioxane (6 mL, 82.636 mmol), DIEA (2.54 g, 19.635 mmol, 3 equiv), benzyl mercaptan (0.98 g, 7.854 mmol, 1.2 equiv), Xantphos (378.68 mg, 0.655 mmol, 0.1 equiv), Pd2(dba)3 (299.65 mg, 0.327 mmol, 0.05 equiv). The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (1.5 g, 65.7%).

[0264] Step 6. tert-Butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate

[0265] [ka]

[0266] In a 50 mL round bottom flask was added tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (5.5 g, 15.850 mmol, 1.00 equiv), MECN (30 mL, 76.099 mmol), CH3COOH (3.6 mL, 21.093 mmol), and H2O (1.8 mL, 21.093 mmol). To the above mixture was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.25 g, 31.700 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at °C for an additional 30 min. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (3.65 g, 70.8%).

[0267] Step 7. Methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)-4-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0268] [ka]

[0269] To a stirred mixture of methyl 2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2 g, 8.358 mmol, 1 equiv.) in pyridine was added tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (3.67 g, 11.283 mmol, 1.35 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 60 min. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography. This gave methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)-4-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (4.2 g, 95.1%).

[0270] Step 8. 2-(5-chloro-2-(N-(3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid

[0271] [ka]

[0272] To a stirred mixture of methyl 2-((2-(2-(tert-butoxy)-2-oxoethyl)-4-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (4.3 g, 8.143 mmol, 1 eq.), 4N HCl in 1,4-dioxane (40 mL, 819.919 mmol, 100.69 eq.) is added at room temperature. The resulting mixture was stirred at 45° C. for 1 h under air atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 2-(5-chloro-2-(N-(3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid (2.4 g, 62.5%).

[0273] Step 9. 2-[4-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0274] [ka]

[0275] To a stirred mixture of BH3.THF (2.92 mL, 2.924 mmol, 1.2 equiv.) was added 2-(5-chloro-2-(N-(3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid (1.15 g, 2.437 mmol, 1 equiv.) in THF (10 ml) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 min. The reaction was quenched by the addition of MeOH (0.5 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave methyl 2-[4-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (770 mg, 63.5%).

[0276] Step 10: Methyl 2-((4-chloro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0277] [ka]

[0278] To a 100 mL round bottom flask was added methyl 2-[4-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (770 mg, 1.681 mmol, 1 equiv.) and DCM (4 mL). To the above mixture was added 2M MsCl in DCM (1.68 mL, 3.844 mmol, 2 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional hour. The reaction was quenched with water. The resulting mixture was extracted with CHCl (3×15 mL). The combined organic layers were washed with brine (1×25 mL) and dried over anhydrous NaSO. The residue was purified by silica gel column chromatography to give methyl 2-((4-chloro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (745 mg, 82.66%).

[0279] Step 11: Methyl 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0280] [ka]

[0281] To a 100 mL 3-neck round bottom flask was added methyl 2-((4-chloro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (740 mg, 1.381 mmol, 1 equiv.) and tetrahydrofuran (7.73 mL, 107.202 mmol, 77.65 equiv.). To the above mixture was added sodium hydride (83 mg, 3.459 mmol, 2.51 equiv.) at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was quenched with water. The residue was purified by reverse phase flash chromatography. This gave methyl 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (600 mg, 98.79%).

[0282] Step 12: 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0283] [ka]

[0284] To a stirred mixture of methyl 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (600 mg, 1.364 mmol, 1 equiv.) and MeOH (5 mL, 123.495 mmol, 90.55 equiv.) in water was added lithium hydroxide (181.22 mg, 4.320 mmol, 5 equiv.) in portions at room temperature. The resulting mixture was stirred at 60° C. for 4 h. The mixture was cooled to room temperature. The mixture was acidified to pH 6 with HCl (2 M). The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (404 mg, 69.6%).

[0285] Step 13. tert-Butyl 2-(2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0286] [ka]

[0287] To a stirred mixture of 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (460 mg, 1.080 mmol, 1 equiv.) and HATU (616.01 mg, 1.620 mmol, 1.5 equiv.) in DCM, tert-butoxycarbohydrazide (214.12 mg, 1.620 mmol, 1.5 equiv.) was added portionwise at room temperature. To the above mixture, DIEA (564.38 μL, 3.240 mmol, 3 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 20 min. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave tert-butyl 2-(2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (583 mg, 99.9%).

[0288] Step 14. 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide

[0289] [ka]

[0290] In a 100 mL round bottom flask, tert-butyl 2-(2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (550 mg, 1.018 mmol, 1 equiv.) and 2,6-lutidine (2372.33 μL, 20.360 mmol, 20 equiv.) were added. To the above mixture, TMSOTf (3621.65 mg, 16.288 mmol, 16 equiv.) was added at 0° C. The resulting mixture was stirred at room temperature for an additional hour. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (430 mg, 95.97%).

[0291] Step 15. 5-(1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0292] [ka]

[0293] To a 20 mL vial was added 2-(6-chloro-1,1-dioxido-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (430 mg, 0.341 mmol, 1 equiv.), DIEA (392.96 μL, 2.255 mmol, 2.5 equiv.), and ditrichloromethyl carbonate (133.90 mg, 0.451 mmol, 0.5 equiv.) in THF. The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 5-(1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (375 mg, 89.19%).

[0294] Step 16. 5-((1S,2S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0295] [ka]

[0296] The crude product was purified by chiral preparative HPLC, which afforded two major products.

[0297] First isomer: (21.6 mg, 4.29%). LC-MS: (ES, m / z): [MH]: 464.00. H-NMR (CD3OD, ppm): 1H NMR (300MHz, methanol-d4) δ7.72(d,J=8.4Hz,1H),7.44-7.36(m,2H),7.02-6.97(dd,J=8.4,5.8Hz,1H),6.77-6.70(dd,J=12.1,8.4Hz,1H) ,5.53-5.48(dd,J=11.7,1.5Hz,1H),4.09-3.80(m,3H),3.21-2.94(m,2H),2.30(s,3H),2.20(s,3H),1.43-1.40(dd,J=6.9,1.2Hz,3H).

[0298] Second isomer: (28.7 mg, 17.94%). LC-MS m / z: 464 (M-1). 1 H NMR (300MHz, methanol-d4) δ7.56(d,J=8.4Hz,1H),7.33(dd,J=8.4,2.1Hz,1H),7.2 2(d,J=2.0Hz,1H),7.00(dd,J=8.4,5.7Hz,1H),6.72(dd,J=12.0,8.4Hz,1H),5. 45(d,J=11.3Hz,1H),3.91(dq,J=13.6,6.9Hz,1H),3.71(dt,J=14.0,7.2Hz,1H) ,3.60-3.45(m,1H),2.92-2.64(m,2H),2.39-2.15(m,6H),1.25(d,J=6.8Hz,3H).

[0299] Examples 9 and 10: 5-((1S,2S)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0300] Step 1. Methyl (2S)-2-(2-bromo-4-chlorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0301] [ka]

[0302] In a 100 mL round bottom flask, methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenylbutanoate (1 g, 4.179 mmol, 1.00 equiv), DMAP (51.05 mg, 0.418 mmol, 0.1 equiv), pyridine (10 mL) were added at room temperature. To the above mixture, 2-bromo-4-chlorobenzenesulfonyl chloride (1.82 g, 6.269 mmol, 1.5 equiv) in DCM (10 mL) was added dropwise at 0° C. The resulting mixture was cooled to room temperature. The mixture was stirred at rt for an additional 2 h. The resulting mixture was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (2S)-2-(2-bromo-4-chlorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.75 g, 84.98%).

[0303] Step 2. Methyl (2S)-2-(4-chloro-2-ethenylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0304] [ka]

[0305] In a 20 mL sealed tube, methyl (2S)-2-(2-bromo-4-chlorobenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1 g, 2.029 mmol, 1 equiv.), potassium ethenyltrifluoroborane (299.01 mg, 2.232 mmol, 1.1 equiv.), Cs2CO3 (1.98 g, 6.087 mmol, 3 equiv.), THF (5 mL), H2O (5 mL), and Pd(PPh3)2Cl2 (142.44 mg, 0.203 mmol, 0.1 equiv.) were added at room temperature. The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 1.5 h. The resulting mixture was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl (2S)-2-(4-chloro-2-ethenylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (780 mg, 87.4%).

[0306] Step 3. (2S)-3-(6-fluoro-2,3-dimethylphenyl)-2-[N-(prop-2-en-1-yl) 4-chloro-2-ethenylbenzenesulfonamido]butanoate

[0307] [ka]

[0308] In a 100 mL round bottom flask, methyl (2S)-2-(4-chloro-2-ethenylbenzenesulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.5 g, 3.410 mmol, 1 eq.), allyl bromide (412.49 mg, 3.410 mmol, 1 eq.), Cs2CO3 (3.33 g, 10.230 mmol, 3 eq.), and DMF (15 mL) were added at room temperature. The resulting mixture was stirred at 60° C. for 1 h under air atmosphere. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (2S)-3-(6-fluoro-2,3-dimethylphenyl)-2-[N-(prop-2-en-1-yl)4-chloro-2-ethenylbenzenesulfonamide]butanoate (1.4 g, 85.54%).

[0309] Step 4. Methyl (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0310] [ka]

[0311] In a 100 mL round bottom flask, methyl (2S)-3-(6-fluoro-2,3-dimethylphenyl)-2-[N-(prop-2-en-1-yl)4-chloro-2-ethenylbenzenesulfonamido]butanoate (1.68 g, 3.500 mmol, 1 equiv.), [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]({[5-(dimethylsulfamoyl)-2-isopropoxyphenyl]methylidene})rutheniumdiuide dichloride (128.41 mg, 0.175 mmol, 0.05 equiv.), and DCM (20 mL) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere overnight. The residue was purified by silica gel column chromatography to obtain methyl (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.36 g, 86.0%).

[0312] Step 5. (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0313] [ka]

[0314] To a 20 mL vial, methyl (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (300 mg, 0.664 mmol, 1 equiv.), LiOH.HO (278.56 mg, 6.639 mmol, 3 equiv.), THF (9 mL), and HO (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere overnight. The residue was purified by reverse phase flash chromatography. This afforded (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (315 mg, 32.51%).

[0315] Step 6. 5-((1S)-1-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0316] [ka]

[0317] To a 10 mL vial, (2S)-2-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (380 mg, 0.868 mmol, 1 eq.), CDI (365.84 mg, 2.257 mmol, 2.6 eq.), and THF (7.6 mL) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 0.5 h. To the above mixture, hydrazine hydrate (130.32 mg, 2.604 mmol, 3 eq.) was added in portions at 0° C. The resulting mixture was stirred at 0° C. for another 1 h. The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. In a 25 mL round-bottom flask, the above crude product in dioxane (0.5 mL) and CDI (365.84 mg, 2.257 mmol, 2.6 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 0.5 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography. This gave 5-((1S)-1-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (340 mg, 82%).

[0318] Step 7. 5-((1S)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0319] [ka]

[0320] To a stirred solution / mixture of 5-((1S)-1-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (280 mg, 0.586 mmol, 1 equiv.) and MeOH (25 mL) was added PtO2 (200 mg, 0.881 mmol, 1.50 equiv.) under hydrogen atmosphere at room temperature. The resulting mixture was stirred under hydrogen atmosphere at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH (2x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (34 mg, 11.9%).

[0321] Step 8. 5-((1S,2R)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2S)-1-(7-chloro-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0322] [ka]

[0323] The pure compound 5-((1S)-1-(7-chloro-1,1-dioxido-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (95 mg) was purified by chiral chromatography, which gave the following:

[0324] First isomer: (40.7 mg).LC-MS: (ES, m / z): [MH]+=478.00. 1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),7.64(d,J=8.4Hz,1H),7.49-7.31(m,2H),6.94(dd,J=8.3,5.8Hz,1H),6.53(s,1H),5.21(d,J=11.1H) z,1H),3.83(dd,J=11.5,6.8Hz,1H),3.50(d,J=8.2Hz,2H),3.02(d,J=10.6Hz,1H),2.95(s,1H),2.22(d,J=15.8Hz,6H),1.52-1.07(m,5H).

[0325] Second isomer (5.9 mg).LC-MS (ES, m / z): [MH]+=478.05. 1 H NMR(300MHz,DMSO-d6)δ12.32(s,1H),7.64(d,J=8.3Hz,1H),7.43(dd,J=8.3,2.2Hz,1H),7.36(d,J=2.2Hz,1H),6.94(t,J=7.0Hz,1H),6.53( s,1H),5.20(d,J=11.1Hz,1H),3.82(s,1H),3.53(d,J=16.6Hz,2H),2.98(dd,J=20.6,7.5Hz,2H),2.21(d,J=15.8Hz,6H),1.55-1.08(m,5H).

[0326] Examples 11 and 12: Synthesis of 5-((1S,2S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0327] Step 1. tert-Butyl 2-(2-bromo-4-chlorophenyl)acetate

[0328] [ka]

[0329] To a 250 mL round bottom flask, (2-bromo-4-chlorophenyl)acetic acid (5 g, 20.041 mmol, 1 equiv.) and t-BuOH (50 mL, 526.152 mmol) were added at room temperature. To the above mixture, (Boc)2O (20 g, 91.638 mmol) was added portionwise at room temperature. The resulting mixture was further stirred at 90° C. overnight. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 2-(2-bromo-4-chlorophenyl)acetate (6.7 g, 98.46%).

[0330] Step 2. tert-Butyl 2-[2-(benzylsulfanyl)-4-chlorophenyl]acetate

[0331] [ka]

[0332] In a 250 mL round bottom flask, tert-butyl 2-(2-bromo-4-chlorophenyl)acetate (6 g, 19.634 mmol, 1 eq.) and dioxane (50 mL, 590.198 mmol) were added at room temperature. To the above mixture, DIEA (10.26 mL, 58.902 mmol, 3 eq.), Xantphos (1.14 g, 1.963 mmol, 0.1 eq.), Pd2(dba)3 (898.95 mg, 0.982 mmol, 0.05 eq.), benzyl mercaptan (2.77 mL, 23.561 mmol, 1.2 eq.) were added in portions at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for an additional 3 h. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3×100 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 to give tert-butyl 2-[2-(benzylsulfanyl)-4-chlorophenyl]acetate (7.3 g, 95.91%).

[0333] Step 3. tert-Butyl 2-[4-chloro-2-(chlorosulfonyl)phenyl]acetate

[0334] [ka]

[0335] In a 50 mL 3-neck round bottom flask, tert-butyl 2-[2-(benzylsulfanyl)-4-chlorophenyl]acetate (3 g, 8.599 mmol, 1 eq.) and CH3CN (20 mL) were added at room temperature. To the above mixture, HO (2 mL), AcOH (3 mL), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.39 g, 17.198 mmol, 2 eq.) were added portionwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for an additional 30 min. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (3x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-[4-chloro-2-(chlorosulfonyl)phenyl]acetate (2.24 g, 80.1%).

[0336] Step 4. Methyl-(2S)-2-((2-(2-(tert-butoxy)-2-oxoethyl)-5-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0337] [ka]

[0338] In a 50 mL round bottom flask, methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.4 g, 5.851 mmol, 1.00 equiv) and DCM (20 mL) were added at room temperature. To the above mixture, pyridine (1.39 mL, 17.553 mmol, 3 equiv) and tert-butyl 2-[4-chloro-2-(chlorosulfonyl)phenyl]acetate (2.28 g, 7.021 mmol, 1.2 equiv) were added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl (2S)-2-((2-(2-(tert-butoxy)-2-oxoethyl)-5-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.64 g, 85.46%).

[0339] Step 5. 2-(4-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid

[0340] [ka]

[0341] In a 100 mL round-bottom flask, methyl (2S)-2-{2-[2-(tert-butoxy)-2-oxoethyl]-5-chlorobenzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (2.64 g, 5.000 mmol, 1 eq.) in 1,4-dioxane (5 mL) and 4N HCl were added at room temperature. The resulting mixture was stirred at 50° C. for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(4-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid (2.25 g, 95.36%).

[0342] Step 6. Methyl (2S)-2-[5-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0343] [ka]

[0344] To a stirred solution of BH3.THF (10.17 mL, 10.172 mmol, 2 equiv.) was added 2-(4-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)acetic acid (2.4 g, 5.086 mmol, 1 equiv.) in tetrahydrofuran (20 mL) dropwise over 10 min at room temperature under nitrogen atmosphere. The reaction was quenched with MeOH at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography. This gave methyl (2S)-2-[5-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.18 g, 50.67%).

[0345] Step 7. Methyl (2S)-2-((5-chloro-2-(2-((methylsulfonyl)oxy)ethyl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0346] [ka]

[0347] In a 100 mL round bottom flask, methyl (2S)-2-[5-chloro-2-(2-hydroxyethyl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (1.18 g, 2.577 mmol, 1 equiv.) and DCM (10 mL) were added at room temperature. To the above mixture, TEA (2.15 mL, 15.462 mmol, 6 equiv.) and methanesulfonyl chloride (2.58 mL, 5.154 mmol, 2 equiv.) were added dropwise at 0° C. The resulting mixture was stirred at 0° C. for an additional 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CHCl (2×20 mL). The combined organic layers were washed with brine (1×60 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (2S)-2-{5-chloro-2-[2-(methanesulfonyloxy)ethyl]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (870 mg, 63%).

[0348] Step 8. Methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate

[0349] [ka]

[0350] In a 50 mL 3-neck round bottom flask, methyl (2S)-2-{5-chloro-2-[2-(methanesulfonyloxy)ethyl]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (870 mg, 1.623 mmol, 1 equiv.) and tetrahydrofuran (10 mL) were added at room temperature. To the above mixture, NaH (58.42 mg, 2.434 mmol, 1.5 equiv.) was added portionwise at 0° C. The resulting mixture was further stirred at room temperature overnight. The reaction was quenched by adding saturated NH4Cl(aq) (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (1×60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (560 mg, 78.4%).

[0351] Step 9. (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid

[0352] [ka]

[0353] To a stirred mixture of methyl (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (550 mg, 1.250 mmol, 1 equiv.) in MeOH (10 mL, 24.699 mmol), NaOH (100.01 mg, 2.500 mmol, 2 equiv.) and HO (2 mL, 11.102 mmol) were added dropwise at room temperature. The resulting mixture was stirred at 60° C. overnight. The mixture was acidified to pH 6 with HCl (2 M). The residue was purified by reverse phase flash chromatography. This gave (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (510 mg, 95.78%).

[0354] Step 10: tert-Butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate

[0355] [ka]

[0356] In a 50 mL round bottom flask, (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (500 mg, 1.174 mmol, 1 equiv.) and DCM (5 mL) were added at room temperature. To the above mixture, HATU (669.58 mg, 1.761 mmol, 1.5 equiv.), DIEA (613.48 μL, 3.522 mmol, 3 equiv.), and tert-butoxycarbohydrazide (232.74 mg, 1.761 mmol, 1.5 equiv.) were added in portions at room temperature. The resulting mixture was stirred at room temperature for an additional hour. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (520 mg, 82.0%).

[0357] Step 11: (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide

[0358] [ka]

[0359] In a 50 mL round bottom flask, tert-butyl 2-((2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (520 mg, 0.963 mmol, 1 eq.) and DCM (20 mL) were added at room temperature. To the above mixture, 2,6-lutidine (2063.55 mg, 19.260 mmol, 20 eq.) was added. To the mixture, trimethylsilyl triflate (3423.98 mg, 15.408 mmol, 16 eq.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (290 mg, 68.5%).

[0360] Step 12: 5-((1S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0361] [ka]

[0362] To a stirred mixture of (2S)-2-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (280 mg, 0.636 mmol, 1 equiv.) in THF (3 mL), DIEA (277.16 μL, 1.590 mmol, 2.5 equiv.) and triphosgene (94.43 mg, 0.318 mmol, 0.5 equiv.) were added dropwise at room temperature. The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (270 mg, 91.05%).

[0363] Step 13. 5-((1S,2S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one and 5-((1S,2R)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0364] [ka]

[0365] The crude product (270 mg) was purified by preparative HPLC to give:

[0366] First isomer: (39.7 mg, 14.56%). LC-MS (ES, m / z): MH=464.05. 1H NMR (300MHz, methanol-d4) δ 7.51 (d, J = 2.2Hz, 1H), 7.44 (dd, J = 8.2, 2.2Hz, 1H), 7.18 (d, J = 8.3Hz, 1H), 7.00 (dd, J = 8.4, 5.7Hz, 1H), 6.73 (dd, J = 11.9, 8.3Hz, 1H), 5.46 (d, J = 11.3Hz, 1H), 3.9 0(dq,J=13.1,6.7Hz,1H),3.69(dt,J=14.0,7.2Hz,1H),3.52(ddd,J=13.4,7.6,5.8Hz,1H),2 .88(dt,J=16.8,6.5Hz,1H),2.82-2.66(m,1H),2.29(s,3H),2.22(s,3H),1.40-1.19(m,3H).

[0367] Second isomer: (32.4 mg, 12.01%). LC-MS (ES, m / z): MH=464.05. 1 H NMR (300MHz, methanol-d4) δ7.74(d,J=2.2Hz,1H),7.51(dd,J=8.3,2.2Hz,1H),7.30(d,J=8.3Hz,1H),7.00(dd,J=8.5,5.8Hz,1H),6.74(dd,J= 12.0,8.4Hz,1H),5.52(dd,J=11.7,1.7Hz,1H),4.18-3.75(m,3H),3.23-2.87(m,2),2.31(s,3H),2.21(s,3H),1.42(dd,J=6.9,1.2Hz,3H).

[0368] Example 13: 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide

[0369] Step 1. tert-Butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate

[0370] [ka]

[0371] A solution of (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (1.0 g, 3.073 mmol, 1.0 equiv), triethylamine (471 μL, 3.379 mmol, 1.1 equiv), and ethyl chloroformate (323 μL, 3.378 mmol, 1.099 equiv) in THF (50 mL) was cooled to −10° C. After 1 h, ammonia solution (25% in H2O, 25 mL) was added dropwise and the reaction was continued overnight. The solvent was removed in vacuuo and the residue was dissolved in EtOAc. The organic layer was washed with 1M Na2HPO4, water, and brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by FCC to give tert-butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate as a single diastereoisomer (550 mg, 1.695 mmol, 52% yield). LC-MS: m / z=325.0[M+H]+. 1 H NMR(300MHz,DMSO-d6)7.02-6.91(m,3H),6.80(dd,J=11.6,8.3Hz,1H),6.70(s,1H),4. 32(t,J=9.9Hz,1H),3.42(t,J=8.5Hz,1H),2.18(s,6H),1.40(s,9H),1.22-1.14(m,3H).

[0372] Step 2. tert-Butyl N-[(1S,2R)-1-cyano-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate

[0373] [ka]

[0374] Trifluoroacetic anhydride (354 μL, 2.547 mmol, 1.502 equiv) was added dropwise to a solution of tert-butyl N-[(1S,2R)-1-carbamoyl-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (550 mg, 1.695 mmol, 1.0 equiv) in pyridine (16.5 mL) at 0° C. The reaction was continued at room temperature overnight. The solvent was removed in vacuo. The residue was purified by FCC to give tert-butyl N-[(1S,2R)-1-cyano-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (400 mg, 1.306 mmol, 76% yield). 1 H NMR(300MHz,DMSO-d6) 7.94(d,J=8.8Hz,1H),7.14(dd,J=8.4,5.9Hz,1H),6.95(dd,J=12.0,8.4Hz,1H),4.78(t,J= 10.1Hz,1H),3.63(dd,J=11.7,7.0Hz,1H),2.25(s,6H),1.44(s,9H),1.21(d,J=6.9Hz,3H).

[0375] Step 3. tert-Butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]carbamate

[0376] [ka]

[0377] To a solution of tert-butyl N-[(1S,2R)-1-cyano-2-(6-fluoro-2,3-dimethylphenyl)propyl]carbamate (400 mg, 1.306 mmol, 1.0 equiv) in DMF (20.0 mL) was added sodium azide (127 mg, 1.954 mmol, 4 equiv) followed by NH4Cl (279 mg, 5.216 mmol, 4 equiv). The reaction was carried out at 110° C. overnight. The mixture was cooled, diluted with EtOAc, washed twice with water, a 10% solution of NaH2PO4, and brine, dried, filtered, and concentrated to give tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]carbamate (360 mg, 1.03 mmol, 75% yield). LC-MS: m / z=349.95 [M+H]+. 1 H NMR(300MHz,DMSO-d6) 7.79(d,J=8.6Hz,1H),6.91(dd,J=8.4,5.8Hz,1H),6.75(dd,J=11.8,8.4Hz,1H),5.41(t ,J=9.9Hz,1H),3.82(q,J=8.1,6.6Hz,1H),2.09(d,J=5.5Hz,6H),1.36(d,J=9.2Hz,12H).

[0378] Step 4. (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine

[0379] [ka]

[0380] A mixture of tert-butyl N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]carbamate (360 mg, 1.03 mmol, 1.0 equiv) and 4M HCl in dioxane (5.152 mL, 20.608 mmol, 20 equiv) was stirred at room temperature for 2 h until complete conversion was observed. The solvent was removed in vacuo, and the residue was then coevaporated twice with toluene and dried under high vacuum to give (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine as the hydrochloride salt (290 mg, 1.02 mmol, 100% yield). LC-MS: m / z=349.95[M+H]+. 1 H NMR(300MHz,DMSO-d6) 9.16(s,3H),6.97(dd,J=8.4,5.9Hz,1H),6.82(dd,J=11.8,8.4Hz,1H),5.06(d,J =10.8Hz,1H),3.99(d,J=18.4Hz,1H),2.05(d,J=10.5Hz,6H),1.55-1.42(m,3H).

[0381] Step 5. Methyl 2-(2-bromo-5-chlorophenyl)acetate

[0382] [ka]

[0383] To a cooled solution of 2-bromo-5-chlorophenylacetic acid (2.0 g, 8.016 mmol, 1.0 equiv) in MeOH (40 mL) was added thionyl chloride (2.339 mL, 32.069 mmol, 4.0 equiv) dropwise. The mixture was warmed to room temperature and stirred for 2 h. After the reaction was complete, the volatiles were removed under reduced pressure. The residue was suspended in saturated NaHCO3 and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure to give methyl 2-(2-bromo-5-chlorophenyl)acetate as a colorless liquid (2.11 g, 100% yield). 1H NMR (300 MHz, chloroform-d) δ 7.49 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.5, 2.5 Hz, 1H), 3.76 (s, 2H), 3.73 (s, 3H).

[0384] Step 6. Methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate

[0385] [ka]

[0386] To a solution of methyl 2-(2-bromo-5-chlorophenyl)acetate (1.91 g, 7.248 mmol, 1.0 equiv.) in dioxane (19 mL) was added DIPEA (2.525 mL, 14.497 mmol, 2.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] (332 mg, 0.363 mmol, 0.05 equiv.), and Xantphos (294 mg, 0.508 mmol, 0.07 equiv.). The mixture was thoroughly degassed and purged with argon with constant stirring for 15 min. The reaction vessel was then immersed in an oil bath preheated to 110 °C, and benzyl mercaptan (0.817 mL, 6.96 mmol, 0.96 equiv.) was added via syringe. The reaction vessel was sealed and the reaction was continued for 20 h. Upon completion, the mixture was cooled to room temperature. The volatiles were removed in vacuo. The residue was redissolved in EtOAc and filtered through a pad of silica gel. The filtrate was concentrated and purified by FCC to give methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (2.18 g, 7.106 mmol, 98% yield). 1 H NMR(300MHz,DMSO-d6)δ7.44(d,J=8.4Hz,1H),7.38(d,J=2.3Hz,1H),7.34-7.20(m,6H),4.16(s,2H),3.72(s,2H),3.60(s,3H).

[0387] Step 7. Methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate

[0388] [ka]

[0389] To a cooled solution of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (530 mg, 1.728 mmol, 1.0 equiv) in glacial acetic acid (7.95 mL) and water (1.6 mL) was added N-chlorosuccinimide (923 mg, 6.912 mmol, 4.0 equiv) in portions. The mixture was stirred at 0° C. for 20 min, the cooling bath was removed, and the reaction was continued at room temperature for 30 min. After completion, the reaction mixture was diluted with Et2O and washed six times with water. The organic layer was dried, filtered, and concentrated. The residue was purified by FCC to give methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (488 mg, 1.724 mmol, 100% yield). 1 H NMR (300 MHz, chloroform-d) δ 8.06 (d, J = 8.4 Hz, 1H), 7.56-7.45 (m, 2H), 4.15 (s, 2H), 3.75 (s, 3H).

[0390] Step 8. Methyl 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetate

[0391] [ka]

[0392] To a solution of (1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propan-1-amine (493 mg, 1.725 mmol, 1.0 equiv.) in pyridine (5 mL) was added methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (0.488 g, 1.724 mmol, 1.0 equiv.) dropwise as a solution in DCM (5 mL) and the mixture was stirred at room temperature overnight. The pyridine was removed under reduced pressure and the solid residue was purified by FCC to give methyl 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetate (655 mg, 1.321 mmol, 77% yield). LC-MS: m / z=494.08[MH]-. 1 H NMR(300MHz,DMSO-d6)δ8.38(s,1H),7.50(d,J=8.5Hz,1H),7.36(d,J=2.2Hz,1H),7.28(dd,J=8.5,2.2Hz,1H),6.80(dd,J=8.4,5.7Hz,1H),6.63(dd ,J=11.8,8.3Hz,1H),5.02(d,J=10.9Hz,1H),3.96(d,J=3.3Hz,2H),3.79- 3.64(m,1H),3.59(s,3H),2.03(s,3H),2.02(s,3H),1.19(d,J=7.0Hz,3H).

[0393] Step 9. 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetic acid

[0394] [ka]

[0395] To a stirred solution of methyl 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetate (350 mg, 0.706 mmol, 1.0 equiv) in THF (7.0 mL) and water (1.75 mL) was added lithium hydroxide monohydrate (65 mg, 1.549 mmol, 2.2 equiv). The reaction was carried out at room temperature overnight. The mixture was acidified to pH 1-2 with 1 M HCl and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetic acid (340 mg, 100% yield) which was used in the next step without further purification. LC-MS: m / z=480.12 [MH]-. 1 H NMR(300MHz,DMSO-d6)δ8.32(s,1H),7.45(d,J=8.5Hz,1H),7.29(d,J=2.2Hz,1H),7.15(dd,J=8.5,2.2Hz,1H),6.80(dd,J=8.4,5.6Hz,1H),6. 65(dd,J=11.7,8.2Hz,1H),5.15(d,J=11.1Hz,1H),3.93(d,J=15.5Hz,1H),3.76-3.65(m,2H),2.01(s,3H),2.00(s,3H),1.30(d,J=6.9Hz,3H).

[0396] Step 10: 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]-2-(2-hydroxyethyl)benzene-1-sulfonamide

[0397] [ka]

[0398] To a solution of 2-(5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenyl)acetic acid (125 mg, 0.259 mmol, 1.0 equiv) in THF (6.25 mL) was added borane dimethylsulfide complex (0.246 mL, 2.594 mmol, 10 equiv). The reaction was continued at room temperature overnight. After completion, the mixture was cooled to 0° C. and slowly quenched with MeOH. The volatiles were removed under reduced pressure and the residue was purified by FCC to give 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]-2-(2-hydroxyethyl)benzene-1-sulfonamide (80 mg, 0.171 mmol, 66% yield). LC-MS: m / z=468.3, 470.2[M+H]+, 466.4, 468.4[MH]-.

[0399] Step 11: 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenethyl methanesulfonate

[0400] [ka]

[0401] To a solution of 4-chloro-N-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-1,2,3,4-tetrazol-5-yl)propyl]-2-(2-hydroxyethyl)benzene-1-sulfonamide (80 mg, 0.171 mmol, 1.0 equiv.) in DCM (4.8 mL) was added triethylamine (0.071 mL, 0.509 mmol, 3 equiv.) and methanesulfonyl chloride (0.026 mL, 0.336 mmol, 1.965 equiv.) at 0° C. The mixture was stirred at 0° C. for 2 h, then the cooling bath was removed and the reaction was continued at room temperature for 2 h. The reaction was quenched with water and extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated to dryness under vacuum. The crude 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenethyl methanesulfonate (96 mg, 100% yield) was used in the next step without further purification. LC-MS: m / z=546.4, 548.3 [M+H]+

[0402] Step 12: 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide

[0403] [ka]

[0404] To a solution of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)sulfamoyl)phenethyl methanesulfonate (96 mg, 0.176 mmol, 1.0 equiv) in THF (9.6 mL) was added sodium hydride (60% in mineral oil, 15 mg, 0.352 mmol, 2 equiv). The reaction was continued at room temperature for 2 h. The mixture was poured into 10% aqueous NaH2PO4 and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by pHPLC to give 6-chloro-2-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(2H-tetrazol-5-yl)propyl)-3,4-dihydro-2H-benzo[e][1,2]thiazine 1,1-dioxide (10 mg, 0.023 mmol, 13% yield). LC-MS: m / z=448.16, 450.19 [M+H]+, 1x-Cl pattern. 1 H NMR (400MHz, methanol-d4) δ7.67(d,J=8.4Hz,1H),7.33(dd,J=8.4,2.1Hz,1H),7.16(d,J= 2.1Hz,1H),6.86(dd,J=8.4,5.7Hz,1H),6.63(dd,J=12.1,8.4Hz,1H),6.05(d,J=11.6H) z,1H),4.14(t,J=6.8Hz,2H),4.05(dq,J=13.3,6.9Hz,1H),3.03(dt,J=15.4,7.1Hz,1H ),2.69(dt,J=16.9,6.4Hz,1H),2.29(s,3H),2.11(s,3H),1.50(dd,J=6.9,1.2Hz,3H).

[0405] Example 14: Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0406] [ka]

[0407] Step 1: Synthesis of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(hydroxymethyl)benzenesulfonamide To a 50 mL round bottom flask was added methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzoate (222 mg, 0.45 mmol, 1.00 equiv.) in THF (2 mL). To the above mixture was added 1 M LiBH4 solution in THF (0.54 mL, 0.54 mmol, 1.2 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature. The residue was purified by reverse phase flash chromatography. This gave 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(hydroxymethyl)benzenesulfonamide (127 mg, 60.6%).

[0408] Step 2: Synthesis of 2-(bromomethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide 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-(hydroxymethyl)benzenesulfonamide (128 mg, 0.27 mmol, 1 equiv.) and carbon tetrabromide (135 mg, 0.41 mmol, 1.5 equiv.) in DCM was added triphenylphosphine (143 mg, 0.54 mmol, 2 equiv.) in portions at 0° C. The resulting mixture was stirred at 40° C. overnight. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE / EtOAc 1:1) to give 2-(bromomethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (87 mg, 60%).

[0409] Step 3: Synthesis of 5-((1S)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To a stirred solution of 2-(bromomethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (87 mg, 0.16 mmol, 1 equiv.) in DMF, Cs2CO3 (106.4 mg, 0.33 mmol, 2 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60° C. for 60 min. The residue was purified by reverse-phase flash chromatography. This afforded 5-((1S)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (50 mg, 67.76%).

[0410] Step 4: Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one The crude product (50 mg) was purified by chiral preparative HPLC. This gave 5-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-3H-1 lambda 6,2-benzothiazole-1,1-dione (25.1 mg, 45.8%). LCMS: (ES, m / z): (MH) = 450.05,. 1 H NMR (400MHz, methanol-d4) δ7.91-7.81(d,J=8.3Hz,1H),7.70-7.66(m,1H),7.65-7. 63(m,1H),7.06-6.97(dd,J=8.4,5.8Hz,1H),6.84-6.79(dd,J=12.0,8.3Hz,1H), 5.30-5.27(dd,J=11.5,1.5Hz,1H),4.89-4.66(d,J=14.6Hz,2H),4.00-3.92(d,J =14.6Hz,1H),2.39-2.36(s,3H),2.33-2.17(s,3H),1.43-1.37(d,J=6.9Hz,3H).

[0411] Example 15: 5-((1R,2S)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0412] [ka]

[0413] Step 1: Synthesis of methyl 2-amino-5-chloro-3-methoxybenzoate To a 100 mL round bottom flask, methyl 2-amino-3-methoxybenzoate (2 g, 11 mmol, 1 equiv.) and NCS (1.62 g, 12.1 mmol, 1.1 equiv.) in DMF (20 mL) were added at room temperature. The resulting mixture was stirred at 50° C. for 2 h. The resulting mixture was extracted with EtOAc (3×15 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. The residue was purified by silica gel column chromatography to give methyl 2-amino-5-chloro-3-methoxybenzoate (2 g, 84%).

[0414] Step 2: Synthesis of methyl 2-bromo-5-chloro-3-methoxybenzoate To a 100 mL round bottom flask, methyl 2-amino-5-chloro-3-methoxybenzoate (1 g, 4.6 mmol, 1 equiv), CuBr2 (2.07 g, 9.3 mmol, 2 equiv), and CH3CN (10 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 20 min. t-BuNO2 (0.86 g, 8.3 mmol, 1.8 equiv) was added. The resulting mixture was stirred at room temperature for 30 min, and then the resulting mixture was stirred at 60 °C overnight. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography to give methyl 2-bromo-5-chloro-3-methoxybenzoate (0.8 g, 61.7%).

[0415] Step 3: Synthesis of methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate A 100 mL round bottom flask was charged with methyl 2-bromo-5-chloro-3-methoxybenzoate (1.6 g, 5.7 mmol, 1 equiv), benzyl mercaptan (0.85 g, 6.9 mmol, 1.2 equiv), DIEA (2.2 g, 17.2 mmol, 3 equiv), Xantphos (0.66 g, 1.15 mmol, 0.2 equiv), Pd2(dba)3 (0.52 g, 0.57 mmol, 0.1 equiv), and dioxane (15 mL). The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The resulting mixture was 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 to obtain methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate (1.2 g, 65%).

[0416] Step 4: Synthesis of methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate In a 250 mL round bottom flask, to a mixture of methyl 2-(benzylsulfanyl)-5-chloro-3-methoxybenzoate (1.3 g, 4 mmol, 1 equiv.) in MeCN, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.6 g, 8 mmol, 2 equiv.), AcOH (0.90 mL, 15.7 mmol, 3.9 equiv.), and H2O (0.70 mL) were added portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate (1 g, 83.1%).

[0417] Step 5: Synthesis of methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate In a 100 mL round bottom flask, to a mixture of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (200 mg, 0.66 mmol, 1 equiv.) in pyridine (5 mL) was added methyl 5-chloro-2-(chlorosulfonyl)-3-methoxybenzoate (400 mg, 1.33 mmol, 2 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with water. The resulting mixture was extracted with EtOAc (3×10 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. The residue was purified by silica gel column chromatography to give methyl 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)-3-methoxybenzoate (100 mg, 28.5%).

[0418] Step 6: Synthesis of 5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3-methoxybenzoic acid To an 8 mL round bottom flask was added methyl 5-chloro-2-{[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl}-3-methoxybenzoate (100 mg, 0.19 mmol, 1 equiv.) in THF (3 mL), water (1 mL), and LiOH.H2O (15.9 mg, 0.38 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 60° C. for 2 h. The mixture was acidified to pH 5. The residue was purified by reverse-phase flash chromatography to give 5-chloro-2-{[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl}-3-methoxybenzoic acid (70 mg, 71.9%).

[0419] Step 7: Synthesis of 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one In a 20 mL round bottom flask, 5-chloro-2-{[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]sulfamoyl}-3-methoxybenzoic acid (120 mg, 0.23 mmol, 1.00 equiv.), EDCI (89.5 mg, 0.47 mmol, 2.0 equiv.), DMAP (2.85 mg, 0.023 mmol, 0.1 equiv.), and DCM (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with CHCl (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. The crude product was purified by chiral preparative HPLC to give 5-((1S,2R)-1-(5-chloro-7-methoxy-1,1-dioxide-3-oxobenzo[d]isothiazol-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (9.4 mg, 8.12%). LC-MS (ES, m / z): [M+H]: 496.10 1 H NMR (400MHz, methanol-d4) δ7.73(d,J=5.8Hz,2H),7.08(dd,J=8.4,5.8Hz,1H),6.83(dd,J=12.1,8.4Hz,1H),5.95(d d,J=11.9,2.9Hz,1H),4.61(dq,J=13.4,7.0Hz,1H),4.12(s,3H),2.40(s,3H),2.28(s,3H),1.38(d,J=7.0Hz,3H).

[0420] Example 16: 5-((1S)-1-(6-chloro-1,1-dioxide-4-oxo-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

[0421] [ka]

[0422] Step 1: Synthesis of methyl 2-(2-bromo-5-chlorophenyl)-2-diazoacetate To a stirred solution / mixture of methyl 2-(2-bromo-5-chlorophenyl)acetate (10 g, 37.9 mmol, 1 equiv) in ACN (100 mL) was added 4-acetamidobenzene-1-sulfonyl azide (13.7 g, 56.9 mmol, 1.5 equiv), DBU (9.98 mL, 66.8 mmol, 1.8 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated NH4Cl(aq) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(2-bromo-5-chlorophenyl)-2-diazoacetate (10 g, 91%).

[0423] Step 2: Synthesis of methyl 2-(benzyloxy)-2-(2-bromo-5-chlorophenyl)acetate To a stirred solution of methyl 2-(2-bromo-5-chlorophenyl)-2-diazoacetate (11 g, 38 mmol, 1 equiv.) and phenylmethanol (41.1 g, 380 mmol, 10 equiv.) was added HClO4 (700 μL, 12.2 mmol, 0.32 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 2-(benzyloxy)-2-(2-bromo-5-chlorophenyl)acetate (9.3 g, 66.2%).

[0424] Step 3: Synthesis of methyl 2-(benzyloxy)-2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate To a stirred mixture of methyl 2-(benzyloxy)-2-(2-bromo-5-chlorophenyl)acetate (9.3 g, 25.2 mmol, 1 equiv.) in dioxane (162 mL), Pd2(dba)3 (2.3 g, 2.52 mmol, 0.1 equiv.), Xantphos (2.54 g, 4.38 mmol, 0.2 equiv.), and DIEA (9.76 g, 75.5 mmol, 3 equiv.), benzyl mercaptan (3.75 g, 30.2 mmol, 1.2 equiv.) were added at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 3 days. The resulting mixture was diluted with EtOAc (200 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(benzyloxy)-2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (7 g, 60.6%).

[0425] Step 4: Synthesis gives methyl 2-(benzyloxy)-2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate. To a stirred solution / mixture of methyl 2-(benzyloxy)-2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (8.83 g, 21.4 mmol, 1 eq) and H2O (3.47 mL) in acetonitrile was added AcOH (6 mL) at 0 °C. To the above mixture was added 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (8.43 g, 42.8 mmol, 2 eq) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. The reaction was quenched by adding water / ice (25 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine (1x400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 2-(benzyloxy)-2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (8.2 g, 98.5%).

[0426] Step 5: Synthesis of methyl 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (5.75 g, 19.1 mmol, 0.9 equiv.) in pyridine (25 ml), methyl 2-(benzyloxy)-2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (8.2 g, 21.1 mmol, 1 equiv.) in DCM (100 ml) was added dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM (100 mL). The resulting mixture was washed with 1×250 mL of brine. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give methyl 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (7.1 g, 65.03%).

[0427] Step 6: Synthesis of 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid To a stirred solution / mixture of methyl 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (6.4 g, 10.4 mmol, 1 equiv.) and HO (32 mL) in MeOH (32 mL) was added LiOH.HO (2172 mg, 51.8 mmol, 5 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (20 mL). The mixture was acidified to pH 6 with HCl (2 M). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (1x200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification.

[0428] Step 7: Synthesis of 2-[1-(benzyloxy)-2-hydroxyethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide To a stirred solution of 2-(benzyloxy)-2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid (6.2 g, 10.3 mmol, 1 equiv.) in THF (62 mL) was added 1M BH3-THF (62 mL, 62 mmol, 6 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for 5 h. The reaction was quenched by the addition of MeOH (2 mL) at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 2-[1-(benzyloxy)-2-hydroxyethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (2.4 g, 39.63%).

[0429] Step 8: Synthesis of 2-[1-(benzyloxy)-2-chloroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide To a stirred solution of 2-[1-(benzyloxy)-2-hydroxyethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (1.32 g, 0.053 mmol, 1 equiv.) and PPh3 (1173 mg, 4.47 mmol, 2 equiv.) in DCE was added CCl4 (619 mg, 4.03 mmol, 1.8 equiv.) at 0° C. The resulting mixture was stirred at 60° C. for 15 min. The resulting mixture was concentrated under vacuum. The residue was purified by reverse-phase flash chromatography. This gave 2-[1-(benzyloxy)-2-chloroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (615 mg, 45.2%).

[0430] Step 9: Synthesis of 5-((1S)-1-(4-(benzyloxy)-6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To a stirred mixture of 2-[1-(benzyloxy)-2-chloroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (325 mg, 0.53 mmol, 1 equiv.) in DMF, Cs2CO3 (522 mg, 1.60 mmol, 3 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60° C. for 60 min. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(4-(benzyloxy)-6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (225 mg, 73.6%).

[0431] Step 10: Synthesis of 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To a stirred solution / mixture of 5-((1S)-1-(4-(benzyloxy)-6-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (225 mg, 0.39 mmol, 1 equiv) in DCM (1.9 mL) was added boron trichloride (1.57 mL, 1.57 mmol, 4 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at 0° C. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (1×20 mL) and dried over anhydrous Na2SO4. The residue was purified by preparative TLC to give 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (130 mg, 68.58%).

[0432] Step 11: Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxide-4-oxo-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 To a stirred solution / mixture of 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (130 mg, 0.27 mmol, 1 equiv.) in DCM was added Dess-Martin (228 mg, 0.54 mmol, 2 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 60 min. The resulting mixture was filtered and the filter cake was washed with DCM (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (55.8 mg, 42.4%).

[0433] LC-MS(ES,m / z):MH=477.95. 1 H NMR (400MHz, methanol-d4) δ7.87-7.61(m,3H),7.02-6.99(dd,J=8.4,5.7Hz,1H),6.77-6.72(dd,J=12.1,8.3Hz,1H),5.61-5.50(dd,J=11.9, 1.9Hz,1H),4.67-4.62(d,1H),3.92-3.86(m,1H),2.34-2.03(m,6H),1.47-1.45(dd,J=6.9,1.2Hz,2H),1.29-1.27(dd,J=21.6,6.8Hz,1H).

[0434] Example 17: 5-((1S)-1-(6-chloro-1,1-dioxide-3-oxo-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

[0435] [ka]

[0436] Step 1: Synthesis of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate In a 100 mL round bottom flask, methyl 2-(2-bromo-5-chlorophenyl)acetate (1 g, 3.80 mmol, 1 eq.), dioxane (10 mL, 118 mmol), and benzyl mercaptan (0.57 g, 4.55 mmol, 1.2 eq.), DIEA (1.47 g, 11.4 mmol, 3 eq.) were added. To the above mixture, Xantphos (0.22 g, 0.38 mmol, 0.1 eq.), Pd2(dba)3 (0.17 g, 0.19 mmol, 0.05 eq.) were added. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×35 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in a vacuum. The residue was purified by silica gel column chromatography to give methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (1 g, 85.9%).

[0437] Step 2: Synthesis of methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate To a 50 mL 3-neck round bottom flask was added methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]acetate (400 mg, 1.30 mmol, 1 equiv) and CH3CN (4 mL). This was followed by dropwise addition of HO (244 μL, 13.5 mmol, 10 equiv), AcOH (280 μL, 4.9 mmol, 3.8 equiv), 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (513 mg, 2.6 mmol, 2 equiv) at 0° C. The resulting mixture was stirred at 0° C. for 30 min under nitrogen atmosphere. The reaction was quenched with water. 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. This gave methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (300 mg, 81.3%).

[0438] Step 3: Synthesis of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate To an 8 mL vial was added 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (50 mg, 0.17 mmol, 1 eq.) and pyridine (2 mL, 25 mmol, 152 eq.). This was followed by the dropwise addition of methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]acetate (141 mg, 0.5 mmol, 3 eq.) in DCM at 0° C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (80 mg, 94.3%).

[0439] Step 4: Synthesis of 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid To an 8 mL vial was added methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (20 mg, 0.039 mmol, 1 equiv), THF (1 mL), lithium hydrate (4.92 mg, 0.12 mmol, 3 equiv), and HO (0.3 mL). The resulting mixture was stirred at 60° C. for an additional 2 h. The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0440] Step 5: Synthesis of 5-((1S)-1-(6-chloro-1,1-dioxide-3-oxo-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 To an 8 mL vial was added 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetic acid (40 mg, 0.080 mmol, 1 equiv.), ACN (2 mL), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (27 mg, 0.096 mmol, 1.2 equiv.), and N-methylimidazole (23 μL, 0.28 mmol, 3.5 equiv.). The resulting mixture was stirred at 60° C. overnight. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC to give 5-((1S)-1-(6-chloro-1,1-dioxide-3-oxo-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 (0.6 mg, 1.56%). LC-MS (ES, m / z): [MH]: 479.00. 1 H NMR (300MHz, methanol-d4) δ7.57(d,J=8.3Hz,1H),7.47(dd,J=8.3,2.0Hz,1H),7.38(d,J=1.9Hz,1H),6.69(dd,J=8.3,5.7Hz,1H),6 .38(dd,J=11.8,8.4Hz,1H),5.86(s,1H),4.62(s,3H),4.48-4.35(m,1H),2.08(d,J=15.7Hz,6H),1.52-1.42(m,3H),1.31(s,3H).

[0441] Example 18: 5-((1S,2R)-1-(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

[0442] [ka]

[0443] In a 50 mL round bottom flask, 5-((1S)-1-(7-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (120 mg, 0.26 mmol, 1 equiv.), MeOH (5 mL), EtOAc (5 mL) were added at room temperature. To the above mixture, Pd / C (10%) (274 mg, 2.6 mmol, 10 equiv.) was added portionwise at room temperature. The resulting mixture was stirred overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 5-((1S,2R)-1-(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 (22.2 mg, 21.56%). LC-MS (ES, m / z): MH=430.10. 1 H NMR (300MHz, methanol-d4) δ7.74(dd,J=7.7,1.4Hz,1H),7.56-7.30(m,2H),7.26(d,J=7.6Hz,1H),6.95(dd,J=8.4,5.7Hz,1H),6.70(dd,J=12.1,8.4Hz,1H) ,5.57(dd,J=11.8,1.2Hz,1H),4.24-3.71(m,3H),3.19-3.01(m,1H),2.89(d t,J=17.2,7.0Hz,1H),2.33(s,3H),2.19(s,3H),1.42(dd,J=7.0,1.2Hz,3H).

[0444] Example 19: 5-((1S,2R)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0445] [ka]

[0446] The crude product (90 mg) from Example 16 (Step 11) was purified by chiral preparative HPLC. This gave 5-((1S,2R)-1-(6-chloro-4-hydroxy-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one. (19.7 mg, 21.9%). LC-MS (ES, m / z): MH=480.08. 1 H NMR (400 MHz, methanol-d4) δ 7.77-7.31 (m, 3H), 6.99-6.63 (m, 1H), 5.55-5.51 (dd, J = 11.9, 1.9 Hz, 1H), 4.87-4.60 (m, 1H), 3.96-3.74 (m, 2H), 3.28-3.25 (m, 1H), 2.33-2.13 (m, 6H), 1.45-1.26 (m. 2H).

[0447] Example 20: 5-((1S)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0448] [ka]

[0449] Step 1: Synthesis of tert-butyl 2-(2-bromo-5-chlorophenyl)propanoate To a 250 mL 3-neck round bottom flask was added tert-butyl 2-(2-bromo-5-chlorophenyl)acetate (4 g, 13 mmol, 1 equiv) and THF (40 mL) at room temperature. To the above mixture was added NaHMDS (3.60 g, 19.6 mmol, 1.5 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 45 min. To the above mixture was added methyl iodide (2.79 g, 19.6 mmol, 1.5 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 3 h. The reaction was quenched with saturated NH4Cl(aq) at 0° C. The resulting mixture was extracted with EtOAc (3×35 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave tert-butyl 2-(2-bromo-5-chlorophenyl)propanoate (3 g, 71.7%).

[0450] Step 2: Synthesis of tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]propanoate To a 40 mL vial was added tert-butyl 2-(2-bromo-5-chlorophenyl)propanoate (2 g, 6.3 mmol, 1 equiv), dioxane (7 mL), DIEA (2426 mg, 18.8 mmol, 3 equiv), and benzyl mercaptan (933 mg, 7.5 mmol, 1.2 equiv), Pd2(dba)3 (286 mg, 0.31 mmol, 0.05 equiv), and Xantphos (362 mg, 0.63 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x25 mL). The combined organic layers were washed with brine (1x35 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]propanoate (1 g, 44%).

[0451] Step 3: Synthesis of tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]propanoate In a 100 mL round bottom flask, tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]propanoate (1.3 g, 3.6 mmol, 1 equiv.) and ACN (20 mL) were added at room temperature. To the above mixture, AcOH (3 mL), HO (2 mL), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.4 g, 7.2 mmol, 2 equiv.) were added dropwise at 0° C. 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 (3×15 mL). The combined organic layers were washed with brine (1×25 mL) and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography to give tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]propanoate (1.1 g, 90.2%).

[0452] Step 4: Methyl-(2S)-2-((2-(1-(tert-butoxy)-1-oxopropan-2-yl)-4-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate To a 40 mL vial, methyl (2S)-2-amino-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 2.1 mmol, 1 eq.) and pyridine (5 mL, 0.44 mmol) were added at room temperature. To the above mixture, tert-butyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]propanoate (1.1 g, 3.2 mmol, 1.6 eq.) in DCM was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave methyl (2S)-2-((2-(1-(tert-butoxy)-1-oxopropan-2-yl)-4-chlorophenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (900 mg, 79.5%).

[0453] Step 5: Synthesis of 2-(5-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)propanoic acid In a 100 mL round bottom flask, methyl (2S)-2-{2-[1-(tert-butoxy)-1-oxopropan-2-yl]-4-chlorobenzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (500 mg, 0.92 mmol, 1 equiv.) and HCl (gas) in 1,4-dioxane (5 mL), DCM (2 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This afforded 2-(5-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)propanoic acid (300 mg, 67%).

[0454] Step 6: Synthesis of methyl (2S)-2-((4-chloro-2-(1-hydroxypropan-2-yl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate To a 20 mL vial was added BH3-THF (1.23 mL, 1.2 mmol, 2 equiv.) and 2-(5-chloro-2-(N-((2S)-3-(6-fluoro-2,3-dimethylphenyl)-1-methoxy-1-oxobutan-2-yl)sulfamoyl)phenyl)propanoic acid (300 mg, 0.62 mmol, 1 equiv.) in tetrahydrofuran (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 20 min. The reaction was quenched with MeOH at 0° C. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC to give methyl (2S)-2-[4-chloro-2-(1-hydroxypropan-2-yl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (40 mg, 41.2%).

[0455] Step 7: Synthesis of methyl (2S)-2-((4-chloro-2-(1-((methylsulfonyl)oxy)propan-2-yl)phenyl)sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate In a 50 mL round bottom flask, methyl (2S)-2-[4-chloro-2-(1-hydroxypropan-2-yl)benzenesulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (120 mg, 0.25 mmol, 1 equiv.) and DCM (5 mL), TEA (212 μL, 1.5 mmol, 6 equiv.) were added at room temperature. To the above mixture, 2M methanesulfonyl chloride in DCM (254 μL, 0.51 mmol, 2 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3×15 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 preparative TLC to give methyl (2S)-2-{4-chloro-2-[1-(methanesulfonyloxy)propan-2-yl]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (40 mg, 85.8%).

[0456] Step 8: Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid A 50 mL 3-neck round bottom flask was charged with methyl (2S)-2-{4-chloro-2-[1-(methanesulfonyloxy)propan-2-yl]benzenesulfonamido}-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg, 0.18 mmol, 1 equiv.) and tetrahydrofuran (10 mL) at room temperature. To the above mixture, sodium hydride (60%) (65.4 mg, 2.73 mmol, 15 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was acidified to pH 6 with 1 M HCl. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (60 mg, 75.0%).

[0457] Step 9: tert-Butyl 2-((2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate In a 50 mL round bottom flask, (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (20 mg, 0.045 mmol, 1 equiv.), DCM (3 mL), tert-butoxycarbohydrazide (7.81 mg, 0.06 mmol, 1.3 equiv.), DIEA (17.6 mg, 0.14 mmol, 3 equiv.), and HATU (25.9 mg, 0.07 mmol, 1.5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with DCM (3x25 mL). The combined organic layers were washed with brine (1x35 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give tert-butyl 2-((2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (20 mg, 79.40%).

[0458] Step 10: Synthesis of (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide In a 20 mL vial, tert-butyl 2-((2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoyl)hydrazine-1-carboxylate (20 mg, 0.04 mmol, 1 equiv.) and DCM (2 mL) were added at room temperature. To the above mixture, trimethylsilyl triflate (128 mg, 0.58 mmol, 16 equiv.) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (10 mg, 61.03%).

[0459] Step 11: Synthesis of 5-((1S)-1-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To an 8 mL vial was added (2S)-2-(6-chloro-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanehydrazide (10 mg, 0.022 mmol, 1 equiv.), DIEA (7.1 mg, 0.055 mmol, 2.5 equiv.), and ditrichloromethyl carbonate (3.3 mg, 0.011 mmol, 0.5 equiv.) in THF (1 mL) at room temperature. The resulting mixture was stirred at 80° C. for 1 h. The resulting mixture was concentrated under vacuum. The crude product was purified by chiral preparative HPLC. This gave 6-chloro-2-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-methyl-3,4-dihydro-1lambda 6,2-benzothiazine-1,1-dione (4.6 mg, 43.4%). LC-MS m / z: 478 (M-1). 1 H NMR(300MHz,DMSO-d6)δ11.98(s,1H),7.77(dd,J=8.4,3.6Hz,1H),7.61-7.48(m,2H) ,7.03(dd,J=8.6,6.0Hz,1H),6.84(ddd,J=12.5,8.4,4.3Hz,1H),5.41(dd,J=11.7,2 .0Hz,1H),4.08-3.94(m,1H),3.81(q,J=8.7,8.2Hz,1H),3.71-3.55(m,1H),3.38(s, 1H),2.27(d,J=8.6Hz,3H),2.17(d,J=2.2Hz,3H),1.30(td,J=13.3,12.5,6.9Hz,6H).

[0460] Example 21: 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0461] [ka]

[0462] Step 1: Synthesis of methyl 2-(2-bromo-5-chlorophenyl)-2-methylpropanoate To a solution of methyl 2-(2-bromo-5-chlorophenyl)acetate (5 g, 18.9 mmol, 1 equiv) in DMF was added sodium hydride (60% in oil, 3 g) at 0 °C. The mixture was stirred for 1 h. CH3I (3.5 mL, 57 mmol, 3 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated NH4Cl (aq) at room temperature. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(2-bromo-5-chlorophenyl)-2-methylpropanoate (4.2 g, 75.9%).

[0463] Step 2: Synthesis of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2-methylpropanoate In a 50 mL round bottom flask, methyl 2-(2-bromo-5-chlorophenyl)-2-methylpropanoate (2.54 g, 8.7 mmol, 1 eq) and dioxane (25 mL) were added at room temperature. To the above mixture, DIEA (4.6 mL, 26.3 mmol, 3 eq), Xantphos (1.01 g, 1.74 mmol, 0.2 eq), Pd2(dba)3 (0.80 g, 0.87 mmol, 0.1 eq), benzyl mercaptan (1.23 mL, 10.4 mmol, 1.2 eq) were added dropwise at room temperature. The resulting mixture was further stirred overnight at 110° C. under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2-methylpropanoate (900 g, 30.85%).

[0464] Step 3: Synthesis of methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]-2-methylpropanoate To a stirred solution of methyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2-methylpropanoate (900 mg, 2.7 mmol, 1 equiv) in CH3CN (10 mL) was added AcOH (1.5 mL), HO (1 mL), and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1060 mg, 5.4 mmol, 2.0 equiv) portionwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. The resulting mixture was extracted with EtOAc (2x10 mL). The combined organic layers were washed with brine (3x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]-2-methylpropanoate (620 g, 74.1%).

[0465] Step 4: Synthesis of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)-2-methylpropanoate To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (620 mg, 2.06 mmol, 1 equiv) in DCM (5 mL, 78.7 mmol) was added pyridine (500 μL, 6.2 mmol, 3 equiv) and methyl 2-[5-chloro-2-(chlorosulfonyl)phenyl]-2-methylpropanoate (767 mg, 2.47 mmol, 1.2 equiv) in portions at 0° C. The resulting mixture was stirred at room temperature overnight. The residue was purified by silica gel column chromatography to give methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)-2-methylpropanoate (764 mg, 69%).

[0466] Step 5: Synthesis of 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide To a stirred solution of methyl 2-(5-chloro-2-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)-2-methylpropanoate (210 mg, 0.39 mmol, 1 equiv.) in DCM was added DIBAL-H (780 μL, 1.2 mmol, 3 equiv.) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added DIBAl-H (390 μL, 0.58 mmol, 1.5 equiv.) dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional 30 min. The reaction was quenched with water at 0° C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide (70 mg, 35.2%).

[0467] Step 6: Synthesis of -(1-bromo-2-methylpropan-2-yl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide 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-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide (50 mg, 0.098 mmol, 1 equiv.) and PPh3 (51 mg, 0.2 mmol, 2 equiv.) in DCM, CBr4 (49 mg, 0.15 mmol, 1.5 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 40° C. for 2 days. The residue was purified by preparative TLC (PE / EtOAc 1:1) to give 2-(1-bromo-2-methylpropan-2-yl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (35 mg, 62.3%).

[0468] Step 7: Synthesis of 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one In a 25 mL round bottom flask, 2-(1-bromo-2-methylpropan-2-yl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (30 mg, 0.052 mmol, 1 equiv.) and DMF (500 μL) were added at room temperature. To the above mixture, Cs2CO3 (34 mg, 0.10 mmol, 2 equiv.) was added at room temperature. The resulting mixture was stirred at 60° C. for 1 h. The crude product (25 mg) was purified by preparative HPLC to give 5-((1S)-1-(6-chloro-4,4-dimethyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (4.0 mg, 15.5%). LC-MS: (ES, m / z): [MH]+=492.05.1 H NMR (400MHz, methanol-d4) δ7.81(d,J=8.5Hz,1H),7.62(d,J=2.0Hz,1H),7.49(dd,J=8.5,2.1Hz,1H),7.04-7.02(dd,J=8.4,5.8Hz,1H) ,6.80-6.75(dd,J=12.0,8.4Hz,1H),5.68-5.65(m,1H),3.92-3.64(m,3H),2.37(s,3H),2.24(s,3H),1.50-1.45(m,3H),1.29(s,3H).

[0469] Example 22: 5-((1S,2R)-1-(6-chloro-4,4-difluoro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0470] [ka]

[0471] Step 1: Synthesis of tert-butyl 2-(2-bromo-5-chlorophenyl)-2,2-difluoroacetate In a 250 mL round bottom flask, to a solution of tert-butyl 2-(2-bromo-5-chlorophenyl)acetate (10 g, 32.7 mmol, 1 equiv) in THF (100 mL) was added LiHMDS (1 M in THF, 163 mL) dropwise under N2 atmosphere at -78 °C. The reaction mixture was stirred for 10 min at -78 °C. Then, a solution of N-fluorobenzenesulfonimide (31 g, 98.2 mmol, 3 equiv) in 3 mL of THF was added dropwise and the mixture was stirred for 10 h. The reaction was quenched with water / saturated NH4Cl (10 mL) and then the mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (300 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was directly purified by flash chromatography (PE). This gave tert-butyl 2-(2-bromo-5-chlorophenyl)-2,2-difluoroacetate (7 g, 62.6%).

[0472] Step 2: Synthesis of tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroacetate In a 250 mL round bottom flask, tert-butyl 2-(2-bromo-5-chlorophenyl)-2,2-difluoroacetate (7 g, 20.5 mmol, 1 equiv.), benzyl mercaptan (3050 mg, 24.6 mmol, 1.2 equiv.), DIEA (7950 mg, 61.5 mmol, 3 equiv.), Xantphos (2372 mg, 4.1 mmol, 0.2 equiv.), and Pd2(dba)3 (1877 mg, 2.1 mmol, 0.1 equiv.) in dioxane (112 mL) were added at room temperature. The resulting mixture was stirred at 110 °C under nitrogen atmosphere for 2 h. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine (3x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroacetate (4.9 g, 59.0%).

[0473] Step 3: Synthesis of 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroethanol A solution of tert-butyl 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroacetate] (3800 mg, 9.9 mmol, 1 equiv.) in THF was added to a 100 mL three-neck round-bottom flask, followed by dropwise addition of LiAlH4 (2 mol / L in THF) (10 mL, 20 mmol, 2.0 equiv.) at room temperature. The resulting mixture was stirred at 60° C. for 30 min under air atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM. 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 reverse-phase flash chromatography to give 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroethanol (1033 mg, 33.2%).

[0474] Step 4: Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-1-(benzylsulfanyl)-4-chlorobenzene A solution of 2-[2-(benzylsulfanyl)-5-chlorophenyl]-2,2-difluoroethanol (1033 mg, 3.3 mmol, 1 equiv.) in THF was added to a 50 mL round-bottom flask and treated with 60% NaH (118 mg, 4.9 mmol, 1.5 equiv.) at 0° C. for 30 min under nitrogen atmosphere, followed by dropwise addition of (bromomethyl)benzene (674 mg, 3.94 mmol, 1.2 equiv.) at 0° C. The resulting mixture was stirred overnight at room temperature under air atmosphere. The residue was purified by silica gel column chromatography to give 2-[2-(benzyloxy)-1,1-difluoroethyl]-1-(benzylsulfanyl)-4-chlorobenzene (1069 mg, 80.5%).

[0475] Step 5: Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chlorobenzenesulfonyl chloride A solution of 2-[2-(benzyloxy)-1,1-difluoroethyl]-1-(benzylsulfanyl)-4-chlorobenzene (1069 mg, 2.6 mmol, 1 equiv.) in MeCN was added to a 50 mL round-bottom flask. HO (590 μL) and AcOH (855 μL) were added to the mixture at 0° C., followed by the addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1040 mg, 5.3 mmol, 2.0 equiv.) in portions at 0° C. The resulting mixture was stirred at 0° C. for 30 min under air atmosphere. The residue was purified by silica gel column chromatography to give 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chlorobenzenesulfonyl chloride (800 mg, 79.5%).

[0476] Step 6: Synthesis of 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide To a stirred solution of 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one hydrochloride (237 mg, 0.79 mmol, 1 equiv.) and pyridine (3 mL) was added 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chlorobenzenesulfonyl chloride] (300 mg, 0.79 mmol, 1 equiv.) in DCM dropwise at 0° C. The resulting mixture was extracted with EtOAc (2×10 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 to give 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (300 mg, 62.5%).

[0477] Step 7: Synthesis of 4-chloro-2-(1,1-difluoro-2-hydroxyethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide To a 25 mL round bottom flask was added 2-[2-(benzyloxy)-1,1-difluoroethyl]-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (587 mg, 0.96 mmol, 1 equiv.) in DCM (2 mL), followed by dropwise addition of BBr3 (2900 μL, 2.9 mmol, 3.0 equiv.) at 0° C. The resulting mixture was stirred at 0° C. for 30 min under air atmosphere. The resulting mixture was then stirred at room temperature under air atmosphere for 2 h. The reaction was quenched with water at 0° C. The resulting mixture was extracted with DCM (2×5 mL). The combined organic layers were dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-chloro-2-(1,1-difluoro-2-hydroxyethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (300 mg, 60%).

[0478] Step 8: Synthesis of 2-(2-bromo-1,1-difluoroethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide In a 25 mL round-bottom flask, a solution of 4-chloro-2-(1,1-difluoro-2-hydroxyethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (232 mg, 0.45 mmol, 1 equiv.) and CBr4 (222 mg, 0.67 mmol, 1.5 equiv.) in DCE (3 mL) was added. To the mixture, PPh3 (234 mg, 0.89 mmol, 2 equiv.) was added in portions at room temperature. The resulting mixture was stirred at 80° C. overnight under air atmosphere. The residue was purified by preparative TLC to give 2-(2-bromo-1,1-difluoroethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (184 mg, 70.8%).

[0479] Step 9: Synthesis of 5-((1S,2R)-1-(6-chloro-4,4-difluoro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To a stirred solution of 2-(2-bromo-1,1-difluoroethyl)-4-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (185 mg, 0.32 mmol, 1 equiv.) in DMF (2 mL, 1.29 mmol), Cs2CO3 (207 mg, 0.63 mmol, 2 equiv.) was added portionwise at room temperature. The resulting mixture was stirred at 60° C. for 1 h. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(6-chloro-4,4-difluoro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (75 mg, 47.1%).

[0480] The product (75 mg) was further purified by preparative HPLC to give 6-chloro-4,4-difluoro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-3H-1lambda 6,2-benzothiazine-1,1-dione (17.7 mg, 23.4%). LC-MS (ES, m / z): [M / 2+H]+=251.90. 1 H NMR(300MHz,DMSO-d6)δ12.28(s,1H),8.05-8.00(m,2H),7.95-7.92(dd,J=8.5,2.1Hz,1H),7.08-7.03(dd,J=8.4,5.8Hz,1H),6.91-6.84(dd ,J=12.3,8.4Hz,1H),5.65-5.60(m,1H),4.62-4.54(m,2H),3.95-3.88 (tt,J=13.5,6.3Hz,1H),2.32(s,3H),2.19(s,3H),1.33-1.24(m,3H).

[0481] Example 23: 5-((1S,2R)-1-(5-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0482] [ka]

[0483] Step 1: Synthesis of methyl 2-(2-bromo-6-chlorophenyl)acetate In a 40 mL round bottom flask, (2-bromo-6-chlorophenyl)acetic acid (3 g, 12 mmol, 1 equiv.), trimethylsilyldiazomethane (2.75 g, 24 mmol, 2.0 equiv.), THF (30 mL), and MeOH (10 mL) were added at room temperature. Then, trimethylsilyldiazomethane (2.75 g, 24 mmol, 2.0 equiv.) was added at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(2-bromo-6-chlorophenyl)acetate (3 g, 94.7%).

[0484] Step 2: Synthesis of methyl 2-[2-(benzylsulfanyl)-6-chlorophenyl]acetate In a 40 mL round bottom flask, methyl 2-(2-bromo-6-chlorophenyl)acetate (3.2 g, 12.1 mmol, 1 equiv), benzyl mercaptan (1809 mg, 14.6 mmol, 1.2 equiv), DIEA (4708 mg, 36 mmol, 3.0 equiv), xantphos (1405 mg, 2.4 mmol, 0.2 equiv), Pd2(dba)3 (1112 mg, 1.2 mmol, 0.1 equiv), and dioxane (20 mL) were added at room temperature. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give methyl 2-[2-(benzylsulfanyl)-6-chlorophenyl]acetate (3 g, 80.5%).

[0485] Step 3: Synthesis of methyl 2-[2-chloro-6-(chlorosulfonyl)phenyl]acetate To an 8 mL vial, 2-[2-(benzylsulfanyl)-6-chlorophenyl]acetate (1000 mg, 3.26 mmol, 1 equiv.) and CH3CN (10 mL) were added at room temperature. To the above mixture, HO (500 μL) and AcOH (700 μL) were added, followed by dropwise addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1284 mg, 6.5 mmol, 2 equiv.) at 0° C. 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. This gave methyl 2-[2-chloro-6-(chlorosulfonyl)phenyl]acetate (800 mg, 86.7%).

[0486] Step 4: Synthesis of methyl 2-(2-chloro-6-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate To a 40 mL vial was added methyl 2-[2-chloro-6-(chlorosulfonyl)phenyl]acetate (1000 mg, 3.5 mmol, 1 equiv), pyridine (2 mL), and DCM (10 mL). To the mixture was added 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (937 mg, 3.53 mmol, 1 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave methyl 2-(2-chloro-6-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (500 mg, 27.7%).

[0487] Step 5: Synthesis of 3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)benzenesulfonamide To a 20 mL vial was added 2-(2-chloro-6-(N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)phenyl)acetate (600 mg, 1.17 mmol, 1 equiv), THF (3 mL), followed by 1 M LiBH4 (879 μL, 1.76 mmol, 1.5 equiv) dropwise. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by reverse phase flash chromatography. This gave 3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)benzenesulfonamide (200 mg, 35.3%).

[0488] Step 6: Synthesis of 2-(2-bromoethyl)-3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide To a 40 mL vial was added 3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)benzenesulfonamide (400 mg, 0.83 mmol, 1 equiv.), DCE (10 mL), PPh3 (433 mg, 1.65 mmol, 2.0 equiv.), and CBr4 (411 mg, 1.24 mmol, 1.5 equiv.). The resulting mixture was stirred at 80 °C overnight. The residue was purified by silica gel column chromatography to give 2-(2-bromoethyl)-3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (90 mg, 19.9%).

[0489] Step 7: Synthesis of 5-((1S,2R)-1-(5-chloro-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To an 8 mL vial was added 2-(2-bromoethyl)-3-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]benzenesulfonamide (80 mg, 0.15 mmol, 1 equiv.), DMF (2 mL), and Cs2CO3 (95.3 mg, 0.29 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred at 60° C. for 30 min. The residue was purified by reverse-phase flash chromatography. The crude product was purified by chiral preparative HPLC. This gave 5-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-3,4-dihydro-1lambda 6,2-benzothiazine-1,1-dione (18.1 mg, 26.5%). LCMS (ES, m / z): MH=464.10. 1H NMR (300 MHz, methanol-d4) δ 7.77 (dd, J = 7.9, 1.2 Hz, 1H), 7.62 (dd, J = 8.1, 1.3 Hz, 1H), 7.48-7.37 (m, 1H), 7.00 (dd, J = 8.5, 5.8 Hz, 1H), 6.74 (dd, J = 12.1, 8.4 Hz, 1H), 5.52 (dd, J = 11. 8,1.7Hz,1H),4.19(dt,J=14.3,7.0Hz,1H),4.04(dt,J=14.8,6.5Hz,1H),3.94-3.84(m, 1H),3.03(td,J=6.8,2.4Hz,2H),2.33(s,3H),2.21(s,3H),1.43(dd,J=6.9,1.2Hz,3H).

[0490] Example 24: 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0491] [ka]

[0492] Step 1: Synthesis of methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate A solution of 3-bromo-6-chloro-2-methylpyridine (5 g, 24.2 mmol, 1 equiv) and LiHMDS (36.3 mL, 36.3 mmol, 1.5 equiv) in THF was stirred at 0° C. for 1 h under nitrogen atmosphere. To the above mixture, dimethyl carbonate (3.06 mL, 36.3 mmol, 1.5 equiv) was added portionwise at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched by adding saturated NH4Cl(aq) (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (1×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (5.54 g, 86.5%).

[0493] Step 2: Synthesis of 2-(3-bromo-6-chloropyridin-2-yl)ethanol To a 50 mL round bottom flask, methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (5.54 g, 20.9 mmol, 1 equiv) and THF (55 mL) were added at room temperature. To the above mixture, LiBH4 (15.7 mL, 31.4 mmol, 1.5 equiv) was added dropwise at 0 °C. The reaction mixture was stirred at 35 °C overnight. The resulting mixture was diluted with EtOAc (30 mL). The solution was washed with 1 × 90 mL of HCl (0.5 M). The aqueous phase was re-extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(3-bromo-6-chloropyridin-2-yl)ethanol (3.36 g, 67.8%).

[0494] Step 3: Synthesis of 3-bromo-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine To a 20 mL vial, 2-(3-bromo-6-chloropyridin-2-yl)ethanol (3.36 g, 14.2 mmol, 1 equiv), DMF (33 mL), imidazole (3.87 g, 56.8 mmol, 4 equiv), and TBDPSCl (5.54 mL, 21.3 mmol, 1.5 equiv) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was quenched with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give 3-bromo-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine (6.69 g, 99.2%).

[0495] Step 4: Synthesis of 3-(benzylsulfanyl)-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine To a 10 mL vial, 3-bromo-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine (520 mg, 1.1 mmol, 1 equiv.), dioxane (3 mL), DIEA (381 μL, 2.19 mmol, 2 equiv.), Xantphos (63 mg, 0.11 mmol, 0.1 equiv.), Pd2(dba)3 (50 mg, 0.06 mmol, 0.05 equiv.), and benzyl mercaptan (166 μL, 1.42 mmol, 1.3 equiv.) were added at room temperature. The resulting mixture was stirred at 85° C. under nitrogen atmosphere for 3 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give 3-(benzylsulfanyl)-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine (210 mg, 37%).

[0496] Step 5: Synthesis of 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloropyridine-3-sulfonyl chloride In a 25 mL round bottom flask, 3-(benzylsulfanyl)-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine (1.5 g, 2.90 mmol, 1 equiv), AcOH (13.5 mL), and HO (4.50 mL) were added at room temperature. To the above mixture, NCS (1.16 g, 8.69 mmol, 3 equiv) was added portionwise at 0° C. The reaction mixture was stirred at room temperature for another 2 h. 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 NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[2-[(tert-butyldiphenylsilyl)oxy]ethyl]-6-chloropyridine-3-sulfonyl chloride (950 mg, 66.4%).

[0497] Step 6: Synthesis of 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-3-sulfonamide To a 20 mL vial, 2-[2-[(tert-butyldiphenylsilyl)oxy]ethyl]-6-chloropyridine-3-sulfonyl chloride (0.93 g, 1.89 mmol, 1 equiv.) and pyridine (3 mL) were added at room temperature. To the above mixture, 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (500 mg, 1.89 mmol, 1 equiv.) in DCM (3 mL) was added dropwise at 0° C. The resulting mixture was stirred at room temperature for an additional hour. The residue was purified by reverse phase flash chromatography. This gave 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-3-sulfonamide (840 mg, 61.6%).

[0498] Step 7: Synthesis of 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)pyridine-3-sulfonamide In a 50 mL round-bottom flask, 2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloro-N-((1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)pyridine-3-sulfonamide (848 mg, 1.17 mmol, 1 equiv.) and TBAF (367 mg, 1.41 mmol, 1.2 equiv.) in THF (17 mL) were added at room temperature. The resulting mixture was stirred overnight at room temperature under air atmosphere. The residue was purified by reverse-phase flash chromatography. This gave 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)pyridine-3-sulfonamide (464 mg, 81.6%).

[0499] Step 8: Synthesis of 6-chloro-2-(2-chloroethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide In a 10 mL round-bottom flask, 6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-2-(2-hydroxyethyl)pyridine-3-sulfonamide (464 mg, 0.96 mmol, 1 equiv.), DCE (2 mL), CBr4 (470 mg, 1.44 mmol, 1.5 equiv.), and PPh3 (501 mg, 1.91 mmol, 2 equiv.) were added at room temperature. The reaction mixture was stirred at 70° C. under air atmosphere for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography. This gave 6-chloro-2-(2-chloroethyl)-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide (278 mg, 57.7%).

[0500] Step 9: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one In a 10 mL vial, 2-(2-bromoethyl)-6-chloro-N-[(1S)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]pyridine-3-sulfonamide (136 mg, 0.25 mmol, 1 equiv.), Cs2CO3 (360 mg, 1.10 mmol, 2 equiv.), and DMF (4.1 mL) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere overnight. The residue was purified by reverse phase flash chromatography. This gave 5-((1S)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (150 mg, 58.2%). The product was further purified by reverse phase flash chromatography. This gave 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[2,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (33.4 mg, 60.42%). LCMS(ES,m / z):[M+H]+=467.05. 1 H NMR (300MHz, methanol-d4) δ 8.17 (d, J = 8.3Hz, 1H), 7.50 (d, J = 8.4Hz, 1H), 7.01 (dd, J = 8.5, 5.7Hz, 1H), 6.75 (dd, J = 12.1, 8.4Hz, 1H), 5.55 (dd, J = 11.7, 1.9Hz, 1H), 4.19 (dt, J = 14.7, 7.2Hz, 1H) ,4.05(ddd,J=15.1,6.9,5.6Hz,1H),3.90(dtd,J=12.7,7.6,6.1Hz,1H),3.21(dt,J=18.6,6. 3Hz,1H), 2.94(dt,J=18.6,7.2Hz,1H),2.34(s,3H),2.22(s,3H),1.43(dd,J=7.0,1.2Hz,3H).

[0501] Example 25: 5-((1S,2R)-1-(6-chloro-4-hydroxy-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0502] [ka]

[0503] To a stirred mixture of Example 16 (20 mg, 0.042 mmol, 1 equiv.) and lanthanum(III) chloride bis(lithium chloride) complex solution (81 μL, 0.042 mmol, 1 equiv.) in THF (0.80 mL), iodo(methyl)magnesium (417 μL, 0.42 mmol, 10 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was quenched at 0° C. by addition of saturated NH4Cl(aq) (2 mL). The resulting mixture was extracted with EtOAc (3×3 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 gave 5-((1S,2R)-1-(6-chloro-4-hydroxy-4-methyl-1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (20 mg, 97%). The crude product (20 mg) was purified by chiral preparative HPLC. This gave 6-chloro-2-[(1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4H-1,3,4-oxadiazol-2-yl)propyl]-4-hydroxy-4-methyl-3H-1 lambda 6,2-benzothiazine-1,1-dione (3.4 mg, 16.5%). LC-MS(ES,m / z):MH=494.05. 1H NMR (400MHz, methanol-d4) δ 7.75-7.71 (d, J = 8.4 Hz, 1H), 7.71-7.70 (d, J = 2.2 Hz, 1H), 7.51-7.49 (dd, J = 8.5, 2.1 Hz, 1H), 7.00-6.96 (dd, J = 8.4, 5.7 Hz, 1H), 6.75-6.70 (dd, J = 11.9, 8.4 Hz, 1H), H),5.63-5.60(d,J=11.4Hz,1H),3.95(d,J=14.6Hz,1H),3.97-3.83(d,J=14.7Hz,1H),3.78 -3.63(d,J=9.0Hz,2H),2.35(s,3H),2.22(s,3H),1.64(s,3H),1.45-1.44(d,J=6.8Hz,3H).

[0504] Example 26: 5-((1S)-1-((4S,5R)-7-chloro-4,5-dihydroxy-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0505] [ka]

[0506] In a 100 mL round-bottom flask, 5-((1S)-1-(7-chloro-1,1-dioxidobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (100 mg, 0.21 mmol, 1 equiv.), acetone (2 mL, NMO (73.5 mg, 0.63 mmol, 3 equiv.), KOsO.2HO (38.6 mg, 0.10 mmol, 0.5 equiv.), and HO (2 mL) were added at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filter cake was dissolved in Et The mixture was washed with OAc (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. The residue was purified by reverse phase flash chromatography. This gave (5-((1S)-1-((4S,5R)-7-chloro-4,5-dihydroxy-1,1-dioxide-4,5-dihydrobenzo[f][1,2]thiazepin-2(3H)-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (4.0 mg, 3.7%). LCMS (ES, m / z): [MH]+=510.10. 1 H NMR (300MHz, methanol-d4) δ7.96(s,1H),7.82(dd,J=16.9,8.3Hz,1H),7.43(d,J=8.9Hz,1H),7.15-6.86(m,1H),6.70(dd,J=12.0 ,8.4Hz,1H),5.74-5.59(m,2H),4.23-3.96(m,2H),3.89-3.51(m,2H),2.25(d,J=24.2Hz,6H),1.39-1.28(m,1H),0.90(s,2H).

[0507] Example 27: 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one

[0508] [ka]

[0509] Step 1: Synthesis of methyl 2-(5-bromo-2-chloropyridin-4-yl)acetate A solution of 3-bromo-6-chloro-2-methylpyridine (5 g, 24.2 mmol, 1 eq) and LiHMDS (51 mL, 51 mmol, 1.5 eq) in THF was stirred at 0° C. for 1 h under nitrogen atmosphere. To the above mixture, dimethyl carbonate (4.3 mL, 51 mmol, 1.5 eq) was added portionwise at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched by adding saturated NH4Cl(aq) (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography. This gave methyl 2-(5-bromo-2-chloropyridin-4-yl)acetate (4.2 g, 46.3%).

[0510] Step 2: Synthesis of 5-bromo-4-{2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine To a 40 mL vial, 2-(5-bromo-2-chloropyridin-4-yl)ethanol (1.91 g, 8.1 mmol, 1 equiv.), DMF (38 mL), imidazole (2.20 g, 32.3 mmol, 4 equiv.), and TBDPSCl (4.20 mL, 16.2 mmol, 2 equiv.) were added at room temperature. The resulting mixture was stirred at 35° C. for 2 h under air atmosphere. The residue was purified by reverse-phase flash chromatography. This afforded 5-bromo-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine (3.66 g, 95.4%).

[0511] Step 3: Synthesis of 5-(benzylthio)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine To a 20 mL vial, 5-bromo-4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-2-chloropyridine (3.7 g, 7.8 mmol, 1 equiv.), dioxane (37 mL), Xantphos (450 mg, 0.8 mmol, 0.1 equiv.), Pd2(dba)3 (356 mg, 0.39 mmol, 0.05 equiv.), and benzyl mercaptan (1.1 mL, 9.3 mmol, 1.2 equiv.) were added at room temperature. The resulting mixture was stirred overnight at 80° C. under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 5-(benzylthio)-4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine (1.6 g, 38.5%).

[0512] Step 4: Synthesis of 4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloropyridine-3-sulfonyl chloride In a 100 mL round bottom flask, 5-(benzylthio)-4-{2-((tert-butyldiphenylsilyl)oxy)ethyl)-2-chloropyridine (1.55 g, 3 mmol, 1 equiv), AcOH (15 mL), and HO (5 mL) were added at room temperature. To the above mixture, N-chlorosuccinimide (1.2 g, 9 mmol, 3 equiv) was added portionwise at 0° C. The resulting mixture was stirred at room temperature for another 2 h. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave 4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine-3-sulfonyl chloride (1.5 g, 100%).

[0513] Step 5: Synthesis of tert-butyl (2S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate To an 8 mL vial was added intermediate III 5-[(1S)-1-amino-2-(6-fluoro-2,3-dimethylphenyl)propyl]-3H-1,3,4-oxadiazol-2-one (500 mg, 1.8 mmol, 1.00 equiv.) and pyridine (719 μL, 8.9 mmol, 5 equiv.) at room temperature. To the above mixture was added 4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine-3-sulfonyl chloride (1255 mg, 1.8 mmol, 1 equiv., 70%) in DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The residue was purified by silica gel column chromatography to give tert-butyl (2S)-2-((4-(2-((tert-butyldiphenylsilyl)oxy)ethyl)-6-chloropyridine)-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (540 mg, 41%).

[0514] Step 6: Synthesis of tert-butyl (2S)-2-[6-chloro-4-(2-hydroxyethyl)pyridine-3-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate In a 100 mL round-bottom flask, tert-butyl (2S)-2-(4-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-6-chloropyridine-3-sulfonamido)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (530 mg, 0.72 mmol, 1 equiv.), THF (10 mL), and TBAF (281 mg, 1.08 mmol, 1.5 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 1 h. The residue was purified by reverse-phase flash chromatography. This afforded tert-butyl (2S)-2-[6-chloro-4-(2-hydroxyethyl)pyridine-3-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (200 mg, 55.7%).

[0515] Step 7: Synthesis of tert-butyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate To a 10 mL vial, tert-butyl (2S)-2-[6-chloro-4-(2-hydroxyethyl)pyridine-3-sulfonamido]-3-(6-fluoro-2,3-dimethylphenyl)butanoate (20 mg, 0.04 mmol, 1 eq.), THF (1.6 mL), and PPh3 (83.8 mg, 0.32 mmol, 2 eq.) were added at room temperature. The resulting mixture was stirred at room temperature for 20 min under nitrogen atmosphere. To the above mixture, DIAD (63.3 μL, 0.32 mmol, 2.00 eq.) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional hour. The residue was purified by reverse phase flash chromatography. This gave tert-butyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (40 mg, 51.9%).

[0516] Step 8: Synthesis of (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid A 25 mL round-bottom flask was charged with tert-butyl (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoate (100 mg, 0.02 mmol, 1 equiv.), DCM (0.9 mL), and TFA (0.3 mL) at room temperature. The resulting mixture was stirred at room temperature under air atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography. This afforded (2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (80 mg, 90.5%).

[0517] Step 9: Synthesis of 5-((1S,2R)-1-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one To a 10 mL vial, 2S)-2-(6-chloro-1,1-dioxide-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-3-(6-fluoro-2,3-dimethylphenyl)butanoic acid (70 mg, 0.16 mmol, 1 equiv.), CDI (79.8 mg, 0.49 mmol, 3 equiv.), and THF (1.4 mL) were added at room temperature. The mixture was stirred at room temperature for 30 min under air atmosphere. To the above mixture, NH2NH2.H2O (23.9 μL, 0.49 mmol, 3 equiv.) was added dropwise at 0° C. The mixture was stirred at 0° C. for another 30 min. The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. To a 10 mL vial, the above crude product, CDI (79.8 mg, 0.49 mmol, 3 equiv.), and dioxane (0.2 mL) were added at room temperature. The mixture was stirred at room temperature under air atmosphere for 1 h. The resulting mixture was poured into water and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by reverse-phase flash chromatography. This gave 5-((1S,2R)-1-(6-chloro-1,1-dioxido-3,4-dihydro-2H-pyrido[4,3-e][1,2]thiazin-2-yl)-2-(6-fluoro-2,3-dimethylphenyl)propyl)-1,3,4-oxadiazol-2(3H)-one (21.8 mg, 25.9%). LCMS (ES, m / z): [MH]+=465.05. 1H NMR (300MHz, methanol-d4) δ 8.72 (s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 7.02 (dd, J = 8.4, 5.7Hz, 1H), 6.76 (dd, J = 12.1, 8.4Hz, 1H), 5.57 (dd, J = 11.8, 1.8Hz, 1H), 4.19 (dt, J = 14.2, 7.1Hz,1H),4.03(dt,J=14.2,6.4Hz,1H),3.88(dq,J=13.3,7.4,6.8Hz,1H),3.18(dt,J=18. 2,6.6Hz,1H),2.95(dt,J=18.1,6.9Hz,1H),2.35(s,3H),2.23(s,3H),1.45(d,J=6.8Hz,3H).

[0518] Example A: RNR enzyme activity A rapid-fire mass spectrometry (RF / MS) assay was used to assess RNR enzyme activity using 384-well plates and a robotic platform.

[0519] The plate layout included two validated reference compounds: Triapine (3-AP) and Hydroxyurea (HU). • Dose response in duplicate, highest concentrations: 5 μM (3-AP) and 250 μM (HU) semi-logarithmic. ●Dilution solution. Spike randomly spotted triplicate wells at four concentrations HU: 250 μM, 100 μM, 30 μM, and 2 μM 3-AP: 5 μM, 2 μM, 0.6 μM, and 0.04 μM

[0520] First, the multi-droplet tubes were saturated with the enzyme solution for 30 min. Afterwards, 30 μL of stop solution was distributed to column 24. Then, 15 μL of enzyme was distributed to columns 1-24. Then, a pre-incubation step of 15 min at room temperature was performed, after which 15 μL of substrate solution was distributed (columns 1-24). Then, the plate was incubated at 37 °C for 45 min. 30 μL of stop solution was distributed to columns 1-23.

[0521] The final parameters of the enzymatic reaction were as follows: Incubation: 37℃, 45 minutes ●[CDP]: 5 μm, [ATP]: 1 mM, [NADPH]: No ●[RNR] Final: 50nM, 1:1 (RNR1:RNR2) ratio Final volume: 30μL Stop solution: 6% HCOOH containing 2 μM 15

[0522] Compounds were screened at concentrations up to 50 μM and the results are shown in Table 2.

[0523] [Table 2]

[0524] Example B: Alphalisa Assay Colo320 DM cells (ATCC#CCL-220 derived from Duke type C, a human colon adenocarcinoma) were seeded in 96-well cell culture treated assay plates at a density of 50,000 cells / well in 200 μL of RPMI-1640 medium supplemented with 10% fetal bovine serum and incubated overnight at 37°C. The following day, test compound dilutions were added directly to the plated cells by Tecan digital dispenser to a final DMSO concentration of <0.5% and incubated overnight (approximately 16 hours) at 37°C. The following day, all cell medium was removed from the cells. 75 μL of 1× AlphaLisa lysis buffer was added to each well and the plate was agitated on a shaker for 30 minutes at room temperature. Cell lysis and detection of PCHK1 (S345) was performed using reagents included in the AlphaLisa Sure Fire assay kit (Perkin Elmer#ALSU-PCHK1-A) according to the manufacturer's instructions. 10 μL of each lysate was then transferred to a white 384-well assay plate (Perkin Elmer #6008280). 5 μL of acceptor mix was added to each well of lysate in the white 384-well assay plate and incubated at room temperature in the dark for 60 minutes. 5 μL of donor mix was added to each well of the white 384-well assay plate in dim light and incubated at room temperature for 60 minutes. Plates were read on an Alpha Technology compatible plate reader using standard AlphaLisa settings.

[0525] The results are shown in Table 3.

[0526] [Table 3]

[0527] Example C: Pharmaceutical Compositions Example C1: Parenteral Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100mg of the water-soluble salt of the compound described herein is dissolved in DMSO, and then mixed with 10mL of 0.9% sterile saline.The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0528] Example C2: Oral Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of the compound described herein is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

[0529] Example C3: Sublingual (hard lozenge) composition To prepare a pharmaceutical composition for buccal delivery, such as a hard lozenge, 100 mg of a compound described herein is mixed with 420 mg of powdered sugar mixed with 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract. The mixture is gently mixed and poured into a mold to form a lozenge suitable for buccal administration.

[0530] The examples and embodiments described herein are for illustrative purposes only and various modifications or variations, depending on the embodiment, are intended to be within the scope of the disclosure and the appended claims.

Claims

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

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring C is a 7-membered heterocycloalkyl optionally containing one additional heteroatom selected from the group consisting of O, S, and N.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring C is a 6-membered heterocycloalkyl optionally containing one additional heteroatom selected from the group consisting of O, S, and N. Claim 4: The compound of (Ia) is represented by the formula (Ic) or the formula (Id): 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, which is:

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 6′ is hydrogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R 5 is independently deuterium, halogen, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl, or two R 5 on the same carbon together form oxo, and p is 0, 1, or 2.

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 1 is hydrogen, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 2 is hydrogen, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 3 is hydrogen, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 4 is hydrogen, halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein R 7 is C 1 -C 6 alkyl and R 8 is hydrogen.

12. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein ring B is phenyl.

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein each R 9 is independently halogen or C 1 -C 6 alkyl and m is 1 to 3. 【Request 14】 【Chemical 3-1】 【Chemistry 3-2】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, selected from the group consisting of:

15. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

16. Use of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, in the manufacture of a medicament for treating cancer in a subject.

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