ACYL SULFONAMIDE COMPOUNDS AS INHIBITORS OF POLYOMAVIRUS FIELD [0001] This disclosure describes compounds, compositions, and methods useful for treating a viral infection caused by polyomavirus, e.g., by inhibiting polyomavirus replication. BACKGROUND [0002] BK polyomavirus (BKV or BKPyV) was first isolated from an immunosuppressed kidney transplant recipient in 1971 (Gardner et al., Lancet 19711:1253) and was one of the first two human polyomaviruses identified (alongside JC polyomavirus [JCV or JCPyV]). To date, there are 14 known human polyomaviruses, only five of which have been confirmed to cause disease with proven histopathology: BKV, JCV, Merkel Cell polyomavirus (MCPyV), Trichodysplasia Spinulosa-associated polyomavirus (TsPyV), and human polyomavirus 7 (HPyV7) (Wu et al., Rev. Med. Virology 202131:e2220). [0003] BKV, like the other members of the polyomavirus family, is a small (40-45 nm in diameter), non-enveloped, icosahedral virion with a closed circular double-stranded DNA genome approximately 5 kb in length. BKV encodes only seven proteins and notably lacks traditional enzymatic targets for antiviral drugs (i.e., kinases, polymerases, and proteases). The genome can be divided into three regions: the early coding region, the late coding region, and a non-coding control region (NCCR). The early coding region encodes for the three regulatory proteins (large, small, and truncated tumor antigens [TAg, tAg, and truncTAg, respectively]), which are the first viral proteins expressed in a newly infected cell and are responsible for facilitating viral DNA replication and establishing a favorable cellular environment. The late coding region encodes the three structural proteins (VPl, VP2, and VP3) that comprise the viral capsid, as well as the agnoprotein, which plays a regulatory role during viral replication. In addition, viral microRNAs are encoded in the direction of the late coding region and may have a role in downregulating early gene expression. The NCCR contains the origin of replication and bidirectional promoter/enhancer elements that drive expression of both the early and late viral gene products. [0004] The lifecycle of BKV begins with virion binding to host GT1b and GD1b ganglioside receptors (Low et al., J. Virol.200680:1361). The virus subsequently undergoes endocytosis via a caveolin-dependent pathway (Eash et al., J. Virol.200478:11583) and is trafficked in endosomes to the endoplasmic reticulum (Jiang et al., J. Virol. 200983:1350; Moriyama and Sorokin, Virology 2008371:336), where host cell enzymes orchestrate capsid disassembly. The partially disassembled particle is ultimately trafficked to the nucleus, where host cell transcription machinery initiates viral gene expression (Helle et al., Viruses 20179:327). [0005] Infection with BKV is essentially ubiquitous, with estimates of seroprevalence ranging from 80 to 90% of the global population (Knowles, Adv. Exp. Med. Biol.2006577:19; Kean et al., PLOS Pathogens 20095:e1000363). Primary infection typically occurs in childhood, resulting in persistent infection of the reno-urinary tract, which is effectively controlled, though never eliminated, by the immune system (Ahsan and Shah, Adv. Exp. Med. Biol.2006577:1; Heritage et al., J. Med. Virol. 19818:143; Shinohara et al., J. Med. Virol.199341:301). Transient asymptomatic viral shedding in the urine (viruria) of immunocompetent adults occurs sporadically but results in no disease or sequelae. Compromised immune function, however, can lead to uncontrolled viral replication and development of disease, the best characterized of which are BKV nephropathy (BKVN) in kidney transplant recipients (KTRs) and hemorrhagic cystitis in hematopoietic cell transplant (HCT) recipients. [0006] BKV nephropathy (BKVN) is a leading cause of premature allograft loss, second only to allograft rejection (Nickeleit, et al., J. Am. Soc. Nephrol.201829:680). BKV reactivation in KTRs is first detected as viruria (30 to 50% of patients), with approximately one-third of these patients progressing to viremia (virus in the blood), and subsequently one-third of viremic patients progressing to biopsy-confirmed BKVN (3 to 4% of all KTRs, published rates ranging from 1 to 10%) (Ambalathingal et al., Clin. Micorbiol. Rev. 201730:503; Nickeleit, et al., J. Am. Soc. Nephrol.201829:680). Despite aggressive approaches to monitor for BKV replication and earlier intervention, 15% to 50% of patients diagnosed with BKVN will suffer graft loss (Nickeleit, et al., J. Am. Soc. Nephrol. 201829:680; Kuypers, Nat Rev Nephrol 20128:390). The current standard of care for BKV reactivation in KTRs is modulation (reduction and/or switching) of the immunosuppressive therapy. Among those undergoing reduction in immunosuppression, up to 30% will experience an acute graft rejection episode (Bohl and Brennan, Clin. J. Am. Soc. Nephrol. 20072 Suppl. 1:S36; Sood et al., Transplantation 2012 94:814). [0007] BKV is the leading viral cause of late hemorrhagic cystitis, a painful infection of the bladder associated with hematuria and affecting approximately 10% of HCT recipients (published rates ranging from 6% to 16%) (Giraud et al., Haematologica 200691:401; El- Zimaity et al., Blood 2004103:4674). The current standard of care is generally supportive, primarily involving forced hydration, bladder irrigation, and pain management measures. BKV- associated hemorrhagic cystitis prolongs hospitalizations, often requires administration of blood products and urologic intervention, and can lead to death in severe cases (Gilis et al., Bone Marrow Transplant.201449:664-670; Lunde et al., Bone Marrow Transplant.201550:1432- 1437). [0008] There are currently no specific or effective antiviral therapies approved for BKV. While a number of reports have described the off-label uses of cidofovir, leflunomide, fluoroquinolones, and commercially available pooled intravenous immunoglobulin (IVIG) preparations to treat patients with BK viremia or BKVN, there are no definitive data confirming their effectiveness (Ambalathingal et al., Clin. Micorbiol. Rev. 201730:503). As such, there is an unmet medical need in the field for therapies that inhibit polyomavirus replication and that can be used to safely treat uncontrolled BKV replication and associated disease in an immunocompromised host. BRIEF SUMMARY [0009] The terms “invention,” “the invention,” “this invention,” and “the present invention,” as used in this document, are intended to refer broadly to all of the subject matter of this patent application and the claims below. Statements containing these terms should be understood not to limit the subject matter described herein or to limit the meaning or scope of the patent claims below. Covered embodiments of the invention are defined by the claims, not this summary. This summary is a high-level overview of various aspects of the invention and introduces some of the concepts that are described and illustrated in the present document and the accompanying figures. This summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures, and each claim. Some of the exemplary embodiments of the present invention are discussed below. [0010] Provided herein are compounds having the structure of Formula I: 1 wherein each R of Formula (I) can independently be C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, -SO ₂ R ¹¹ , or -P(R ¹¹ ) ₃ . R ² of Formula (I) can be absent, hydrogen, or C _1-20 alkyl. Alternatively, R ² can be combined with an R ⁹ and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups. R ³ of Formula (I) can be hydrogen, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ³ can be combined with R ⁴ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ³ can be combined with an R ¹⁰ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. R ⁴ of Formula (I) can be hydrogen, C _1-20 alkyl, C _2-20 alkynyl, C _{2- 9} carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ⁴ can be combined with R ³ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. R ⁵ of Formula (I) can be hydrogen, C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkylhydroxy, halogen, C _1-20 haloalkyl, or C _3-12 cycloalkyl. R ⁶ and R ⁷ of Formula (I) can each independently be C _1-20 alkyl. Alternatively, R ⁶ and R ⁷ can be combined with the carbon to which they are attached to form a C _3-12 cycloalkyl or a 3- to 15-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups. R ⁸ of Formula (I) can be C _3-12 cycloalkyl, C _6-14 aryl, or 5- to 16-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1-4 R ¹¹ groups. Each R ⁹ of Formula (I) can independently be hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl. Alternatively an R ⁹ can be combined with R ² and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups. Each R ¹⁰ of Formula (I) can independently be hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, - NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl. Alternatively, an R ¹⁰ can be combined with R ³ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. Each R ¹¹ can independently be C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, 2- to 12-membered heteroalkyl, C _3-12 cycloalkyl, 5- to 16-membered heteroaryl, C _3-12 cycloalkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, oxo, -NH ₂ , nitro, cyano, or diazirine, wherein the cycloalkyl, heteroaryl, and cycloalkoxy are optionally substituted with one or more hydroxy or halogen groups or a combination thereof. X ¹ , X ² , A ¹ , and A ² of Formula (I) can each independently be C, N, O, or S. Subscripts m, n, and p of Formula (I) can each independently be an integer from 0 to 4. The provided compounds can alternatively have the formula of a pharmaceutically acceptable salt, solvate, or isomer of Formula (I). [0011] Also provided herein are pharmaceutical compositions including a disclosed compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof) and a pharmaceutically acceptable carrier. [0012] In addition, methods of treating a disorder are provided. The methods include administering a therapeutically effective amount of a disclosed compound (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof), or a therapeutically effective amount of a disclosed pharmaceutical composition including a provided compound and a pharmaceutically acceptable carrier, to a subject in need thereof. DETAILED DESCRIPTION A. GENERAL [0013] The present disclosure provides compounds capable of interfering with polyomavirus function, e.g., by inhibiting polyomavirus replication, and therefore providing beneficial therapeutic effects. The disclosure also provides methods of treating diseases and disorders by administering to a patient in need thereof compositions with the compounds disclosed herein. [0014] The various aspects of the disclosure generally include a small molecule having inhibitory activity against polyomaviruses including BK virus genotypes I, II, III, and IV; JC virus, Merkel Cell polyomavirus, Simian virus 40, and Murine polyomavirus. Unlike a neutralizing antibody, the provided inhibitory compounds advantageously act on an intracellular target. Further, the provided compounds are beneficially characterized by high potency, good solubility, low lipophilicity, and low interaction with the hERG potassium channel. The compounds may avoid toxicity liabilities, such as thrombocytopenia and neutropenia, unfavorable for BK virus and JC virus indications. Treatment methods applying the provided compounds can be used to intervene after kidney transplant to block BK virus replication and prevent BK virus-associated nephropathy. Additional disclosed methods can be effective in treating JC virus-induced progressive multifocal leukoencephalopathy. B. DEFINITIONS [0015] The abbreviations used herein have their conventional meaning within the chemical and biological arts. Description of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, or physiological conditions. Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH ₂ O- is equivalent to -OCH ₂ -. [0016] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a polymer” optionally includes a combination of two or more polymers, and the like. [0017] As used herein, the term “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). [0018] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field, for example ± 20%, ± 10%, or ± 5%, are within the intended meaning of the recited value. [0019] As used herein, the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited. As used herein, the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified. As used herein, the phrase “consisting essentially of” limits the scope of the described feature to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the disclosed feature. [0020] As used herein, the term “alkyl,” by itself or as part of another substituent, refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. A branched alkyl may include one or branches having a geminal, vicinal, and/or isolated pattern. For example, an alkyl may include gem-methyl groups. Alkyl may include any number of carbons, such as C _1-2 , C _1-3 , C _1-4 , C _1-5 , C _1-6 , C _1-7 , C _1-8 , C _1-9 , C _1-10 , C _2-3 , C _2-4 , C _2-5 , C _2-6 , C _3-4 , C _3-5 , C _3-6 , C _4-5 , C _4-6 and C _5-6 . For example, C _1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. In some aspects, alkyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0021] As used herein, the term “alkenyl,” by itself or as part of another substituent, refers to an alkyl group having at least one carbon-carbon double bond. Alkenyl may include any number of carbons, such as C ₂ , C _2-3 , C _2-4 , C _2-5 , C _2-6 , C _2-7 , C _2-8 , C _2-9 , C _2-10 , C ₃ , C _3-4 , C _3-5 , C _3-6 , C ₄ , C _4-5 , C _4-6 , C ₅ , C _5-6 , and C ₆ . Alkenyl groups may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, and 1,3,5-hexatrienyl. In some aspects, alkenyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0022] As used herein, the term “alkynyl,” by itself or as part of another substituent, refers to an alkyl group having at least one carbon-carbon triple bond. Alkynyl may include any number of carbons, such as C ₂ , C _2-3 , C _2-4 , C _2-5 , C _2-6 , C _2-7 , C _2-8 , C _2-9 , C _2-10 , C ₃ , C _3-4 , C _3-5 , C _3-6 , C ₄ , C _4-5 , C _4-6 , C ₅ , C _5-6 , and C ₆ . Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. In some aspects, alkynyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0023] As used herein, the term “alkoxy” refers to a substituted alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for the (unsubstituted) alkyl group, alkoxy groups may have any suitable number of carbon atoms, such as C ₁₆ . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, etc. [0024] As used herein, the terms “hydroxyalkyl” or “alkylhydroxy” refer to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group. As for the alkyl group, alkylhydroxy groups can have any suitable number of carbon atoms, such as C _1-6 . Exemplary alkylhydroxy groups include, but are not limited to, hydroxy-methyl, hydroxyethyl (where the hydroxy is in the 1- or 2-position), hydroxypropyl (where the hydroxy is in the 1-, 2- or 3-position), hydroxybutyl (where the hydroxy is in the 1-, 2-, 3- or 4-position), hydroxypentyl (where the hydroxy is in the 1-, 2-, 3-, 4- or 5-position), hydroxyhexyl (where the hydroxy is in the 1-, 2-, 3-, 4-, 5- or 6-position), 1,2-dihydroxyethyl, and the like. [0025] As used herein, the term “halogen” refers to fluorine, chlorine, bromine, and iodine. [0026] As used herein, the term “haloalkyl” refers to alkyl, as defined above, where some or all of the hydrogen atoms are replaced with halogen atoms. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as C _1-6 . For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some instances, the term “perfluoro” can be used to define a compound or radical where all the hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. [0027] As used herein, the term “carboxy” refers to a carboxylic acid group of the formula -C(O)OH or -CO ₂ H. [0028] As used herein, the term “carboxyalkyl” refers to a carboxy group linked to an alkyl, as described above, and generally having the formula -C _1-20 alkyl-C(O)OH. [0029] As used herein, the term “cyano,” by itself or as part of another substituent, refers to a carbon atom triple-bonded to a nitrogen atom (i.e., the moiety –C≡N). [0030] As used herein, the term “cyanoalkyl” refers to a cyano group linked to an alkyl, as described above, and generally having the formula -C _1-20 alkyl-C≡N. [0031] As used herein, the term “heteroalkyl,” by itself or as part of another substituent, refers to an alkyl group of any suitable length and having from 1 to 3 heteroatoms such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O) ₂ -. For example, heteroalkyl may include ethers, thioethers and alkyl-amines. The heteroatom portion of the heteroalkyl may replace a hydrogen of the alkyl group to form a hydroxy, thio, or amino group. Alternatively, the heteroatom portion may be the connecting atom, or be inserted between two carbon atoms. [0032] As used herein, the term “cycloalkyl,” by itself or as part of another substituent, refers to a saturated or partially unsaturated, monocyclic, fused polycyclic, spiro polycyclic, or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl may include any number of carbons, such as C _3-6 , C _4-6 , C _5-6 , C _3-8 , C _4-8 , C _5-8 , C _6-8 , C _3-9 , C _3-10 , C _3-11 , and C _3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo[1.1.1]pentane, norbornane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. When cycloalkyl is a saturated monocyclic C _3-8 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a saturated monocyclic C _3-6 cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some aspects, cycloalkyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0033] As used herein the term “heterocyclyl,” by itself or as part of another substituent, refers to a saturated heterocyclyl ring system having from 3 to 15 ring members, a partially unsaturated non-aromatic ring, or a partially unsaturated, non-aromatic fused, spiro, or bridged multiple-ring system in which one or more of the carbon atoms are each independently replaced with the same or different heteroatom such as N, O and S. Additional heteroatoms may also be useful, including, but not limited to, B, Al, Si and P. The heteroatoms may be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heterocyclyl groups may include any number of ring atoms, such as, C _3-6 , C _4-6 , C _5-6 , C _3-8 , C _4-8 , C _5-8 , C _6-8 , C _3-9 , C _3-10 , C _3-11 , C _3-12 , or C _3-15 , wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of carbon ring atoms may be replaced with heteroatoms in the heterocyclyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocyclyl group may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. One or more heterocycloalkyl rings of heterocyclyl groups may also be fused to aromatic or non-aromatic rings to form members including, but not limited to, indoline. Heterocyclyl groups thus include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines, e.g., 3,4- dihydroquinoline, dihydroisoquinolines, e.g., 1,2- dihydroisoquinoline, tetrahydroquinolines, e.g., 1,2,3,4-tetrahydroquinoline, tetrahydroisoquinoline, dihydroimidazole, tetrahydroimidazole, etc., isoindoline, isoindolones (e.g., isoindolin-1-one), isatin, dihydrophthalazine, quinolinone, spiro[cyclopropane-1,1'- isoindolin]-3'-one, and the like. Heterocyclyl groups may have 3-15 members, or 3-12 members, or 3-10 members, or 3-7 members, or 5-6 members. In some aspects, heterocyclyl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0034] The heterocyclyl groups may be linked via any position on the ring. For example, aziridine may be 1- or 2-aziridine, azetidine may be 1- or 2- azetidine, pyrrolidine may be 1-, 2- or 3-pyrrolidine, piperidine may be 1-, 2-, 3- or 4-piperidine, pyrazolidine may be 1-, 2-, 3-, or 4- pyrazolidine, imidazolidine may be 1-, 2-, 3- or 4-imidazolidine, piperazine may be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran may be 1- or 2-tetrahydrofuran, oxazolidine may be 2-, 3-, 4- or 5- oxazolidine, isoxazolidine may be 2-, 3-, 4- or 5-isoxazolidine, thiazolidine may be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine may be 2-, 3-, 4- or 5- isothiazolidine, and morpholine may be 2-, 3- or 4-morpholine. [0035] As used herein, the term “heterocyclylene” refers to a heterocyclyl group, as defined above, linking at least two other groups. The two moieties linked to the heterocyclyl are linked to different atoms of the heterocyclyl. [0036] As used herein, the term “aryl” refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups may include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups may be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. In some aspects, aryl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0037] As used herein, the term “heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms may also be useful, including, but not limited to, -S(O)- and -S(O) ₂ -. Heteroaryl groups may include any number of ring atoms, such as C _5-6 , C _3-8 , C _4-8 , C _5-8 , C _6-8 , C _3-9 , C _3-10 , C _3-11 , or C _3-12 , wherein at least one of the carbon atoms is replaced by a heteroatom. Any suitable number of heteroatoms may be included in the heteroaryl groups, such as 1, 2, 3, 4; or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups may have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. The heteroaryl group may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups may also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. In some aspects, heteroaryl groups may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, oxo, nitro, cyano, and alkoxy. [0038] The heteroaryl groups may be linked via any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole, pyridine includes 2-, 3-, and 4-pyridine, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, triazole includes 1-, 4-, and 5- triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-, and 6- pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5-, and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3- thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4-, and 5-thiazole, isothiazole includes 3-, 4-, and 5-isothiazole, oxazole includes 2-, 4-, and 5-oxazole, isoxazole includes 3-, 4-, and 5-isoxazole, indole includes 1-, 2-, and 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3-, and 4-quinoline, isoquinoline includes 1-, 3-, and 4-isoquinoline, quinazoline includes 2- and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran. [0039] Some heteroaryl groups include those having from 5 to 10 ring members and from 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having from 5 to 8 ring members and from 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having from 9 to 12 ring members and from 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having from 5 to 6 ring members and from 1 to 2 ring heteroatoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. [0040] Some heteroaryl groups include from 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups include from 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups include from 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups include from 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline. [0041] As used herein, the term “oxo,” by itself or as part of another substituent, refers to an oxygen atom that is double-bonded to a compound (i.e., O=). [0042] As used herein, the term “nitro,” by itself or as part of another substituent, refers to the moiety –NO ₂ . [0043] As used herein, the term “fused” refers to a ring substituent which is joined by two bonds at adjacent atoms. Decahydronaphthalene is an example of a fused ring system. [0044] As used herein, the term “spiro” refers to a ring substituent which is joined by two bonds at the same atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl- dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents. [0045] As used herein, the term “bridged” refers to a ring substituent which is joined by two bonds at non-adjacent atoms. Quinuclidinyl and adamantyl are examples of bridged ring systems [0046] As used herein, the term “salt” refers to acid or base salts of the compounds of the present disclosure. An “agriculturally acceptable salt” is one that is compatible with other ingredients of a formulation composition containing the compound, and that is not deleterious to a recipient thereof. It is thus understood that the agriculturally acceptable salts are non-toxic. Illustrative examples of salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. Salts of the acidic compounds of the present disclosure are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyl-ammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts. Similarly acid addition salts, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. [0047] As used herein, the term “solvate” refers to a compound that is complexed to at least one solvent molecule. The compounds of the present disclosure may be complexed with from 1 to 10 solvent molecules. In some embodiments, the solvent is water and the solvate is a hydrate. [0048] As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. Isomers thus include compounds having different arrangements of the same formula of atoms in a molecule possessing one or more asymmetric carbon atoms or double bonds. Isomers may include racemates, enantiomers, diastereomers, geometric isomers, and individual isomers. [0049] As used herein, the term “subject” refers to a vertebrate, and preferably to a mammal. Mammalian subjects for which the provided composition is suitable include, but are not limited to, mice, rats, simians, humans, farm animals, sport animals, and pets. In some embodiments, the subject is human. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the subject is an adult. In some embodiments, the subject is an adolescent. In some embodiments, the subject is a child. In some embodiments, the subject is above 10 years of age, e.g., above 20 years of age, above 30 years of age, above 40 years of age, above 50 years of age, above 60 years of age, above 70 years of age, or above 80 years of age. In some embodiments, the subject is less than 80 years of age, e.g., less than 70 years of age, less than 60 years of age, less than 50 years of age, less than 40 years of age, less than 30 years of age, less than 20 years of age, or less than 10 years of age. [0050] As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and may be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients and carriers include water, NaCl, normal saline solutions, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, and the like. One of skill in the art will recognize that other pharmaceutically acceptable excipients and carriers are useful in the present disclosure. [0051] As used herein, the term “administering” refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject. [0052] As used herein, the term “therapeutically effective amount” refers to an amount or dose of a compound, composition, or formulation that produces therapeutic effects for which it is administered. The exact amount or dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0053] As used here, the terms “treat”, “treating” and “treatment” refers to a procedure resulting in any indicia of success in the elimination or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of one or more symptoms. The treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination or laboratory test. C. COMPOUNDS [0054] The present disclosure provides many inhibitors of polyomavirus. In some embodiments, the polyomavirus inhibitor is an acyl sulfonamide compound having the structure 1 wherein each R of Formula (I) can independently be C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, -SO ₂ R ¹¹ , or -P(R ¹¹ ) ₃ . R ² of Formula (I) can be absent, hydrogen, or C _1-20 alkyl. Alternatively, R ² can be combined with an R ⁹ and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups. R ³ of Formula (I) can be hydrogen, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ³ can be combined with R ⁴ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ³ can be combined with an R ¹⁰ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. R ⁴ of Formula (I) can be hydrogen, C _1-20 alkyl, C _2-20 alkynyl, C _{2- 9} carboxyalkyl, or 2- to 20-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. Alternatively, R ⁴ can be combined with R ³ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. R ⁵ of Formula (I) can be hydrogen, C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkylhydroxy, halogen, C _1-20 haloalkyl, or C _3-12 cycloalkyl. R ⁶ and R ⁷ of Formula (I) can each independently be C _1-20 alkyl. Alternatively, R ⁶ and R ⁷ can be combined with the carbon to which they are attached to form a C _3-12 cycloalkyl or a 3- to 15-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups. R ⁸ of Formula (I) can be C _3-12 cycloalkyl, C _6-14 aryl, or 5- to 16-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1-4 R ¹¹ groups. Each R ⁹ of Formula (I) can independently be hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl. Alternatively an R ⁹ can be combined with R ² and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups. Each R ¹⁰ of Formula (I) can independently be hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, - NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl. Alternatively, an R ¹⁰ can be combined with R ³ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. Each R ¹¹ can independently be C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, 2- to 12-membered heteroalkyl, C _3-12 cycloalkyl, 5- to 16-membered heteroaryl, C _3-12 cycloalkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, oxo, -NH ₂ , nitro, cyano, or diazirine, wherein the cycloalkyl, heteroaryl, and cycloalkoxy are optionally substituted with one or more hydroxy or halogen groups or a combination thereof. X ¹ , X ² , A ¹ , and A ² of Formula (I) can each independently be C, N, O, or S. Subscripts m, n, and p of Formula (I) can each independently be an integer from 0 to 4. The provided compounds can alternatively have the formula of a pharmaceutically acceptable salt, solvate, or isomer of Formula (I). [0055] In some embodiments, at least one R ¹ of Formula (I) is halogen, nitro, or cyano. In some embodiments, each R ¹ is independently halogen, nitro, or cyano. In some embodiments, at least one R ¹ is fluorine, chlorine, nitro, or cyano. In some embodiments, each R ¹ is independently fluorine, chlorine, nitro, or cyano. In some embodiments, at least one R ¹ is fluorine, nitro, or cyano. In some embodiments, each R ¹ is independently fluorine, nitro, or cyano. In some embodiments, at least one R ¹ is fluorine or cyano. In some embodiments, each R ¹ is independently fluorine or cyano. In some embodiments, at least one R ¹ is nitro. In some embodiments, each R ¹ is nitro. In some embodiments, at least one R ¹ is halogen. In some embodiments, each R ¹ is independently halogen. In some embodiments, at least one R ¹ is chlorine or fluorine. In some embodiments, each R ¹ is independently chlorine or fluorine. In some embodiments, at least one R ¹ is fluorine. In some embodiments, each R ¹ is fluorine. In some embodiments, at least one R ¹ is chlorine. In some embodiments, each R ¹ is chlorine. In some embodiments, at least one R ¹ is cyano. In some embodiments, each R ¹ is cyano. [0056] In some embodiments, e.g., when X ¹ is C, R ² of Formula (I) is hydrogen. In some embodiments, e.g., when X ¹ is O, R ² is absent. In some embodiments, R ² is C _1-6 alkyl. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is propyl. In some embodiments, R ² is isopropyl. In some embodiments, R ² is butyl. In some embodiments, R ² is isobutyl. In some embodiments, R ² is sec-butyl. In some embodiments, R ² is tert-butyl. In some embodiments, R ² is pentyl. In some embodiments, R ² is isopentyl. In some embodiments, R ² is 2-methylbutyl. In some embodiments, R ² is pentan-2-yl. In some embodiments, R ² is 3-methylbutan-2-yl. In some embodiments, R ² is pentan-3-yl. In some embodiments, R ² is neopentyl. In some embodiments, R ² is tert-pentyl. In some embodiments, R ² is hexyl. In some embodiments, R ² is 4-methylpentyl. In some embodiments, R ² is 3- methylpentyl. In some embodiments, R ² is 2-methylpentyl. In some embodiments, R ² is hexan-2- yl. In some embodiments, R ² is 2,3-dimethylbutyl. In some embodiments, R ² is 4-methylpentan- 2-yl. In some embodiments, R ² is 3-methylpentan-2-yl. In some embodiments, R ² is 2-ethylbutyl. In some embodiments, R ² is hexan-3-yl. In some embodiments, R ² is 3,3-dimethylbutyl. In some embodiments, R ² is 2,2-dimethylbutyl. In some embodiments, R ² is 2-methylpentan-2-yl. [0057] In some embodiments, R ³ and R ⁴ of Formula (I) are each independently hydrogen, C _1-6 alkyl, C _2-12 alkynyl, C _2-9 carboxyalkyl, or 2- to 12-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are each independently C _1-6 alkyl or C _2-12 alkynyl. In some embodiments, R ³ and R ⁴ are each independently C _1-6 alkyl or C _2-9 carboxyalkyl. In some embodiments, R ³ and R ⁴ are each independently C _1-6 alkyl or 2- to 12-membered heteroalkyl. In some embodiments, R ³ and R ⁴ are each independently methyl or C _2-12 alkynyl. In some embodiments, R ³ and R ⁴ are each independently methyl or C _2-9 carboxyalkyl. In some embodiments, R ³ and R ⁴ are each independently methyl or 2- to 12-membered heteroalkyl. In some embodiments, R ³ and R ⁴ are each independently methyl or hexynyl. In some embodiments, R ³ and R ⁴ are each independently methyl or methyl-d ₃ . In some embodiments, R ³ and R ⁴ are each independently methyl or propyl. In some embodiments, R ³ and R ⁴ are each independently methyl or diazirinylheptynyl. In some embodiments, R ³ and R ⁴ are each independently methyl or mehoxyethyl. In some embodiments, R ³ and R ⁴ are each independently methyl or methoxyoxobutyl. In some embodiments, R ³ and R ⁴ are each methyl. [0058] In some embodiments, R ³ and R ⁴ of Formula (I) are combined with the nitrogen to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form an azetidinyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a fluoroazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a methylazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a methoxyazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoroazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a methylfluoroazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a methoxyfluoroazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoromethylazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a triifluoromethylazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoromethoxyazetidinyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a cyclopropoxyazetidinyl. [0059] In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form an azabicyclo[3.1.0]hexyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoroazabicyclo[3.1.0]hexyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form an azaspiro[2.3]hexyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoroazaspiro[2.3]hexyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form an azaspiro[3.3]heptyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoroazaspiro[3.3]heptyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form an oxaazaspiro[3.3]heptyl . [0060] In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a pyrrolidyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a fluoropyrrolidyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a difluoropyrrolidyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a methoxypyrrolidyl. In some embodiments, R ³ and R ⁴ are combined with the nitrogen to which they are attached to form a morpholyl optionally substituted with 1-4 R ¹¹ groups. [0061] In some embodiments, R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, C _1-6 haloalkyl, or C _3-6 cycloalkyl. In some embodiments, R ⁵ is hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, or cyclopropyl. In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is C _1-6 alkyl. In some embodiments, R ⁵ is methyl. In some embodiments, R ⁵ is ethyl. In some embodiments, R ⁵ is C _1-6 alkoxy. In some embodiments, R ⁵ is methoxy. In some embodiments, R ⁵ is halogen. In some embodiments, R ⁵ is fluorine. In some embodiments, R ⁵ is chlorine. In some embodiments, R ⁵ is C1-6 haloalkyl. In some embodiments, R ⁵ is difluoromethyl. In some embodiments, R ⁵ is trifluoromethyl. In some embodiments, R ⁵ is C _3-6 cycloalkyl. In some embodiments, R ⁵ is cyclopropyl. [0062] In some embodiments, R ⁶ and R ⁷ are each independently C _1-6 alkyl. In some embodiments, at least one of R ⁶ and R ⁷ is methyl. In some embodiments, R ⁶ and R ⁷ are each methyl. In some embodiments, at least one of R ⁶ and R ⁷ is ethyl. In some embodiments, at least one of R ⁶ and R ⁷ is propyl. In some embodiments, at least one of R ⁶ and R ⁷ is isopropyl. In some embodiments, at least one of R ⁶ and R ⁷ is butyl. In some embodiments, at least one of R ⁶ and R ⁷ is isobutyl. In some embodiments, at least one of R ⁶ and R ⁷ is sec-butyl. In some embodiments, at least one of R ⁶ and R ⁷ is tert-butyl. In some embodiments, at least one of R ⁶ and R ⁷ is pentyl. In some embodiments, at least one of R ⁶ and R ⁷ is isopentyl. In some embodiments, at least one of R ⁶ and R ⁷ is 2-methylbutyl. In some embodiments, at least one of R ⁶ and R ⁷ is pentan-2-yl. In some embodiments, at least one of R ⁶ and R ⁷ is 3-methylbutan-2-yl. In some embodiments, at least one of R ⁶ and R ⁷ is pentan-3-yl. In some embodiments, at least one of R ⁶ and R ⁷ is neopentyl. In some embodiments, at least one of R ⁶ and R ⁷ is tert-pentyl. In some embodiments, at least one of R ⁶ and R ⁷ is hexyl. In some embodiments, at least one of R ⁶ and R ⁷ is 4- methylpentyl. In some embodiments, at least one of R ⁶ and R ⁷ is 3-methylpentyl. In some embodiments, at least one of R ⁶ and R ⁷ is 2-methylpentyl. In some embodiments, at least one of R ⁶ and R ⁷ is hexan-2-yl. In some embodiments, at least one of R ⁶ and R ⁷ is 2,3-dimethylbutyl. In some embodiments, at least one of R ⁶ and R ⁷ is 4-methylpentan-2-yl. In some embodiments, at least one of R ⁶ and R ⁷ is 3-methylpentan-2-yl. In some embodiments, at least one of R ⁶ and R ⁷ is 2-ethylbutyl. In some embodiments, at least one of R ⁶ and R ⁷ is hexan-3-yl. In some embodiments, at least one of R ⁶ and R ⁷ is 3,3-dimethylbutyl. In some embodiments, at least one of R ⁶ and R ⁷ is 2,2-dimethylbutyl. In some embodiments, at least one of R ⁶ and R ⁷ is 2- methylpentan-2-yl. [0063] In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a C _3-8 cycloalkyl or a 3- to 15-membered heterocyclyl wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a C _3-8 cycloalkyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a cyclobutyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a cyclopentyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a cyclohexyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a methylcyclohexyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a difluorocyclohexyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a trifluoromethylcyclohexyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a cycloheptyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a spiro[3.3]heptyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a bicyclo[2.2.2]octyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a methylbicyclo[2.2.2]octyl. [0064] In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a tetrahydropyryl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a difluorotetrahydropyryl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a tetrohydrofuryl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form an oxepanyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a hydroxyfluorooxepanyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a hydroxyfluorooxepanyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a methyldioxepanyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form an oxabicyclo[4.1.0]heptyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a difluorooxabicyclo[4.1.0]heptyl. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form an oxabicyclo[2.2.1]heptyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁶ and R ⁷ are combined with the carbon to which they are attached to form an oxaspiro[2.4]heptyl optionally substituted with 1-4 R ¹¹ groups. [0065] In some embodiments, R ⁸ of Formula (I) is C _3-8 cycloalkyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁸ is cyclohexyl. In some embodiments, R ⁸ is cycloheptyl. In some embodiments, R ⁸ is C _6-12 aryl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁸ is phenyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁸ is fluorophenyl. In some embodiments, R ⁸ is difluorophenyl. In some embodiments, R ⁸ is chlorophenyl. In some embodiments, R ⁸ is fluorochlorophenyl. In some embodiments, R ⁸ is trifluoromethylphenyl. In some embodiments, R ⁸ is aminoethylphenyl. In some embodiments, R ⁸ is 5- to 16-membered heteroaryl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, R ⁸ is a saturated cyclic amine. In some embodiments, R ⁸ is pyridyl. In some embodiments, R ⁸ is pyrazyl. [0066] In some embodiments, each R ⁹ and R ¹⁰ of Formula (I) is independently hydrogen, C _1-6 alkoxy, or halogen. In some embodiments, at least one R ⁹ and/or at least one R ¹⁰ is hydrogen. In some embodiments, each R ⁹ and R ¹⁰ is hydrogen. In some embodiments, at least one R ⁹ and/or at least one R ¹⁰ is C _1-6 alkoxy. In some embodiments, at least one R ⁹ and/or at least one R ¹⁰ is methoxy. In some embodiments, each R ⁹ and R ¹⁰ is C _1-6 alkoxy. In some embodiments, at least one R ⁹ and/or at least one R ¹⁰ is C _1-6 halogen. In some embodiments, each R ⁹ and R ¹⁰ is C _1-6 halogen. In some embodiments, at least one R ⁹ and/or at least one R ¹⁰ is C _1-6 fluorine. [0067] In some embodiments, one R ⁹ is combined with R ² and X ¹ to form a 3- to 15- membered heterocyclylene optionally substituted with 1-4 R ¹¹ groups. In some embodiments, one R ⁹ is combined with R ² and X ¹ to form a piperidinylene optionally substituted with 1-4 R ¹¹ groups. In some embodiments, one R ⁹ is combined with R ² and X ¹ to form a pyrrolidinylene optionally substituted with 1-4 R ¹¹ groups. [0068] In some embodiments, one R ¹⁰ is combined with R ³ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, one R ¹⁰ is combined with R ³ and the nitrogen to which R ³ is attached to form a morpholyl optionally substituted with 1-4 R ¹¹ groups. In some embodiments, one R ¹⁰ is combined with R ³ and the nitrogen to which R ³ is attached to form a oxazepanyl optionally substituted with 1-4 R ¹¹ groups. [0069] In some embodiments, each R ¹¹ is independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, C _3-12 cycloalkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, or diazirine. In some embodiments, each R ¹¹ is independently methyl, methoxy, 2-methoxyethyl, 2- aminoethyl, fluorine, chlorine, cyclopropoxy, trifluoromethyl, difluoromethoxy, or diazirine. In some embodiments, at least one R ¹¹ is C _1-6 alkyl. In some embodiments, at least one R ¹¹ is methyl. In some embodiments, at least one R ¹¹ is C _1-6 alkoxy. In some embodiments, at least one R ¹¹ is methoxy. In some embodiments, at least one R ¹¹ is hydroxy. In some embodiments, at least one R ¹¹ is 2- to 8-membered heteroalkyl. In some embodiments, at least one R ¹¹ is 2- methoxyethyl. In some embodiments, at least one R ¹¹ is 2-aminoethyl. In some embodiments, at least one R ¹¹ is halogen. In some embodiments, at least one R ¹¹ is fluorine. In some embodiments, at least one R ¹¹ is chlorine. In some embodiments, at least one R ¹¹ is C _1-6 haloalkyl. In some embodiments, at least one R ¹¹ is difluoromethyl. In some embodiments, at least one R ¹¹ is trifluoromethyl. In some embodiments, at least one R ¹¹ is diazirine. In some embodiments, at least one R ¹¹ is C _3-12 cycloalkoxy. In some embodiments, at least one R ¹¹ is cyclopropoxy. In some embodiments, at least one R ¹¹ is C _1-6 haloalkoxy. In some embodiments, at least one R ¹¹ is difluoromethoxy. [0070] In some embodiments, at least one of X ¹ , X ² , A ¹ , and A ² of Formula (I) is C. In some embodiments, A ¹ , and A ² are each C. In some embodiments, X ² is C. In some embodiments, at least one of X ¹ , X ² , A ¹ , and A ² is N. In some embodiments, X ¹ is N. In some embodiments, at least one of X ¹ , X ² , A ¹ , and A ² is O. In some embodiments, X ¹ is O and R ² is absent. In some embodiments, at least one of X ¹ , X ² , A ¹ , and A ² is S. In some embodiments, X ² is S. [0071] In some embodiments, at least one of the subscripts m, n, and p is an integer from 0 to 3. In some embodiments, the subscripts m, n, and p are each independently an integer from 0 to 3. In some embodiments, at least one of the subscripts m, n, and p is an integer from 1 to 4. In some embodiments, the subscripts m, n, and p are each independently an integer from 1 to 4. In some embodiments, at least one of the subscripts m, n, and p is an integer from 0 to 2. In some embodiments, the subscripts m, n, and p are each independently an integer from 0 to 2. In some embodiments, at least one of the subscripts m, n, and p is an integer from 1 to 3. In some embodiments, the subscripts m, n, and p are each independently an integer from 1 to 3. In some embodiments, at least one of the subscripts m, n, and p is an integer from 2 to 4. In some embodiments, the subscripts m, n, and p are each independently an integer from 2 to 4. In some embodiments, at least one of the subscripts m, n, and p is 1 or 2. In some embodiments, the subscripts m, n, and p are each independently 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, p is 1. In some embodiments, p is 2. [0072] In some embodiments, the compound of Formula (I) has the following structure:

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , A ¹ , A ² , and n are as defined above. [0073] In some embodiments, the compound of Formula (I) has the following structure: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and n are as defined above. [0074] In some embodiments, the compound of Formula (I) has the following structure: wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as defined above, and R ^1a , R ^1b , and R ^1c are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, nitro, or cyano. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is hydrogen, halogen, nitro, or cyano. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently hydrogen, halogen, nitro, or cyano. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is hydrogen, fluorine, chlorine, nitro, or cyano. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently hydrogen, fluorine, chlorine, nitro, or cyano. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is hydrogen, fluorine, nitro, or cyano. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently hydrogen, fluorine, nitro, or cyano. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is fluorine or cyano. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently fluorine or cyano. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is nitro. In some embodiments, R ^1a , R ^1b , and R ^1c are each nitro. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is halogen. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently halogen. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is chlorine or fluorine. In some embodiments, R ^1a , R ^1b , and R ^1c are each independently chlorine or fluorine. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is fluorine. In some embodiments, R ^1a , R ^1b , and R ^1c are each fluorine. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is chlorine. In some embodiments, R ^1a , R ^1b , and R ^1c are each chlorine. In some embodiments, at least one of R ^1a , R ^1b , and R ^1c is cyano. In some embodiments, R ^1a , R ^1b , and R ^1c are each cyano. [0075] In some embodiments, the compound of Formula (I) has the following structure: wherein R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ¹¹ are as defined above. [0076] In some embodiments, the compound of Formula (I) has the following structure: wherein R ^1a , R ^1b , R ³ , R ⁴ , R ⁵ , R ⁶ , and R ⁷ are as defined above. [0077] In some embodiments, the compound of Formula (I) has the structure:

wherein R ^1a and R ^1b are as defined above. R ^11a , R ^11b , R ^11c , and R ^11d are each independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, halogen, C _3-12 cycloalkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, or diazirine, wherein the cycloalkoxy is optionally substituted with one or more hydroxy or halogen groups or a combination thereof. [0078] In some embodiments, the compound of Formula (I) is:

[0079] In some embodiments, the compound of Formula I is:

[0080] In some embodiments, the compound of Formula I is: [0081] In some embodiments, the compound of Formula I is: [0082] In some embodiments, the compound of Formula I is: [0083] In some embodiments, the compound of Formula (I) is:

[0084] The compounds provided herein may also be the salts, solvates, and isomers of any on the structures disclosed above. Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in art. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. [0085] Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, for example, Berge et al., Journal of Pharmaceutical Science 66, (1977):1). Certain specific compounds of the present disclosure contain basic acidic functionalities that allow the compounds to be converted into base addition salts. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. [0086] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. he parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. [0087] Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. [0088] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. [0089] Unless otherwise stated, the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present disclosure may be radiolabeled with radioactive isotopes, such as for example deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon- 13 ( ¹³ C), or carbon-14 ( ¹⁴ C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present invention. [0090] The present invention further includes compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide any of the compounds disclosed above. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. D. PHARMACEUTICAL COMPOSITIONS [0091] In another aspect, the present disclosure provides pharmaceutical compositions including one or more pharmaceutically acceptable carriers, diluents, excipients, or buffers and one or more of the compounds provided herein. In some embodiments, the pharmaceutically acceptable carrier, diluent, excipient, or buffer is suitable for use in a subject, for example, a human. Pharmaceutically acceptable excipients include, but are not limited to, liquids such as water, saline, glycerol, sugars and ethanol. The preparation of pharmaceutically acceptable carriers and excipients is described in, e.g., Remington: The Science and Practice of Pharmacy, 22nd edition, Loyd V. Allen et al, editors, Pharmaceutical Press (2012). [0092] In some embodiments, the composition also includes an additional active compound or other chemotherapeutic agent. In some embodiments, the pharmaceutical composition further includes one or more stabilizing compounds, which may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water. In some embodiments, the pharmaceutical compositions also contain a pharmaceutically acceptable salt. Pharmaceutically acceptable salts can include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in the provided pharmaceutical compositions. The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization. E. FORMULATIONS [0093] The compositions provided herein can be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a subject, e.g., a human patient. The compositions of the present invention can also be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compositions described herein can be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention can be administered transdermally. The compositions of this invention can also be administered by intraocular, intravaginal, and intrarectal routes including suppositories, insufflation, powders and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35, (1995):1187-1193; Tjwa, Ann. Allergy Asthma Immunol. 75, (1995):107). [0094] For preparing pharmaceutical formulations including the compounds of the present disclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature. [0095] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% by weight of the compounds of the present disclosure. [0096] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; a low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. [0097] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound (i.e., dosage). Pharmaceutical preparations of the invention may also be used orally using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the compounds of the present invention mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the compounds of the present invention may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. [0098] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compounds of the present disclosure are dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. [0099] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations may be formulated in solution in aqueous polyethylene glycol solution. [0100] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations may be adjusted for osmolarity. [0101] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. [0102] Oil suspensions may be formulated by suspending the compounds of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil; or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents, such as glycerol, sorbitol or sucrose, may be added to provide a palatable oral preparation. These formulations may be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther.281, (1997):93. The pharmaceutical formulations of the disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil, described above, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan mono- oleate. The emulsion may also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, a preservative, or a coloring agent. [0103] The compositions of the present invention may also be delivered as microspheres for slow release in the body. For example, microspheres may be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7, (1995):623); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12, (1995):857); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49, (1997):669). Both transdermal and intradermal routes may afford constant delivery for weeks or months. [0104] In other embodiments, the compositions of the present disclosure are formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Such formulations for administration will commonly comprise a solution of the compositions of the present disclosure dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that may be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH-adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present disclosure in these formulations may vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3-butanediol. [0105] In another embodiment, formulations of the compositions of the present disclosure are delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, delivery may be focused into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13, (1996):293; Chonn, Curr. Opin. Biotechnol. 6, (1995):698; Ostro, Am. J. Hosp. Pharm. 46, (1989):1576-1587). [0106] Lipid-based formulations include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present disclosure include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, LABRAFIL®, LABRASOL®, CREMOPHOR®, SOLUTOL®, TWEEN®, CAPRYOL®, CAPMUL®, CAPTEX®, and PECEOL®. F. METHODS OF TREATING A DISORDER [0107] In another aspect, the present disclosure provides a method of treating a disorder. The method includes administering to a subject in need of such a treatment a therapeutically effective amount of a compound disclosed herein or a formulation thereof as disclosed herein, thereby treating the disorder. In some embodiments, the treatment is given with a curative intent. In some embodiments, the treatment is given with an aim to prolong the life of the subject. In some embodiments, the treatment is given for the purpose of reducing symptoms associated with the disorder. In some embodiments, symptoms reduced by the treatment include viruria. In some embodiments, the reduced symptoms include viremia. In some embodiments, the treatment is given prophylactically to a subject, e.g., a kidney transplant recipient, considered to be at an elevated risk of developing a disorder or symptoms typically associated with a disorder. [0108] In some embodiments, the disorder is an infection with a polyomavirus. In some embodiments, the disorder is an infection with a genotype I BK virus. In some embodiments, the disorder is an infection with a genotype II BK virus. In some embodiments, the disorder is an infection with a genotype III BK virus. In some embodiments, the disorder is an infection with a genotype IV BK virus. In some embodiments, the disorder is an infection with JC virus. In some embodiments, the disorder is an infection with a Merkel virus. [0109] Thus, as a further embodiment, the present disclosure provides the use of any of the compounds disclosed herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or isomer thereof) for the manufacture of a medicament. In a particular embodiment, the medicament is for treatment of an infection with a polyomavirus such as a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus. A further embodiment of the present disclosure provides the use of any of the compounds disclosed herein for the manufacture of a medicament for the treatment of a polyomavirus infection. For example, the present disclosure provides the use of a compound of Formula (I) or a salt, solvate, or isomer thereof for the manufacture of a medicament for the treatment of an infection with a genotype I BK virus, a genotype II BK virus, a genotype III BK virus, a genotype IV BK virus, a JC virus, and/or a Merkel virus. [0110] In some embodiments, the subject is an organ transplant patient. The subject can be, for example, the recipient of renal or hematopoietic stem cell transplantation. In some embodiments, the subject is an immunocompromised patient. The subject can be, for example, a transplant recipient who is immunocompromised from immunosuppressive therapy used to prevent transplant rejection. The subject can be, for example, an HIV-positive patient. Examples of disorders or conditions suitable for treatment with the provide methods include, but are not limited to, nephropathy, hemorrhagic cystitis, pneumonitis, retinitis, meningoencephalitis, and/or progressive multifocal leukoencephalopathy. G. EXEMPLARY EMBODIMENTS [0111] The following embodiments are contemplated. All combinations of features and embodiments are contemplated. [0112] Embodiment 1: A compound having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein each R ¹ is independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, -SO ₂ R ¹¹ , or -P(R ¹¹ ) ₃ ; R ² is absent, hydrogen, or C _1-20 alkyl; or is combined with R ⁹ and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups; R ³ is hydrogen, C _1-20 alkyl, C _2-20 alkenyl, C _2-20 alkynyl, C _2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl; is combined with R ⁴ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group; or is combined with R ¹⁰ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group; wherein the alkynyl, carboxyalkyl, and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups; R ⁴ is hydrogen, C _1-20 alkyl, C _2-20 alkynyl, C _2-9 carboxyalkyl, or 2- to 20-membered heteroalkyl; or is combined with R ³ and the nitrogen to which R ³ and R ⁴ are attached to form a 3- to 15-membered heterocyclyl group; wherein the alkynyl, carboxyalkyl, and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups; R ⁵ is hydrogen, C _1-20 alkyl, C _1-20 alkoxy, C _1-20 alkylhydroxy, halogen, C _1-20 haloalkyl, or C _3-12 cycloalkyl; R ⁶ and R ⁷ are each independently C _{1- 20} alkyl or are combined with the carbon to which they are attached to form a C _3-12 cycloalkyl or a 3- to 15-membered heterocyclyl, wherein the cycloalkyl and heterocyclyl are optionally substituted with 1-4 R ¹¹ groups; R ⁸ is C _3-12 cycloalkyl, C _6-14 aryl, or 5- to 16-membered heteroaryl, wherein the cycloalkyl, aryl, and heteroaryl are optionally substituted with 1-4 R ¹¹ groups; each R ⁹ is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl; or is combined with R ² and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups; each R ¹⁰ is independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, oxo, -NH ₂ , nitro, cyano, or C _1-6 cyanoalkyl; or is combined with R ³ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups each R ¹¹ is independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, C _1-6 hydroxyalkyl, 2- to 12-membered heteroalkyl, C _3-12 cycloalkyl, 5- to 16-membered heteroaryl, C _3-12 cycloalkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, oxo, -NH ₂ , nitro, cyano, or diazirine, wherein the cycloalkyl, heteroaryl, and cycloalkoxy are optionally substituted with one or more hydroxy or halogen groups or a combination thereof; X ¹ , X ² , A ¹ , and A ² are each independently selected from the group consisting of C, N, O, and S; and the subscripts m, n, and p are each independently an integer from 0 to 4. [0113] Embodiment 2: An embodiment of embodiment 1, wherein each R ¹ is halogen, nitro, or cyano. [0114] Embodiment 3: An embodiment of embodiment 2, wherein each R ¹ is fluorine, chlorine, nitro, or cyano. [0115] Embodiment 4: An embodiment of any one of embodiments 1-3, wherein R ² is absent, hydrogen, or C _1-20 alkyl. [0116] Embodiment 5: An embodiment of embodiment 4, wherein R ² is absent, hydrogen, or methyl. [0117] Embodiment 6: An embodiment of any one of embodiments 1-5, wherein R ³ and R ⁴ are each independently hydrogen, C _1-6 alkyl, C _2-12 alkynyl, C _2-9 carboxyalkyl, or 2- to 12-membered heteroalkyl, wherein the alkynyl and carboxyalkyl are optionally substituted with 1-4 R ¹¹ groups. [0118] Embodiment 7: An embodiment of embodiment 6, wherein R ³ and R ⁴ are each independently methyl, methyl-d ₃ , propyl, hexynyl, diazirinylheptynyl, methoxyoxobutyl, and mehoxyethyl. [0119] Embodiment 8: An embodiment of embodiment 7, wherein R ³ and R ⁴ are each methyl. [0120] Embodiment 9: An embodiment of any one of embodiments 1-5, wherein R ³ and R ⁴ are each combined with the nitrogen to which they are attached to form a 3- to 15-membered heterocyclyl optionally substituted with 1-4 R ¹¹ groups. [0121] Embodiment 10: An embodiment of embodiment 9, wherein R ³ and R ⁴ are each combined with the nitrogen to which they are attached to form an azetidinyl group, a methylazetidinyl group, a methylfluoroazetidinyl group, a methoxyfluoroazetidinyl group, a difluoromethylazetidinyl group, a triifluoromethylazetidinyl group, a fluoroazetidinyl group, a difluoroazetidinyl group, a methoxyazetidinyl group, a difluoromethoxyazetidinyl group, a cyclopropoxyazetidinyl group, a fluoropyrrolidyl group, a difluoropyrrolidyl group, a methoxypyrrolidyl group, an azabicyclo[3.1.0]hexyl group, a difluoro-azabicyclo[3.1.0]hexyl group, a morpholyl group, an azaspiro[2.3]hexyl group, a difluoroazaspiro[2.3]hexyl group, a difluoroazaspiro[3.3]heptyl group, or an oxaazaspiro[3.3]heptyl group. [0122] Embodiment 11: An embodiment of any one of embodiments 1-10, wherein R ⁵ is hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halogen, C _1-6 haloalkyl, or C _3-6 cycloalkyl. [0123] Embodiment 12: An embodiment of embodiment 11, wherein R ⁵ is hydrogen, methyl, ethyl, methylethyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, or cyclopropyl. [0124] Embodiment 13: An embodiment of any one of embodiments 1-12, wherein R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a C _3-8 cycloalkyl or a 3- to 15- membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with 1-4 R ¹¹ groups. [0125] Embodiment 14: An embodiment of embodiment 13, wherein R ⁶ and R ⁷ are combined with the carbon to which they are attached to form a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methylcyclohexyl group, a difluorocyclohexyl group, a trifluoromethylcyclohexyl group, a cycloheptyl group, a spiro[3.3]heptyl group, a tetrahydropyryl group, a difluorotetrahydropyryl group, a tetrohydrofuryl group, an oxepanyl group, a hydroxyfluorooxepanyl group, a methyldioxepanyl group, an oxabicyclo[4.1.0]heptyl group, a difluorooxabicyclo[4.1.0]heptyl group, an oxabicyclo[2.2.1]heptyl group, an oxaspiro[2.4]heptyl group, a methylbicyclo[2.2.2]octyl group. [0126] Embodiment 15: An embodiment of any one of embodiments 1-12, wherein R ⁶ and R ⁷ are each independently C _1-6 alkyl. [0127] Embodiment 16: An embodiment of embodiment 15, wherein R ⁶ and R ⁷ are each methyl. [0128] Embodiment 17: An embodiment of any one of embodiments 1-16, wherein R ⁸ is C _6-12 aryl or C _3-8 cycloalkyl, wherein the aryl and cycloalkyl are optionally substituted with 1-4 R ¹¹ groups. [0129] Embodiment 18: An embodiment of any one of embodiments 17, wherein R ⁸ is phenyl, fluorophenyl, difluorophenyl, chlorophenyl, fluorochlorophenyl, trifluoromethylphenyl, or cycloheptyl. [0130] Embodiment 19: An embodiment of any one of embodiments 1-18, wherein each R ⁹ and R ¹⁰ is independently hydrogen, C _1-6 alkoxy, or halogen. [0131] Embodiment 20: An embodiment of embodiment 19, wherein each R ⁹ and R ¹⁰ is independently hydrogen, methoxy, or fluorine. [0132] Embodiment 21: An embodiment of any one of embodiments 1-18, wherein one R ⁹ is combined with R ² and X ¹ to form a 3- to 15-membered heterocyclylene group optionally substituted with 1-4 R ¹¹ groups. [0133] Embodiment 22: An embodiment of embodiment 21, wherein one R ⁹ is combined with R ² and X ¹ to form a piperidinylene group or a pyrrolidinylene group. [0134] Embodiment 23: An embodiment of any one of embodiments 1-18, wherein one R ¹⁰ is combined with R ³ and the nitrogen to which R ³ is attached to form a 3- to 15-membered heterocyclyl group optionally substituted with 1-4 R ¹¹ groups. [0135] Embodiment 24: An embodiment of embodiment 23, wherein one R ¹⁰ is combined with R ³ and the nitrogen to which R ³ is attached to form a morpholyl group or an oxazepanyl group. [0136] Embodiment 25: An embodiment of any one of embodiments 1-24, wherein each R ¹¹ is independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, halogen, C _3-12 cycloalkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, or diazirine, wherein the cycloalkoxy is optionally substituted with one or more hydroxy or halogen groups or a combination thereof. [0137] Embodiment 26: An embodiment of embodiment 25, wherein each R ¹¹ is independently methyl, methoxy, hydroxy, 2-methoxyethyl, 2-aminoethyl, fluorine, chlorine, cyclopropoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, or diazirine. [0138] Embodiment 27: An embodiment of any one of embodiments 1-26, wherein X ¹ is N. [0139] Embodiment 28: An embodiment of any one of embodiments 1-26, wherein R ² is absent and X ¹ is O. [0140] Embodiment 29: An embodiment of any one of embodiments 1-28, wherein X ² is S. [0141] Embodiment 30: An embodiment of any one of embodiments 1-28, wherein X ² is C. [0142] Embodiment 31: An embodiment of any one of embodiments 1-30, wherein A ¹ and A ² are each C. [0143] Embodiment 32: An embodiment of any one of embodiments 1-31, wherein n is 2. [0144] Embodiment 33: An embodiment of any one of embodiments 1-32, wherein m is 2. [0145] Embodiment 34: An embodiment of any one of embodiments 1-33, wherein p is 1. [0146] Embodiment 35: An embodiment of embodiment 1, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof. [0147] Embodiment 36: An embodiment of embodiment 35, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof. [0148] Embodiment 37: An embodiment of embodiment 36, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein R ^1a , R ^1b , and R ^1c are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, nitro, or cyano. [0149] Embodiment 38: An embodiment of embodiment 36, having the formula: or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof. [0150] Embodiment 39: An embodiment of embodiment 38, having the formula:

[0151] Embodiment 40: An embodiment of embodiment 1, having the formula:

or the formula of a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein R ^1a and R ^1b are each independently hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, halogen, C _1-6 haloalkyl, nitro, or cyano; and R ^11a , R ^11b , R ^11c , and R ^11d are each independently C _1-6 alkyl, C _1-6 alkoxy, hydroxy, 2- to 8-membered heteroalkyl, halogen, C _3-12 cycloalkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, or diazirine, wherein the cycloalkoxy is optionally substituted with one or more hydroxy or halogen groups or a combination thereof. [0152] Embodiment 41: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0153] Embodiment 42: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0154] Embodiment 43: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0155] Embodiment 44: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0156] Embodiment 45: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0157] Embodiment 46: An embodiment of embodiment 1, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or isomer thereof. [0158] Embodiment 47: A pharmaceutical composition comprising the compound of any one of embodiments 1-46 and a pharmaceutically acceptable carrier. [0159] Embodiment 48: A method of treating a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of embodiments 1-46 or the composition of embodiment 47. [0160] Embodiment 49: An embodiment of embodiment 48, wherein the disorder is an infection with a polyomavirus. [0161] Embodiment 50: An embodiment of embodiment 49, wherein the polyomavirus is selected from the group consisting of BK virus, JC virus, and Merkel cell virus. [0162] Embodiment 51: An embodiment of any one of embodiments 48-50, wherein the subject is an organ transplant patient. [0163] Embodiment 52: An embodiment of any one of embodiments 48-51, wherein the subject is an immunocompromised patient EXAMPLES [0164] The present disclosure will be better understood in view of the following non-limiting examples. The following examples are intended for illustrative purposes only and do not limit in any way the scope of the present invention. The provided compounds can be synthesized by a variety of methods known to one of skill in the art (see Comprehensive Organic Transformations Richard C. Larock, 1989) or by an appropriate combination of generally well known synthetic methods. Techniques useful in synthesizing the disclosed compounds are both readily apparent and accessible to those of skill in the relevant art. The examples below are offered to illustrate certain of the diverse methods available for use in assembling the provided compounds. However, the examples are not intended to define the scope of reactions or reaction sequences that are useful in preparing the compounds. Exemplary structures below are named according to standard IUPAC nomenclature using the CambridgeSoft ChemDraw naming package. Table 1. Exemplary compounds and anti-viral assay results [0165] Additional compounds were tested and shown to have BK virus entry assay EC50 results greater than 1 μM. These additional compounds include (S)-N-((3-cyano-4-((1- (dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3- yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide, (S)-N-((3-cyano-4-(((R)-4- (dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyl- 1,4-dioxane-2-carboxamide, (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyl-1,4-dioxane-2- carboxamide, (R)-N-((4-((4-(dimethylamino)-1-(phenylthiol)butan-2-yl)amin o)-3- nitrophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-4-carboxam ide, (S)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfo nyl)-1-fluorocyclohexane-1- carboxamide, (R)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nit rophenyl)sulfonyl)- 1-fluorocyclohexane-1-carboxamide, (R)-N-((4-((4-(dimethylamino)-1-(phenylthiol)butan-2- yl)amino)-3-nitrophenyl)sulfonyl)-1-methoxycyclobutane-1-car boxamide, (R)-N-((4-((4- (dimethylamino)-4-oxo-1-(phenylthiol)butan-2-yl)amino)-3-nit rophenyl)sulfonyl)-1- methoxycyclobutane-1-carboxamide, and (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2- yl)amino)-3-nitrophenyl)sulfonyl)-4,4-difluorocyclohexane-1- carboxamide. EXAMPLE 1. BK VIRUS ENTRY ASSAY [0166] Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) or RPTE cells immortalized with human telomerase reverse transcriptase (RPTE-hTERT; Zhao and Imperiale, Microbiol. Resour. Announc.20098:e01129-19) were pre-incubated with compound for 2 hours, then infected with BK virus serotype I (MOI 0.1-0.5 infectious units/cell [IU/cell]) and incubated for 48 hours to allow for viral entry and gene expression. Cells were fixed with 4% paraformaldehyde and analyzed by immunofluorescence to detect large T antigen (TAg, early gene) expression (Calbiochem DP02, pAb416 mouse anti-SV40 TAg antibody). The immunofluorescence was analyzed by high content image analysis using the CellInsight platform (Thermo Scientific) to quantify the percent of BK virus-infected cells (TAg-positive, DAPl- positive), with data presented as percent inhibition of infection relative to DMSO-treated control wells. [0167] As shown in Table 1, the compounds disclosed herein inhibited an early stage of BK virus entry and/or trafficking, preventing the expression of BK virus TAg which is required for the subsequent steps of virus replication. The most potent of these analogs had EC50 values ranging from 12 to 100 nM. EXAMPLE 2. BK VIRUS SPREAD ASSAY [0168] Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) were pre-incubated with compound for 2 hours, then infected with BK virus serotype I (MOI 0.1 IU/cell) and incubated for 120 hours (5 days) to allow for viral entry, propagation, and progeny virion release from the first round of infection, as well as viral entry and gene expression resulting from the second round of infection. Cells were fixed with ice-cold methanol and analyzed by immunocytochemistry using DELFIA time-resolved fluorescence technology (PerkinElmer) to detect expression of the major capsid protein VP1 (late gene; anti-BKV VP1 mouse hybridoma antibody, in-house, Novartis). Total VP1 expression in each well was analyzed on a PHERAstar Microplate Reader (BMG LabTech) by Europium time-resolved fluorescence, with data presented as percent inhibition of infection relative to DMSO-treated control wells. [0169] As shown in Table 1, the compounds disclosed herein were able to inhibit viral replication and spread to new cells, in alignment with the ability to inhibit TAg expression (which is required for all subsequent steps of virus replication). The most potent of these analogs had EC50 values ranging from 39 to 436 nM. There was a 1.3- to 6.4-fold shift in EC50 values between the two orthogonal antiviral assays (BK virus entry assay and the BK virus spread assay), which is primarily due to the difference in readouts, assay design, and overall variability. EXAMPLE 3. HEK293 CYTOTOXICITY ASSAY [0170] Human embryonic kidney (HEK293) epithelial cells (ATCC, cat# CRL-1573) were incubated with compound (top concentration of 100 μM) for 72 hours (3 days) and analyzed by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) to generate CC50 values relative to DMSO-treated control wells. As shown in Table 1, the compounds disclosed herein did not generally show cytotoxicity in this cell line after incubation with the compounds. More specifically, the majority of the most potent analogs that were tested in the HEK293 cytotoxicity assay (92 out of 95 analogs exemplified with EC50 values ≤ 100 nM in the BKV entry assay) had CC50 values > 50 μM; 75 out of 95 of these analogs had CC50 values > 100 μM. EXAMPLE 4. RPTE CYTOTOXICITY ASSAY [0171] Primary renal proximal tubule epithelial (RPTE) cells (ATCC, cat# PCS-400-010) were incubated with compound (top concentration of 71 μM) for 120 hours (5 days) and analyzed by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) to generate CC50 values relative to DMSO-treated control wells. Alternatively, RPTE cells immortalized with human telomerase reverse transcriptase were incubated with compound (top concentration of 10 μM) for 48 hours and nuclei count (relative to DMSO-treated control wells) was reported as a measure of viability to generate CC50 values. As shown in Table 1, the compounds disclosed herein did not generally show cytotoxicity on either cell type after incubation with the compounds. More specifically, the majority of the most potent analogs (33 out of 36 analogs exemplified with EC50 values ≤ 100 nM in the BKV entry assay) had CC50 values > 71 μM. EXAMPLE 5. BCL-2/BCL-XL SURFACE PLASMON RESONANCE ASSAY [0172] The binding of the provided compounds to Bcl-2 and Bcl-xL was analyzed by surface plasmon resonance (SPR) in single cycle and multicycle modes. Human Bcl-2 (UniProt ID P10415) and Bcl-2-like protein 1 (Bcl-xL, UniProt ID Q07817) were cloned with C-terminal Avi-tags, expressed in E. coli, and purified (> 95% purity) in a final buffer of 25 mM Tris-HCl pH 8.0, 150 mM NaCl, 1 mM TCEP, and 5% Glycerol. Biotinylated Bcl-2 and Bcl-xL were immobilized on a Series S streptavidin sensor chip to approximately 20 response units (RUs) and remaining free streptavidin sites were blocked with biotin-PEG2. Serial dilutions of test compounds (concentrations of 0.412 μM, 1.23 μM, 3.70 μM, 11.1 μM, 33.3 μM, and 100 μM) were then flowed over the surface (flow rate 100 μI/minute) and allowed to bind Bcl-2 and Bcl- xL during the association phase (60 seconds), followed by a buffer wash during the dissociation phase (120 seconds). Serial dilutions (concentrations of either 0.312 μM, 0.625 μM, 1.25 μM, 2.5 μM, and 5 μM; or 0.412 μM, 1.23 μM, 3.70 μM, 11.1 μM, 33.3 μM, and 100 μM) of five known Bcl-2 and/or Bcl-xL inhibitor control compounds including ABT-737 (IUPAC: 4-{4-[(4′- Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl}-N-(4-{[( 2R)-4-(dimethylamino)-1- (phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl) benzamide) and four proprietary compounds, were also tested. Experiments were performed at 25 °C in phosphate buffered saline (PBS) supplemented with 0.02% Tween 20 detergent (Calbiochem #655206), 1 mM EDTA, and 3% DMSO. Samples were run on a Biacore T-200 instrument (GE Healthcare Life Sciences) and data analysis was done in the GE BiaEvaluation software. [0173] SPR was used to evaluate binding of a panel of nine of the provided compounds to Bcl- 2/Bcl-xL. The proprietary control compounds had Kd values for Bcl-2 and Bcl-xL, respectively, of 3.6 nM and 7.1 nM, 34 nM and 49 nM, 513 nM and 311 nM, and 4.8 μM and 4.4 μM. ABT- 737 bound tightly to both proteins with no observable dissociation, and thus an accurate Kd value could not be determined. The results from these control compounds were comparable to historical data. In contrast, as shown in Table 2, none of the tested compounds exhibited any significant binding to Bcl-2, as would be indicated by a Kd value below 100 μM with respect to Bcl-2. Low affinity binding to Bcl-xL was observed for some provided compounds, with Kd values ranging from 7.5 to 45.1 μM), however, these Kd values did not correlate with antiviral potency (EC50 values) in the BK virus entry assay (Tables 1 and 2). These data therefore demonstrate that compounds disclosed herein do not have significant binding to Bcl-2/Bcl-xL Table 2. Surface plasmon resonance assay results EXAMPLE 6. BCL-2/BCL-XL CELL-BASED ASSAYS [0174] Toledo cell line (ATCC CRL-2631, human diffuse large cell lymphoma [DLCL] cell line) expresses high levels of Bcl-2 and Bcl-xL and has previously been shown to be dependent on Bcl-2 signaling for survival (Stang et al., Exp Hematol 2009; 37(1):122-134). NCI-H146 cell line (ATCC HTB-173, human small cell lung cancer [SCLC] cell line) expresses high levels of Bcl-2 and Bcl-xL and has previously been shown to be sensitive to Bcl-2/-xL inhibitors (Hann et al., Cancer Res 2008; 68(7):2321-2328). Toledo and NCI-H146 cells were incubated with test compounds or control compounds (known Bcl-2 and/or Bcl-xL inhibitors including ABT-737, ABT-199, and ABT-263) for 72 hours (3 days) and analyzed by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) to generate CC50 values relative to DMSO-treated control wells. [0175] A panel including (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide and thirty related provided compounds with varying potencies in the BK virus entry assay were evaluated for inhibition of Bcl-2/Bcl-xL activity in cell lines dependent on these signaling cascades for survival. [0176] The panel of known Bcl-2/Bcl-xL inhibitors had potent EC50 values on both cell lines ranging from 32 nM to 596 nM. In contrast, none of the tested provided compounds showed any activity in these cell-based assays (all EC50 values > 20 μM). These data further demonstrate that the provided compounds do not have activity against Bcl-2/Bcl-xL. Thus, the mechanism of action of the provided compounds to inhibit BK virus replication does not involve activity against Bcl-2/Bcl-xL. EXAMPLE 7. BONE MARROW PROLIFERATION ASSAY [0177] A panel of four of the provided compounds with varying potencies in the BK virus entry assay were evaluated for inhibition of bone marrow proliferation. As shown in the data of Table 3, none of the tested provided compounds showed any activity/inhibition of bone marrow proliferation in this cell-based assay (all EC50 values > 10 μM). In contrast, the known Bcl- 2/Bcl-xL inhibitor, ABT-737, inhibited bone marrow proliferation in this assay with an EC50 value of 4 μM. These data further demonstrate that the provided compounds do not have activity against Bcl-2/Bcl-xL Table 3. Results from Bcl-2/Bcl-xL cell-based assays and bone marrow proliferation assays EXAMPLE 8. (R)-N ¹ ,N ¹ -DIMETHYL-4-(PHENYLTHIO)BUTANE-1,3-DIAMINE (AMINE 2) [0178] To a solution of Me2NH (2 M, 89.91 mL) was added compound 2-1 (9.00 g, 38.3 mmol). The mixture was stirred at 60 °C for 8 hrs. TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.35) showed compound 2-1 (Rf = 0.75) was consumed, and a main new spot with lower polarity was formed. The solution was evaporated on a water bath under reduced pressure using a rotary evaporator. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1/1 to 0/1) to give compound 2-2 (10.0 g, 93.2% yield) as a brown solid. [0179] To a solution of compound 2-2 (9.00 g, 32.1 mmol), tributylphosphane (9.74 g, 48.2 mmol, 11.9 mL) and compound 2-3 (5.09 g, 46.2 mmol, 4.71 mL) in THF (90.0 mL) was added DIAD (9.74 g, 48.2 mmol, 9.36 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hrs. And then the mixture was stirred at 20 °C for 5 hrs. TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.52) showed compound 2-2 (Rf = 0.35) was consumed, and a main new spot with lower polarity was formed. LCMS showed compound 2-2 was consumed, and a main peak with desired MS was detected. The reaction mixture was quenched by addition of H2O (200 mL), and then extracted with EtOAc (150 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 5/1 to 0/1) to give compound 2-4 (13.0 g, theory amount: 13.29 g, 88.0% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.30-7.40 (m, 8H), 6.23-6.25 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H), 4.10- 4.16 (m, 1H), 3.20-3.37 (m, 2H), 2.85-2.91 (m, 7H), 2.48-2.53 (m, 4H), 1.24-1.27 (m, 3H). [0180] To a solution of compound 2-4 (6.90 g, 18.5 mmol) was added HBr (35.0 mL, 33% purity). The mixture was stirred at 20 °C for 2 hrs. LCMS showed compound 2-4 was consumed, and a main peak with desired MS was detected. The ether was removed on a rotary evaporator. The mixture was adjusted to pH = 9 with NH3•H2O. The ether was removed on a rotary evaporator. The residue was purified by column chromatography (SiO2, dichloromethane/methanol = 1/0 to 5/1, 0.1 % NH3•H2O), TLC (dichloromethane/methanol = 10/1, product Rf = 0.35) to give compound 2-5 (3.40 g, 69.9% yield, 90.8% purity) as a yellow oil.1H NMR: (400 MHz, CDCl3) δ 7.44-7.46 (m, 2H), 7.29 (m, 2H), 7.19-7.22 (m, 1H), 6.21 (s 2H), 3.66-3.7 (s, 2H), 3.30-3.36 (s, 1H), 2.90-2.93 (m, 8H). [0181] A mixture of compound 2-5 (5.00 g, 21.0 mmol), BH3-Me2S (10 M, 10.5 mL) in THF (50 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 hrs under N2 atmosphere. LCMS showed compound 2-5 was consumed, and a main peak with desired MS was detected. HPLC showed compound 2-5 was consumed, and a main peak with desired MS was detected. The mixture was cooled to 0 ° C, and treated dropwise with MeOH (15.0 mL), followed by 2 M HCl (30.0 mL), stirred overnight, and concentrated. The crude product was purified by reverse-phase HPLC (MeCN/H2O condition) to give Amine 2 (2.78 g, 59.0% yield) as a yellow oil.1H NMR: (400 MHz, MeOD) δ 7.53-7.55 (m, 2H), 7.31- 7.41 (m, 3H), 3.31-3.39 (m, 2H), 3.26-3.29 (m 3H), 2.70 (s, 6H), 2.18-2.25 (m, 2 H). EXAMPLE 9. (R)-4-((4-FLUOROPHENYL)THIO)-N ¹ ,N ¹ -DIMETHYLBUTANE-1,3- DIAMINE (AMINE 1) [0182] Compound 1-3 (52 g, crude) was obtained as a yellow oil according to the general procedure of compound 2-4. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.41-7.27 (m, 7H), 7.01 (s, 2H), 6.19 (s, 1H), 5.11 (s, 2H), 4.15-4.07 (m, 1H), 3.19-3.17 (m, 1H), 3.16-3.14 (m, 1H), 2.90-2.85 (m, 6H), 2.55-2.51 (m, 1H).

[0183] To a solution of compound 1-3 (47.0 g, 120.37 mmol) in a mixture of DCM (250 mL) was added Me ₂ S (74.8 g, 1.20 mol, 88.40 mL) followed by addition of BF ₃ •Et ₂ O (85.4 g, 602 mmol, 74.3 mL) at 0 °C and the mixture was stirred at 25 °C for 2 hours. LCMS showed the starting material was consumed completely. The mixture was washed with saturated NaHCO ₃ (aq.) (150 mL) and diluted with EtOAc (30.0 mL x 3), and then the organic layers were washed with brine (25.0 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound 1-4 (23 g, crude) as yellow oil.1H NMR: (400 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 2H), 7.02-6.97 (m, 2H), 3.47-3.40 (m, 1H), 3.12-3.07 (m,1H), 2.98-2.92 (m, 8H), 2.58-2.57 (m, 1H), 2.46-2.42 (m, 1H). [0184] To a solution of LiAlH ₄ (2.5 M, 71.78 mL) in THF (150 mL) was added compound 1-4 (23.0 g, 89.7 mmol) in one portion at 0 °C under N ₂ . The mixture returned to 25 °C and was stirred for 2 hours. LCMS showed the starting material was consumed completely. The mixture was cooled to 0 °C. The mixture was poured into H ₂ O (7.00 mL), 15% aqueous sodium hydroxide (7.00 mL) and H ₂ O (21.0 mL). The mixture returned to 25 °C and was stirred for 15 minutes. Then the mixture was added with anhydrous Na ₂ SO ₄ , stirred for 15 minutes, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*70mm*10um;mobile phase: [water(NH ₃ H ₂ O)-ACN];B%: 15%-45%, 20min) to give compound Amine 1 (9.00 g, 41.4% yield, 100% purity) as yellow oil. 1H NMR: (400 MHz, MeOD) δ 7.47-7.44 (m, 2H), 7.08-7.04 (m, 2H), 3.06-3.04 (m, 1H), 2.84-2.82 (m, 1H), 2.42-2.36 (m, 2H), 2.23 (s, 6H), 1.77-1.74 (m, 1H), 1.55-1.53 (m, 1H). LCMS (ESI) m/z 243.3 (M+H+). EXAMPLE 10. (S)-5-(4-FLUOROPHENYL)-N ¹ ,N ¹ -DIMETHYLPENTANE-1,3-DIAMINE (AMINE 4) [0185] To a solution of NaHCO ₃ (23.6 g, 281 mmol), TBAB (7.26 g, 22.5 mmol) in DMF (170 mL) was added prop-2-en-1-ol (10.8 g, 186 mmol), Pd (OAc) ₂ (1.52 g, 6.76 mmol) and compound 4-1 (25.0 g, 112 mmol). The mixture was stirred at 50 °C for 6 hrs. TLC (petroleum ether/ethyl acetate = 10/1, compound 1 Rf = 0.55, compound 4-2 Rf = 0.35) indicated compound 4-1 was consumed completely. The reaction mixture was quenched by H ₂ O (250 mL). The combined organic layers were washed with EtOAc (25.0 mL), extracted with EtOAc (50.0 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 0/1) to give compound 4-2 (10.1 g, 59.0% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 7.27-7.14 (m, 2H), 7.07-6.96 (m, 2H), 2.96-2.92 (m, 2H), 2.79-2.75 (m, 2H).

[0186] To a solution of compound 4-2 (10.1 g, 66.5 mmol) in THF (70.0 mL) was added compound 2A (8.87 g, 73.1 mmol). The mixture was stirred at 60 °C for 6 hrs. LCMS showed no compound 4-2 remained. Several new peaks were shown on LCMS and 48.2% of compound 4-3 was detected. The reaction mixture was diluted with H2O (100 mL) and washed with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 0/1; TLC: petroleum ether/ethyl acetate = 5/1, product Rf = 0.40) to give compound 4-3 (11.3 g, 66.5% yield) as a light-yellow oil. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.11-8.09 (m, 1H), 7.18-7.15 (m, 2H), 6.99-6.95 (m, 2H), 2.95-2.94 (m, 2H), 2.87-2.85 (m, 2H), 1.13 (s, 9H). [0187] To a solution of Zn (10.4 g, 159 mmol) in THF (85.0 mL) was added compound 2-A (650 mg, 3.89 mmol) and DIBAL-H (1 M, 7.88 mL) at 25 °C. Compound 2-A (12.5 g, 75.2 mmol, 8.32 mL) was added at 40 °C. The mixture was stirred at 40 °C for 1 hour. Compound 4-3 (11.3 g, 44.3 mmol) in THF (29.0 mL) was added to the mixture at -10 °C. The mixture was stirred at 50 °C for 2 hrs. TLC (petroleum ether/ethyl acetate = 5/1, compound 4-3 Rf = 0.35, compound 4-4 Rf = 0.15) indicated compound 4-3 was consumed completely. The reaction mixture was quenched by addition of brine (100 mL). The combined organic layers were washed with EtOAc (100 mL) and saturated citric acid (50.0 mL), extracted with EtOAc (150 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 50/1 to 0/1). The crude product was purified by prep-HPLC (column: Phenomenex C1875 x 30 mm x 3 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 8 min) to give compound 4-4 (2.00 g, 12.8% yield, 97.3% purity) as a white solid. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.13-7.10 (m, 2H), 6.98-6.94 (m, 2H), 4.30 (d, J = 8.8 Hz, 1H), 4.17-4.11 (m, 2H), 3.55-3.54 (m, 1H), 2.85-2.80 (m, 2H), 2.64-2.58 (m, 2H), 1.94-1.78 (m, 2H), 1.27-1.23 (m, 12H). [0188] To a solution of LiBH4 (2 M, 4.31 mL) in THF (15.0 mL) was added compound 4-4 (1.60 g, 4.66 mmol) in THF (15.0 mL) at 0 °C. The mixture was stirred at 20 °C for 1 hour. TLC (petroleum ether/ethyl acetate = 1/1, compound 4-4 Rf = 0.40, compound 4-5 Rf = 0.25) indicated compound 4-4 was consumed completely. The reaction solution was slowly poured into ice water (30.0 mL), then extracted with EtOAc (30.0 mL x 2). The combined organic phases were washed with brine (15.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuum to give compound 4-5 (1.38 g, 79.7% yield, 81.1% purity) as a white solid.1H NMR: (400 MHz, CDCl ₃ ) δ 7.13-7.10 (m, 2H), 7.00- 6.95 (m, 2H), 3.85-3.79 (m, 3H), 3.47-3.45 (m, 1H), 2.75-2.60 (m, 2H), 1.95-1.79 (m, 1H), 1.78-1.75 (m, 2H), 1.75-1.64 (m, 2H), 1.27 (s, 9H). LCMS (ESI) m/z 302.2 (M+H+).

[0189] To a solution of compound 4-5 (1.30 g, 4.31 mmol) in THF (10.0 mL) was added Et3N (2.18 g, 21.5 mmol). Then MsCl (830 mg, 7.25 mmol) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. LCMS showed no compound 4-5 remained. Several new peaks were shown on LCMS and 59.4% of compound 4-5A was detected. The reaction mixture of compound 4-5A (1.64 g) in THF (10.0 mL) as a white liquid was used into next step directly. [0190] To a solution of compound 4-5A (1.64 g, 4.32 mmol) in THF (10.0 mL) was added compound A (2 M, 43.2 mL) at 0 °C. The mixture was stirred at 25 °C for 16 hrs. LCMS showed no compound 4-5A remained. Several new peaks were shown on LCMS and 47.9% of compound 4-6 was detected. The reaction mixture was diluted with H ₂ O (25.0 mL) and washed with EtOAc (25.0 mL x 3). The combined organic layers were washed with brine (25.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 50/1 to 0/1, ethyl acetate, Rf = 0.15) to give compound 4-6 (820 mg, 49.2% yield, 85.3% purity) as a yellow oil. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.14-7.11 (m, 2H), 6.98-6.94 (m, 2H), 6.18 (s, 1H), 3.44 (s, 1H), 2.65-2.51 (m, 2H), 2.49-2.48 (m, 2H), 2.26 (s, 6H), 1.74-1.73 (m, 4H), 1.23 (s, 9H). LCMS (ESI) m/z 329.2 (M+H+). [0191] To a solution of compound 4-6 (820 mg, 2.50 mmol) in EtOAc (5.00 mL) was added HCl/EtOAc (4 M, 3.74 mL). The mixture was stirred at 20 °C for 4 hours. LCMS showed no compound 4-6 remained. Several new peaks were shown on LCMS and 38.6% of Amine 4 was detected. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator to give compound Amine 4 (1.00 g, 68.5% yield, 38.4% purity) as a light- yellow oil.1H NMR: (400 MHz, MeOD) δ 7.31-7.28 (m, 2H), 7.05-7.01 (m, 2H), 3.38-3.32 (m, 1H), 2.93 (s, 6H), 2.77-2.75 (m, 2H), 2.16-2.02 (m, 2H), 2.01-1.98 (m, 4H). LCMS (ESI) m/z 225.2 (M+H+). EXAMPLE 11. (S)-N ¹ ,N ¹ -DIMETHYL-5-PHENYLPENTANE-1,3-DIAMINE (AMINE 3)

[0192] Compound 3-2 (120 g) was obtained as a yellow oil in 83.9% yield according to the general procedure of compound 4-3. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.17-8.15 (m, 1H), 7.34- 7.21 (m, 5H), 3.03-2.90 (m, 4H), 1.17 (s, 9H). [0193] Compound 3-3 (32.0 g) was obtained as a yellow oil in 45.9% yield according to the general procedure of compound 4-4. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.37-7.34 (m, 2H), 7.30- 7.24 (m, 3H), 4.42-4.24 (m, 1H), 4.23-4.17 (m, 5H), 3.66-3.64 (m, 1H), 2.93-2.66 (m, 4H), 2.04- 1.91 (m, 2H), 1.35-1.27 (m, 12H). [0194] Compound 3-4 (22 g) was obtained as a yellow oil in 84.2% yield according to the general procedure of compound 6-5. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.29-7.15 (m, 5H), 3.95- 3.81 (m, 3H), 3.46 (s, 1H), 2.74-2.60 (m, 2H), 1.91-1.80 (m, 4H), 1.78-1.26 (m, 9H). [0195] Compound 3-4A (1.28 g, crude) in THF was obtained as a colorless liquid according to the general procedure of compound 4-5A. [0196] Compound 3-5 (900 mg) was obtained as a yellow oil in 81.8% yield according to the general procedure of compound 4-6. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.37-7.24 (m, 5H), 6.19- 6.18 (m, 1H), 3.51 (s, 1H), 2.77-2.73 (m, 4H), 2.72-2.34 (m, 6H), 1.96-1.92 (m, 4H), 1.84-1.30 (m, 9H).

[0197] Compound Amine 3 (1.00 g, HCl) was obtained as a yellow oil in 78.0% yield according to the general procedure of compound Amine 4.1H NMR: (400 MHz, MeOD) δ 7.68- 7.58 (m, 5H), 3.78-3.68 (m, 3H), 3.17-3.13 (m, 2H), 2.59-2.37 (m, 5H), 1.82 (m, 1H), 1.58-1.53 (m, 6H). EXAMPLE 12. (S)-N-((S)-1-(DIMETHYLAMINO)-5-(6- (TRIFLUOROMETHYL)PYRIDIN-3-YL)PENTAN-3-YL)-2-METHYLPROPANE-2 - SULFINAMIDE (AMINE 6) [0198] A mixture of compound 6-B (6.57 g, 34.4 mmol), CuCl (85.2 mg, 861 umol, 20.6 uL), Pd(OAc) ₂ (387 mg, 1.72 mmol), 2-(2-pyridyl)pyridine (807 mg, 5.17 mmol), and prop-2-en-1-ol (1.00 g, 17.2 mmol, 1.17 mL) in DMSO (30.0 mL) was stirred at 80 °C for 12 hours under air atmosphere and then prop-2-en-1-ol (1.85 g, 31.9 mmol, 2.17 mL) was added at 25 °C, then the mixture was stirred at 80 °C 6 hours under air atmosphere. TLC (petroleum ether/ethyl acetate = 1/1) showed compound 6-B (Rf = 0.35) was consumed and one new spot (Rf = 0.60) was formed. The reaction solution was poured into ice water (100 mL), and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine (50.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1) to give compound 6-2 (1.96 g, 44.7% yield) as yellow solid. 1H NMR: (400 MHz, CDCl ₃ ) δ 9.84 (s , 1H), 8.60 (s, 1H), 7.62-7.75 (m, 2H), 3.03-3.07 (m, 2H), 2.86-2.90 (m, 2H). [0199] Compound 6-3 (1.10 g) was obtained as a yellow oil in 37.2% yield according to the general procedure of compound 4-3. 1H NMR: HNMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 8.04- 8.06 (m, 1H), 7.64-7.66 (m, 1H), 7.54-7.56 (m, 1H), 3.01-3.04 (m, 2H), 2.85-2.89 (m, 2H), 1.05 (s, 9H). [0200] Compound 6-4 (100 mg) was obtained as a yellow oil in 7.06% yield according to the general procedure of compound 4-4. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.60-7.68 (m, 2H), 3.83-7.86 (m, 3H), 3.49 (s, 1H), 2.82-2.88 (m, 1H), 2.71-2.75 (m, 1H), 1.80-1.95 (m, 5H) 1.25-1.41 (m, 12H). Chiral SFC e.e.% = 100%. [0201] To a solution of Red-Al (1.49 g, 5.17 mmol, 1.44 mL, 70% purity) in Tol. (1.80 mL) was added compound 6-4 (600 mg, 1.52 mmol) in Tol. (4.20 mL) at 0 °C. The mixture was stirred at 0 °C for 3 hrs. TLC (ethyl acetate, compound 6-5 Rf = 0.25) showed compound 6-4 (Rf = 0.55) was consumed, and a main new spot with larger polarity was formed. showed compound 6-4 was consumed, and a main peak with desired MS was detected. The reaction solution was slowly poured into 5% NaOH aq (6.00 mL), then extracted with EtOAc (10.0 mL x 2). The combined organic phases were washed with saturated brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuum. HPLC indicated ~59.1% of product was detected. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 100/1 to 1/1) to give compound 6-5 (433 mg, 80.7% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.60-7.68 (m, 2H), 3.81-7.86 (m, 3H), 3.49 (s, 1H), 2.82-2.88 (m, 1H), 2.71-2.74 (m, 1H), 1.81-2.04 (m, 5H) 1.28 (s, 9H).

[0202] Compound 6-6 (742 mg) was obtained as a yellow liquid in 100% yield according to the general procedure of compound 4-5A. [0203] Compound 6-7 (544 mg) was obtained as a yellow solid in 71.4% yield according to the general procedure of compound 4-6. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 7.66-7.68 (m, 1H), 7.59-7.61 (m, 1H), 6.42 (s, 1H), 3.48 (s, 1H), 2.73-2.79 (m, 2H), 2.24-2.46 (m, 2H) 2.24 (s, 6H), 1.79-1.82 (m, 4H) 1.23 (s, 9H).

[0204] Compound Amine 6 (270 mg, HCl) was obtained as a yellow oil in 66.5% yield according to the general procedure of compound Amine 4.1H NMR: (400 MHz, MeOD) δ 8.67 (s, 1H), 8.02 (m, d = 6.8 Hz, 1H), 7.79 (m, d = 4.0 Hz, 1H), 3.37-3.49 (m, 3H), 2.90-2.95 (m, 7H), 2.01-2.23 (m, 5H). EXAMPLE 13. (S)-N-((S)-1-(DIMETHYLAMINO)-5-(6- (TRIFLUOROMETHYL)PYRIDIN-3-YL)PENTAN-3-YL)-2-METHYLPROPANE-2 - SULFINAMIDE (AMINE 8) [0205] A mixture of compound 8-5A (30.0 g, 127 mmol) and TEA (91.1 g, 900 mmol, 125 mL) in MeOH (120 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 40 °C for 12 hours under N ₂ atmosphere. TLC (petroleum ether/ethyl acetate = 1/2 product Rf = 0.49) showed ~40% of compound 8-5A (Rf =0.71) remained, and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to give compound 8-5B (30.0 g, crude) as a white solid).

[0206] To a solution of compound 8-5B (30.0 g, 112 mmol) in 2-MeTHF (210 mL) was added MsCl (15.6 g, 135 mmol, 10.5 mL) and TEA (17.0 g, 168 mmol, 23.4 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether/ethyl acetate = 1/1, product Rf = 0.55) showed starting material (Rf = 0.25) was consumed completely and one main new spot was formed. The reaction mixture was quenched by addition of sat. NaHCO ₃ (300 mL) at 0 °C and extracted with 2-MeTHF (200 mL x 3). The combined organic layers were washed with sat. brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give (34.9 g, 90.03% yield) as a yellow oil. [0207] To a solution of compound 8-5D (34.0 g, 98.5 mmol) in DMF (306 mL) was added phenylsulfanylsodium (13.0 g, 98.5 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 hour. TLC (petroleum ether/ethyl acetate = 1/1 product Rf = 0.85) showed compound 8-5D (Rf =0.48) was consumed completely and one new spot formed. The reaction mixture was quenched by addition of H ₂ O (300 mL), and then extracted with MTBE (150 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1 to 0/1) to give 8-5E (10.0 g, 28.2% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl ₃ ) δ 7.11-7.50 (m, 10H), 5.04 (s, 2H), 4.02-4.18 (m, 1H), 3.60 (s, 3H), 2.99-3.20 (m, 2H), 2.48-2.79 (m, 2H).

[0208] To a solution of compound 8-5E (4.00 g, 11.1 mmol) in THF (40.0 mL) was added LiBH ₄ (2 M, 11.1 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. HPLC indicated ~63.1% of product was detected. TLC (petroleum ether/ethyl acetate = 1/1, product Rf = 0.55) showed compound 8-5E (Rf = 0.70) was consumed, and a main new spot with larger polarity was formed. The reaction mixture was quenched by addition of 1 M HCl (20.0 mL), and then extracted with ethyl acetate (10.0 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to give compound 8-5C (2.60 g, 70.4% yield) as a yellow oil.1H NMR: (400 MHz, MeOD) δ 7.26-7.42 (m, 10H), 5.07 (s, 2H), 3.82-3.95 (m, 1H), 3.58-3.62 (m, 2H), 3.09-3.12 (m, 2H), 1.92-1.95 (m, 1H), 1.67-1.72 (m, 1H). [0209] To a solution of compound 8-5C (2.60 g, 7.84 mmol) in MeCN (21.0 mL) was added MsCl (3.11 g, 27.2 mmol, 2.10 mL) and TEA (3.97 g, 39.2 mmol, 5.46 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. LCMS showed compound 8-5C was consumed, a main peak with desired MS was detected. The reaction mixture of compound 8-5H (3.12 g) in MeCN (21.0 mL) was used into the next step without further purification.

[0210] To a solution of compound 8-5H (3.21 g, 7.84 mmol), compound C (3.50 g, 31.4 mmol, HCl) in MeCN (5.00 mL) was added TEA (3.97 g, 39.2 mmol, 5.46 mL). The mixture was stirred at 25 °C for 24 hours. LCMS showed compound 8-5H was consumed, and a main peak with desired MS was detected. TLC (petroleum ether/ethyl acetate = 0/1, product R _f = 0.50) showed compound 8-5H (R _f = 0.75) was consumed, and a main new spot with larger polarity was formed. The reaction mixture was quenched by addition of H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 0/1) to give compound 8-5I (1.90 g, 62.3% yield) as a yellow oil. ¹ H NMR: (400 MHz, MeOD-d ₆ ) δ 7.11-7.50 (m, 9H), 4.9-5.22 (m, 3H), 3.68-3.85 (m, 1H), 3.47-3.66 (m, 2H), 2.95-3.26 (m, 4H), 2.44-2.56 (m, 2H), 1.44-1.92 (m, 2H). [0211] To a solution of compound 8-5I (1.60 g, 4.12 mmol) in DCM (16.0 mL) was added methylsulfanylmethane (2.86 g, 46.0 mmol, 3.38 mL) and diethyloxonio(trifluoro)boranuide (2.92 g, 20.6 mmol, 2.54 mL). The mixture was stirred at 20 °C for 2 hrs. LCMS showed compound 8-5I was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by saturated NaHCO ₃ solution (50.0 mL), and then extracted with DCM (50.0 mL x 5). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give Amine 8 (1.00 g, 95.4% yield) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.29-7.50 (m, 5H), 5.04-5.21 (m, 1H), 3.63-3.69 (m, 2H), 3.13-3.33 (m, 4H), 2.71-2.73 (m, 2H), 1.61-1.88 (m, 2H). EXAMPLE 14. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(6- (TRIFLUOROMETHYL)PYRIDIN-3-YL)PENTAN-3-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0212] A mixture of Amine 6 (100 mg, 322 umol, HCl), sulfonamide 3 (70.0 mg, 321 umol),and DIEA (207 mg, 1.60 mmol, 279 uL) in DMSO (3.00 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 90 °C for 16 hours under N ₂ atmosphere. LCMS showed compound Amine 6 was consumed, and a main peak with desired MS was detected. The reaction mixture was quenched by addition of H ₂ O (30.0 mL) at 15 °C, and then extracted with EtOAc (5.00 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. HPLC indicated ~54.2% of product was detected. The crude product was purified by prep-HPLC (column: Phenomenex C1880*40mm*3um;mobile phase: [water(NH ₄ HCO ₃ )-ACN];B%: 25%- 55%,8min) to give compound D6-2 (50.0 mg, 30.9% yield, 94.0% purity) as a yellow solid. ¹ H NMR: (400 MHz, MeOD) δ 8.54 (s, 1H), 7.62-7.91 (m, 5H), 4.58 (s, 1H), 4.35-4.38 (m, 1H), 2.85-2.92 (m, 2H), 2.44-2.53 (m, 2H), 2.26 (s, 6H), 1.85-2.06 (m, 4H).

[0213] To a solution of compound D6-2 (45.0 mg, 95.0 umol) in DCM (5.00 mL) was added DMAP (26.7 mg, 219 umol) and EDCI (41.9 mg, 218.6 umol) and Acid 1 (32.0 mg, 219 umol). The mixture was stirred at 30 °C for 16 hours. showed ~12.3% of compound D6-2 (RT = 0.663 min) remained, and several new peaks were shown on LC-MS with ~50.3% of desired product detected. The reaction mixture was quenched by addition of H ₂ O (5.00 mL) and extracted with DCM (5.00 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. HPLC indicated ~81.9% of product was detected. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 25%-55%, 8min) to give (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide (20.2 mg, 35.3% yield, 100% purity) as a white solid. ¹ H NMR: ET55642-243- P1A1 (400 MHz, MeOD) δ 8.57 (s, 1H), 7.71-7.82 (m, 4H), 4.25-4.28 (m, 1H), 3.24-3.31 (m, 3H), 2.84-2.92 (m, 8H), 2.02-2.09 (m, 4H), 1.56-1.77 (m, 10H), 1.30 (s, 1H). LCMS (ESI) m/z 602.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%.

EXAMPLE 15. (R)-N-((4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3-NITROPHENYL)SULFONYL)- 1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0214] Compound D1-1 (350 mg, 93.0% purity) was obtained as a yellow solid in 39.7% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 8.59 (s, 1H), 7.83-7.80 (m, 1H), 7.40-7.36 (m, 2H), 7.04-6.97 (m, 3H), 4.13-4.11 (m, 1H), 3.25-3.20 (m, 1H), 2.69 (s, 1H), 2.47-2.42 (m, 2H), 2.40 (s, 6H), 2.25-2.07 (m, 1H), 1.93-1.91 (m, 1H). LCMS (ESI) m/z 443.1 (M+H ⁺ ).

[0215] (R)-N-((4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (3.49 mg, 98.8% purity) was obtained as a yellow solid in 5.35% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.60 (s, 1H), 7.87-7.84 (m, 1H), 7.35-7.32 (m, 2H), 6.99-6.87 (m, 3H), 4.09-4.06 (m, 1H), 3.17-3.13 (m, 4H), 2.81 (s, 6H), 2.27-2.25 (m, 2H), 1.86-1.53 (m, 10H), 1.30- 1.29 (m, 1H). LCMS (ESI) m/z 571.2 (M+H ⁺ ). Chiral SFC e.e.% = 100 ^% . EXAMPLE 16. (R)-N-((4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3-NITROPHENYL)SULFONYL)- 1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE

[0216] Compound D1-1 (350 mg, 93.0% purity) was obtained as a yellow solid in 39.7% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 8.59 (s, 1H), 7.83-7.80 (m, 1H), 7.40-7.36 (m, 2H), 7.04-6.97 (m, 3H), 4.13-4.11 (m, 1H), 3.25-3.20 (m, 1H), 2.69 (s, 1H), 2.47-2.42 (m, 2H), 2.40 (s, 6H), 2.25-2.07 (m, 1H), 1.93-1.91 (m, 1H). LCMS (ESI) m/z 443.1 (M+H ⁺ ). [0217] (R)-N-((4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3- nitrophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (19.0 mg, 94.9% purity) was obtained as a yellow solid in 26.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.62 (s, 1H), 7.88-7.86 (m, 1H), 7.35-7.32 (m, 2H), 6.99-6.91 (m, 3H), 4.11-4.07 (m, 1H), 3.24-3.22 (s, 2H), 3.12 (s, 3H), 3.02 (s, 2H), 2.73-2.70 (m, 6H), 1.89- 1.84 (m, 3H), 1.82 (s, 4H), 1.56-1.49 (m, 7H). LCMS (ESI) m/z 597.2 (M+H ⁺ ). EXAMPLE 17. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0218] Compound D1-3 (85.0 mg, 83.8% purity) was obtained as a brown oil in 39.2% yield according to the general procedure of compound D6-3. ¹ H NMR(400 MHz, MeOD) δ 7.70-7.59 (m, 2H), 7.34-7.31 (m, 2H), 7.04-6.99 (m, 2H), 4.47-4.40 (m, 1H), 3.37-3.18 (m, 6H), 2.54-2.48 (m, 2H), 2.27 (s, 6H), 2.02-1.87 (m, 2H). LCMS (ESI) m/z 441.0 (M+H ⁺ ).

[0219] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (24.4 mg, 96.4% purity) was obtained as a white solid in 19.2% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.56-7.52 (m, 2H), 7.22-7.09 (m, 4H), 6.21-6.18 (m, 1H), 4.12-4.08 (m, 1H), 3.26-3.12 (m, 5H), 2.72(s, 6H), 2.03-2.01 (m, 2H), 1.63-1.20 (m, 9H), 1.19 (s, 1H). LCMS (ESI) m/z 569.2 (M+H ⁺ ). EXAMPLE 18. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE

[0220] Compound D1-3 (85.0 mg, 83.8% purity) was obtained as a brown oil in 39.2% yield according to the general procedure of compound D6-3. ¹ H NMR(400 MHz, MeOD) δ 7.70-7.59 (m, 2H), 7.34-7.31 (m, 2H), 7.04-6.99 (m, 2H), 4.47-4.40 (m, 1H), 3.37-3.18 (m, 6H), 2.54-2.48 (m, 2H), 2.27 (s, 6H), 2.02-1.87 (m, 2H). LCMS (ESI) m/z 441.0 (M+H ⁺ ). [0221] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (10.2 mg, 92.6% purity) was obtained as a white solid in 8.23% yield according to the general procedure of Example 10. ¹ H NMR(400 MHz, DMSO-d ₆ ) δ 7.55-7.52 (m, 1H), 7.26-7.11 (m, 2H), 6.28 (s, 1H), 4.16 (s, 1H), 3.58 (s, 1H), 3.32-3.26 (m, 3H), 3.07 (s, 3H), 2.57-2.50 (m, 4H), 1.93-1.89 (m, 2H), 1.77-1.74 (m, 2H), 1.60-1.56 (m, 1H), 1.47-1.44 (m, 7H), 1.10-1.05 (m, 1H). LCMS (ESI) m/z 595.2 (M+H ⁺ ). EXAMPLE 19. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3-NITROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE [0222] Compound D2-1 (280 mg) was obtained as a yellow solid in 59.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD-d ₆ ) δ 8.53 (m, 1H), 7.75- 7.78 (m, 1H), 7.31-7.34 (m, 2H), 7.17-7.22 (m, 3H), 6.96-6.98 (m, 1H), 4.09-4.12 (m, 1H), 2.66 (s, 5H), 2.42-2.47 (m, 2H), 2.40 (s, 6H), 1.92-2.24 (m, 2H).

[0223] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (15.4 mg, 96.2% purity) was obtained as a yellow solid in 28.5% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.59-8.60 (d, J = 4.0 Hz, 1H), 7.81-7.83 (s,1H), 7.32-7.34 (m, 2H), 7.20- 7.22 (m, 3H), 6.84-6.86 (d, J = 8.0 Hz, 1H), 4.10-4.12 (m, 1H), 3.33-3.36 (m, 1H), 3.15-3.33 (m, 3H), 2.83 (s, 6H), 2.16-2.28 (m, 2 H), 1.59-1.80 (m, 9H), 1.31-1.32 (m, 1H). LCMS (ESI) m/z 553.0 (M+H ⁺ ). Chiral SFC e.e.% = 100.0%. EXAMPLE 20. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3-NITROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE-1- CARBOXAMIDE

[0224] Compound D2-1 (280 mg) was obtained as a yellow solid in 59.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD-d ₆ ) δ 8.53 (m, 1H), 7.75- 7.78 (m, 1H), 7.31-7.34 (m, 2H), 7.17-7.22 (m, 3H), 6.96-6.98 (m, 1H), 4.09-4.12 (m, 1H), 2.66 (s, 5H), 2.42-2.47 (m, 2H), 2.40 (s, 6H), 1.92-2.24 (m, 2H). [0225] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (30.4 mg, 100% purity) was obtained as a yellow solid in 37.2% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.60-8.61 (d, J = 4.0 Hz, 1H), 7.82-7.85 (s,1H), 7.30-7.33 (m, 2H), 7.20-7.23 (m, 3H), 6.86-6.88 (d, J = 8.0 Hz, 1H), 4.09-4.10 (m, 1H), 3.36-3.40 (m, 1H), 3.24- 3.31 (m, 1H), 3.12 (s, 2H), 2.66 (s, 6H), 2.21-2.31 (m, 2H) 1.81-1.87 (m, 4H), 1.51-1.57 (m, 8H). LCMS (ESI) m/z 579.0 (M+H ⁺ ). Chiral SFC e.e.% = 100.0%. EXAMPLE 21. (S)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)AMINO)- 3-NITROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0226] Compound D3-1 (300 mg) was obtained as a white solid in 64.5% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.27-7.12 (m, 5H), 2.96-2.85 (m, 1H), 2.79-2.59 (m, 3H), 2.53-2.37 (m, 3H), 2.25 (s, 6H), 1.83-1.66 (m, 4H), 1.64- 1.52 (m, 1H). [0227] (S)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)amino)-3-n itrophenyl)sulfonyl)-1- fluorocyclohexane-1-carboxamide (23.6 mg, 94.4% purity) was obtained as a yellow solid in 42.4% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.71 - 8.64 (m, 1H), 7.90 - 7.82 (m, 1H), 7.25 - 7.18 (m, 2H), 7.18 - 7.10 (m, 3H), 6.95 - 6.90 (m, 1H), 3.96 - 3.83 (m, 1H), 3.20 - 3.09 (m, 2H), 2.87 - 2.69 (m, 8H), 2.21 - 1.95 (m, 4H), 1.91 - 1.70 (m, 5H), 1.68 - 1.50 (m, 5H), 1.39 - 1.22 (m, 1H). LCMS (ESI) m/z 535.3 (M+H ⁺ ). EXAMPLE 22. (S)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)AMINO)- 3-NITROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0228] Compound D3-1 (300 mg) was obtained as a white solid in 64.5% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.27-7.12 (m, 5H), 2.96-2.85 (m, 1H), 2.79-2.59 (m, 3H), 2.53-2.37 (m, 3H), 2.25 (s, 6H), 1.83-1.66 (m, 4H), 1.64- 1.52 (m, 1H).

[0229] (S)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)amino)-3-n itrophenyl)sulfonyl)-1- methoxycycloheptane-1-carboxamide (25.4 mg, 94.9% purity) was obtained as a yellow solid in 43.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.67 (d, J = 2.4 Hz, 1H), 7.90-7.82 (m, 1H), 7.25-7.19 (m, 2H), 7.18-7.08 (m, 3H), 6.97-6.88 (m, 1H), 3.97-3.81 (m, 1H), 3.14-3.09 (m, 3H), 3.07-2.95 (m, 2H), 2.80-2.62 (m, 8H), 2.17-1.93 (m, 5H), 1.91-1.71 (m, 4H), 1.66-1.38 (m, 9H). LCMS (ESI) m/z 561.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 23. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE

[0230] Compound D3-3 (170 mg) was obtained as a yellow solid in 43.6% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.71-7.60 (m, 2H), 7.24-7.13 (m, 5H), 4.32-4.29 (m, 1H), 2.76-2.49 (m, 2H), 2.44-2.24 (m, 2H), 2.43-1.99 (m, 6H), 1.97-1.82 (m, 4H). [0231] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (18.3 mg, 97.2% purity) was obtained as a yellow solid in 27.8% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.78-7.69 (m, 2H), 7.23-7.07 (m, 5H), 4.19-4.15 (m, 1H), 3.21-3.16 (m, 2H), 2.80-2.65 (m, 8H), 2.01-1.96 (m, 5H), 1.76-1.58 (m, 8H), 1.57-1.29 (m, 1H). LCMS (ESI) m/z 533.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 24. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE-1- CARBOXAMIDE [0232] Compound D3-3 (170 mg) was obtained as a yellow solid in 43.6% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.71-7.60 (m, 2H), 7.24-7.13 (m, 5H), 4.32-4.29 (m, 1H), 2.76-2.49 (m, 2H), 2.44-2.24 (m, 2H), 2.43-1.99 (m, 6H), 1.97-1.82 (m, 4H).

[0233] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (13.1 mg, 99.7% purity) was obtained as a white solid in 19.0% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.79-7.69 (m, 2H), 7.22-7.07 (m, 5H), 4.58 (s, 1H), 4.20-4.17 (m, 1H), 3.22-3.10 (m, 5H), 2.80-2.64 (m, 8H), 2.03-1.80 (m, 8H), 1.54-1.49 (m, 8H). LCMS (ESI) m/z 559.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 25. (S)-N-((4-((1-(DIMETHYLAMINO)-5-(4-FLUOROPHENYL)PENTAN-3- YL)AMINO)-3-NITROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE

[0234] Compound D4-1 (202 mg, 97.7% purity) was obtained as an orange solid in 52.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.70 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.09-7.08 (m, 2H), 6.99-6.94 (m, 3H), 4.85- 4.83 (m, 2H), 3.88 (S, 1H), 2.70-2.67 (m, 2H), 2.33 (s, 6H), 2.04-1.93 (m, 4H). LCMS (ESI) m/z 425.3 (M+H ⁺ ). [0235] (S)-N-((4-((1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl) amino)-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (15.3 mg, 99.2% purity) was obtained as a yellow solid in 22.6% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.69 (d, J = 2.0 Hz, 1H), 7.92-7.89 (m, 1H), 7.16-7.13 (m, 2H), 6.97-6.93 (m, 3H), 3.88 (s, 1H), 2.74-2.72 (m, 6H), 2.21-1.77 (m, 6H),1.74-1.56 (m, 10H), 1.29-1.19 (m, 2H). LCMS (ESI) m/z 553.3 (M+H ⁺ ). Chiral SFC e.e.% = 92.9%. EXAMPLE 26. (S)-N-((4-((1-(DIMETHYLAMINO)-5-(4-FLUOROPHENYL)PENTAN-3- YL)AMINO)-3-NITROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE-1- CARBOXAMIDE [0236] Compound D4-1 (202 mg, 97.7% purity) was obtained as an orange solid in 52.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.76 (s, 1H), 8.70 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.09-7.08 (m, 2H), 6.99-6.94 (m, 3H), 4.85- 4.83 (m, 2H), 3.88 (S, 1H), 2.70-2.67 (m, 2H), 2.33 (s, 6H), 2.04-1.93 (m, 4H). LCMS (ESI) m/z 425.3 (M+H ⁺ ).

[0237] (S)-N-((4-((1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl) amino)-3- nitrophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (35.4 mg, 97.5% purity) was obtained as a yellow solid in 50.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.69 (d, J = 2.4 Hz, 1H), 7.90-7.87 (m, 1H), 7.15-7.11 (m, 2H), 7.00-6.92 (m, 3H), 3.91-3.89 (m, 1H), 3.21 (s, 3H), 3.11-3.05 (m, 2H), 2.75 (s, 8H), 2.03-2.01 (m, 4H), 1.86-1.81 (m, 4H), 1.56-1.48 (m, 10H). LCMS (ESI) m/z 579.3 (M+H ⁺ ). EXAMPLE 27. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE

[0238] Compound D4-3 (180 mg, 88.3% purity) was obtained as a yellow oil in 42.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.73-7.60 (m, 2H), 7.17-7.13 (m, 2H), 6.97-6.93 (m, 2H), 4.31- 4.28 (m, 1H), 2.75-2.65 (m, 2H), 2.64-2.48 (m, 2H), 2.23 (s, 6H), 2.01-1.94 (m, 2H), 1.92-1.83 (m, 2H). LCMS (ESI) m/z 423.0 (M+H ⁺ ). [0239] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (16.9 mg, 97.6% purity) was obtained as a white solid in 30.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.79-7.78 (m, 1H), 7.73-7.69 (m, 1H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.18-4.17 (m, 1H), 2.77 (d, J = 6.8 Hz, 6H), 2.02-1.95 (m, 6H), 1.83-1.74 (m, 3H), 1.74-1.73 (m, 3H), 1.59-1.55 (m, 6H), 1.38-1.25 (m, 2H). LCMS (ESI) m/z 551.3 (M+H ⁺ ). Chiral SFC e.e.% = 98.7%). EXAMPLE 28. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0240] Compound D4-3 (180 mg, 88.3% purity) was obtained as a yellow oil in 42.1% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.73-7.60 (m, 2H), 7.17-7.13 (m, 2H), 6.97-6.93 (m, 2H), 4.31- 4.28 (m, 1H), 2.75-2.65 (m, 2H), 2.64-2.48 (m, 2H), 2.23 (s, 6H), 2.01-1.94 (m, 2H), 1.92-1.83 (m, 2H). LCMS (ESI) m/z 423.0 (M+H ⁺ ).

[0241] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (8.60 mg, 96.5% purity) was obtained as a white solid in 12.1% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.72-7.69 (m, 1H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.19-4.18 (m, 1H), 3.10 (s, 3H), 2.73 (s, 6H),2.70-2.64 (m, 2H), 2.02-1.95 (m, 4H), 1.94 - 1.80 (m, 4H), 1.56-1.48 (m, 10H). LCMS (ESI) m/z 577.3 (M+H ⁺ ). EXAMPLE 29. (R)-1-FLUORO-N-((4-((4-(3-FLUOROAZETIDIN-1-YL)-1- (PHENYLTHIO)BUTAN-2-YL)AMINO)-3- NITROPHENYL)SULFONYL)CYCLOHEXANE-1-CARBOXAMIDE

[0242] Compound D8-1 (150 mg, crude) was obtained as a yellow oil according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 8.53 (s, 1H), 7.74-7.77 (m 1H), 7.312-7.34 (m ,2H), 7.19-7.21 (m, 3H), 6.94-6.96 (d, J = 8.0 Hz, 1H), 5.04-5.20 (m, 1H), 4.58 (s, 2H), 4.02-4.17 (m, 1H), 3.17-3.20 (m, 3H), 3.34 (br d, J=5.75 Hz, 1H), 2.71-2.73 (m, 2H), 2.56- 69 (m, 1H), 1.74 - 1.99 (m, 2H). [0243] (R)-1-fluoro-N-((4-((4-(3-fluoroazetidin-1-yl)-1-(phenylthio )butan-2-yl)amino)-3- nitrophenyl)sulfonyl)cyclohexane-1-carboxamide (42.3 mg, 97.1% purity) was obtained as a yellow solid in 25.8% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.62-8.63 (d, J = 4.0 Hz, 1H), 7.84-7.86 (m, 1H), 7.30-7.32 (m, 2H), 7.19-7.21 (m, 3H), 6.93-9.95 (d, J = 8.0 Hz, 1H), 5.24-5.39 (m, 1H), 4.16-4.23 (m, 3H), 3.78-3.95 (m, 2H), 3.42-3.40 (m, 1H), 3.27-3.33 (m, 1H), 3.14-3.15 (m, 2H), 1.92-2.01 (m, 2H), 1.69-1.91 (m,7H), 1.51-1.67 (m, 7H), 1.31-1.35 (m, 2H). LCMS (ESI) m/z 583.1 (M+H ⁺ ). Chiral SFC e.e.% = 100.0%. EXAMPLE 30. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3,5-DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1 - CARBOXAMIDE [0244] To a solution of Amine 2 (0.5 g, 2.23 mmol) and sulfonamide 2 (659 mg, 3.12 mmol) in thiolane 1,1-dioxide (1.5 mL) was added DIEA (1.44 g, 11.1 mmol, 1.94 mL). The mixture was stirred in a microwave tube at 130 °C for 6 hrs. LCMS showed Amine 2 was consumed, and a main peak with desired MS was detected. The reaction mixture was quenched by addition of H ₂ O (20.0 mL), and then extracted with DCM (20.0 mL x 5). The combined organic layers were washed with brine (30.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. HPLC indicated ~59.4% of product was detected, and that a main peak with desired was detected. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; B%: 30%- 60%,8 min), to give D2-2 (150 mg, 361 umol, 16.2% yield) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.19-7.34 (m, 7 H), 3.96-3.98 (m, 1H), 3.16-3.18 (d, J = 8.0 Hz, 2H), 2.50-2.24 (m, 2H), 2.45 (s, 6H), 1.87-2.09 (m, 1H), 1.78-1.79 (m, 1H). [0245] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3,5- difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (7.97 mg, 96.9% purity) was obtained as a yellow solid in 19.6% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.37-7.39 (m, 2H), 7.20-7.24 (m, 5H), 4.58 (s,1H), 3.79-3.80 (m, 2H), 3.10-3.17 (m, 4H), 2.81 (s, 6H), 2.16-2.41 (m, 1H), 1.83-1.99 (m, 2H), 1.75-1.78 (m, 3H), 1.56-1.60 (m, 5H), 1.29-1.39 (m, 2H). LCMS (ESI) m/z 544.1 (M+H ⁺ ). Chiral SFC e.e.% = 96.3%. EXAMPLE 31. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3,5-DIFLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE - 1-CARBOXAMIDE [0246] To a solution of Amine 2 (0.5 g, 2.23 mmol) and sulfonamide 2 (659 mg, 3.12 mmol) in thiolane 1,1-dioxide (1.5 mL) was added DIEA (1.44 g, 11.1 mmol, 1.94 mL). The mixture was stirred in a microwave tube at 130 °C for 6 hrs. LCMS showed Amine 2 was consumed, and a main peak with desired MS was detected. The reaction mixture was quenched by addition of H ₂ O (20.0 mL), and then extracted with DCM (20.0 mL x 5). The combined organic layers were washed with brine (30.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. HPLC indicated ~59.4% of product was detected, and that a main peak with desired was detected. The crude product was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water( NH4 _H CO ₃ )-ACN];B%: 30%- 60%,8min), to give D2-2 (150 mg, 361 umol, 16.2% yield) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.19-7.34 (m, 7 H), 3.96-3.98 (m, 1H), 3.16-3.18 (d, J = 8.0 Hz, 2H), 2.50-2.24 (m, 2H), 2.45 (s, 6H), 1.87-2.09 (m, 1H), 1.78-1.79 (m, 1H). [0247] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3,5- difluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (7.99 mg, 100% purity) was obtained as a yellow solid in 11.6% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.25-7.40 (m, 2H), 7.19-7.23 (m, 5H), 3.80-3.82 (m, 1H), 3.25-3.5 (m, 2H), 3.10-3.16 (m, 3H), 2.73 (s, 6H), 1.81-1.92 (m, 7H), 1.49-1.58 (m, 9H). LCMS (ESI) m/z 570.2 (M+H ⁺ ). Chiral SFC e.e.% = 100.0%. EXAMPLE 32. (R)-N-((4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0248] Compound D1-2 (160 mg, 65.5% purity) was obtained as a brown oil in 29.3% yield according to the general procedure of compound D2-2. ¹ H NMR: (400 MHz, MeOD) δ7.40-7.30 (m, 4H), 7.02-6.98 (m, 2H), 3.94-3.87 (m, 1H), 3.12-3.10 (m, 2H), 2.52-2.31 (m, 2H), 2.43 (s, 6H), 1.77 (s, 1H), 1.29 (s, 1H). LCMS (ESI) m/z 434.0 (M+H ⁺ ).

[0249] (R)-N-((4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3,5- difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (12.4 mg, 100% purity, FA) was obtained as a white solid in 12.0% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.41-7.39 (m, 2H), 7.26-7.23 (m, 2H), 7.05-7.00 (m, 2H), 3.78 (m, 1H), 3.38-3.36 (m, 1H), 3.29-3.25 (m, 1H), 3.13-3.12 (m, 2H), 2.89 (s, 6H), 2.19-2.18 (m, 1H), 1.87-1.76 (m, 5H), 1.65-1.55 (m, 5H), 1.32-1.29 (s, 1H). LCMS (ESI) m/z 562.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 33. (R)-N-((4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE-1- CARBOXAMIDE

[0250] Compound D1-2 (160 mg, 65.5% purity) was obtained as a brown oil in 29.3% yield according to the general procedure of compound D2-2. ¹ H NMR: (400 MHz, MeOD) δ7.40-7.30 (m, 4H), 7.02-6.98 (m, 2H), 3.94-3.87 (m, 1H), 3.12-3.10 (m, 2H), 2.52-2.31 (m, 2H), 2.43 (s, 6H), 1.77 (s, 1H), 1.29 (s, 1H). LCMS (ESI) m/z 434.0 (M+H ⁺ ). [0251] (R)-N-((4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3,5- difluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (7.22 mg, 99.0% purity) was obtained as a white solid in 6.59% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.43-7.28 (m, 2H), 7.27-7.24 (m, 2H), 7.06-7.01 (m, 2H), 3.81 (m, 1H), 3.32 (s, 1H), 3.17 (s, 1H), 3.13 (s, 4H), 2.82 (s, 6H), 2.16 (s, 1H), 1.93-1.84 (m, 6H), 1.57- 1.50 (m, 9H). LCMS (ESI) m/z 588.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 34. (S)-N-((4-((1-(DIMETHYLAMINO)-5-(4-FLUOROPHENYL)PENTAN-3- YL)AMINO)-3,5-DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1 - CARBOXAMIDE [0252] Compound D4-2 (202 mg, 90.3% purity) was obtained as a light-yellow gum in 11.7% yield according to the general procedure of compound D2-2. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.37-7.34 (m, 2H), 7.13-7.11 (m, 2H), 6.97-6.92 (m, 2H), 3.82-3.75 (m, 1H), 2.73-2.64 (m, 2H), 2.44-2.43 (m, 2H), 2.23 (s, 6H), 1.88-1.75 (m, 4H). LCMS (ESI) m/z 416.1 (M+H ⁺ ).

[0253] (S)-N-((4-((1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl) amino)-3,5- difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (10.9 mg, 98.1% purity) was obtained as a white solid in 20.4% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.41-7.38 (m, 2H), 7.10-7.08 (m, 2H), 6.96-6.92 (m, 2H), 3.73 (s, 1H), 2.84-2.60 (m, 4H), 2.46 (s, 6H), 2.03-1.82 (m, 6H), 1.77-1.73 (m, 4H), 1.58-1.55 (m, 5H). LCMS (ESI) m/z 544.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 35. (S)-N-((4-((1-(DIMETHYLAMINO)-5-(4-FLUOROPHENYL)PENTAN-3- YL)AMINO)-3,5-DIFLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEPTANE - 1-CARBOXAMIDE

[0254] Compound D4-2 (202 mg, 90.3% purity) was obtained as a light-yellow gum in 11.7% yield according to the general procedure of compound D2-2. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.37-7.34 (m, 2H), 7.13-7.11 (m, 2H), 6.97-6.92 (m, 2H), 3.82-3.75 (m, 1H), 2.73-2.64 (m, 2H), 2.44-2.43 (m, 2H), 2.23 (s, 6H), 1.88-1.75 (m, 4H). LCMS (ESI) m/z 416.1 (M+H ⁺ ). [0255] (S)-N-((4-((1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl) amino)-3,5- difluorophenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamide (13.9 mg, 93.0% purity) was obtained as a white solid in 31.6% yield according to the general procedure of Example 10. ¹ H NMR(400 MHz, MeOD) δ 7.42 (d, J = 9.6 Hz, 2H), 7.09-7.06 (m, 2H), 6.96-6.92 (m, 2H), 3.72 (s, 2H), 3.20 (s, 1H), 3.17 (s, 1H), 3.10 (s, 1H), 2.71 (m, 6H), 2.71-2.51 (m, 2H),1.91-1.85 (m, 8H), 1.58-1.48 (m, 9H). LCMS (ESI) m/z 570.3 (M+H ⁺ ). EXAMPLE 36. (R)-N-((4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOPENTANE-1- CARBOXAMIDE [0256] (R)-N-((4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3,5- difluorophenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamide (32.8 mg, 99.3% purity) was obtained as a white solid in 25.8% yield according to the general procedure of Example 10. ¹ H NMR(400 MHz, MeOD) δ 7.40-7.38 (m, 2H), 7.26-7.22 (m, 2H), 7.03-7.00 (m, 2H), 3.78-3.75 (m, 1H), 3.24-3.22 (m, 1H), 3.14-3.09 (m, 6H), 2.78 (s, 6H), 1.94-1.92 (m, 1H), 1.91-1.90 (m, 3H), 1.81 (s, 2H), 1.65-1.62 (m, 4H). LCMS (ESI) m/z 560.1 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 37. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0257] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (34.1 mg, 97.0% purity) was obtained as a white solid in 50.2% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.77 (s, 1H), 7.72-7.68 (m, 1H), 7.25-7.22 (m, 2H), 7.05-7.00 (m, 2H), 4.26-4.21 (m, 1H), 3.31-3.24 (m, 2H), 3.20 (s, 3H), 2.77 (s, 6H), 1.74-1.66 (m, 3H), 1.56- 1.55 (m, 5H), 1.53-1.47 (m, 6H), 1.22-1.20 (m, 2H). LCMS (ESI) m/z 581.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 38. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOPENTANE-1-CARBOXAMIDE [0258] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamide (30.5 mg, 99.6% purity) was obtained as a white solid in 47.3% yield according to the general procedure of Exampl310. ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.75-7.71 (m, 1H), 7.26-7.22 (m, 2H), 7.06-7.02 (m, 2H), 4.25-4.22 (m, 1H), 3.28-3.25 (m, 3H), 3.24 (s, 3H), 3.23-3.15 (m, 1H), 2.82 (s, 6H), 1.95- 1.94 (m, 2H), 1.93-1.92 (m, 2H), 1.84-1.83 (m, 2H), 1.67-1.65 (m, 2H). LCMS (ESI) m/z 567.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 39. (S)-N-((3-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CYANO-4- (((R)-4-(DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)A MINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0259] A mixture of diastereomers (65.0 mg, 96.2% purity) comprising (S)-N-((3-cyano-4- (((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)a mino)-5-fluorophenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide and (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1- ((4-fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfo nyl)-2-methyltetrahydro-2H- pyran-2-carboxamide was obtained as a white solid in 60.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.73-7.81 (m, 2H), 7.24-7.27 (m, 2H), 7.02-7.07 (m, 2H), 4.23-4.25 (d= 11.2 Hz, 1H), 3.66-3.74 (m, 1H), 3.27-3.22 (m, 4H), 3.11-3.16 (m, 5H), 2.83 (s, 6H), 2.16-2.26 (m, 2H), 1.22-1.62 (m, 7H), 1.21 (s, 3H). Chiral separation yielding (S)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl )thio)butan-2-yl)amino)- 5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbo xamide (20.8 mg, 34.2% yield, 98.6% purity) and (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl )thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide (22.8 mg, 37.8% yield, 99.3% purity) was accomplished by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D. 10 um; mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 33%-33%, 12 min). (S)-N-((3- cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide: ¹ H NMR: (400 MHz, MeOD) δ 7.78 (s, 1H), 7.69-7.73 (m, 1H), 7.22-7.25 (m, 2H), 7.00-7.04 (m, 2H), 4.21-4.22 (m, 1H), 3.90-3.96 (m, 1H), 3.60-3.73 (m, 2H), 3.08-3.28 (m, 4H), 2.80 (s, 6H), 2.15-2.24 (m, 2H), 1.40-1.60 (m, 5H), 1.19 (s, 3H). LCMS (ESI) m/z 567.3 (M+H ⁺ ), SFC e.e. % = 87.9%. (R)-N- ((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio) butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide: ¹ H NMR: (400 MHz, MeOD) δ 7.78 (s, 1H), 7.69-7.73 (m, 1H), 7.22-7.25 (m, 2H), 7.00-7.04 (m, 2H), 4.21-4.22 (m, 1H), 3.90-3.96 (m, 1H), 3.60-3.73 (m, 2H), 3.08-3.28 (m, 4H), 2.80 (s, 6H), 2.15-2.24 (m, 2H), 1.40-1.60 (m, 5H), 1.19 (s, 3H). LCMS (ESI) m/z 567.3 (M+H ⁺ ), SFC e.e.% = 95.7 %.

EXAMPLE 40. (S)-N-((3-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -2- METHYL-1,4-DIOXANE-2-CARBOXAMIDE AND (R)-N-((3-CYANO-4-(((R)-4- (DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYL-1,4-DIOXANE-2-CARBOXAMIDE [0260] A mixture of diastereomers (37.0 mg, 98.2% purity) comprising (S)-N-((3-cyano-4- (((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)a mino)-5-fluorophenyl)sulfonyl)-2- methyl-1,4-dioxane-2-carboxamide and (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyl-1,4-dioxane-2- carboxamide was obtained as a white solid in 35.1% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.74-7.81 (m, 2H), 7.24-7.26 (m, 2H), 7.03-7.07 (m, 2H), 4.28 (d= 11.2 Hz, 1H), 3.87-3.94 (m, 1H), 3.55-3.58 (m, 4H), 3.26-3.00 (m, 5H), 3.15- 3.16 (m, 1H), 2.86 (s, 6H), 2.07-2.19 (m, 2H), 1.18 (s, 3H). Chiral separation yielding (S)-N-((3- cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyl-1,4-dioxane-2-carboxamide and (R)-N-((3-cyano-4-(((R)-4- (dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyl- 1,4-dioxane-2-carboxamide was accomplished by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10um); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 45%-45%, 10 min). (S)-N- ((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio) butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyl-1,4-dioxane-2-carboxamide: ¹ H NMR: (400 MHz, MeOD) δ 7.75-7.82 (m, 2H), 7.24-7.27 (m, 2H), 7.04-7.08 (m, 2H), 4.28-4.31 (m, 1H), 3.89-3.96 (m, 1H), 3.56-3.65 (m, 4H), 3.21-3.28 (m, 4H), 3.11-3.17 (m, 1H), 2.87 (s, 6H), 2.02-2.21 (m, 2H), 1.17- 1.23 (m, 5H). LCMS (ESI) m/z 569.2 (M+H ⁺ ), SFC e.e.% = 99.6%. (R)-N-((3-cyano-4-(((R)-4- (dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyl- 1,4-dioxane-2-carboxamide: ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.71-7.74 (m, 1H), 7.22-7.25 (m, 2H), 7.01-7.05 (m, 2H), 4.25-4.29 (m, 1H), 3.90-3.96 (m, 1H), 3.53-3.58 (m, 4H), 3.24-3.27 (m, 4H), 3.12-3.14 (m, 1H), 2.84 (s, 6H), 2.02-2.23 (m, 2H), 1.15-1.20 (m, 4H). LCMS (ESI) m/z 569.2 (M+H ⁺ ), SFC e.e.% = 98.0%. EXAMPLE 41. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) - 4,4-DIFLUORO-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0261] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-4,4-difluoro-1-methoxycyclohexane-1-c arboxamide (19.5 mg, 99.5% purity, FA) was obtained as a white solid in 25.8% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 7.77 (s, 1H), 7.73-7.69 (m, 1H), 7.24-7.21 (m, 2H), 7.05-7.00 (m, 2H), 4.22 (s, 1H), 3.27-3.24 (m, 3H), 3.15-3.10 (m, 5H), 2.86 (s, 6H), 1.92-1.91 (m, 1H), 1.90 (s, 1H), 1.86 (m, 10H). LCMS (ESI) m/z 617.2 (M+H ⁺ ). EXAMPLE 42. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3-NITROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0262] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (30.08 mg, 97.8% purity) was obtained as yellow solid in 55.3% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.62-8.56 (m, 1H), 7.85-7.77 (m, 1H), 7.35-7.28 (m, 2H), 7.26-7.14 (m, 3H), 6.91-6.81 (m, 1H), 4.15-4.00 (m, 1H), 3.38-3.34 (m, 1H), 3.27-3.19 (m, 1H), 3.15-3.10 (m, 3H), 3.08-2.99 (m, 2H), 2.80-2.63 (m, 6H), 2.33-2.18 (m, 1H), 2.16-2.02 (m, 1H), 1.81-1.71 (m, 2H), 1.70-1.59 (m, 2H), 1.58 - 1.43 (m, 5H), 1.33-1.18 (m, 1H). LCMS (ESI) m/z 565.2 (M+H ⁺ ). EXAMPLE 43. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3-NITROPHENYL)SULFONYL)CYCLOHEXANECARBOXAMIDE [0263] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)cyclohexanecarboxamide (20.71 mg, 97.7% purity) was obtained as yellow solid in 48.7% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.59 (d, J = 2.0 Hz, 1H), 7.86-7.78 (m, 1H), 7.35-7.28 (m, 2H), 7.24-7.15 (m, 3H), 6.91-6.85 (m, 1H), 4.17-4.01 (m, 1H), 3.38-3.34 (m, 1H), 3.27-3.21 (m, 1H), 2.99-2.87 (m, 2H), 2.72-2.55 (m, 6H), 2.30-2.01 (m, 3H), 1.80-1.60 (m, 5H), 1.40-1.15 (m, 5H). LCMS (ESI) m/z 535.2 (M+H ⁺ ). EXAMPLE 44. (R)-N-((4-((4-(DIMETHYLAMINO)-1-(PHENYLTHIO)BUTAN-2- YL)AMINO)-3-NITROPHENYL)SULFONYL)-4-METHYLTETRAHYDRO-2H-PYRA N- 4-CARBOXAMIDE [0264] (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3- nitrophenyl)sulfonyl)-4-methyltetrahydro-2H-pyran-4-carboxam ide (27.54 mg, 97.7% purity) was obtained as yellow solid in 48.1% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.62-8.56 (m, 1H), 7.85-7.78 (m, 1H), 7.37-7.29 (m, 2H), 7.26- 7.15 (m, 3H), 6.89-6.80 (m, 1H), 4.13-4.02 (m, 1H), 3.73-3.64 (m, 2H), 3.52-3.41 (m, 2H), 3.39- 3.33 (m, 1H), 3.26-3.09 (m, 4H), 2.87-2.74 (m, 6H), 2.35-2.11 (m, 2H), 2.10-2.00 (m, 2H), 1.40- 1.29 (m, 2H), 1.11-1.06 (m, 3H). LCMS (ESI) m/z 551.2 (M+H ⁺ ). EXAMPLE 45. (S)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)OXY)-3- NITROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE AND (R)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)OXY)-3- NITROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE

[0265] To a solution of DMA (23.5 g, 269 mmol, 25.0 mL) in THF (80.0 mL) was added LDA (2 M, 135 mL) drop wise at -60 °C. The reaction solution was stirred at -60 °C for 0.5 hr under N _2. Then a solution of compound 1 (40.0 g, 224 mmol) in THF (80.0 mL) was added drop wise at -60 °C. The mixture was slowly warmed to 20 °C and stirred for 2 hrs under N _2. TLC (petroleum ether/ethyl acetate = 1/1) showed ~20% of compound 1 (R _f = 0.70) remained and one main new spot (R _f = 0.20) was formed. The reaction solution was adjusted to pH = 7 with 10% citric acid aqueous at 0 °C. Then the mixture was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/2) to give compound 2 (28.0 g, 55.3% yield, 97.2% purity) as a colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.29-7.22 (m, 2H), 7.21-7.13 (m, 3H), 3.59-3.37 (m, 2H), 3.03-2.77 (m, 10H). LCMS (ESI) m/z 220.1 (M+H ⁺ ). [0266] LiAlH ₄ (2 M, 27.4 mL) was slowly added to the container. Then a solution of compound 2 (10.0 g, 45.6 mmol) in THF (10.0 mL) was added drop wise (keeping the temperature at 0-10 °C). The mixture was warmed to 20 °C and stirred for 72 hrs. LCMS showed compound 2 was consumed and one main peak with desired MS was formed. The reaction solution was slowly quenched with H ₂ O (1.04 g) at 0 °C. Then 15% NaOH aqueous (1.04 g), H ₂ O (3.12 g) was slowly added at 0-10 °C. The mixture was stirred at 20 °C for 30 mins and then filtered. The filtrate was concentrated in vacuum to give Alcohol 1 (6.00 g, 63.5% yield) as a colorless oil, which was used for the next step directly, without further purification. ¹ H NMR: (400 MHz, MeOD) δ 7.31-7.08 (m, 5H), 3.66-3.55 (m, 1H), 2.85-2.73 (m, 1H), 2.70-2.52 (m, 2H), 2.50-2.39 (m, 1H), 2.32-2.23 (m, 6H), 1.79-1.71 (m, 2H), 1.70-1.56 (m, 2H). [0267] To a solution of Alcohol 1 (500 mg, 2.41 mmol) in THF (5.00 mL) was added Sulfonamide 1 (637 mg, 2.89 mmol) at 20 °C. Then LiHMDS (1 M, 9.65 mL) was added at 0 °C. The mixture was stirred at 20 °C for 12 hrs. LCMS showed Alcohol 1 remained and one main peak with desired MS was formed. The reaction solution was slowly quenched with saturated NH ₄ Cl aqueous (30.0 mL). The mixture was extracted with EtOAc (30.0 mL x 3). The combined organic phases were washed with saturated brine (30.0 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol = 1/0 to 10/1; TLC: dichloromethane/methanol = 10/1, product R _f = 0.24) to give compound A1-1 (290 mg, 20.8% yield, 70.6% purity) as a yellow oil. LCMS (ESI) m/z 408.2 (M+H ⁺ ).

[0268] A racemic mixture (150 mg, 280 μmol, 100% purity) comprising (S)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfo nyl)-1-fluorocyclohexane-1- carboxamide and (R)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)oxy)-3- nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide was obtained as a white solid in 39.4% yield according to the general procedure of Example 10. ¹ H NMR: (400 MHz, MeOD) δ 8.33 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 2.4, 8.8 Hz, 1H), 7.28-7.21 (m, 2H), 7.21-7.13 (m, 4H), 4.80-4.74 (m, 2H), 4.58 (br s, 3H), 3.29-3.21 (m, 2H), 2.86 (s, 4H), 2.91-2.83 (m, 1H), 2.82-2.70 (m, 2H), 2.33-1.94 (m, 5H), 1.90-1.69 (m, 5H), 1.65 (br d, J = 12.8 Hz, 1H), 1.60-1.47 (m, 4H), 1.35-1.22 (m, 1H). Chiral separation yielding (S)-N-((4-((1-(dimethylamino)-5-phenylpentan-3- yl)oxy)-3-nitrophenyl)sulfonyl)-1-fluorocyclohexane-1-carbox amide and (R)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfo nyl)-1-fluorocyclohexane-1- carboxamide was accomplished by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D. 10 um; mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: 55%-55%, 15 min). (S)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfo nyl)-1-fluorocyclohexane-1- carboxamide: ¹ H NMR: (400 MHz, MeOD) δ 8.32 (d, J = 2.4 Hz, 1H), 8.00 (dd, J = 2.4, 8.8 Hz, 1H), 7.29-7.21 (m, 2H), 7.20-7.15 (m, 4H), 4.79-4.73 (m, 1H), 4.58 (s, 1H), 3.36-3.34 (m, 1H), 3.27-3.21 (m, 2H), 2.85 (s, 6H), 2.76 (br dd, J = 8.4, 11.8 Hz, 2H), 2.28-2.15 (m, 2H), 2.12-2.00 (m, 2H), 1.87-1.78 (m, 1H), 1.77-1.70 (m, 3H), 1.65 (br d, J = 13.2 Hz, 1H), 1.60-1.49 (m, 4H), 1.35-1.24 (m, 1H). LCMS (ESI) m/z 536.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. (R)-N-((4-((1- (dimethylamino)-5-phenylpentan-3-yl)oxy)-3-nitrophenyl)sulfo nyl)-1-fluorocyclohexane-1- carboxamide: ¹ H NMR: (400 MHz, MeOD) δ 8.32 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 2.4, 8.8 Hz, 1H), 7.28-7.21 (m, 2H), 7.20-7.14 (m, 4H), 4.80-4.73 (m, 1H), 3.29-3.20 (m, 2H), 2.85 (s, 6H), 2.83-2.72 (m, 2H), 2.24-2.00 (m, 4H), 1.88-1.69 (m, 4H), 1.65 (br d, J = 12.8 Hz, 1H), 1.60-1.54 (m, 3H), 1.35-1.23 (m, 1H). LCMS (ESI) m/z 536.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 46.3,5-DICHLORO-4-FLUOROBENZENESULFONAMIDE (SULFONAMIDE 10) [0269] To a solution of compound 1A (10.0 g, 41.0 mmol), in dioxane (100 mL) was added Pd ₂ (dba) ₃ (934 mg, 1.02 mmol) and Xantphos (1.07 g, 1.84 mmol) and DIEA (10.6 g, 82.0 mmol) , phenylmethanethiol (6.06 g, 48.7 mmol). The mixture was stirred at 100 °C for 12 hrs. TLC (petroleum ether/ethyl acetate = 20/1, compound 1A R _f = 0.30, compound 2A R _f = 0.50) indicated compound 1A was consumed completely. The reaction mixture was quenched by ice H ₂ O (150 mL). The combined organic layers were washed with EtOAc (100 mL), and extracted with EtOAc (200 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 200/1 to 0/1) to give compound 2A (8.6 g, 73.5% yield) as a yellow oil.

[0270] To a solution of compound 2A (5.00 g, 17.4 mmol) in H ₂ O (2.25 mL) and MeCN (123 mL) was added AcOH (1.05 g, 17.4 mmol) and compound A-2 (5.15 g, 26.1 mmol). The mixture was stirred at -10°C for 6 hrs. TLC (petroleum ether/ethyl acetate = 10/1, compound 2A Rf = 0.25, compound 3A Rf = 0.45) indicated compound 2A was consumed completely. The reaction mixture was diluted with H ₂ O (100 mL) and washed with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1; TLC: petroleum ether/ethyl acetate = 5/1, product Rf = 0.45) to give compound 3A (2.0 g, 43.5% yield) as a light-yellow oil. [0271] To a solution of compound 3A (400 mg, 1.52 mmol) in THF (6.00 mL) was added NH3.H2O (2.13 mg, 15.1 mmol). The mixture was stirred at 0 °C for 2 hrs. LCMS showed no compound 3A remained. The reaction mixture was adjusted PH=2 with 2 mol HCl. The combined organic layers were washed with EtOAc (20.0 mL) and extracted with EtOAc (400 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO ₂ , petroleum ether/ethyl acetate =20 /1 to give compound Sulfonamide 10 (160 mg, 43.2% yield) as white oil. 1H NMR: (400 MHz, CDCl ₃ ) δ 8.08-8.02 (m, 1H). EXAMPLE 47. (R)-N-((3,5-DICHLORO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0272] Compound D1-10 (100 mg) was obtained as a yellow oil in 27.6% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD-d ₆ ) δ 7.91 (m, 1H), 7.91- 7.80 (m, 1H), 7.29-7.26 (m, 2H), 7.01-6.96 (m, 2H), 4.59 (m, 1H) 3.36-3.32 (m, 2H), 3.19-3.14 (m, 1H), 2.55-2.44 (m, 2H), 2.24 (s, 6H), 2.00-1.72 (m, 2H).

[0273] (R)-N-((3,5-dichloro-4-((4-(dimethylamino)-1-((4-fluoropheny l)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (16.9 mg, 97.4% purity) was obtained as a white solid in 25.9 % yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.80 ( S, 2H), 7.18-7.15 (m, 2H), 7.03-6.99 (m, 2H), 3.96-3.95 (m, 1H), 3.13-3.10 (m, 3H), 3.10- 3.03 (m, 2H), 3.01-2.77 (m, 6H), 1.72-1.71 (m, 1H), 1.70-1.51 (m, 1H), 1.51-1.51 (m, 4H), 1.49- 1.41 (m, 6H), 1.46-1.25 (m, 2H). LCMS (ESI) m/z 597.1 (M+H ⁺ ). [0274] (R)-N-((3,5-dichloro-4-((4-(dimethylamino)-1-((4-fluoropheny l)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamid e(10.5 mg, 98.2% purity) was obtained as a white solid in 15.7 % yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.80 ( S, 2H), 7.18-7.14 (m, 2H), 7.03-6.99 (m, 2H), 3.96-3.95 (m, 1H), 3.13-3.10 (m, 3H), 3.10- 3.03 (m, 2H), 3.01-2.80 (m, 6H), 1.88-1.78 (m, 1H), 1.56-1.52 (m, 6H), 1.52-1.48 (m, 9H). LCMS (ESI) m/z 597.1 (M+H ⁺ ). EXAMPLE 48. (S)-N-((3-CYANO-4-(((S)-1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CYANO-4- (((S)-1-(DIMETHYLAMINO)-5-(4-FLUOROPHENYL)PENTAN-3-YL)AMINO) -5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0275] (S)-N-((3-cyano-4-(((S)-1-(dimethylamino)-5-(4-fluorophenyl) pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide and (R)-N-((3-cyano-4- (((S)-1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl)amino) -5-fluorophenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide were purified from a mixture by SFC (column: DAICEL CHIRALCEL OX (250mm x 30mm, 10um); mobile phase: [CO ₂ - EtOH (0.1%NH ₃ H ₂ O)]; 40%% B isocratic elution mode). (S)-N-((3-cyano-4-(((S)-1-(dimethylamino)- 5-(4-fluorophenyl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl )-2-methyltetrahydro-2H-pyran-2- carboxamide (36.0 mg, 44.6 yield, 99.1% purity) was obtained as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.82 (s, 1H), 7.75-7.72 (m, 1H), 7.11-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.19 (s, 1H), 3.69-3.66 (m, 2H), 3.19-3.18 (m, 2H), 2.80 (s, 6H), 2.74-2.64 (m, 2H), 2.04-2.03 (m, 1H), 2.01-1.98 (m, 2H), 1.96-1.94 (m, 2H), 1.68-1.54 (m, 1H), 1.46-1.44 (m, 3H), 1.43-1.29 (m, 2H), 1.25 (s, 3H). LCMS (ESI) m/z 549.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. (R)-N-((3-cyano-4- (((S)-1-(dimethylamino)-5-(4-fluorophenyl)pentan-3-yl)amino) -5-fluorophenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide (27.8 mg, 34.4% yield, 99.2% purity) was obtained as a white solid.1H NMR: (400 MHz, MeOD) δ 7.81 (s, 1H), 7.75-7.72 (m, 1H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.20-4.19 (m, 1H), 3.69-3.68 (m, 2H), 3.21-3.17 (m, 2H), 2.81 (s, 6H), 2.74-2.64 (m, 2H), 2.20-2.06 (m, 1H), 2.06-1.92 (m, 4H), 1.65-1.53 (m, 1H), 1.47-1.46 (m, 3H), 1.46-1.43 (m, 1H), 1.29 (s, 3H). LCMS (ESI) m/z 549.2 (M+H+). Chiral SFC e.e.% = 100%. EXAMPLE 49. (R)-N-((3-CYANO-4-((4-(3-(DIFLUOROMETHYL)AZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0276] (R)-N-((3-cyano-4-((4-(3-(difluoromethyl)azetidin-1-yl)-1-(( 4-fluorophenyl)thio)butan- 2-yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1- carboxamide (30.2 mg, 98.6% purity) was obtained as a white solid in 46.6% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.72 (dd, J = 13.6 Hz, 1H), 7.27-7.24 (m, 2H), 7.03-6.98 (m, 2H), 5.99 (t, J = 58.4 Hz, 1H), 4.36 (s, 1H), 3.83-3.62(m, 2H), 3.60-3.50 (m, 1H), 3.26-3.24 (m, 1H), 3.23 (s, 3H), 3.18-3.13 (m, 1H), 3.11-2.90 (m, 2H), 1.87-1.74 (m, 4H),1.57-1.49 (m, 8H) , 1.47-1.20 (m, 2H) . LCMS (ESI) m/z 643.0 (M+H ⁺ ). EXAMPLE 50. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUORO-3- METHYLAZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0277] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoro-3-methylazetidin-1- yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-1-methox ycyclohexane-1-carboxamide (28.4 mg, 90.7% purity) was obtained as a white solid in 43.5% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan- 3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-c arboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.78 (s, 1H), 7.68 (dd, J = 12 Hz, 1H), 7.30-7.27 (m, 2H), 7.05-7.01 (m, 2H), 4.39-4.38 (m, 1H), 3.54-3.46 (m, 2H), 3.28-3.22 (m, 2H), 3.15-3.22 (m, 1H), 3.11 (s, 3H), 2.84- 2.80 (m, 1H), 2.78 (s, 3H), 2.01-1.82 (m, 2H), 1.81-1.71 (m, 4H),1.69-1.61 (m, 2H) , 1.53-1.45 (m, 6H) . LCMS (ESI) m/z 625.0 (M+H ⁺ ). EXAMPLE 51. (R)-N-((3-CYANO-4-((4-(1,1-DIFLUORO-5-AZASPIRO[2.3]HEXAN-5- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE

[0278] Compound 9-L1 (60.0 mg) was obtained as yellow oil in 70.9% yield according to the general procedure of compound D6-3. [0279] (R)-N-((3-cyano-4-((4-(1,1-difluoro-5-azaspiro[2.3]hexan-5-y l)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -1-methoxycyclohexane-1- carboxamide (41.7 mg) was obtained as a white solid in 65.5% yield according to the general procedure of (R)-N-((4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino )-3,5- difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80-7.67 (m, 2H), 7.27-6.99 (m, 4H), 4.39-4.35 (m, 1H), 3.73-3.58 (m, 5H), 3.13-2.93 (m, 6H), 1.88-1.23 (m, 15H). LCMS (ESI) m/z 655.2 (M+H ⁺ ). EXAMPLE 52. (R)-N-((3-CYANO-5-FLUORO-4-((1-((4-FLUOROPHENYL)THIO)-4-(5- AZASPIRO[2.3]HEXAN-5-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0280] Compound 9-M1 (50.0 mg) was obtained as yellow oil in 46.5% yield according to the general procedure of compound D6-3. [0281] (R)-N-((3-cyano-5-fluoro-4-((1-((4-fluorophenyl)thio)-4-(5-a zaspiro[2.3]hexan-5- yl)butan-2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1- carboxamide (7.64 mg) was obtained as a off-white solid in 13.4% yield according to the general procedure of compound VNDC-0106. ¹ H NMR: (400 MHz, MeOD) δ 7.75-7.67 (m, 2H), 7.26-7.00 (m, 4H), 4.25-3.93 (m, 5H), 3.11-2.50 (m, 7H), 1.86-1.48 (m, 17H), 1.46-0.71 (m, 4H). LCMS (ESI) m/z 619.0 (M+H ⁺ ). EXAMPLE 53. N-((3-CYANO-4-(((2R)-4-(6,6-DIFLUORO-3- AZABICYCLO[3.1.0]HEXAN-3-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2 - YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0282] Compound 9-N1 (30.0 mg) was obtained as yellow oil in 78.1% yield according to the general procedure of compound D6-3.

[0283] N-((3-cyano-4-(((2R)-4-(6,6-difluoro-3-azabicyclo[3.1.0]hexa n-3-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -1-methoxycyclohexane-1- carboxamide (13.5 mg) was obtained as a white solid in 53.0% yield according to the general procedure of compound VNDC-0106. ¹ H NMR: (400 MHz, MeOD) δ 7.80-7.66 (m, 2H), 7.29- 6.98 (m, 4H), 4.45-4.41 (m, 1H), 3.15-2.93 (m, 8H), 2.71-1.85 (m, 4H), 1.77-1.55 (m, 12H), 1.53-1.22 (m, 1H). LCMS (ESI) m/z 655.2 (M+H ⁺ ). EXAMPLE 54.3-CHLORO-4,5-DIFLUOROBENZENESULFONAMIDE (SULFONAMIDE 11) [0284] To a solution of compound 1-1 (2.00 g, 8.79 mmol) in dioxane (20.0 mL) was added Pd ₂ (dba) ₃ (201 mg, 220 μmol) and Xantphos (254 mg, 440 μmol). The suspension was degassed under vacuum and purged with N ₂ several times. Then DIPEA (2.27 g, 17.6 mmol, 3.06 mL), phenylmethanethiol (1.64 g, 13.2 mmol, 1.55 mL) was added and purged with N ₂ several times. The reaction mixture was heated to 10°C and stirred for 12 hrs under N ₂ . TLC (Petroleum ether/Ethyl acetate = 20/1) showed reactant 1 (R _f = 0.70) was consumed and new spots (R _f = 0.60) were formed. The reaction solution was slowly poured into ice water (15.0 mL), then extracted with EtOAc (10.0 mL x 3). The combined organic phases were washed with saturated brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate (SiO2, Petroleum ether/Ethyl acetate = 20/1, product R _f = 0.60) to give compound 1-2 (2.00 g, 7.39 mmol, 84.0% yield) as colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.29-7.23 (m, 5H), 7.06-7.05 (m, 1H), 7.00-6.96 (m, 1H), 4.05 (s, 2H). [0285] To the solution of compound 1-2 (1.00 g, 3.69 mmol) in MeCN (24.6 mL) was added AcOH (222 mg, 3.69 mmol, 211μL) and H ₂ O (0.46 mL), the mixture was cooled to - 10 °C. Then the mixture was added compound A (1.09 g, 5.54 mmol) at -10°C, the mixture was stirred at -10°C for 3 hrs. LCMS (Product RT = 2.12 min) showed one new peak with desired mass was detected. The mixture was added H ₂ O (20.0 mL), then the aqueous layer was extracted with EtOAc (30.0 mL x 3). The combined organic layers were washed with saturated brine (30.0 mL) and dried over Na ₂ SO ₄ . The solution was filtered and concentrated in vacuum. The mixture was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 100/0 to 20 /1 to give compound 1-3 (600 mg, 2.43 mmol, 65.8% yield) as colorless oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.39-7.37 (m, 2H).

[0286] To the solution of compound 1-3 (600 mg, 2.43 mmol) in THF (5.00 mL) was added NH ₃ .H ₂ O (2.84 g, 24.3 mmol, 3.12 mL, 30% purity) at 0 °C, the mixture was stirred at 20°C for 2 hrs. LCMS (product RT = 1.48 min) showed one new peak with desired mass was detected. The mixture was concentrated in vacuum. The mixture was triturated with petroleum ether (5.00 mL) at 25°C for 15 mins to give Sulfonamide 11 (432 mg, 1.90 mmol, 78.2% yield) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.83-7.81 (m, 1H), 7.71-7.69 (m, 1H), 4.93 (s, 2H). EXAMPLE 55. (R)-N-((3-CHLORO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0287] To the solution of Amide 1 (200 mg, 879 μmol) in DMSO (1.00 mL) was added DIPEA (568 mg, 4.39 mmol, 765 μL) and Sulfonamide 11 (213 mg, 879 μmol) at 25 °C, the mixture was stirred at 90 °C for 8 hrs. LCMS (ET70370-30-P1A, product RT = 1.33 min) showed one peak with desired mass was detected. The mixture was cooled to 25 °C, quenched with ice water, extracted with EtOAc ( 10.0 mL x 3), the organic layers were combined, washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give a residue. The crude product was purified by prep-TLC (DCM/MeOH = 10/1, product Rf = 0.30) to give compound D1-11 (150 mg, 293 μmol, 33.4% yield, 88.0% purity) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.60 (s, 1H), 7.41-7.23 (m, 3H), 7.00-6.95 (m, 2H), 6.24-6.23 (m,1H), 4.22-4.20 (m,1H), 3.18-3.14 (m,1H),3.06-3.01 (m,1H), 2.62-2.54 (m,1H), 2.47-2.38 (m,1H), 2.96 (s, 6H), 2.04-1.98 (m, 1H), 1.89-1.82 (m, 1H). [0288] To the solution of compound D1-11 (50.0 mg, 111 μmol) in CH ₃ CN (1.00 mL) was added EDCI (27.7 mg, 144 μmol) and DMAP (17.7 mg, 144 μmol), then added acid 7 (22.9 mg, 144 μmol), the mixture was stirred at 25 °C for 12 hrs. LCMS (Product RT = 1.63 min) showed one new peak with desired mass was detected. The mixture was directly purified without work- up. The mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-55% B over 8.0 min) to give (R)-N-((3-chloro-4-((4-(dimethylamino)-1-((4-fluorophenyl)th io)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide (17.7 mg, 29.7 μmol, 26.7% yield, 99.1% purity) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.50- 7.46 (m, 1H), 7.24-7.21 (m, 2H), 7.03-6.99 (m,2H), 3.85-3.82 (m,1H), 3.30-3.25 (m,2H),3.11 (s,6H), 2.77 (s,6H), 2.14-2.10 (m,1H), 1.98-1.96 (m, 1H), 1.75-1.66 (m, 5H), 1.54-1.46 (m, 5H),1.25-1.22 (m, 1H). EXAMPLE 56. (R)-N-((3-CHLORO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0289] To the solution of compound D1-11 (50.0 mg, 111 μmol) in CH ₃ CN (1.00 mL) was added EDCI (27.7 mg, 144 μmol) and DMAP (17.7 mg, 144 μmol), then added acid 2 (24.9 mg, 144 μmol), the mixture was stirred at 25 °C for 12 hrs. LCMS (Product RT= 1.70 min) showed one new peak with desired mass was detected. The mixture was used to directly purify without work-up. The mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H ₂ O (10mM NH4HCO3)-ACN]; gradient: 30%-65% B over 8.0 min) to give (R)-N-((3-chloro-4-((4-(dimethylamino)-1-((4-fluorophenyl)th io)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycycloheptane-1-c arboxamide (12.4 mg, 20.4 μmol, 18.4% yield, 99.5% purity) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.67 (s, 1H), 7.50-7.46 (m, 1H), 7.24-7.21 (m, 2H), 7.03-6.99 (m,2H), 3.85-3.82 (m,1H), 3.30-3.25 (m,2H),3.11 (s,6H), 2.77 (s,6H), 2.14-2.10 (m,1H), 1.98-1.96 (m, 1H), 1.75-1.66 (m, 5H), 1.57- 1.51 (m, 7H). EXAMPLE 57. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUORO-3- (METHOXYMETHYL)AZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN- 2- YL)AMINO)PHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0290] To a solution of compound 4 (20 g, 52.99 mmol) in THF (140 mL) was added LiBH ₄ (2 M, 52.99 mL) in one portion at 0 °C under N ₂ . The mixture returned to 20 °C and was stirred for 8 hours. LCMS (compound 5 RT = 0.491 min) showed the starting material was consumed completely. The mixture was cooled to 0 °C. The reaction solution was cautiously quenched by HCl (1.00 mol/L 100.0 mL). The residue was poured into ice-water (100 mL) and extracted with ethyl acetate (40 mLx3). The combined organic phase was washed with brine (50 mLx2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=50/1, 1/1) to give compound 5 (12 g, 64.81% yield, 100% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.30 (m, 7H), 7.04-6.89 (m, 2H), 5.05 (s, 2H), 3.85-3.83 (m,1H), 3.59-3.56 (m, 2H), 3.05-3.03 (m, 2H), 1.91- 1.87 ^m, 1H ^, 1.69-1.62 (m, 1H). LCMS (ET60921-222-P1E1) (ESI) m/z 350.1 (M+H ⁺ ).

[0291] To a solution of compound 5 (200 mg, 572.38 μmol) in THF (2 mL) was added MsCl (98.35 mg, 858.57 μmol, 66.45 μL) and TEA (289.60 mg, 2.86 mmol, 398.34 μL) at 0 °C was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 3 hrs under N ₂ atmosphere. LCMS (compound 6 RT = 1.948 min) showed one main peak with desired mass was detected. The solution of compound 6 (200 mg, 467.83 μmol, 81.73% yield) as colorless oil in THF (2 mL) was obtained and the solution was used into the next step without further purification. [0292] To a solution of compound 6 (0.2 g, 467.83 μmol) in THF (2 mL) was added TEA (236.70 mg, 2.34 mmol, 325.58 μL) and compound P1 (145.59 mg, 935.65 μmol, HCl) at 0 °C was degassed and purged with N ₂ for 3 times, and then the mixture was heated to 40°C and stirred for 72 hrs under N ₂ atmosphere. LCMS (compound 7-P1 RT = 0.432min) showed the starting material was consumed completely. The mixture was cooled to 20 °C and concentrated in reduced pressure. The residue was poured into ice-water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether : Ethyl acetate= 1:1) to give compound 7-P1 (120 mg, 53.00% yield, 93.1% purity) as colorless oil. ¹ H NMR: ET60921-241-P1F1 (400 MHz, MeOD) δ 7.45-7.30 (m, 7H), 7.04-6.91 (m, 2H), 5.05 (s, 2H), 4.11-3.58 (m, 3H), 3.44-3.39 (m, 5H), 3.00-2.98 (m, 4H), 2.55-2.51 (m, 2H), 1.73-1.70 ^m, 1H ^, 1.53-1.50 (m, 1H). LCMS (ESI) m/z 451.3 (M+H ⁺ ). [0293] To a solution of compound 7-P1 (120 mg, 266.35 μmol) in DCM (1 mL) was added Me ₂ S (165.48 mg, 2.66 mmol, 195.60 μL) followed by addition of BF _3• Et ₂ O (189.01 mg, 1.33 mmol, 163.79 μL) at 0 °C and the mixture was stirred at 20 °C for 12 hours. LCMS (compound 8-P1 RT = 0.293 min) showed the starting material was consumed completely. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC: column: Phenomenex Luna C18100*30mm*3um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%- 25% B over 8.0 min to give compound 8-P1 (60 mg, 54.39% yield, 76.4% purity) as yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.60-7.56 (m, 2H), 7.17-7.13 (m, 2H), 4.47-4.33 (m, 4H), 3.69- 3.66 (m, 2H), 3.48 (s, 3H), 3.40-3.35 (m, 4H), 3.26-3.16 (m, 1H), 2.05-1.97 ^m, 2H). LCMS (ET60921-253-P1E1) (ESI) m/z 317.2 (M+H ⁺ ).

[0294] Compound 9-P1 (100 mg, 93.4% purity) was obtained as yellow oil in 60.4% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.68 (s, 1H), 7.60-7.57 (m, 1H), 7.32-7.29 (m, 2H), 7.02-6.98 (m, 2H), 4.50-4.47 (m, 1H), 3.67 (s,1H), 3.61 (s,1H), 3.46-3.41 (m, 2H), 3.35 (s, 3H), 3.31-3.30 (m. 1H), 3.16-3.11 (m, 3H), 2.69-2.65 (m, 3H), 1.85-1.74 ^m, 2H). LCMS (ET60921-267-P1B1) (ESI) m/z 515.1 (M+H ⁺ ). [0295] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoro-3-(methoxymethyl)az etidin-1-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-1-methox ycyclohexane-1-carboxamide (39.8 mg, 95.5% purity) was obtained as a white solid in 59.8% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan- 3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-c arboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.69-7.66 (m, 1H), 7.29-7.25 (m, 2H), 7.03-6.98 (m, 2H), 4.43 (s, 1H), 3.66 (s, 1H), 3.61 (s, 1H), 3.41 (s, 3H), 3.31-3.30 (m.1H), 3.29-3.27 (m, 5H), 3.19-2.84 (m, 4H), 2.03 (s, 2H), 1.77-1.74 (m, 1H), 1.60-1.57 (m, 4H), 1.53-1.48 (m, 9H), 1.21-1.18 ^m, 3H). LCMS (ET60921-272-P1B1) (ESI) m/z 655.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 58.3-FLUORO-3-(METHOXYMETHYL)AZETIDINE (P1) [0296] A solution of compound 1 (0.5 g, 2.44 mmol) in THF (5 mL) was added NaH (146.18 mg, 3.65 mmol, 60% purity) at 0°C for 30 min. The mixture was added MeI (691.62 mg, 4.87 mmol, 303.34 μL) and stirred at 20 °C for 3 hrs. TLC (Petroleum ether/Ethyl acetate = 5/1, compound 1 R _f = 0.1) showed the reaction was completed. The mixture was washed with sat’d NH ₄ Cl (aq) (40 mL) and diluted with ethyl acetate (20 mL*3) , then with sat’d NaCl(aq)(30 mL), dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=30/1, 5/1) to give compound 2 (0.4 g, 1.82 mmol, 74.88% yield) as yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 4.06-3.94 (m, 4H), 3.68-3.63 (m, 2H), 3.42 (s, 3H), 1.45-1.39 (m, 9H). [0297] To a solution of compound 2 (0.5 g, 2.28 mmol) in dioxane (10 mL) was added HCl/dioxane (4 M, 10 mL) . The mixture was stirred at 20°C for 12 hrs. TLC (Petroleum ether/Ethyl acetate = 5/1, compound 2 R _f = 0.4) showed the reaction was completed. The mixture was concentrated in reduced pressure to give compound (300 mg, 1.93 mmol, 84.55% yield, HCl) as a yellow solid. ¹ H NMR: (400 MHz, MeOD) δ 4.32-4.25 (m, 4H), 3.70-3.66 (m, 2H), 3.48 (s, 3H). EXAMPLE 59. (R)-N-((3-CYANO-4-((4-(3,3-DIFLUOROPYRROLIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0298] Compound 7-O1 (500 mg, crude) was obtained as yellow oil according to the general procedure of compound 7-P1. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.30 (m, 7H), 7.04-6.90 (m, 2H), 5.05 (s, 2H), 3.77-3.74 (m, 1H), 3.03-3.01 (m, 2H), 2.85-2.84 (m, 2H), 2.69-2.68 (m, 2H), 2.50-2.46 (m, 2H) , 2.22-2.20 (m, 2H), 1.86-1.84 (m, 1H), 1.63-1.62 (m, 1H). LCMS (ESI) m/z 439.3 (M+H ⁺ ). B. Step 2

[0299] Compound 8-O1 (100 mg, 90.1% purity) was obtained as yellow oil in 25.9% yield according to the general procedure of compound 8-P1. ¹ H NMR: (400 MHz, MeOD) δ 7.61-7.57 (m, 2H), 7.17-7.13 (m, 2H), 3.92-3.71 (m, 4H), 3.35-3.33 (m, 4H), 3.30-3.14 (m, 1H), 2.71-2.66 (m, 2H), 2.22-2.18 (m, 2H). LCMS (ESI) m/z 305.2 (M+H ⁺ ). [0300] Compound 9-O1 (50 mg, 98.2% purity) was obtained as yellow oil in 59.4% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.68-7.67 (m, 1H), 7.59-7.56 (m, 1H), 7.32-7.29 (m, 2H), 7.01-6.97 (m, 2H), 3.36 (s, 1H), 3.30-3.15 (m, 1H), 2.89-2.70 (m, 7H), 2.24-2.21 (m, 2H), 2.00-1.88 (m, 2H). LCMS (ESI) m/z 501.9 (M+H ⁺ ).

[0301] (R)-N-((3-cyano-4-((4-(3,3-difluoropyrrolidin-1-yl)-1-((4-fl uorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide (27.6 mg, 95.1% purity) was obtained as a white solid in 41.1% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.69-7.65 (m, 1H), 7.31-7.27 (m, 2H), 7.02-6.98 (m, 2H), 3.28 (s, 1H), 3.20-3.12 (m, 4H), 2.89-2.63 (m. 8H), 2.23-2.21 (m, 2H), 1.74-1.73 (m, 5H), 1.58-1.51 (m, 8H), 1.23-1.20 (m, 2H). LCMS (ESI) m/z 643.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 60. (R)-N-((3-CHLORO-5-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0302] (R)-N-((3-chloro-5-cyano-4-((4-(dimethylamino)-1-((4-fluorop henyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamid e (51.5 mg, 92.7% purity) was obtained as a white solid in 59.5% yield according to the general procedure of compound VNDC-0172. ¹ H NMR: (400 MHz, MeOD) δ 8.02-8.01 (m, 1H), 7.90-7.89 (m, 1H), 7.22-7.16 (m, 2H), 7.06-7.01 (m, 2H), 4.36-4.32 (m, 1H), 3.28-3.27 (m, 1H), 3.19-3.12 (m, 7H), 2.77 (s, 6H), 2.76-2.71 (m, 1H), 2.12-2.00 (m, 3H), 1.89-1.80 (m.5H), 1.60-1.49 (m, 10H). LCMS (ESI) m/z 611.2 (M+H ⁺ ). EXAMPLE 61. (1S,5R)-N-((3,5-DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1 - ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE AND (1R,5S)-N-((3,5- DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE [0303] (1S,5R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide (35.4 mg, 97.2% purity) was obtained as a white solid in 23.6% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin- 3-yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyc lohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 2H), 7.16-6.98 (m, 4H), 5.37-5.23 (m, 1H), 5.22-4.56 (m, 1H), 4.24-3.97 (m, 10H), 3.61-3.03 (m, 2H), 2.25-1.67 (m, 4H), 1.57-1.14 (m, 3H). LCMS (ESI) m/z 636.1 (M+H ⁺ ). Chiral SFC e.e.% = 100%. [0304] (1R,5S)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide (35.3 mg, 99.3% purity) was obtained as a white solid in 23.5% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin- 3-yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyc lohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 2H), 7.17-6.98 (m, 4H), 5.36-5.34 (m, 1H), 5.21-4.56 (m, 1H), 4.21-3.92 (m, 10H), 3.04-3.03 (m, 2H), 2.25-1.70 (m, 5H), 1.58-1.14 (m, 4H). LCMS (ESI) m/z 636.0 (M+H ⁺ ). Chiral SFC e.e.% = 96.6%. EXAMPLE 62. (R)-N-((3-CYANO-5-FLUORO-4-((2-((4-FLUOROPHENYL)THIO)-1-(1- METHYLAZETIDIN-3-YL)ETHYL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0305] To a solution of cpd.24-1 (4.50 g, 21.9 mmol), cpd. A (6.52 g, 21.9 mmol) in DCM (35.0 mL) was added dropwise DBU (4.01 g, 26.3 mmol, 3.97 mL) with stirring at 20 ^o C, the mixture was stirred at 20 ^o C for 4 hrs. TLC: (petroleum ether/ethyl acetate = 3/1, cpd. 24-2 Rf = 0.4) showed cpd. 24-1 (R _f = 0.6) was consumed, a main new spot with larger polarity was formed. The mixture was concentrated in vacuum. The mixture was added to H ₂ O (20.0 mL) and the solution was made acidic with the additional of 2N HCl (5.00 mL), the mixture was extracted with DCM (60.0 mL), the organic layers were combined, washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a residue. The crude product was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate = 100/1 to 3/1 to give cpd.24-2 (6.10 g, 73.9% yield) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.38- 7.27 (m, 4H), 5.13-4.81 (m, 6H), 3.81 (s, 3H), 1.60-1.45 (m, 9H). [0306] To a solution of cpd.24-2 (3.00 g, 7.97 mmol) in THF (10.0 mL) was added Pd/C (4.24 g, 3.99 mmol, 10% purity) and H ₂ (16.07 mg, 7.97 mmol, 50 Psi). The mixture was stirred at 25 °C for 12 hrs. TLC (dichloromethane/methanol = 8/1, cpd.24-3: R _f = 0.40) showed the cpd. 24- 2 (R _f = 0.50) was consumed completely and one new spot formed. The reaction mixture was filtered and concentrated under reduced pressure to give cpd.24-3 (2.27 g, crude) as yellow oil. [0307] To a solution of cpd.24-3 (2.20 g, 9.01 mmol) in DCM (17.0 mL) was added CH ₂ O (2.19 g, 27.0 mmol, 2.01 mL, 37.0% purity) and NaBH(OAc) ₃ (11.4 g, 54.0 mmol). The mixture was stirred at 25 °C for 1 hr. LCMS (ET60464-293-P1A2, cpd.24-4: RT = 1.110 min) showed cpd.24-3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by H ₂ O (15.0 mL). The combined organic layers were extracted with DCM 40 mL (20 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give cpd. 24-4 (2.00 g, crude) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 4.50- 4.32 (m, 1H), 4.11-4.02 (m, 1H), 3.87 (s, 1H), 3.74 (s, 3H), 3.35-.329 (m, 1H), 2.72 (s, 2H), 2.27 (s, 1H), 1.45 (s, 9H), 1.29-1.25 (m, 1H). [0308] To a solution of cpd.24-4 (1.70 g, 6.58 mmol) in THF (12.0 mL) was added LiAlH ₄ (2.5 M, 3.16 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (cpd.24-5: RT = 0.356 min) showed cpd.24-4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by H ₂ O (0.30 mL), 15% sat. NaOH (0.30 mL) and MgSO ₄ . The mixture was stirred at 25 °C for 15 mins. The reaction mixture was filtered and combined organic layers were extracted with EtOAc 45.0 mL (15 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give cpd. 24-5 (0.75 g, crude) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 6.93 (s, 1H), 5.33-5.31 (m, 1H), 5.02 (s, 1H), 3.71- 3.68 (m, 4H), 3.56-3.53 (m, 2H), 3.28-3.24 (m, 2H), 3.03-2.94 (m, 2H), 2.23-2.22(m, 3H), 1.83- 1.79 (m, 3H), 1.39 (s, 9H). [0309] To a solution of cpd.24-5 (0.75 g, 3.26 mmol) in THF (20.0 mL) was added cpd. B (459 mg, 3.58 mmol, 383 μL) and Bu ₃ P (922 mg, 4.56 mmol, 1.12 mL). Then the ADDP (1.15 g, 4.56 mmol) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS (cpd.24-6: RT = 1.647 min) showed cpd. 24-5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by H ₂ O 50.0 mL. The combined organic layers were extracted with DCM 180 mL (60 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give cpd.24-6 as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.86-7.75 (m, 2H), 7.17-7.11 (m, 3H), 7.09-6.98 (m, 2H), 3.96-3.90 (m, 3H), 3.67-3.48 (m, 4H), 3.21-3.18 (m, 2H), 2.61-2.57 (m, 2H), 1.93-1.89 (m, 2H), 1.50 (s, 9H). 6 e [0310] Compound Amine 24 (1.00 g, HCl) was obtained as yellow oil in 70.0% yield according to the general procedure of compound Amine 4. [0311] Compound 24-7 (60.0 mg) was obtained as yellow oil in 19.7% yield according to the general procedure of compound D6-3.

[0312] (R)-N-((3-cyano-5-fluoro-4-((2-((4-fluorophenyl)thio)-1-(1-m ethylazetidin-3- yl)ethyl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carbo xamide (5.67 mg, 96.1% purity) was obtained as a white solid in 37.8% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.90-7.78 (m, 2H), 7.39-7.36 (m, 2H), 7.05-7.01 (m, 2H), 4.66-3.90 (m, 6H), 3.66-3.04 (m, 7H), 1.85-0.87 (m, 13H). LCMS (ESI) m/z 579.0 (M+H ⁺ ). Chiral SFC e.e.% = 99.3%. EXAMPLE 63. (S)-N-((3-CYANO-5-FLUORO-4-((2-((4-FLUOROPHENYL)THIO)-1-(1- METHYLAZETIDIN-3-YL)ETHYL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0313] (S)-N-((3-cyano-5-fluoro-4-((2-((4-fluorophenyl)thio)-1-(1-m ethylazetidin-3- yl)ethyl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carbo xamide (4.79 mg, 100% purity) was obtained as a white solid in 31.9% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.90-7.78 (m, 2H), 7.40-7.37 (m, 2H), 7.05-7.01 (m, 2H), 4.64-3.91 (m, 6H), 3.66-3.04 (m, 7H), 1.85-0.88 (m, 13H). LCMS (ESI) m/z 579.0 (M+H ⁺ ). Chiral SFC e.e.% = 99.4%. EXAMPLE 64. N-((3-CYANO-4-((2S,4S)-2-(2-(DIMETHYLAMINO)ETHYL)-4- PHENYLPYRROLIDIN-1-YL)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0314] To a solution of cpd.1A (1.00 g, 3.43 mmol) in THF (12.0 mL) was added dropwise BH ₃ -THF (1 M, 6.86 mL) at 15 °C. The resulting mixture was stirred at 80 °C for 0.5 hr. TLC (petroleum ether/ethyl acetate = 2/1, cpd.2A R _f = 0.37) showed cpd.1A (R _f = 0.30) was consumed, a main new spot with lower polarity was formed. The mixture was cooled to -10 to 0 °C. The reaction mixture was quenched by addition MeOH (20.0 mL), the mixture was stirred at -10-0 °C for 0.5 hr, at 20 °C for 0.5 hr, the mixture was poured into H ₂ O (30.0 mL) and extracted with EtOAc (20.0 mL x 3). The combined organic layers were washed with brine (40.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 30/1 to 1/1) to give cpd.2A (828 mg, 71.7% yield) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.34- 7.30 (m, 2H), 7.24-7.20 (m, 3H), 4.23-4.20 (m, 1H), 3.80-3.70 (m, 3H), 3.42 (s, 2H), 2.19-2.16 (m, 1H), 2.04-2.00 (m, 1H), 1.48 (s, 9H).

[0315] To a solution of cpd.2A (828 mg, 2.99 mmol) in DCM (9.00 mL) was added MsCl (0.48 g, 4.19 mmol), TEA (634 mg, 6.27 mmol) at 0 °C. The mixture was stirred at 15 °C for 1 hr. LCMS (cpd.3A = 0.918 min) showed cpd. 2A was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (15.0 mL) and extracted with MTBE (10.0 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give cpd.3A (1.03 g, 97.0% yield) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.36-7.32 (m, 2H), 7.28-7.23 (m, 3H), 4.42- 4.38 (m, 1H), 4.24-4.12 (m, 1H), 3.83-3.79 (m, 1H), 3.54-3.34 (m, 2H), 3.05 (s, 3H), 2.38-2.35 (m, 1H), 2.25-2.17 (m, 1H), 1.52-1.47 (m, 9H). [0316] To a solution of cpd.3A (900 mg, 2.53 mmol) in DMF (8.00 mL) was added TEA (512 mg, 5.06 mmol) and NaCN (186 mg, 3.80 mmol) at 15 °C. The resulting mixture was stirred at 90 °C for 16 hrs. LCMS (ET55642-503-P1A2, cpd.4A RT = 0.536 min) showed cpd. 3A was consumed, several new peaks were shown on LCMS and ~36.2% of desired product was detected. The reaction mixture was quenched by addition NaHCO ₃ (20.0 mL) and extracted with EtOAc (15.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give cpd.4A (700 mg, crude) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.38-7.25 (m, 5H), 4.25-3.87 (m, 2H), 3.72-3.37 (m, 2H), 2.92-2.79 (m, 2H), 2.36-2.32 (m, 2H), 1.54-1.50 (m, 10H).

[0317] To a solution of cpd.4A (0.20 g, 698 μmol) in THF (2 mL) and MeOH (2.00 mL) was added Raney-Ni (119 mg, 1.40 mmol) and H ₂ (1.41 mg, 698 μmol). The mixture was stirred at 50 °C (15 Psi) for 12 hrs. LCMS (cpd. 5A: RT = 0.396 min) showed cpd.4A was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give cpd.5A (186 mg, 91.7% yield) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 2H), 7.25-7.23 (m, 3H), 4.13-4.00 (m, 1H), 3.77-3.73 (m, 1H), 3.49-3.28 (m, 2H), 2.77 (s, 2H), 2.14-2.02 (m, 3H), 1.61-1.58 (m, 1H), 1.56-1.44 (m, 10H). [0318] To a solution of cpd.5A (186 mg, 640 μmol) in MeOH (2.00 mL) was added HCHO (311 mg, 3.84 mmol, 286 μL, 37.0% purity) and NaBH ₃ CN (201 mg, 3.20 mmol). The mixture was stirred at 25 °C for 12 hrs. LCMS (cpd. 6A: RT = 0.491 min) showed cpd.5A was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by H ₂ O 15.0 mL. The combined organic layers were extracted with DCM 40 mL (20 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150x40 mm x 10 um; mobile phase: [H ₂ O (10 mM NH ₄ HCO ₃ )-ACN]; gradient: 25%-55% B over 8.0 mins) to give cpd. 6A (110 mg, 53.9% yield) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 2H), 7.25-7.23 (m, 3H), 4.01-3.97 (m, 1H), 3.93-3.92 (m, 1H), 3.77-3.27 (m, 2H), 2.41-2.27 (m, 8H), 2.15-2.02 (m, 3H), 1.60 (s, 1H), 1.59-1.47 (m, 9H). [0319] Compound Amine 25A (80.0 mg, HCl) was obtained as yellow oil in 65.0% yield according to the general procedure of compound Amine 4. [0320] Compound 7A (30.0 mg) was obtained as yellow oil in 22.4% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.65-7.61 (m, 1H), 7.32-7.30 (m, 2H), 7.20 (s, 1H), 7.19-7.18 (m, 2H), 4.69-4.54 (m, 2H), 3.64-3.61 (m, 2H), 2.35-2.27 (m, 10H), 1.64-1.62 (m, 1H), 1.28-1.26 (m, 1H), 0.07 (s, 1H).

[0321] N-((3-cyano-4-((2S,4S)-2-(2-(dimethylamino)ethyl)-4-phenylpy rrolidin-1-yl)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (13.8 mg, 99.3% purity) was obtained as a white solid in 35.0% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.91-7.21 (m, 7H), 4.52-4.37 (m, 2H), 3.67-3.51 (m, 2H), 3.13-2.23 (m, 10H), 1.77-1.24 (m, 15H). LCMS (ESI) m/z 557.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 65. (R)-N-((3,5-DIFLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLSPIRO[3.3]HEPTANE-2-CARBOXAMIDE [0322] (R)-N-((3,5-difluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methylspiro[3.3]heptane-2-carbox amide (22.53 mg, 98.3% purity) was obtained as a white solid in 34.2% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.40-7.38 (m, 2H), 7.31-7.24 (m, 2H), 7.05-6.97 (m, 2H), 5.27-5.17 (m, 1H), 3.99-3.77 (m, 3H), 3.58-3.48 (m, 2H), 3.10-3.08 (m, 2H), 2.95-2.79 (m, 2H), 2.34-2.33 (m, 2H), 2.02-1.99 (s, 2H), 1.90-1.83 (m, 3H), 1.81-1.74 (m, 4H), 1.26 (s, 3H) LCMS (ESI) m/z 600.2 (M+H ⁺ ). EXAMPLE 66. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLSPIRO[3.3]HEPTANE-2-CARBOXAMIDE [0323] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-2-methylspiro[3.3]heptane-2-carb oxamide (13.78 mg, 98.1% purity) was obtained as a white solid in 20.9% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.77-7.67 (m, 1H), 7.31-7.24 (m, 2H), 7.05-6.00 (m, 2H), 5.30-5.12 (m, 1H), 4.44- 4.38 (m, 1H), 3.91-3.88 (m, 2H), 3.58-3.50 (m, 2H), 3.18-3.08 (m, 1H), 2.98-2.83 (m, 2H), 2.39- 2.36 (m, 2H), 2.05-2.02 (m, 2H), 1.90-1.87 (m, 3H), 1.84-1.78 (m, 5H), 1.29 (s, 3H) LCMS (ESI) m/z 607.0 (M+H ⁺ ). EXAMPLE 67. (R)-N-((3,5-DIFLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0324] (R)-N-((3,5-difluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (37.00 mg, 97.0% purity) was obtained as a white solid in 55.11% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.44-7.42 (m, 2H), 7.34-7.27 (m, 2H), 7.05-7.01 (m, 2H), 5.31-5.08 (m, 1H), 3.97-3.78 (m, 3H), 3.57-3.49 (m, 2H), 3.17-3.08 (m, 5H), 2.96-2.80 (m, 2H), 1.94-1.84 (m, 1H), 1.81-1.74 (s, 2H), 1.62-1.49 (m, 7H), 1.38-1.20 (m, 2H). LCMS (ESI) m/z 604.2 (M+H ⁺ ).

EXAMPLE 68. (R)-N-((3,5-DIFLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0325] (R)-N-((3,5-difluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamid e (25.89 mg, 97.2% purity) was obtained as a white solid in 47.21% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.41 (m, 2H), 7.33-7.27 (m, 2H), 7.06-7.00 (m, 2H), 5.28-5.08 (m, 1H), 3.95-3.79 (m, 3H), 3.55-3.46 (m, 2H), 3.13-3.09 (m, 5H), 2.90-2.81 (m, 2H), 1.86-1.81 (m, 4H), 1.64-1.46 (m, 10H). LCMS (ESI) m/z 618.0 (M+H ⁺ ).

EXAMPLE 69. (1R,5S)-N-((3,5-DIFLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1 - ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE AND (1S,5R)-N-((3,5- DIFLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE [0326] A mixture of (1R,5S)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide and (1S,5R)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide (70.0 mg) was obtained as a white solid in 59.72% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan- 3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-c arboxamide. [0327] The mixture was purified by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:45%, isocratic elution mode) to give (1R,5S)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide (14.4 mg, 34.2% yield, 100% purity) as a white solid, and (1S,5R)-N-((3,5- difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluoropheny l)thio)butan-2- yl)amino)phenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-ca rboxamide (21.22 mg, 30.31% yield, 100% purity) as a white solid. CDCl ₃ NMR for (1R,5S)-N-((3,5-difluoro-4-(((R)-4-(3- fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)butan-2-yl)amin o)phenyl)sulfonyl)-2,6- dioxabicyclo[3.2.1]octane-1-carboxamide ¹ H NMR: (400 MHz, CDCl3) δ 7.46-7.37 (m, 2H), 7.31-7.24 (m, 2H), 6.94-6.87 (m, 2H), 5.93-5.86 (m, 1H), 5.14-4.93 (m, 1H), 4.63-4.57 (m, 1H), 4.08-4.03 (m, 2H), 3.99-3.93 (m, 3H), 3.66-3.51 (m, 2H),3.13-3.07 (m, 1H), 2.98-2.90 (m, 1H), 2.66 (s, 1H), 2.54-2.45 (m, 1H), 2.31-2.17 (m, 2H), 1.98 (s, 2H), 1.76-1.68 (m, 3H), 1.65-1.61 (m, 2H)). LCMS (ESI) m/z 604.1 (M+H ⁺ ), SFC (ET55012-484-P1M1) e.e. % = 100%. NMR for (1S,5R)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4-fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-ca rboxamide ^1H NMR: (400 MHz, CDCl3) δ 7.44-7.38 (m, 2H), 7.30-7.24 (m, 2H), 6.94-6.87 (m, 2H), 5.93-5.86 (m, 1H), 5.14-4.92 (m, 1H), 4.62-4.58 (m, 1H), 4.05-4.04 (m, 2H), 3.99-3.94 (m, 3H), 3.65-3.53 (m, 2H),3.13-3.07 (m, 1H), 2.97-2.91 (m, 1H), 2.76-2.62 (m, 1H), 2.55-2.45 (m, 1H), 2.25-2.21 (m, 1H), 1.76-1.68 (s, 3H), 1.65-1.59 (m, 2H), 1.18 (s, 1H)). LCMS (ESI) m/z 604.1 (M+H+), SFC e.e. % = 100%.

EXAMPLE 70. (R)-N-((3,5-DIFLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLOXEPANE-2-CARBOXAMIDE AND (S)-N-((3,5-DIFLUORO-4-(((R)-4-(3- FLUOROAZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLOXEPANE-2-CARBOXAMIDE [0328] A mixture (70.0 mg) was obtained as a white solid in 52.4% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3- yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclo hexane-1-carboxamide. [0329] The mixture was purified by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D.10um;mobile phase: [CO2-EtOH(0.1% NH3H2O)];B%:30%, isocratic elution mode) to give (R)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyloxepane-2-carboxamide (21.25 mg, 30.35% yield, 100% purity) as a white solid, and (S)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 - fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl oxepane-2-carboxamide (21.30 mg, 29.45% yield, 96.8% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.47-7.44 (m, 2H), 7.32-7.28 (m, 2H), 7.05-7.01 (m, 2H), 5.24-4.92 (m, 1H), 3.94-3.93 (m, 1H), 3.85-3.96 (m, 4H), 3.57-3.50 (m, 2H), 3.12-3.11 (m, 2H), 2.90-2.76 (m, 2H),2.14-2.05 (m, 1H), 1.92-1.77 (m, 2H), 1.74-1.61 (m, 3H), 1.56-1.47 (m, 3H), 1.43-1.40 (m, 1H), 1.22 (s, 3H). LCMS (ESI) m/z 604.0 (M+H ⁺ ), SFC e.e. % = 100%. ¹ H NMR (400 MHz, MeOD) δ 7.46-7.44 (m, 2H), 7.33-7.27 (m, 2H), 7.05-7.01 (m, 2H), 5.25-5.07 (m, 1H), 3.99-3.90 (m, 1H), 3.84-3.67 (m, 4H), 3.58-3.49 (m, 2H), 3.16-3.10 (m, 2H), 2.90-2.76 (m, 2H),2.13-2.056 (m, 1H), 1.92-1.77 (m, 2H), 1.73-1.62 (m, 3H), 1.57-1.47 (m, 3H), 1.46-1.37 (m, 1H), 1.22 (s, 3H). LCMS (ESI) m/z 604.0 (M+H ⁺ ), SFC (ET55012-507-P2M1) e.e. % = 98.8%. EXAMPLE 71. (1S,5R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL )-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE AND (1R,5S)-N-((3-CHLORO-5- CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2,6- DIOXABICYCLO[3.2.1]OCTANE-1-CARBOXAMIDE [0330] To a solution of Amine 7 (1.13 g, 3.12 mmol), Sulfonamide 7 (1.00 g, 3.12 mmol) in DMSO (7.00 mL) was added DIEA (2.02 g, 15.6 mmol). The mixture was stirred at 90 °C for 12hrs. LCMS (product RT = 1.96 min) showed Amine 7 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1), TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.55) to give compound D7-7 (1.00 g, 65.8% yield) was obtained as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.95-7.82 (m, 2H), 7.34-7.27 (m, 2H), 7.05-6.96 (m, 2H) 5.22-5.01 (m, 1H), 4.65-4.62 (m, 1H), 3.72-3.57 (m, 2H), 3.68-3.59 (m, 1H), 3.27-3.14 (m, 3H), 2.79-2.59 (m, 2H), 1.92-1.79 (m, 2H). [0331] N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1- carboxamide (mixture, 150 mg) was obtained as a white solid in 74.9% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide.

[0332] The mixture was purified by SFC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-70% B over 8.0 min) to give (1S,5R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-y l)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2,6-diox abicyclo[3.2.1]octane-1- carboxamide (24.66 mg, 20.12% yield, 97.9% purity) as a white solid, and (1R,5S)-N-((3-chloro- 5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluorophenyl )thio)butan-2- yl)amino)phenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-ca rboxamide (35.12 mg, 29.15% yield, 99.6% purity) as a white solid. (1S,5R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin- 1-yl)-1-((4-fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfon yl)-2,6-dioxabicyclo[3.2.1]octane- 1-carboxamide- ¹ H NMR: (400 MHz, MeOD) δ 7.95-7.76 (m, 2H), 7.13-7.05 (m, 2H), 6.97-6.84 (m, 2H), 5.30-5.04 (m, 1H), 4.50-4.47 (m, 1H), 4.37-4.28 (m, 1H), 4.11-3.99 (m, 3H), 3.94-3.83 (m, 3H), 3.82-3.65 (m, 2H), 3.09-2.96 (m, 3H), 2.17-2.08 (m, 1H), 1.92-1.75 (m, 2H), 1.71-1.68 (m, 1H), 1.64-1.55 (m, 1H), 1.50-1.43 (m, 1H), 1.23-1.16 (m, 1H),. LCMS (ESI) m/z 627.1 (M+H ⁺ ), SFC (ET55012-561-P1M1) e.e. % = 100%. (1R,5S)-N-((3-chloro-5-cyano-4-(((R)-4-(3- fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)butan-2-yl)amin o)phenyl)sulfonyl)-2,6- dioxabicyclo[3.2.1]octane-1-carboxamide ¹ H NMR: (400 MHz, MeOD) δ 7.94-7.79 (m, 2H), 7.11-7.08 (m, 2H), 6.94-6.85 (m, 2H), 5.27-5.06 (m, 1H), 4.50-4.47 (m, 1H), 4.34-4.41 (m, 1H), 4.12-3.99 (m, 3H), 3.93-3.83 (m, 4H), 3.82-3.70 (m, 2H), 3.09-2.96 (m, 3H), 2.17-2.08 (m, 1H), 1.91-1.79 (m, 2H), 1.71-1.68 (m, 1H), 1.65-1.55 (m, 1H), 1.51-1.43 (m, 1H). LCMS (ESI) m/z 627.1 (M+H ⁺ ), SFC (ET55012-561-P2M1) e.e. % = 100%. EXAMPLE 72. (R)-N-((3-CHLORO-5-CYANO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0333] (R)-N-((3-chloro-5-cyano-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxami de (63.13 mg, 96.0% purity) was obtained as a white solid in 34.2% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 8.04-7.91 (m, 2H), 7.29-7.23 (m, 2H), 7.07-7.00 (m, 2H), 5.28-5.07 (m, 1H), 4.55-4.53 (m, 1H), 3.86-3.80 (m, 2H), 3.55-3.44 (m, 2H), 3.23-3.20 (m, 1H), 3.18-3.07 (m, 5H), 2.97-2.78 (s, 4H), 1.93-1.85 (m, 2H), 1.79-1.73 (m, 2H), 1.70-1.57 (m, 4H) 1.54-1.46 (m, 3H) LCMS (ESI) m/z 627.0 (M+H ⁺ ). EXAMPLE 73. (R)-N-((3-CHLORO-5-CYANO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0334] (R)-N-((3-chloro-5-cyano-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-methoxycycloheptane-1-carboxam ide (24.38 mg, 95.1% purity) was obtained as a white solid in 44.0% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 8.04-7.93 (m, 2H), 7.31-7.24 (m, 2H), 7.06-7.01 (m, 2H), 5.27-5.06 (m, 1H), 4.56-4.53 (m, 1H), 3.83-3.78 (m, 2H), 3.49-3.38 (m, 2H), 3.21-3.19 (m, 1H), 3.13 (s, 3H), 2.89-2.84 (s, 3H), 2.09- 2.08 (m, 1H), 1.89-1.82 (m, 4H), 1.63-1.62 (m, 3H) 1.53-1.50 (m, 3H) LCMS (ESI) m/z 641.0 (M+H ⁺ ).

EXAMPLE 74. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLOXEPANE-2-CARBOXAMIDE AND (S)-N-((3-CHLORO-5-CYANO-4-(((R)-4- (3-FLUOROAZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLOXEPANE-2-CARBOXAMIDE [0335] A mixture was obtained as a white solid in 74.9% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan- 3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-c arboxamide. The mixture was purified by SFC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-70% B over 8.0 min) to give (R)-N-((3-chloro-5- cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluorophenyl)t hio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyloxepane-2-carboxamide (41.06 mg, 27.37% yield, 100% purity) as a white solid, and (S)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl oxepane-2-carboxamide (43.41 mg, 28.94% yield, 96.8% purity) as a white solid. (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3- fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)butan-2-yl)amin o)phenyl)sulfonyl)-2- methyloxepane-2-carboxamide- ¹ H NMR: (400 MHz, MeOD) δ 8.07-7.96 (m, 2H), 7.30-7.21 (m, 2H), 7.07-7.00 (m, 2H), 5.31-5.06 (m, 1H), 4.58-4.55 (m, 1H), 3.93-3.81 (m, 2H), 3.76-3.70 (m, 2H), 3.58-3.45 (m, 3H), 3.38-3.37 (m, 1H), 3.17-3.12 (m, 1H), 2.99-2.80 (m, 2H), 2.12-2.06 (m, 1H), 1.95-1.78 (m, 3H), 1.67-1.64 (m, 2H), 1.57-1.41 (m, 4H), 1.23 (s, 3H). LCMS (ESI) m/z 627.2 (M+H ⁺ ), SFC e.e. % = 100%. (S)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1- yl)-1-((4-fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl )-2-methyloxepane-2- carboxamide- ¹ H NMR: (400 MHz, MeOD) δ 8.08-7.96 (m, 2H), 7.29-7.20 (m, 2H), 7.08-6.98 (m, 2H), 5.28-5.07 (m, 1H), 4.53-4.62 (m, 1H), 3.92-3.80 (m, 2H), 3.76-3.71 (m, 1H), 3.58-3.50 (m, 3H), 3.37-3.36 (m, 1H), 3.20-3.11 (m, 1H), 3.01-2.81 (m, 2H), 2.13-2.10 (m, 1H), 1.95-1.79 (m, 3H), 1.71-1.62 (m, 2H), 1.60-1.40 (m, 4H), 1.22 (s, 3H). LCMS (ESI) m/z 627.2 (M+H ⁺ ), SFC e.e. % = 100%. EXAMPLE 75. (R)-N-((3,5-DICHLORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0336] To a solution of compound Sulfonamide 10 (1.31 g, 4.30 mmol), Amine 7 (1.50 g, 3.58 mmol) in DMSO (10.0 mL) was added DIEA (2.31 g, 17.9 mmol). The mixture was stirred at 90 °C for 12 hrs. LCMS (ET55012-516-P1A1, product RT = 1.85 min) showed Amine 7 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 0/1), TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.55), to give compound D7-10 (0.900 g, 30.69% yield, 60.6% purity) as a yellow solid. Checked by HNMR LCMS ¹ H NMR: (400 MHz, MeOD) δ 7.74 (s, 2H), 7.29-7.26 (m, 2H), 7.05-7.00 (m, 2H) 5.23-5.08 (m, 1H), 4.21-4.17 (m, 1H), 3.77-3.71 (m, 2H), 3.41-3.38 (m, 2H), 310-3.09 (m, 2H), 2.85-2.70 (m, 2H), 1.94-1.73 (m, 2H). [0337] (R)-N-((3,5-dichloro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (21.56 mg, 94.3% purity) was obtained as a white solid in 22.6% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR:(400 MHz, MeOD) δ 7.81 (s, 2H), 7.31-7.24 (m, 2H), 7.06-7.01 (m, 2H), 5.32-5.09 (m, 1H), 4.16-4.08 (m, 1H), 3.96- 3.83 (m, 2H), 3.62-3.48 (m, 2H), 3.12 (s, 3H), 3.08-3.06 (m, 2H), 3.02-2.83 (m, 1H), 2.02-1.92 (m, 1H), 1.80-1.71 (m, 3H) 1.68-1.61 (m, 2H), 1.58-1.45 (m, 5H), 1.29-1.19 (m, 1H). LCMS (ESI) m/z 636.0 (M+H ⁺ ). EXAMPLE 76. (R)-N-((3,5-DICHLORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEPTANE-1-CARBOXAMIDE [0338] (R)-N-((3,5-dichloro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycycloheptane-1-carboxamid e (21.8 mg, 96.5% purity) was obtained as a white solid in 40.1% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.82 (s, 2H), 7.27-7.19 (m, 2H), 7.06-7.02 (m, 2H), 5.30-5.10 (m, 1H), 4.15-4.12 (m, 1H), 3.98- 3.84 (m, 2H), 3.66-3.48 (m, 3H), 3.20-3.19 (m, 2H), 3.12 (m, 3H), 3.08-3.06 (m, 2H), 2.87-2.85 (m, 1H), 2.14-2.05 (m, 1H), 2.03-1.92 (m, 2H) 1.87-1.78 (m, 4H), 1.62 (s, 3H), 1.56-1.54 (m, 3H), 1.51-1.46 (m, 3H). LCMS (ESI) m/z 650.1 (M+H ⁺ ). EXAMPLE 77. BENZYL (R)-(1-((4-FLUOROPHENYL)THIO)-4-HYDROXYBUTAN-2- YL)CARBAMATE

[0339] A mixture of compound 1 (42.0 g, 178 mmol), TEA (127 g, 1.26 mol) in MeOH (168 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 40 °C for 12 hrs under N ₂ atmosphere. HPLC (product RT = 1.35 min) indicated ~71.0% of compound 2 was detected, a main peak with desired was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give compound 2 (47.0 g, crude) as a yellow oil. [0340] To a solution of compound 2 (30.0 g, 112 mmol) in 2-MeTHF (210 mL) was added MsCl (27.0 g, 235 mmol) and TEA (22.7 g, 225 mol) at 0 °C. The mixture was stirred at 20 °C for 1 hr. LCMS (product RT = 0.417 min) showed compound 3 was consumed, a main peak with desired MS was detected. HPLC (product RT = 1.73 min) indicated ~43.4% of compound 3 was detected, a main peak with desired was detected. The reaction mixture was quenched by addition saturated NaHCO ₃ solution (300 mL) at 0 °C, and extracted with 2-MeTHF (100 mL x 3). The combined organic layers were washed with sat. brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give compound 3 (39.0 g, crude) as a yellow solid.

[0341] To a solution of compound A (25.9 g, 202 mmol) in DMF (100 mL) was added K ₂ CO ₃ (31.0 g, 225 mmol) at 20 °C. The mixture was stirred at 20 °C for 0.5 hr. And then compound 3 (38.8 g, 112 mmol) in DMF (170 mL) was added at 0 °C. The mixture was stirred at 0 °C for 2 hrs. HPLC (product RT = 2.53 min) indicated ~35.0% of compound 4 was detected, a main peak with desired was detected. The reaction mixture was quenched by addition H ₂ O (100 mL), and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1), TLC (petroleum ether/ethyl acetate = 3/1, product Rf = 0.55), to give compound 4 (31.0 g, 64.1% yield, 87.7% purity) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.48-7.32 (m, 7H), 7.07-7.03 (m, 2H), 5.06 (s, 2H), 4.11-4.06 (m, 1H), 3.63 (s, 3H), 3.09-3.07 (m, 2H), 2.76-2.71 (m, 1H), 2.61-2.55 (m, 1H). [0342] To a solution of compound 4 (20 g, 52.99 mmol) in THF (140 mL) was added LiBH ₄ (2 M, 52.99 mL) in one portion at 0 °C under N ₂ . The mixture returned to 20 °C and was stirred for 8 hours. LCMS (ET60921-222-P1A1, compound 5 RT = 0.491 min) showed the starting material was consumed completely. The mixture was cooled to 0 °C. The reaction solution was cautiously quenched by HCl (1.00 mol/L 100.0 mL). The residue was poured into ice-water (100 mL) and extracted with ethyl acetate (40 mLx3). The combined organic phase was washed with brine (50 mLx2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=50/1, 1/1) to give compound 5 (12 g, 64.81% yield, 100% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.30 (m, 7H), 7.04-6.89 (m, 2H), 5.05 (s, 2H), 3.85-3.83 (m,1H), 3.59-3.56 (m, 2H), 3.05-3.03 (m, 2H), 1.91-1.87 ^m, 1H ^, 1.69-1.62 (m, 1H). LCMS (ESI) m/z 350.1 (M+H ⁺ ). EXAMPLE 78. (R)-N-((3-CYANO-4-((4-(6,6-DIFLUORO-2-AZASPIRO[3.3]HEPTAN-2- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0343] To a solution of compound 5 (0.5 g, 1.43 mmol) in MeCN (3.50 mL) was added MsCl (0.630 g, 5.50 mmol) and TEA (724 mg, 7.15 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. LCMS (product RT = 0.535 min) showed compound 5 was consumed, a main peak with desired MS was detected. TLC (petroleum ether/ethyl acetate = 1/1, product Rf = 0.60) showed compound 5 (Rf = 0.45) was consumed, a main new spot with lower polarity was formed. The solution of compound 6 in MeCN (3.50 mL) as a yellow liquid and the solution was used into the next step without further purification. [0344] To a solution of compound 6 (0.611 g, 1.43 mmol), compound E (707 mg, 2.86 mmol, TFA) in MeCN (10.0 mL) was added TEA (723 mg, 7.15 mmol). The mixture was stirred at 25 °C for 24 hrs. LCMS (product RT = 1.65 min) showed compound 6 was consumed, a main peak with desired MS was detected. TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.50) showed Reactant 1 (Rf = 0.75) was consumed, a main new spot with larger polarity was formed. The reaction mixture was quenched by addition H ₂ O (100 mL), and then extracted with ethyl acetate (50.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=20/1 to 0/1) to give compound 7-E1 (0.6 g, 75.0% yield, 83% purity) as a yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.49-7.31 (m, 7H), 7.07-7.02 (m, 2H), 5.07 (s, 2H), 3.70-3.66 (m, 1H), 3.39 (s, 3H), 3.07-2.96 (m, 2H), 2.73-2.67 (m, 4H), 2.60-2.51 (m, 2H), 1.79-1.45 (m, 2H).

[0345] To a solution of compound 7-E1 (0.56 g, 1.21 mmol) in DCM (56.0 mL) was added methylsulfanylmethane (1.42 g, 22.9 mmol) and diethyloxonio(trifluoro)boranuide (856 mg, 6.03 mmol). The mixture was stirred at 25 °C for 6 hrs. LCMS (product RT = 0.895 min) showed compound 7-E1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by saturated NaHCO ₃ solution (40.0 mL), and then extracted with DCM (20.0 mL x 5). The combined organic layers were washed with brine (50.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*3 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:5%-35% B over 18.0 min) to compound 8-E1 (330 mg, 74.6% yield, HCl) as a yellow oil. Checked by HNMR. ¹ H NMR: (400 MHz, MeOD) δ 7.61- 7.53 (m, 2H), 7.19-7.10 (m, 2H), 4.44-4.15 (m, 4H), 3.30-3.25 (m, 1H), 3.16-3.07 (m, 1H), 3.02- 2.77 (m, 4H), 2.09-1.85 (m, 2H). [001] To a solution of compound 8-E1 (50.0 mg, 137 μmol, HCl), compound sulfonamide 3 (29.7 mg, 137 μmol) in DMSO (1.00 mL) was added DIEA (88.1 mg, 681 μmol). The mixture was stirred at 90 °C for 12 hrs. LCMS (ET55012-454-P1A1, product RT = 2.07 min) showed Reactant 1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 5). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 9-E1 (42.0 mg, 58.3% yield) as a yellow oil. [0346] To a solution of compound compound 9-E1 (42.0 mg, 79.5 μmol), compound Acid 7 (18.9 mg, 120 μmol) in MeCN (2.00 mL) was added EDCI (22.9 mg, 120 μmol) and DMAP (14.6 mg, 120 μmol). The mixture was stirred at 25 °C for 6 hrs. LCMS (product RT = 1.81 min) showed compound 9-E1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 5). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-65% B over 8.0 min) to give (R)-N-((3- cyano-4-((4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-1-((4- fluorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide (20.0 mg, 37.3% yield, 99.0% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.80 (m, 1H), 7.74-7.70 (m, 1H), 7.29-7.22 (m, 2H), 7.08-7.01 (m, 2H), 4.29(s, 1H), 4.03-3.85 (m, 4H), 3.29-3.23 (m, 1H), 3.17-3.08 (m, 6H), 2.86-2.80 (m, 4H), 7.97-1.94 (m, 1H), 1.85-1.75 (m, 3H), 1.68-1.61 (m, 2H), 1.59-1.49 (m, 5H), 1.29-1.24 (m, 1H). EXAMPLE 79. (R)-N-((3-CYANO-4-((4-(3-CYCLOPROPOXYAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0347] To a solution of compound 6 (123 mg, 287 μmol), compound D3 (43.1 mg, 287 μmol, HCl) in MeCN (2.00 mL) was added TEA (145 mg, 1.44 mmol. The mixture was stirred at 25 °C for 24 hrs. LCMS (product RT = 1.631 min) showed compound 6 was consumed, a main peak with desired MS was detected. TLC (petroleum ether/ethyl acetate = 0/1, product Rf = 0.50) showed compound 6 (Rf = 0.75) was consumed, a main new spot with lower/larger polarity was formed. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , Petroleum ether : Ethyl acetate = 0:1 ) to give. Compound 7-D1 (70 mg, 54.73% yield) as a yellow oil. [0348] To a solution of compound 7-D1 (70.0 mg, 157 μmol) in DCM (1.00 mL) was added methylsulfanylmethane (97.8 mg, 1.57 mmol) and diethyloxonio(trifluoro)boranuide (111 mg, 787 μmol). The mixture was stirred at 25 °C for 6 hrs. LCMS (ET55012-459-P1A1, product RT = 0.972 min) showed compound 7-D1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by saturated NaHCO ₃ solution (40.0 mL), and then extracted with DCM (20.0 mL x 5). The combined organic layers were washed with brine (50.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) to compound 8-D1 (30.0 mg, 61.3% yield) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.63- 7.55 (m, 2H), 7.21-7.13 (m, 2H), 4.55-4.52 (m, 2H), 3.48-3.34 (m, 5H), 3.32-3.31 (m, 2H), 3.20- 3.12 (m, 1H), 2.05-1.00 (m, 2H), 0.63-0.54 (m, 4H).

[0349] To a solution of compound 8-D1 (30.0 mg, 86.5 μmol, HCl), Sulfonamide 3 (18.9 mg, 86.5 μmol) in DMSO (1.00 mL) was added DIEA (11.2 mg, 86.5 μmol,). The mixture was stirred at 90 °C for 12 hrs. LCMS (product RT = 0.395 min) showed compound 8-D1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 5). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue to give compound 9-D1 (30.0 mg, 68.2% yield) as a yellow oil. [0350] To a solution of compound 9-D1 (30.0 mg, 59.0 μmol), Acid 7 (14.0 mg, 88.5 μmol) in MeCN (2.00 mL) was added EDCI (17.0 mg, 88.5 μmol) and DMAP (10.8 mg, 88.5 μmol). The mixture was stirred at 25 °C for 6 hrs. LCMS (product RT = 1.77 min) showed compound 9-D1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (10.0 mL), and then extracted with ethyl acetate (5.00 mL x 5). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H ₂ O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min ), to give (R)-N-((3-cyano-4-((4-(3- cyclopropoxyazetidin-1-yl)-1-((4-fluorophenyl)thio)butan-2-y l)amino)-5-fluorophenyl)sulfonyl)- 1-methoxycyclohexane-1-carboxamide (23.87 mg, 36.24 μmol, 61.44% yield, 98.5% purity) was obtained as a white solid. Checked by HNMR, FNMR, LCMS. ¹ H NMR: (400 MHz, MeOD) δ 7.80 (m, 1H), 7.74-7. 70 (m, 1H), 7.30-7.21 (m, 2H), 7.06-7.02 (m, 2H), 4.43 (s, 1H), 4.28 (s, 1H), 4.18 (s, 2H), 3.77 (s, 2H), 3.39-3.37 (m, 1H), 3.25-3.21 (m, 3H), 3.14 (s, 3H), 3.13- 3.09 (m, 1H), 2.00-1.97 (m, 1H), 1.90-1.85 (m, 1H), 1.78-1.75 (m, 2H), 1.67-1.63 (m, 2H), 1.58- 1.50 (m, 5H), 1.28-1.25 (m, 1H), 0.61-0.50 (m, 4H). EXAMPLE 80. (R)-N-((3-CYANO-5-FLUORO-4-((1-((4-FLUOROPHENYL)THIO)-4-(3- (TRIFLUOROMETHYL)AZETIDIN-1-YL)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0351] (R)-N-((3-cyano-5-fluoro-4-((1-((4-fluorophenyl)thio)-4-(3-( trifluoromethyl)azetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1- carboxamide (5.42 mg, 99.3% purity) was obtained as a white solid in 26.5% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.68 (dd, J = 12.0 Hz, 1H), 7.30-7.25 (m, 2H), 7.03-6.98 (m, 2H), 4.43-4.42 (m, 1H), 3.56-3.54 (m, 2H), 3.48 (s, 1H), 3.28-3.26(m, 2H), 3.24-3.14 (m, 2H), 3.11 (s, 3H), 2.73- 2.63 (m, 2H), 1.79-1.74 (m, 4H), 1.57-1.49 (m, 7H),1.29-1.24 (m, 1H). LCMS (ESI) m/z 661.0 (M+H ⁺ ). EXAMPLE 81. (S)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-(1- PHENYLCYCLOPROPYL)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) - 1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0352] (S)-N-((3-cyano-4-((4-(dimethylamino)-1-(1-phenylcyclopropyl )butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (25.7 mg, 98.9% purity) was obtained as a white solid in 38.3% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.71-7.65 (m, 2H), 7.18-7.11 (m, 3H), 7.05-7.03 (m, 2H), 4.11 (s, 1H), 3.18 (s, 3H), 3.09 (s, 2H), 2.74 (s, 6H), 2.28-2.17 (m, 1H), 1.92-1.76 (m, 2H), 1.73-1.67 (s, 5H), 1.59-1.41 (m, 6H), 1.47- 1.30 (m, 1H), 0.85-0.81 (m, 2H),0.71-0.68 (m, 2H). LCMS (ESI) m/z 571.1 (M+H ⁺ ).

EXAMPLE 82. (S)-N-((3,5-DIFLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0353] (S)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (9.33 mg, 100% purity) was obtained as a white solid in 24.4% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.44-7.40 (m, 2H), 7.30-7.26 (m, 2H), 7.03-6.98 (m, 2H), 5.24-5.09 (m, 2H), 3.92-3.89 (m, 3H), 3.78-3.60 (m, 1H), 3.10-3.08 (m, 2H), 2.88-2.85 (m, 2H), 2.18-2.06 (m, 2H), 1.93-1.82 (m, 1H),1.76-1.56 (m, 2H), 1.48-1.40 (m, 3H), 1.32-1.29 (m, 1H),1.20 (s, 3H). LCMS (ESI) m/z 590.0 (M+H ⁺ ). EXAMPLE 83. (R)-N-((3,5-DIFLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0354] (R)-N-((3,5-difluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (15.8 mg, 100% purity) was obtained as a white solid in 41.6% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.46-7.44 (m, 2H), 7.31-7.28 (m, 2H), 7.05-7.00 (m, 2H), 5.26-5.12 (m, 1H), 3.39-3.89 (m, 3H), 3.81-3.72 (m, 1H), 3.66-3.46 (m, 3H), 3.12-3.10 (m, 2H), 2.94-2.91 (m, 2H), 2.19-2.14 (m, 1H),1.98-1.82 (m, 1H), 1.73-1.57 (m, 2H), 1.56-1.38 (m, 3H), 1.34-1.31 (m, 1H), 1.21 (s, 3H). LCMS (ESI) m/z 590.0 (M+H ⁺ ). EXAMPLE 84. (R)-N-((3-CYANO-4-((4-(DIMETHYLAMINO)-1-(1- PHENYLCYCLOPROPYL)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) - 1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0355] (R)-N-((3-cyano-4-((4-(dimethylamino)-1-(1-phenylcyclopropyl )butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (6.22 mg, 97.5% purity) was obtained as a white solid in 30.5% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.71-7.65 (m, 2H), 7.17-7.12 (m, 3H), 7.11-7.03 (m, 2H), 4.10 (s, 1H), 3.19 (s, 3H), 3.18-3.13 (m, 2H), 2.73 (s, 5H), 2.32-2.16 (m, 1H), 2.03-1.93 (m, 2H), 1.93-1.70 (m, 6H),1.60-1.42 (m, 6H), 1.32-1.31 (m, 2H), 0.85-0.81 (m, 2H),0.71-0.69 (m, 2H). LCMS (ESI) m/z 571.1 (M+H ⁺ ). EXAMPLE 85. (S)-1-(3-FLUOROAZETIDIN-1-YL)-5-(4-FLUOROPHENYL)PENTAN-3- AMINE (AMINE 10) [0356] To a solution of compound 4-5A (4.67 g, 12.3 mmol) in DMF (46.0 mL) was added Et ₃ N (6.23 g, 61.5 mmol) and compound C (5.49 g, 49.2 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hrs. LCMS (compound 10-1: RT = 0.55 min) showed no compound 4-5A remained. One new peaks were shown on LCMS and 40.2% of compound 10-1 was detected. The reaction mixture was diluted with H ₂ O (25.0 mL) and washed with EtOAc (25.0 mL x 3). The combined organic layers were washed with sat brine (25.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , ethyl acetate, R _f = 0.15) to give compound 10-1 (2.48 g, 50.6% yield, 90.0% purity) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.13-7.10 (m, 2H), 6.99-6.94 (m, 2H), 5.69 (d, J = 5.2 Hz, 1H), 5.11-4.96 (m, 1H), 3.75-3.60 (m, 2H), 3.40 (s, 1H), 3.19-3.16 (m, 2H), 2.76-2.58 (m, 4H), 1.82-1.71 (m, 4H), 1.48-1.28 (m, 1H), 1.22 (s, 9H). LCMS (ESI) m/z 359.2 (M+H ⁺ ).

[0357] To a solution of compound 10-1 (2.00 g, 5.58 mmol) in EtOAc (3.00 mL) was added HCl/EtOAc (0.2 M, 167 mL). The mixture was stirred at 20 °C for 4 hrs. LCMS (Amine 10: RT = 0.127) showed no compound 10-1 remained. Several new peaks were shown on LCMS and 87.3% of Amine 10 was detected. Evaporate the solution on a water bath under reduced pressure using a rotary evaporator to give Amine 10 (1.50 g, 92.2% yield, 87.3% purity) as a light- yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.30-7.26 (m, 2H), 7.06-7.01 (m, 2H), 5.50-5.36 (m, 1H), 4.83-4.61 (m, 1H), 4.51-4.46 (m, 2H), 3.49-3.39 (m, 3H), 2.76-2.73 (m, 2H), 2.03-1.92 (m, 5H). LCMS (ESI) m/z 255.2 (M+H ⁺ ). EXAMPLE 86. (S)-1-FLUORO-N-((4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-3- NITROPHENYL)SULFONYL)CYCLOHEXANE-1-CARBOXAMIDE

[0358] Compound D10-1 (60.0 mg, 86.1% purity) was obtained as a yellow oil in 28.9% yield according to the general procedure of compound D6-3. LCMS (ESI) m/z 455.2 (M+H ⁺ ). [0359] (S)-1-fluoro-N-((4-((1-(3-fluoroazetidin-1-yl)-5-(4-fluoroph enyl)pentan-3-yl)amino)-3- nitrophenyl)sulfonyl)cyclohexane-1-carboxamide (19.9 mg, 100% purity) was obtained as a yellow solid in 38.9% yield according to the general procedure of (S)-N-((3-cyano-4-((1- (dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3- yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 8.72 (d, J = 2.0 Hz, 1H), 7.92-7.89 (m, 1H), 7.16-7.12 (m, 2H), 7.01-6.92 (m, 3H), 5.32 (s, 1H), 4.16-4.08 (m, 2H), 3.89-3.65 (m, 4H), 2.74-2.71 (m, 2H), 2.01-1.79 (m, 4H), 1.78-1.74 (m, 6H), 1.74-1.56 (m, 7H), 1.30-1.29 (m, 2H). LCMS (ESI) m/z 583.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 87. (S)-N-((3,5-DIFLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0360] Compound D10-2 (120 mg, 90.9% purity) was obtained as a colorless oil in 10.3% yield according to the general procedure of compound D6-3. LCMS (ESI) m/z 446.0 (M+H ⁺ ). [0361] (S)-N-((3,5-difluoro-4-((1-(3-fluoroazetidin-1-yl)-5-(4-fluo rophenyl)pentan-3- yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (12.0 mg, 100% purity) was obtained as a white solid in 18.70% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ7.44-7.41 (m, 2H), 7.10-7.08 (m, 2H), 7.07-6.92 (m, 2H), 4.26-4.03 (m, 2H), 3.98-3.82 (m, 2H), 3.80-3.71 (m, 2H), 2.86-2.63 (m, 1H), 1.86-1.77 (m, 10H), 1.73-1.56 (m, 6H), 1.31-1.29 (m, 2H). LCMS (ESI) m/z 574.2 (M+H ⁺ ). EXAMPLE 88. (S)-N-((3,5-DIFLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0362] (S)-N-((3,5-difluoro-4-((1-(3-fluoroazetidin-1-yl)-5-(4-fluo rophenyl)pentan-3- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (5.72 mg, 97.8% purity) was obtained as a white solid in 8.51% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.45 (d, J = 10 Hz, 2H), 7.11-7.08 (m, 2H), 6.96-6.92 (m, 2H), 5.24 (s, 1H), 3.82-3.79 (m, 3H), 3.48-3.47 (m, 3H), 3.10 (s, 3H), 2.86-2.84 (m, 2H), 2.68-2.62 (m, 2H), 1.87-1.85 (m, 2H), 1.84- 1.59 (m, 4H), 1.56-1.49 (m, 7H), 1.48-1.47 (m, 1H). LCMS (ESI) m/z 586.3 (M+H ⁺ ). EXAMPLE 89. (S)-N-((3,5-DIFLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOPENTANE-1-CARBOXAMIDE [0363] (S)-N-((3,5-difluoro-4-((1-(3-fluoroazetidin-1-yl)-5-(4-fluo rophenyl)pentan-3- yl)amino)phenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamid e (12.4 mg, 100% purity) was obtained as a white solid in 24.2% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.48 (d, J = 10 Hz, 2H), 7.13-7.09 (m, 2H), 6.99-6.94 (m, 2H), 5.27 (s, 1H), 3.90-3.88 (m, 2H), 3.83-3.80 (m, 1H), 3.68-3.57 (s, 3H), 3.13 (s, 3H), 2.91-2.87 (m, 2H), 2.71-2.65 (m, 2H), 1.91- 1.84 (m, 6H), 1.69-1.64 (m, 6H). LCMS (ESI) m/z 572.2 (M+H ⁺ ). EXAMPLE 90. (S)-N-((3-CYANO-5-FLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE

[0364] Compound D10-3 (386 mg, 87.5% purity) was obtained as a yellow oil in 37.9% yield according to the general procedure of compound D6-3. LCMS (ESI) m/z 453.0 (M+H ⁺ ). [0365] (S)-N-((3-cyano-5-fluoro-4-((1-(3-fluoroazetidin-1-yl)-5-(4- fluorophenyl)pentan-3- yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (19.1 mg, 95.0% purity) was obtained as a white solid in 35.3% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.71-7.68 (m, 1H), 7.13-7.09 (m, 2H), 6.97-6.92 (m, 2H), 5.31 (s, 1H), 4.23-4.20 (m, 1H), 4.08-4.06 (s, 2H), 3.79-3.75 (s, 2H), 2.78-2.56 (m, 2H), 1.92-1.83 (m, 10H), 1.61-1.56 (m, 8H). LCMS (ESI) m/z 581.2 (M+H ⁺ ). EXAMPLE 91. (S)-1-(3-FLUOROAZETIDIN-1-YL)-5-PHENYLPENTAN-3-AMINE (AMINE 9) [0366] Compound 3-6 (3.83 g, crude) in DMF was obtained as a colorless liquid according to the general procedure of compound 4-5A. [0367] Compound 3-7 (1.90 g) was obtained as a yellow oil in 52.6% yield according to the general procedure of compound 4-6. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.27-7.15 (m, 5H), 5.65- 5.64 (m, 1H), 5.11-4.94 (m, 1H), 3.72-3.40 (m, 2H), 3.21-3.14 (m, 1H), 2.75-2.65 (m, 2H), 2.64- 2.60 (m, 4H), 1.82-1.75 (m, 3H), 1.74-1.72(m, 1H), 1.48-1.24 (m, 9H).

[0368] Compound Amine 9 (1.00 g, HCl) was obtained as a yellow oil in 70.0% yield according to the general procedure of compound Amine 4. ¹ H NMR: ET60464-95-P1A1 (400 MHz, MeOD) δ 7.32-7.20 (m, 5H), 5.52-5.38 (m, 1H), 4.74-4.30 (m, 4H), 3.63-3.44 (m, 4H), 3.43-2.79 (m, 2H), 2.77-2.02 (m, 2H), 1.19-1.15 (m, 3H). EXMAPLE 92. (S)-1-FLUORO-N-((4-((1-(3-FLUOROAZETIDIN-1-YL)-5- PHENYLPENTAN-3-YL)AMINO)-3-NITROPHENYL)SULFONYL)CYCLOHEXANE- 1- CARBOXAMIDE [0369] Compound D9-1 (250 mg) was obtained as a white solid in 78.1% yield according to the general procedure of compound D2-1. ¹ H NMR: (400 MHz, MeOD) δ 8.63-8.62 (m, 1H), 7.85-7.82 (m, 1H), 7.24-7.03 (m, 6H), 5.31-5.13 (m, 1H), 4.01-3.90 (m, 3H), 3.74-3.69 (m, 3H), 3.23-2.93 (m, 1H), 2.92-2.83 (m, 3H), 2.48-2.00 (m, 1H), 1.98-1.42 (m, 5H), 1.39-1.33 (m, 6H). [0370] (S)-1-fluoro-N-((4-((1-(3-fluoroazetidin-1-yl)-5-phenylpenta n-3-yl)amino)-3- nitrophenyl)sulfonyl)cyclohexane-1-carboxamide (22.9 mg, 94.2% purity) was obtained as a yellow solid in 23.4% yield according to the general procedure of (R)-N-((4-((4- (dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitropheny l)sulfonyl)-1-fluorocyclohexane- 1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 8.73-8.72 (m, 1H), 7.91-7.88 (m, 1H), 7.24-6.96 (m, 6H), 5.36-5.34 (m, 2H), 5.21-4.22 (m, 2H), 4.21-3.90 (m, 3H), 3.14-3.10 (m, 2H), 2.75-2.05 (m, 2H), 2.03-1.65 (m, 7H), 1.64-1.29 (m, 14H). LCMS (ESI) m/z 565.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 93. (S)-N-((3,5-DIFLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5- PHENYLPENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE - 1-CARBOXAMIDE

[0371] Compound D9-2 (60.0 mg) was obtained as yellow oil in 12.7% yield according to the general procedure of compound D2-2. LCMS (RT = 0.725 min). [0372] (S)-N-((3,5-difluoro-4-((1-(3-fluoroazetidin-1-yl)-5-phenylp entan-3- yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (16.0 mg) was obtained as a white solid in 30.9% yield according to the general procedure of (R)-N-((4-((4-(dimethylamino)- 1-(phenylthio)butan-2-yl)amino)-3,5-difluorophenyl)sulfonyl) -1-fluorocyclohexane-1- carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.46-7.43 (m, 2H), 7.21-7.06 (m, 5H), 5.40-5.38 (m, 1H), 5.26-4.36 (m, 2H), 4.35-4.30 (m, 2H), 4.16-3.79 (m, 1H), 3.78-2.70 (m, 2H), 2.69-1.86 (m, 11H), 1.77-1.62 (m, 7H), 1.59-1.29 (m, 2H). LCMS (ESI) m/z 556.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 94. (S)-N-((3-CYANO-5-FLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5- PHENYLPENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE - 1-CARBOXAMIDE [0373] Compound D9-3 (60.0 mg) was obtained as a yellow solid in 37.6% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.72-7.60 (m, 2H), 7.22-7.12 (m, 5H), 5.18-5.01 (m, 1H), 4.32-4.30 (m, 1H), 3.65-3.59 (m, 2H), 3.23-3.16 (m, 2H), 2.74-2.59 (m, 5H), 1.97-1.69 (m, 4H). [0374] (S)-N-((3-cyano-5-fluoro-4-((1-(3-fluoroazetidin-1-yl)-5-phe nylpentan-3- yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (37.2 mg) was obtained as a white solid in 47.8% yield according to the general procedure of compound VNDC-0106. ¹ H NMR: (400 MHz, MeOD) δ 7.82-7.70 (m, 2H), 7.23-7.07 (m, 5H), 5.41-5.25 (m, 1H), 4.85-4.15 (m, 5H), 3.31-2.61 (m, 2H), 1.98-1.62 (m, 17H), 1.58-1.28 (m, 2H). LCMS (ESI) m/z 563.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 95. (S)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)AMINO)- 3,5-DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE [0375] Compound D3-2 (400 mg) was obtained as yellow oil in 34.9% yield according to the general procedure of compound D2-2. LCMS (RT = 0.733 min).

[0376] (S)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)amino)-3,5 - difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (14.1 mg) was obtained as a white solid in 21.4% yield according to the general procedure of (R)-N-((4-((4-(dimethylamino)-1- (phenylthio)butan-2-yl)amino)-3,5-difluorophenyl)sulfonyl)-1 -fluorocyclohexane-1- carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.43-7.23 (m, 2H), 7.21-7.06 (m, 5H), 3.72-3.71 (m, 1H), 2.82-2.64 (m, 8H), 1.94-1.77 (m, 9H), 1.74-1.29 (m, 8H). LCMS (ESI) m/z 526.2 (M+H ⁺ ). EXAMPLE 96. (S)-N-((4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3-YL)AMINO)- 3,5-DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE [0377] (S)-N-((4-((1-(dimethylamino)-5-phenylpentan-3-yl)amino)-3,5 - difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (10.2 mg) was obtained as a yellow solid in 14.7% yield according to the general procedure of (R)-N-((4-((4- (dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3,5-difluoro phenyl)sulfonyl)-1- fluorocyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.06 (m, 7H), 3.77-3.72 (m, 1H), 3.21-2.73 (m, 5H), 2.71-2.63 (m, 8H), 1.94-1.52 (m, 20H). LCMS (ESI) m/z 552.2 (M+H ⁺ ). EXAMPLE 97. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0378] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxami de (40.7 mg) was obtained as a white solid in 62.2% yield according to the general procedure of (R)-N-((4-((4-(dimethylamino)- 1-(phenylthio)butan-2-yl)amino)-3,5-difluorophenyl)sulfonyl) -1-fluorocyclohexane-1- carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.81-7.68 (m, 2H), 7.13-6.92 (m, 4H), 5.24-4.81 (m, 1H), 4.61-4.26 (m, 1H), 3.87-3.47 (m, 2H), 3.34-3.30 (m, 2H), 3.20-2.86 (m, 4H), 2.84-1.74 (m, 5H), 1.73-1.16 (m, 12H). LCMS (ESI) m/z 593.3 (M+H ⁺ ).

EXAMPLE 98. (S)-N-((3-CYANO-5-FLUORO-4-((1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOPENTANE-1-CARBOXAMIDE [0379] (S)-N-((3-cyano-5-fluoro-4-((1-(3-fluoroazetidin-1-yl)-5-(4- fluorophenyl)pentan-3- yl)amino)phenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamid e (36.2 mg) was obtained as a white solid in 56.7% yield according to the general procedure of (R)-N-((4-((4-(dimethylamino)- 1-(phenylthio)butan-2-yl)amino)-3,5-difluorophenyl)sulfonyl) -1-fluorocyclohexane-1- carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.83-7.69 (m, 2H), 4.13-6.92 (m, 4H), 5.27-5.11 (m, 1H), 4.95-3.86 (m, 5H), 3.34-3.30 (m, 3H), 3.17-2.65 (m, 5H), 1.94-1.17 (m, 13H). LCMS (ESI) m/z 579.2 (M+H ⁺ ). EXAMPLE 99. (S)-N1,N1-DIMETHYL-5-(4- (TRIFLUOROMETHYL)PHENYL)PENTANE-1,3-DIAMINE (AMINE 5)

[0380] Compound 5-2 (10.0 g) was obtained as colorless oil in 66.2% yield according to the general procedure of compound 4-3. [0381] Compound 5-3 (6.00 g) was obtained as yellow oil in 56.5% yield according to the general procedure of compound 4-4. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.53-7.26 (m, 4H), 4.32- 4.10 (m, 3H), 3.56-3.53 (m, 1H), 2.85-2.58 (m, 4H), 1.96-1.79 (m, 2H), 1.26-1.22 (m, 12H). [0382] Compound 5-4 (4.00 g) was obtained as yellow oil in 85.1% yield according to the general procedure of compound 6-5. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.54-7.26 (m, 4H), 4.14- 3.46 (m, 5H), 3.45-2.66 (m, 2H), 2.03-1.80 (m, 5H), 1.78-1.25 (m, 9H). [0383] Compound 5-5 (2.93 g, crude) in THF was obtained as a colorless liquid according to the general procedure of compound 6-6. [0384] Compound 5-6 (2.30 g) was obtained as yellow oil in 85.5% yield according to the general procedure of compound 6-7. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.52-7.26 (m, 4H), 6.26 (s, 1H), 3.45-3.43 (m, 1H), 2.73-2.68 (m, 4H), 2.48-2.23 (m, 6H), 1.85-1.59 (m, 4H), 1.26-1.21 (m, 9H).

[0385] Compound Amine 5 (1.30 g) was obtained as a yellow solid in 93.1% yield according to the general procedure of compound Amine 6. ¹ H NMR: (400 MHz, MeOD) δ 7.62-7.49 (m, 4H), 3.44-3.31 (m, 4H), 3.30-2.18 (m, 2H), 2.04-2.00 (m, 6H), 1.22-1.15 (m, 5H). EXAMPLE 100. (S)-N-((4-((1-(DIMETHYLAMINO)-5-(4- (TRIFLUOROMETHYL)PHENYL)PENTAN-3-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0386] Compound D5-2 (50.0 mg) was obtained as yellow oil in 11.1% yield according to the general procedure of compound D3-2. LCMS (RT = 0.787 min).

[0387] (S)-N-((4-((1-(dimethylamino)-5-(4-(trifluoromethyl)phenyl)p entan-3-yl)amino)-3,5- difluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (10.4 mg) was obtained as a yellow solid in 20.4% yield according to the general procedure of VNDC-0107. ¹ H NMR: (400 MHz, MeOD) δ 7.53-7.26 (m, 6H), 3.73 (s, 1H), 2.78 (s, 8H), 1.96-1.74 (m, 8H), 1.73-1.28 (m, 7H). EXAMPLE 101. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- (TRIFLUOROMETHYL)PHENYL)PENTAN-3-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1-CARBOXAMIDE

[0388] Compound D5-3 (60.0 mg) was obtained as a yellow solid in 39.4% yield according to the general procedure of compound D9-3. ¹ H NMR: (400 MHz, MeOD) δ 7.73-7.35 (m, 6H), 4.35-4.32 (m, 1H), 2.84-2.50 (m, 2H), 2.48-2.43 (m, 2H), 2.42-2.24 (m, 7H), 2.03-1.83 (m, 5H). [0389] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-(trifluoromethyl) phenyl)pentan-3- yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-car boxamide (39.7 mg) was obtained as a yellow solid in 62.5% yield according to the general procedure of (S)-N-((3-cyano-5-fluoro- 4-((1-(3-fluoroazetidin-1-yl)-5-phenylpentan-3-yl)amino)phen yl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide. ¹ H NMR: (400 MHz, MeOD) δ 7.79-7.29 (m, 6H), 4.22-4.19 (m, 1H), 3.78-3.25 (m, 2H), 2.87-2.07 (m, 8H), 2.01-1.76 (m, 8H), 1.74-1.27 (m, 6H). EXAMPLE 102. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- FLUOROCYCLOHEXANE-1-CARBOXAMIDE [0390] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamid e (12.4 mg, 98.7% purity) was obtained as a white solid in 19.2% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.73-7.69 (m, 1H), 7.27-7.24 (m, 2H), 7.05-7.01 (m, 2H), 5.36-5.06 (m, 1H), 4.29- 4.15 (m, 3H), 3.93-3.86 (m ,2 H), 3.17-3.14 (m, 3H), 2.01-1.93 (m, 1H), 1.90-1.75 (m, 5H), 1.70- 1.53 (m, 6H), 1.34-1.27 (m, 1H). LCMS (ESI) m/z 599.2 (M+H ⁺ ). .

EXAMPLE 103. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-4- METHYL-2-OXABICYCLO[2.1.1]HEXANE-1-CARBOXAMIDE [0391] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-4-methyl-2-oxabicyclo[2.1.1]hexa ne-1-carboxamide (33.2 mg, 97.1% purity) was obtained as a white solid in 63.7% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan-3-yl)amino)- 5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.73-7.70 (m, 1H), 7.26-7.23 (m, 2H), 7.04-7.00 (m, 2H), 5.37-5.30 (m, 1H), 4.32- 4.15 (m, 3H), 3.93-3.85 (m ,2 H), 3.57 (s, 2H), 3.27-3.08 (m, 4H), 2.02-1.82 (m, 4H), 1.65-1.64 (m, 1H), 1.30 (s, 3H). LCMS (ESI) m/z 595.2 (M+H ⁺ ). .

EXAMPLE 104. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- OXABICYCLO[2.1.1]HEXANE-1-CARBOXAMIDE [0392] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-2-oxabicyclo[2.1.1]hexane-1-carb oxamide(30.3 mg, 99.1% purity) was obtained as a white solid in 60.8% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.79 (s, 1H), 7.73-7.69 (m, 1H), 7.27-7.21 (m, 2H), 7.03-6.98 (m, 2H), 5.53-5.19 (m, 1H), 4.29- 4.28 (m, 1H), 4.20-4.15 (m ,2 H), 3.90-3.87 (m, 2H), 3.79 (s, 2H), 3.28-3.23 (m, 1H), 3.14-3.10 (m, 3 H), 2.89-2.86 (m, 1H), 2.11 (s, 2H), 1.98-1.85 (m, 2H), 1.59-1.58 (m, 2H). LCMS (ESI) m/z 581.2 (M+H ⁺ ). .

EXAMPLE 105. (R)-N-((3-CYANO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLOXEPANE-2-CARBOXAMIDE AND (S)-N-((3-CYANO-5-FLUORO-4-(((R)-4- (3-FLUOROAZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLOXEPANE-2-CARBOXAMIDE [0393] A mixture (70.0 mg) was obtained as a white solid in 53.9% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3- yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclo hexane-1-carboxamide .

[0394] The mixture was purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [0.1%NH3H2O MEOH];B%: 35%-35%,6min) to give (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4-fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyloxepane-2-carboxamide (20.0 mg, 27.9% yield, 97.9% purity) as a white solid, and (S)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl oxepane-2-carboxamide (24.6 mg, 33.5% yield, 95.1% purity) as a white solid. (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3- fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)butan-2-yl)amin o)phenyl)sulfonyl)-2- methyloxepane-2-carboxamide ¹ H NMR: (400 MHz, MeOD) δ 7.82 (s, 1H), 7.73-7.69 (m, 1H), 7.28-7.25 (m, 2H), 7.03-6.99 (m, 2H), 5.25-5.08 (m, 1H), 4.40-4.37 (m, 1H), 3.89-3.80 (m, 2H), 3.73-3.69 (m, 1H), 3.55-3.42 (m, 3H), 3.28-3.25 (m, 1H), 3.13-3.08 (m, 1H), 2.90-2.82 (m, 2H), 2.13-2.04 (m, 1H), 1.87-1.78 (m, 3H), 1.64-1.42 (m, 6H) 1.20 (s, 3H). LCMS (ESI) m/z 611.1 (M+H ⁺ ), SFC e.e. % = 100%. (S)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl oxepane-2-carboxamide ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.71-7.68 (m, 1H), 7.29-7.26 (m, 2H), 7.03-6.99 (m, 2H), 5.22-5.04 (m, 1H), 4.39-4.36 (m, 1H), 3.81-3.69 (m, 4H), 3.54-3.50 (m, 2H), 3.26-3.23 (m, 1H), 3.14-3.08 (m, 1H), 2.84-2.74 (m, 3H), 1.87-1.77 (m, 3H), 1.66-1.56 (m, 4H), 1.50-1.41 (m, 4H), 1.21 (s, 3H). LCMS (ESI) m/z 611.2 (M+H ⁺ ), SFC e.e.% = 97.6%. EXAMPLE 106. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0395] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxami de (28.3 mg, 96.2% purity) was obtained as a white solid in 65.2% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR:(400 MHz, MeOD) δ 7.79 (s, 1H), 7.70-7.66 (m, 1H), 7.28-7.26 (m, 2H), 7.03-6.99 (m, 2H), 5.25-5.08 (m, 1H), 4.37- 4.35 (m, 1H), 3.87-3.81 (m ,2 H), 3.28-3.19 (m, 2H), 3.13-3.08 (m, 3H), 2.89-2.82 (m, 3H), 2.13- 1.98 (m, 1H), 1.90-1.84 (m, 1H), 1.80-1.74 (m, 3H), 1.63-1.48 (m, 7H), 1.24-1.17 (m, 1H). LCMS (ESI) m/z 611.2 (M+H ⁺ ).

EXAMPLE 107. (R)-N-((3-CYANO-5-FLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOPENTANE-1-CARBOXAMIDE [0396] (R)-N-((3-cyano-5-fluoro-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-1-methoxycyclopentane-1-carboxam ide (31.2 mg, 97.4% purity) was obtained as a white solid in 61.5% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.71-7.67 (m, 1H), 7.29-7.25 (m, 2H), 7.03-6.99 (m, 2H), 5.24-5.09 (m, 1H), 4.38- 4.37 (m, 1H), 3.86-3.82 (m ,2 H), 3.48-3.42 (m, 2H), 3.27-3.24 (m, 2H), 3.18-3.09 (m, 4H), 2.91- 2.83 (m, 3H), 2.12-2.00 (m, 1H), 1.89-1.83 (m, 5H), 1.68-1.62 (m, 4H). LCMS (ESI) m/z 611.2 (M+H ⁺ ).

EXAMPLE 108. (R)-N-((3,5-DIFLUORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- (PHENYLTHIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- [0397] (R)-N-((3,5-difluoro-4-((4-(3-fluoroazetidin-1-yl)-1-(phenyl thio)butan-2- yl)amino)phenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide (7.41 mg, 98.8% purity) was obtained as a white solid in 18.9% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.40-7.38 (m, 2H), 7.24-7.17 (m, 4H), 5.34-5.20 (m, 1H), 4.22-4.16 (m, 2H), 3.96-3.84 (m ,3H), 3.19-3.09 (m, 3H), 2.00-1.95 (m, 1H), 1.84-1.75 (m, 5H), 1.67-1.53 (m, 5H), 1.31-1.27 (m, 1H). LCMS (ESI) m/z 574.2 (M+H ⁺ ). EXAMPLE 109. (R)-N-((3-CYANO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (S)-N-((3-CYANO-5- FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE

[0398] A mixture (51.0 mg, 98.6% purity) was obtained as a white solid in 39.6% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide . [0399] The mixture was purified by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D.10um;mobile phase: [EtOH (0.1%IPAm)];B%: 50%-50%,10min) to give (R)-N-((3-cyano- 5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluoropheny l)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (20.0 mg, 39.2 % yield, 100% purity) as a white solid, and (S)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 - ((4-fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-me thyltetrahydro-2H-pyran-2- carboxamide (20.2 mg, 39.2% yield, 100% purity) as a white solid. (R)-N-((3-cyano-5-fluoro-4- (((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)buta n-2-yl)amino)phenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide ¹ H NMR: (400 MHz, MeOD) δ 7.76-7.67 (m, 2H), 7.33-7.30 (m, 2H), 7.06-7.01 (m, 2H), 5.21-5.03 (m, 2H), 4.36-4.35 (m, 1H), 3.72-3.69 (m, 4H), 3.44-3.41 (m, 2H), 3.26-3.13 (m, 4H), 2.73-2.68 (m, 2H), 2.27-2.26 (m, 1H), 1.60-1.46 (m, 6H) 1.22 (s, 3H). LCMS (ESI) m/z 597.2 (M+H ⁺ ), SFC e.e. % = 100%. (S)-N-((3-cyano-5-fluoro-4- (((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluorophenyl)thio)buta n-2-yl)amino)phenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide ¹ H NMR: (400 MHz, MeOD) δ 7.74-7.64 (m, 2H), 7.30-7.27 (m, 2H), 7.03-7.00 (m, 2H), 5.18-4.96 (m, 2H), 4.32-4.31 (m, 1H), 3.68-3.65 (m, 4H), 3.42-3.38 (m, 2H), 3.24-3.12 (m, 4H), 2.71-266 (m, 2H), 2.21-2.21 (m, 1H), 1.78-1.39 (m, 6H) 1.19 (s, 3H). LCMS (ESI) m/z 597.2 (M+H ⁺ ), SFC e.e.% = 99.1%. EXAMPLE 110. (S)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE AND (R)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0400] A mixture (100 mg, 99.5% purity) was obtained as a white solid in 43.0% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide . [0401] The mixture was purified by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D.10um;mobile phase: [EtOH (0.1%IPAm)];B%: 45%-45%,9min) to give (S)-N-((4-(((R)-4- (dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)amino)-3, 5-difluorophenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide (43.7 mg, 43.7 % yield, 100% purity) as a white solid, and (R)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan-2-yl)amino)-3,5- difluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbo xamide (44.4 mg, 44.4% yield, 100% purity) as a white solid. (S)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan- 2-yl)amino)-3,5-difluorophenyl)sulfonyl)-2-methyltetrahydro- 2H-pyran-2-carboxamide- ¹ H NMR: (400 MHz, MeOD)δ 7.40-7.26 (m, 4H), 7.04-7.00 (m, 2H), 3.80-3.71 (m, 4H), 3.65-3.40 (m, 5H), 3.11-3.25 (m, 4H), 2.55 (s, 6H), 2.26-2.06 (m, 3H), 1.57-1.20 (m, 10H). LCMS (ESI) m/z 560.2 (M+H ⁺ ), SFC e.e. % = 100%. (R)-N-((4-(((R)-4-(dimethylamino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3,5-difluorophenyl)sulfo nyl)-2-methyltetrahydro-2H- pyran-2-carboxamide- ¹ H NMR: (400 MHz, MeOD) δ 7.40-7.26 (m, 4H), 7.04-7.00 (m, 2H), 3.80-3.72 (m, 3H), 3.65-3.40 (m, 5H), 3.10-3.07 (m, 2H), 3.10-2.95 (m, 4H), 2.50 (s, 6H), 2.26- 2.04 (m, 3H), 1.47-1.19 (m, 11H). LCMS (ESI) m/z 560.2 (M+H ⁺ ), SFC e.e.% = 98.2%. EXAMPLE 111. (S)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYL-1,4-DIOXANE-2-CARBOXAMIDE AND (R)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)BU TAN-2- YL)AMINO)-3,5-DIFLUOROPHENYL)SULFONYL)-2-METHYL-1,4-DIOXANE- 2- CARBOXAMIDE [0402] A mixture (40.0 mg, 85.4% purity) was obtained as a white solid in 29.3% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide .

[0403] The mixture was purified by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 50%-50%,10min) to give (S)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan-2-yl)amino)-3,5- difluorophenyl)sulfonyl)-2-methyl-1,4-dioxane-2-carboxamide (14.9 mg, 37.3% yield, 100% purity) as a white solid, and (R)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan-2- yl)amino)-3,5-difluorophenyl)sulfonyl)-2-methyl-1,4-dioxane- 2-carboxamide(15.9 mg, 39.8% yield, 100% purity) as a white solid. (S)-N-((4-(((R)-4-(dimethylamino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3,5-difluorophenyl)sulfo nyl)-2-methyl-1,4-dioxane-2- carboxamide 1H NMR: (400 MHz, MeOD) δ 7.32-7.30 (m, 2H), 7.16-7.13 (m, 2H), 6.95-6.89 (m, 2H), 4.48-4.16 (m, 1H), 3.81-3.44 (m, 5H), 3.18-2.99 (m, 5H), 2.73 (s, 6H), 2.09-2.06 (m, 1H), 1.87-1.84 (m, 1H), 1.21-1.05 (m, 4H). LCMS (ESI) m/z 562.2 (M+H+), SFC e.e.% = 100%. (R)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan-2-yl)amino)-3,5- difluorophenyl)sulfonyl)-2-methyl-1,4-dioxane-2-carboxamide1 H NMR: (400 MHz, MeOD) δ 7.32-7.30 (m, 2H), 7.17-7.13 (m, 2H), 6.94-6.90 (m, 2H), 4.17-4.14 (m, 1H), 4.04-4.02 (m, 1H), 3.82-3.43 (m, 6H), 3.15-2.99 (m, 5H), 2.71 (s, 6H), 2.05-2.04 (m, 2H), 1.22-1.05 (m, 4H). LCMS (ESI) m/z 562.2 (M+H+), SFC e.e.% = 96.1%. EXAMPLE 112. (1S,5R)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2,6-DIOXABICYCLO[3.2.1]OCTANE-1- CARBOXAMIDE AND (1R,5S)-N-((4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2,6-DIOXABICYCLO[3.2.1]OCTANE-1- CARBOXAMIDE [0404] A mixture (50.0 mg, 82.9% purity) was obtained as a white solid in 31.3% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide .

[0405] The mixture was purified by SFC (column: DAICEL CHIRALPAK IC(250mm*30mm,10um); mobile phase: [0.1%NH3H2O ETOH];B%: 60%-60%,10min) to give (1S,5R)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-3,5- difluorophenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-car boxamide (15.3 mg, 30.6% yield, 100% purity) as a white solid, and (1R,5S)-N-((4-(((R)-4-(dimethylamino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3,5-difluorophenyl)sulfo nyl)-2,6- dioxabicyclo[3.2.1]octane-1-carboxamide (16.7 mg, 33.2% yield, 99.3% purity) as a white solid. (1S,5R)-N-((4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl)thi o)butan-2-yl)amino)-3,5- difluorophenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-car boxamide 1H NMR: (400 MHz, MeOD)δ 7.34-7.32 (m, 2H), 7.14-7.11 (m, 2H), 6.93-6.89 (m, 2H), 4.51-4.50 (m, 1H), 4.04-4.02 (m, 1H), 3.90-3.85 (m, 4H), 3.17-3.02 (m, 3H), 2.78 (s, 6H), 2.12-2.09 (m, 2H), 1.71-1.50 (m, 4H), 0.80-0.77 (m, 2H). LCMS (ESI) m/z 574.2 (M+H+), SFC e.e. % = 100%. (1R,5S)-N-((4- (((R)-4-(dimethylamino)-1-((4-fluorophenyl)thio)butan-2-yl)a mino)-3,5- difluorophenyl)sulfonyl)-2,6-dioxabicyclo[3.2.1]octane-1-car boxamide 1H NMR: (400 MHz, MeOD) δ 7.34-7.32 (m, 2H), 7.14-7.71 (m, 2H), 6.93-6.89 (m, 2H), 4.02-3.87 (m, 5H), 3.16-3.02 (m, 4H), 3.90-3.96 (m, 1H), 2.78 (s, 6H), 2.11-1.94 (m, 3H), 1.72-1.90 (m, 4H). LCMS (ESI) m/z 574.2 (M+H+), SFC e.e.% = 100%. EXAMPLE 113. N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)OXY)-5-FLUOROPHENYL)SULFONYL)-1-FLUOROCYCLOHEXANE-1- CARBOXAMIDE [0406] To a solution of cpd.A1-1 (50.0 mg, 123 umol) in DCM (3.00 mL) was added DMAP (19.6 mg, 160 umol) and EDCI (30.7 mg, 160 umol), acid 1 (23.4 mg, 160 umol). The mixture was stirred at 30 °C for 16 hrs. LCMS (RT = 1.703 min) showed cpd.A1-1 was consumed, a main peak with desired MS was detected. The reaction mixture was quenched by addition H ₂ O (5.00 mL) and extracted with DCM (5.00 mL x 3). The combined organic layers were washed with brine (5.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Waters X bridge BEH C18100*30mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 35%-65%, 8min) to give N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)oxy)-5 -fluorophenyl)sulfonyl)-1- fluorocyclohexane-1-carboxamide (92.9% purity) (27.1 mg, theory amount: 72.3 mg, 34.8% yield) as a white solid and the product was purified by prep-HPLC(column: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(TFA)-ACN];B%: 30%-50%,8min) as a white solid. 1H NMR: (400 MHz, MeOD) δ 8.17-8.10 (m, 2H), 7.28-7.17 (m, 5H), 3.48-3.42 (m, 2H), 2.96 (m, 6H), 2.80-2.76 (m, 2H), 2.31-2.27 (m, 5H), 1.67-1.31 (m, 10H). LCMS (ESI) m/z 534.2 (M+H ⁺ ). EXAMPLE 114. (R)-N-((3-CHLORO-4-(((R)-4-(DIMETHYLAMINO)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0407] Charge THF (100 mL) to a 500 mL three-neck bottle (R1) equipped with a N ₂ balloon. Charge compound 1 (10.0 g, 45.6 mmol, 1.00 eq) to R1 at 25 °C. Charge imidazole (9.32 g, 136 mmol, 3.00 eq) to R1 at 25 °C. Charge TBDPS-Cl (37.6 g, 136 mmol, 35.0 mL, 3.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 2 hrs. TLC (Dichloromethane: Methanol = 10: 1, R _f = 0.78) showed compound 1 was consumed and a new major spot was observed. Water (200 mL) was added slowly to R1 keeping the internal temperature at 10 ~ 20 °C. The mixture in R1 was transferred to a 1000 mL separating funnel(R2). EtOAc (100 mL) was added to R2, the organic layer was separated, the aqueous phase was extracted with EtOAc (100 mL x2). The combined organic layers were brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude product. The crude product (Dichloromethane: Methanol = 10: 1, R _f = 0.78) was purified by column chromatography on silicagel (EtOAc: petroleum ether = 0-10%) to give compound 2 (17.1 g, 37.4 mmol, 81.9% yield) as a light yellow oil. [0408] Charge compound 2 (17.1 g, 37.4 mmol, 1.00 eq) to a 500 mL three neck bottle (R1) at 25°C. Charge THF (171 mL) to R1 at 25°C. Charge LAH (2.50 M, 14.9 mL, 1.00 eq) to R1 at 0°C. Stir R1 at 0°C for 2 hrs. Charge LAH (2.5 M, 7.47 mL, 0.5 eq) to R1 at 0°C;. Stir R1 at 25°C for 6 hrs. TLC (Petroleum ether: Ethyl acetate = 5 : 1)showed the starting material was consumed and a new major spot was observed (R _f = 0.27). NaSO ₄ ^. 10H ₂ O (20.0 g) was added slowly to R1 keeping the internal temperature at 10 ~ 20 ℃. The mixture in R1 was filtered. The filtrate was transferred to a 100 mL round bottom flask and concentrated to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 100: 1 – 3: 1) to give compound 3 (7.00 g, 15.60 mmol, 41.76% yield, 98.9% purity) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.70 - 7.63 (m, 4H), 7.50 - 7.36 (m, 6H), 5.51 (br s, 1H), 3.87 - 3.80 (m, 1H), 3.76 (t, J = 5.6 Hz, 2H), 3.72 - 3.64 (m, 2H), 1.89 - 1.69 (m, 2H), 1.44 (s, 9H), 1.07 (s, 9H). [0409] Charge compound 3 (4.50 g, 10.14 mmol, 1.00 eq) to 100 mL three neck bottle (R1) at 25 °C. Charge toluene (50.0 mL) to R1 at 25 °C. Charge compound 2-1 (5.69 g, 50.7 mmol, 5.00 eq) to R1 at 25 °C. Charge PPh ₃ (13.3 g, 50.7 mmol, 5.00 eq) to R1 at 25 °C. Charge (3E)-3- (dimethylcarbamoylimino)-1,1-dimethyl-urea (8.73 g, 50.7 mmol, 5.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 1 hr. TLC (Petroleum ether: Ethyl acetate = 5 : 1) showed compound 3 was consumed and a new major spot was observed (R _f = 0.46). Water (100 mL) was added slowly to R1. The mixture in R1 was transferred to a 250 mL separating funnel (R2). EtOAc (50.0 mL) was added to R2, the organic layer was separated, the aqueous phase was extracted with EtOAc (50.0 mL x 2). The combined organic layers were washed with brine (2.00 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude product. The crude product (Petroleum ether: Ethyl acetate = 5 : 1) was purified by column chromatography on silica gel (petroleum ether: EtOAc = 100: 1 – 10: 1) to give compound 4 (5.73 g, crude) as a yellow oil. [0410] Charge THF (20 mL) to a 100 mL three neck bottle (R1) equipped with a N ₂ balloon. Charge compound 4 (5.73 g, 10.66 mmol, 1.00 eq) to R1 at 25 °C. Charge TBAF (1.00 M, 10.6 mL, 1.00 eq) to R1 at 25 °C. Stir R1 at 25°C for 16 hrs. TLC (Petroleum ether: Ethyl acetate = 5 : 1) showed compound 4 was consumed and a new major spot was observed (R _f = 0.12). Water (50.0 mL) was added slowly to R1. The mixture in R1 was transferred to a 250 mL separating funnel (R2). EtOAc (50.0 mL) was added to R2, the organic layer was separated, the aqueous phase was extracted with EtOAc (50.0 mL x 2). The combined organic layers were washed with brine (2 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: EtOAc = 100 : 1–10 : 1) to give compound 5 (930 mg, 3.11 mmol, 29.2% yield) (confirmed by HNMR: EB11178-22-P1N2) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.05 - 6.93 (m, 2H), 6.89 - 6.79 (m, 2H), 5.13 - 4.97 (m, 1H), 4.18 (br s, 1H), 4.07 (br dd, J = 3.6, 9.2 Hz, 1H), 3.95 (dd, J = 3.2, 9.2 Hz, 1H), 3.81 - 3.62 (m, 2H), 1.95 - 1.76 (m, 2H), 1.47 (s, 9H) [0411] Charge compound 5 (500 mg, 1.67 mmol, 1.00 eq) to 50.0 mL round bottle flasks (R1) at 25°C. Charge dioxane (2.00 mL) to R1 at 25°C. Charge HCl/dioxane (4.00 M, 1.67 mL, 4.00 eq) to R1 at 25°C. Stir R1 at 25°C for 16 hrs. TLC (Petroleum ether: Ethyl acetate = 1:1) showed compound 5 was consumed. The mixture was concentrated to give compound 6 (545 mg, crude) as a yellow solid ¹ H NMR: (400 MHz, CD ₃ OD) δ = 7.11 - 6.95 (m, 4H), 4.25 (dd, J = 3.6, 10.4 Hz, 1H), 4.09 (dd, J = 6.8, 10.4 Hz, 1H), 3.84 - 3.74 (m, 3H), 1.98 (q, J = 6.4 Hz, 2H). [0412] Charge compound 6 (200 mg, 560 μmol, 1.00 eq, HCl) to a 50 mL round bottom flask(R1). Charge DMSO (0.5 mL) to R1 at 25°C. Charge DIEA (362 mg, 2.80 mmol, 488 μL, 5.00 eq) to R1 at 25 °C. Charge S11 (127 mg, 560 μmol, 1.00 eq) to R1 at 25°C. Stir R1 at 90 °C for 12hrs. LCMS showed that compound 6 was remained (R _t = 0.768 min) and the desired mass (R _t = 1.343 min) was observed. The mixture was quenched by addition of water (20.0 mL) and extracted with EtOAc (10.0 mL x 3), all organic layer was combined and washed with water (10.0 ml x 3), brine (20.0 mL ), dried over Na ₂ SO ₄ , filtered and the filtrate concentrated to give a crude product. The crude product (Dichloromethane: Methanol = 10: 1, R _f = 0.33) was purified by column chromatography on silica gel (Methanol: Dichloromethane = 0-10%) to give compound 7 (120 mg, 295 μmol, 52.7% yield) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.11 - 6.95 (m, 4H), 4.25 (dd, J = 3.6, 10.4 Hz, 1H), 4.09 (dd, J = 6.8, 10.4 Hz, 1H), 3.84 - 3.74 (m, 3H), 3.66 (s, 9H), 1.98 (q, J = 6.4 Hz, 2H)

[0413] Charge THF (1.00 mL) to a 8 mL seal tube. Charge compound 7 (100 mg, 245 μmol, 1.00 eq) to R1 at 25°C. Charge Py (38.9 mg, 491 μmol, 39.6 μL, 2.00 eq) to R1 at 0 °C. Charge methylsulfonyl methanesulfonate (64.2 mg, 368 μmol, 1.50 eq) to R1 at 0 °C. Stir R1 at 25 °C for 2 hrs. LCMS showed that compound 7 was consumed and the desired mass (R _t = 1.595 min) was observed. Water (5.00 mL) was added slowly to R1. The mixture in R1 was transferred to a 60 mL separating funnel (R2). CH ₂ Cl ₂ (5.00 mL) was added to R2, the organic layer was separated, the aqueous phase was extracted with CH ₂ Cl ₂ (5.00 mL x 2). The combined organic layers were washed with NaHCO ₃ (1.00 mL x 2) and brine (5.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give compound 8 (140 mg, crude) as a yellow oil. [0414] Charge THF (1.00 mL) to a 8 mL seal tube (R1) equipped with N ₂ . Charge compound 7 (80.0 mg, 165 μmol, 1.00 eq) to R1 at 25 °C. Charge N-methylmethanamine (2.00 M, 412 μL, 5.00 eq) to R1 at 25°C. Stir R1 at 40 °C for 72 hrs. LCMS showed that compound 7 was consumed and the desired mass (R _t = 1.005 min) was observed. The mixture was purified by pre- HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 28%-68% B over 32 min) to give compound 9 (19.0 mg, 40.4 μmol, 24.5% yield, 92.3% purity) as a light yellow solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.64 (s, 1H), 7.48 (dd, J = 2.0, 12.4 Hz, 1H), 7.03 - 6.91 (m, 2H), 6.87 - 6.77 (m, 2H), 4.22 (br dd, J = 4.8, 8.4 Hz, 1H), 4.03 (d, J = 4.8 Hz, 2H), 2.71 - 2.52 (m, 2H), 2.31 (s, 6H), 2.09 - 1.79 (m, 2H). [0415] Charge Acid 9 (12.6 mg, 87.6 μmol, 2.00 eq) to a 8 mL seal tube (R1). Charge ACN (1.00 mL) to R1 at 25 °C. Charge EDCI (16.8 mg, 87.6 μmol, 2.00 eq) to R1 at 25 °C. Charge DMAP (10.7 mg, 87.6 μmol, 2.00 eq) to R1 at 25 °C. Charge compound 9 (19.0 mg, 43.8 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs. LCMS showed that compound 9 was consumed and the desired mass (R _t = 1.456 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 8%-48% B over 32 min) to give (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenox y)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide (26.6 mg, crude) as a white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.47 (s, 1H), 7.36 (dd, J = 1.2, 12.4 Hz, 1H), 7.06 (dd, J = 8.8 Hz, 2H), 6.85 - 6.73 (m, 2H), 3.98 (br s, 3H), 3.62 - 3.51 (m, 1H), 3.47 - 3.44 (m, 1H), 3.26 - 3.08 (m, 2H), 2.71 (s, 6H), 2.12 (br d, J = 12.0 Hz, 1H), 2.00 (br d, J = 6.4 Hz, 2H), 1.46 (br s, 1H), 1.37 - 1.21 (m, 3H), 1.02 (s, 4H)

EXAMPLE 115. (R)-N-((3-CHLORO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1- YL)-1-(4-FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0416] Compound 10 (14.0 mg) was obtained as yellow solid in 18.1% yield according to the general procedure of compound 9. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.63 (s, 1H), 7.48 (dd, J = 2.0, 12.4 Hz, 1H), 7.02 - 6.90 (m, 2H), 6.86 - 6.78 (m, 2H), 5.25 - 4.99 (m, 1H), 4.24 (br dd, J = 4.8, 7.6 Hz, 1H), 4.02 (d, J = 4.8 Hz, 2H), 3.74 - 3.58 (m, 2H), 3.29 - 3.25 (m, 1H), 3.21 (br dd, J = 4.0, 8.4 Hz, 1H), 2.81 - 2.68 (m, 2H), 1.92 - 1.72 (m, 2H) [0417] (R)-N-((3-chloro-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)- 1-(4-fluorophenoxy)butan- 2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-ca rboxamide (20.0 mg, 99.6% purity) was obtained as colorless oil according to the general procedure of (R)-N-((3-chloro-4- (((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2-yl)amino) -5-fluorophenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.49 (s, 1H), 7.38 (dd, J = 1.6, 12.4 Hz, 1H), 7.05 (dd, J = 8.8 Hz, 2H), 6.80 (dd, J = 4.4, 8.8 Hz, 2H), 5.35 - 5.07 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 (br d, J = 4.8 Hz, 2H), 3.91 - 3.74 (m, 2H), 3.51 - 3.49 (m, 2H), 2.87 (br s, 2H), 2.08 (br d, J = 12.4 Hz, 1H), 1.75 (br d, J = 6.8 Hz, 2H), 1.52 - 1.41 (m, 1H), 1.29 (br s, 3H), 1.18 - 0.97 (m, 4H) EXAMPLE 116. (R)-N-((3-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0418] Compound 11 (560 mg) was obtained as yellow solid according to the general procedure of compound 8.

[0419] Compound 12 (150 mg, 72.7% purity) was obtained as yellow oil in 45.0% yield according to the general procedure of compound 9. ¹ H NMR: (400 MHz, CDCl ₃ ) δ = 7.04 - 6.92 (m, 2H), 6.85 (br dd, J = 4.4, 8.8 Hz, 2H), 5.38 (br d, J = 3.4 Hz, 1H), 4.08 - 3.88 (m, 3H), 2.47 (br d, J = 7.2 Hz, 2H), 2.30 (s, 6H), 1.89 (br dd, J = 6.8, 14.0 Hz, 2H), 1.46 (s, 9H) [0420] Compound Amine 11 (150 mg) was obtained as light yellow solid according to the general procedure of compound 6. [0421] Compound 12-1 (52.0 mg, 98.8% purity) was obtained as white solid in 63.6% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.76 (s, 1H), 7.66 (dd, J = 2.0, 12.0 Hz, 1H), 7.04 - 6.91 (m, 2H), 6.89 - 6.79 (m, 2H), 4.65 (br dd, J = 5.6, 7.2 Hz, 1H), 4.10 (t, J = 5.6 Hz, 2H), 2.69 - 2.52 (m, 2H), 2.31 (s, 6H), 2.11 - 1.87 (m, 2H) [0422] (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy )butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide (25.0 mg, 99.3% purity) was obtained as white solid in 67.9% yield according to the general procedure of (R)-N-((3- chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2- yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.46 (br s, 1H), 7.86 (s, 1H), 7.76 (dd, J = 1.6, 12.0 Hz, 1H), 7.02 - 6.90 (m, 2H), 6.87 - 6.74 (m, 2H), 4.52 (br dd, J = 4.4, 7.6 Hz, 1H), 4.08 (br dd, J = 5.2, 10.0 Hz, 2H), 3.67 (br s, 2H), 3.44 - 3.32 (m, 2H), 2.88 (s, 6H), 2.18 (br d, J = 8.0 Hz, 3H), 1.66 - 1.55 (m, 1H), 1.53 - 1.37 (m, 3H), 1.32 (br d, J = 10.0 Hz, 1H), 1.20 (s, 3H)

EXAMPLE 117. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0423] Compound 12-2 (53.0 mg, 99.2% purity) was obtained as white solid in 62.6% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.08 - 7.74 (m, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.84 (dd, J = 4.4, 9.2 Hz, 2H), 4.82 - 4.79 (m, 1H), 4.13 (d, J = 4.8 Hz, 2H), 2.71 - 2.52 (m, 2H), 2.30 (s, 6H), 2.16 - 1.91 (m, 2H) [0424] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(dimethylamino)-1-(4-fluo rophenoxy)butan-2- yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (27.0 mg, 99.6% purity) was obtained as white solid in 74.4% yield according to the general procedure of (R)-N- ((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.46 (s, 1H), 8.04 (dd, J = 2.0, 13.6 Hz, 2H), 6.97 (t, J = 8.8 Hz, 2H), 6.85 - 6.75 (m, 2H), 4.70 - 4.51 (m, 2H), 4.07 (br dd, J = 4.8, 8.4 Hz, 2H), 3.67 (br s, 2H), 3.50 - 3.35 (m, 3H), 2.89 (s, 6H), 2.31 - 2.11 (m, 3H), 1.66 - 1.25 (m, 6H), 1.21 (s, 3H) EXAMPLE 118. (R)-N-((3,5-DICHLORO-4-(((R)-4-(DIMETHYLAMINO)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0425] Compound 12-3 (12.0 mg, 93.9% purity) was obtained as a light yellow solid in 13.2% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.76 (s, 2H), 6.96 (dd, J = 8.8 Hz, 2H), 6.83 - 6.71 (m, 2H), 4.39 (br dd, J = 4.8, 8.0 Hz, 1H), 3.99 (d, J = 4.4 Hz, 2H), 2.86 - 2.74 (m, 1H), 2.70 - 2.59 (m, 1H), 2.37 (s, 6H), 2.10 - 1.88 (m, 2H) B. Step 2 [0426] Compound (R)-N-((3,5-dichloro-4-(((R)-4-(dimethylamino)-1-(4-fluoroph enoxy)butan- 2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-ca rboxamide (15.0 mg, 99.6% purity) was obtained as white solid in 97.3% yield according to the general procedure of (R)-N- ((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.44 (s, 1H), 7.83 (s, 2H), 6.96 (dd, J = 8.8 Hz, 2H), 6.75 (dd, J = 4.4, 9.2 Hz, 2H), 4.29 (br dd, J = 4.4, 8.8 Hz, 1H), 3.94 (d, J = 4.4 Hz, 2H), 3.71 - 3.56 (m, 3H), 3.46 - 3.36 (m, 1H), 2.93 (s, 6H), 2.19 (br d, J = 5.2 Hz, 3H), 1.65 - 1.54 (m, 1H), 1.53 - 1.24 (m, 5H), 1.21 (s, 3H) EXAMPLE 119. (R)-N-((3-CYANO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-(4-FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE

A. Step 1 [0427] Compound 13 (160 mg, 79.5% purity) was obtained as yellow oil in 48.1% yield according to the general procedure of compound 9. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.05 - 6.92 (m, 2H), 6.90 - 6.78 (m, 2H), 5.28 - 4.96 (m, 2H), 4.09 - 3.85 (m, 3H), 3.81 - 3.61 (m, 3H), 3.24 - 3.07 (m, 2H), 2.63 (br dd, J = 6.4, 12.8 Hz, 2H), 1.83 - 1.63 (m, 3H), 1.50 - 1.44 (m, 9H) B. Step 2 [0428] Compound Amine 12 (180 mg) was obtained as light yellow solid according to the general procedure of compound 6. C. Step 3

[0429] Compound 13-1 (52.0 mg) was obtained as white solid in 55.8% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.76 (dd, J = 1.2, 2.0 Hz, 1H), 7.66 (dd, J = 2.0, 12.0 Hz, 1H), 7.03 - 6.91 (m, 2H), 6.89 - 6.79 (m, 2H), 5.25 - 5.01 (m, 1H), 4.71 - 4.61 (m, 1H), 4.09 (t, J = 5.2 Hz, 2H), 3.76 - 3.63 (m, 2H), 3.28 - 3.15 (m, 2H), 2.86 - 2.64 (m, 2H), 1.95 - 1.74 (m, 2H) D. Step 4 [0430] Compound (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetr ahydro-2H-pyran-2-carboxamide (21.0 mg, 98.5% purity) was obtained as white solid in 57.7% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenox y)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.39 (s, 1H), 7.88 (s, 1H), 7.76 (dd, J = 1.6, 12.0 Hz, 1H), 7.03 - 6.91 (m, 2H), 6.86 - 6.77 (m, 2H), 5.36 - 5.11 (m, 1H), 4.63 (br dd, J = 5.2, 7.2 Hz, 2H), 4.15 - 3.95 (m, 4H), 3.79 - 3.52 (m, 4H), 3.12 - 2.98 (m, 2H), 2.19 - 2.07 (m, 1H), 2.02 - 1.84 (m, 2H), 1.61 (br d, J = 4.0 Hz, 1H), 1.52 - 1.28 (m, 4H), 1.22 (s, 3H)

EXAMPLE 120. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-(4-FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0431] Compound 13-2 (61.0 mg) was obtained as a white solid in 63.2% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.03 - 7.84 (m, 2H), 7.03 - 6.91 (m, 2H), 6.88 - 6.79 (m, 2H), 5.23 - 5.01 (m, 1H), 4.81 (br s, 1H), 4.12 (d, J = 5.2 Hz, 2H), 3.67 (br d, J = 10.0 Hz, 2H), 3.29 - 3.20 (m, 2H), 2.87 - 2.67 (m, 2H), 1.96 - 1.82 (m, 2H) B. Step 2 [0432] Compound (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetr ahydro-2H-pyran-2-carboxamide (25.0 mg, 97.9% purity) was obtained as white solid in 64.4% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenox y)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.36 (s, 1H), 8.05 (dd, J = 2.0, 10.8 Hz, 2H), 7.03 - 6.91 (m, 2H), 6.87 - 6.76 (m, 2H), 5.38 - 5.10 (m, 1H), 4.79 - 4.69 (m, 2H), 4.16 - 3.99 (m, 4H), 3.85 - 3.69 (m, 3H), 3.67 - 3.52 (m, 1H), 3.21 - 3.08 (m, 2H), 2.20 - 1.92 (m, 3H), 1.68 - 1.57 (m, 1H), 1.52 - 1.28 (m, 4H), 1.21 (s, 3H) EXAMPLE 121. (R)-N-((3,5-DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0433] Compound 13-3 (20.0 mg, 97.5% purity) was obtained as a light yellow solid in 19.8% yield according to the general procedure of compound 7. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.76 (s, 2H), 6.99 - 6.88 (m, 2H), 6.82 - 6.71 (m, 2H), 5.26 - 5.01 (m, 2H), 4.45 - 4.34 (m, 1H), 4.03 - 3.93 (m, 2H), 3.76 - 3.60 (m, 2H), 3.26 - 3.22 (m, 1H), 2.90 - 2.68 (m, 2H), 1.84 (td, J = 5.2, 8.8 Hz, 2H) B. Step 2 [0434] Compound (R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetr ahydro-2H-pyran-2- carboxamide(15.0 mg, 97.4% purity) was obtained as white solid in 57.8% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenox y)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide . ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.40 (s, 1H), 7.84 (s, 2H), 6.95 (dd, J = 8.8 Hz, 2H), 6.83 - 6.66 (m, 2H), 5.41 - 5.17 (m, 1H), 4.40 - 4.29 (m, 1H), 4.26 - 4.11 (m, 2H), 3.99 - 3.81 (m, 4H), 3.76 - 3.65 (m, 1H), 3.65 - 3.54 (m, 1H), 3.41 - 3.34 (m, 1H), 3.28 - 3.18 (m, 1H), 2.13 (br d, J = 12.4 Hz, 1H), 2.04 - 1.85 (m, 2H), 1.66 - 1.55 (m, 1H), 1.55 - 1.25 (m, 5H), 1.21 (s, 3H) EXAMPLE 122. (R)-N-((3-CHLORO-5-FLUORO-4-(((R)-1-((4- FLUOROPHENYL)THIO)-4-(3-METHOXYAZETIDIN-1-YL)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

A. Step 1 [0435] Charge compound 1-1 (4.40 g, 14.2 mmol, 1.00 eq) to a 250 mL three neck bottle (R1). Charge CH ₂ Cl ₂ (25.0 mL) to R1. Charge Py (2.25 g, 28.5 mmol, 2.30 mL, 2.00 eq) to R1. Charge methylsulfonyl methanesulfonate (3.22 g, 18.5 mmol, 1.30 eq) to R1 at 0 °C. Stir R1 at 25 °C for 1 hr. TLC (Dichloromethane : Methanol = 10 : 1) showed compound 1-1 was consumed and a new major spot was observed. The reaction solution was poured into ice water (100 mL); The mixture was extracted with CH2Cl2 (30.0 mL x 3); The combined organic phases were washed with saturated brine (50.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel ( petroleum ether : EtOAc = 8 : 2) to give compound 1-2 (3.40 g, 7.79 mmol, 54.8% yield, 88.8% purity) (confirmed by HNMR: EB11172-38-P1N1) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.45 - 7.32 (m, 5H), 5.16 (s, 3H), 4.39 - 4.26 (m, 3H), 3.00 (s, 3H), 2.78 - 2.66 (m, 2H), 1.46 (s, 9H) B. Step 2 [0436] Charge compound 1-2 (3.40 g, 8.78 mmol, 1.00 eq) to a 100 mL three-neck bottle(R1). Charge DMF ( 24.0 mL) to R1. Charge compound 2A (1.35 g, 10.5 mmol, 1.20 eq) to R1. Charge K ₂ CO ₃ (2.43 g, 17.6 mmol, 2.00 eq) to R1. Stir R1 at 40 °C for 12 hrs. TLC( Petroleum ether : Ethyl acetate = 5 : 1) showed that the compound 1-2 was consumed and a new major spot was observed. The reaction solution was poured into ice water (150 mL). The mixture was extracted with EtOAc (40.0 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc = 100 : 1 – 10 : 1) to give compound 1-3 (3.10 g, 6.39 mmol, 72.8% yield, 86.5% purity) (confirmed by HNMR: EB11172-39-P1N1) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.45 (dd, J = 5.2, 8.4 Hz, 2H), 7.38 - 7.25 (m, 5H), 7.04 (dd, J = 8.8 Hz, 2H), 5.11 (s, 2H), 4.15 - 3.98 (m, 1H), 3.11 - 2.92 (m, 2H), 2.83 - 2.52 (m, 2H), 1.49 - 1.33 (m, 9H). [0437] Charge compound 1-3 (2.10 g, 5.01 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1) at 25 °C. Charge THF (5.00 mL) to R1 at 25 °C. Charge LAH (2.5 M, 2.00 mL, 1.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 2 hrs. TLC( Petroleum ether : Ethyl acetate = 5 : 1) showed that the compound 1-3 was consumed and a new major spot was observed. NaSO ₄ ·10H ₂ O (2.00 g) was added slowly to R1 keeping the internal temperature at 10 ~ 20 °C. The mixture in R1 was filtered. The filtrate was transferred to a 1000 mL round bottom flaskand concentrated to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether : EtOAc = 100 : 1 – 10 : 1) to give compound 1-4 (1.70 g, crude) as a colorless oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.45 (dd, J = 5.2, 8.8 Hz, 2H), 7.04 (dd, J = 8.8 Hz, 2H), 3.81 - 3.69 (m, 1H), 3.57 (br t, J = 6.4 Hz, 2H), 3.01 (br d, J = 6.0 Hz, 2H), 1.93 - 1.81 (m, 1H), 1.71 - 1.57 (m, 1H), 1.42 (s, 9H)

D. Step 4 [0438] Charge compound 1-4 ( 1.20 g, 3.80 mmol, 1.00 eq) to a 40 mL seale dtube. Charge THF ( 15.0 mL) to R1 at 25 °C. Charge Py ( 602 mg, 7.61 mmol, 614 μL, 2.00 eq) to R1 at 0 °C. Charge methylsulfonyl methanesulfonate ( 994 mg, 5.71 mmol, 1.50 eq) to R1 at 0 °C. Stir R1 at 25 °C for 72 hrs. LCMS( EB11172-50-IPCL1 ) showed that the compound 1-4 was consumed and the desired mass (R _t = 1.704 min) was observed. The mixture was quenched by addition of H ₂ O (10.0 mL) and extracted with CH ₂ Cl ₂ (20.0 mL x 2), the combined organic layers were washed with NaHCO ₃ (20.0 mL x 3) and brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 1-5 (1.40 g, 3.56 mmol, 93.5% yield) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD). δ 7.49 (dd, J = 5.2, 8.8 Hz, 2H), 7.07 (br dd, J = 8.8 Hz, 2H), 4.33 - 4.18 (m, 2H), 3.79 (br dd, J = 3.6, 6.8 Hz, 1H), 3.12 - 2.90 (m, 5H), 2.23 - 2.04 (m, 1H), 1.85 - 1.72 (m, 1H), 1.44 (s, 9H) E. Step 5 [0439] Charge compound 1-5 ( 1.4 g, 3.56 mmol, 1.00 eq) to a 40 mL sealed tube(R1) equipped with N ₂ . Charge THF ( 10.0 mL) to R1 at 25 °C. Charge compound 5A ( 4.40 g, 35.58 mmol, 10.0 eq) to R1 at 25 °C. Charge TEA ( 5.76 g, 56.9 mmol, 7.92 mL, 16.0 eq) to R1 at 25°C. Stir R1 at 40 °C for 72 hr. LCMS showed that the compound 1-5 was consumed and the desired mass (R _t = 1.226 min) was observed. The mixture was concentrated to give crude product. The crude product (Dichloromethane : Methanol = 10 : 1) was purified by column chromatography on silica gel (Dichloromethane : Methanol = 100 : 1 – 10 : 1) to give compound 1-6 (3.00 g, crude) (confirmed by HNMR: EB11172-53-P1N2) as a yellow solid. The crude product (500 mg) was purified by pre-HPLC( column: Xtimate C18150*40mm*10um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; gradient: 30% - 70% B over 32 min) to give compound 1-6 (100 mg, 259.55 μmol, 19.96% yield, 99.8% purity) as a yellow oil. ¹ H NMR: EB11172-53- P1N2 (400 MHz, DMSO-d ₆ ) δ 7.41 (dd, J = 5.2, 8.8 Hz, 2H), 7.16 (dd, J = 8.8 Hz, 2H), 6.86 (br d, J = 8.4 Hz, 1H), 3.94 (quin, J = 5.6 Hz, 1H), 3.56 - 3.40 (m, 2H), 3.14 (s, 3H), 2.91 (br d, J = 6.0 Hz, 2H), 1.98 (s, 1H), 1.58 (br dd, J = 5.2, 12.8 Hz, 1H), 1.50 - 1.42 (m, 1H), 1.36 (s, 9H). F. Step 6 [0440] Charge compound 1-6 ( 100 mg, 260 μmol, 1.00 eq) to a 50.0 mL round bottom flask (R1) equipped with N ₂ . Charge HCl/dioxane (4 M, 1.00 mL, 15.4 eq) to R1 at 25 °C. Stir R1 at 25 °C for 1 hr. TLC( Dichloromethane : Methanol = 10 : 1) showed compound 1-6 was consumed and a new major spot was observed. The mixture was concentrated to give compound 1-7 ( 80.0 mg, crude, HCl) as a yellow solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.57 - 7.39 (m, 2H), 7.05 (dd, J = 8.8 Hz, 2H), 4.43 (br dd, J = 6.8, 10.2 Hz, 1H), 4.25 - 4.13 (m, 2H), 4.10 - 4.01 (m, 1H), 3.89 - 3.76 (m, 1H), 3.56 (s, 4H), 3.29 (br d, J = 8.4 Hz, 2H), 3.18 (d, J = 5.6 Hz, 1H), 3.12 - 2.98 (m, 1H), 2.03 - 1.76 (m, 2H)

G. Step 7 [0441] Charge compound 1-7 (40.0 mg, 125 μmol, 1.00 eq, HCl) to a 8 mL seal tube (R1) at 25 °C. Charge DMSO (0.50 mL) to R1 at 25 °C. Charge DIEA (80.6mg, 623 μmol, 109 μL, 5.00 eq) to R1 at 25 °C. Charge S11 (28.4 mg, 125 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS (EB11172-80-IPCL3) showed that the compound 1-7 was consumed and the desired mass (R _t = 1.081 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC(column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl) - ACN];gradient: 10% - 50% B over 20 min) to give compound 1-8 (20.0 mg, 40.7 μmol, 32.6% yield) (confirmed by HNMR: EB11172-80- P1N1) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD). δ 7.67 (s, 1H), 7.54 - 7.40 (m, 1H), 7.26 (dd, J = 5.2, 8.8 Hz, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 4.57 - 4.44 (m, 1H), 4.35 - 4.12 (m, 3H), 4.00 - 3.87 (m, 2H), 3.53 - 3.44 (m, 2H), 3.38 - 3.36 (m, 3H), 3.15 (br dd, J = 6.0, 10.6 Hz, 2H), 2.19 - 1.95 (m, 2H). H. Step 8 [0442] Charge Acid 9 (11.7 mg, 81.3 μmol, 2.00 eq) to a 8 mL seal tube (R1) at 25 °C. Charge ACN (1.00 mL) to R1 at 25 °C. Charge EDCI (15.6 mg, 81.3 μmol, 2.00 eq) to R1 at 25 °C. Charge DMAP (9.93 mg, 81.3 μmol, 2.00 eq) to R1 at 25 °C. Charge compound 1-8 (20.0 mg, 40.7 μmol, 1.00 eq)to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs. LCMS( EB11172-88-IPCL1) showed that the compound 1-8 was consumed and the desired mass (R _t = 1.267 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC(column: Welch Xtimate C18150*25mm*5um; mobile phase: [water(FA) - ACN]; gradient: 8% - 48% B over 20 min) to give (R)-N-((3-chloro-5-fluoro-4-(((R)-1-((4- fluorophenyl)thio)-4-(3-methoxyazetidin-1-yl)butan-2-yl)amin o)phenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide (8.30 mg, 13.4 μmol, 33.0% yield, 99.9% purity) as a white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.47 (s, 1H), 7.37 - 7.28 (m, 1H), 7.25 (dd, J = 5.2, 8.8 Hz, 2H), 7.18 - 7.09 (m, 2H), 5.25 (br t, J = 4.4 Hz, 1H), 4.16 - 4.05 (m, 1H), 4.04 - 3.96 (m, 1H), 3.85 - 3.74 (m, 1H), 3.57 - 3.43 (m, 4H), 3.20 (s, 3H), 3.13 (br d, J = 6.0 Hz, 2H), 3.05 - 2.99 (m, 1H), 2.19 - 2.05 (m, 1H), 1.77 (br d, J = 6.4 Hz, 2H), 1.54 - 1.43 (m, 1H), 1.40 - 1.23 (m, 4H), 1.05 (s, 4H) EXAMPLE 123. (R)-N-((3,5-DICHLORO-4-(((R)-1-((4-FLUOROPHENYL)THIO)-4-(3- METHOXYAZETIDIN-1-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0443] Compound 1-9 (20.0 mg, 39.3 μmol) was obtained as yellow oil in 31.6% yield according to the general procedure of compound 1-8 HPLC: column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water( HCl) - ACN]; gradient: 10% -50% B over 20 min. B. Step 2 [0444] Compound (R)-N-((3,5-dichloro-4-(((R)-1-((4-fluorophenyl)thio)-4-(3- methoxyazetidin-1-yl)butan-2-yl)amino)phenyl)sulfonyl)-2-met hyltetrahydro-2H-pyran-2- carboxamide (7.20 mg, 10.4 μmol, 98.3% purity, FA) was obtained as white solid in 26.4% yield according to the general procedure of (R)-N-((3-chloro-5-fluoro-4-(((R)-1-((4- fluorophenyl)thio)-4-(3-methoxyazetidin-1-yl)butan-2-yl)amin o)phenyl)sulfonyl)-2- methyltetrahydro-2H-pyran-2-carboxamide. HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water( FA) - ACN]; gradient:8% - 48% B over 20 min. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.57 (s, 2H), 7.27 - 7.01 (m, 4H), 5.01 (br d, J = 10.8 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.95 - 3.85 (m, 1H), 3.84 - 3.70 (m, 2H), 3.62 - 3.51 (m, 2H), 3.46 - 3.42 (m, 1H), 3.17 (s, 3H), 3.13 - 2.96 (m, 3H), 2.14 (br d, J = 12.8 Hz, 1H), 1.83 - 1.64 (m, 2H), 1.47 (br d, J = 1.2 Hz, 1H), 1.40 - 1.19 (m, 4H), 1.03 (s, 4H). EXAMPLE 124. (R)-N-((3,5-DICHLORO-4-(((R)-1-((4-FLUOROPHENYL)THIO)-4-(3- METHOXYAZETIDIN-1-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE

A. Step 1 [0445] Compound 1-10 (50.0 mg, 104 μmol) was obtained as yellow oil in 79.2% yield according to the general procedure of compound 1-8 .HPLC: column: Xtimate C18 150*40mm*10um; mobile phase: [ water( HCl) - ACN]; gradient: 0% - 40% B over 36 min. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.74 (s, 1H), 7.68 (br d, J = 11.6 Hz, 1H), 7.26 (dd, J = 5.2, 8.8 Hz, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 4.54 (br dd, J = 6.4, 9.0 Hz, 1H), 4.37 - 4.15 (m, 4H), 3.96 (dt, J = 5.6, 10.8 Hz, 1H), 3.51 - 3.40 (m, 3H), 3.36 (br d, J = 9.6 Hz, 3H), 3.20 - 3.09 (m, 1H), 2.14 - 1.94 (m, 2H). B. Step 2 [0446] (R)-N-((3-cyano-5-fluoro-4-(((R)-1-((4-fluorophenyl)thio)-4- (3-methoxyazetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-p yran-2-carboxamide (8.00 mg, 13.1 μmol, 100% purity) was obtained as white solid in 25.4% yield according to the general procedure of (R)-N-((3-chloro-5-fluoro-4-(((R)-1-((4-fluorophenyl)thio)-4 -(3-methoxyazetidin- 1-yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H -pyran-2-carboxamide. HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water( NH ₄ HCO ₃ )-ACN]; gradient: 6% -46% B over 32 min. ¹ H NMR: (400 MHz, DMSO-d ₆ )δ 7.64 - 7.47 (m, 2H), 7.30 - 7.19 (m, 2H), 7.17 - 7.08 (m, 2H), 6.43 - 6.19 (m, 1H), 4.23 - 3.94 (m, 4H), 3.61 - 3.45 (m, 3H), 3.30 - 3.24 (m, 3H), 3.21 (s, 3H), 3.18 - 3.13 (m, 1H), 3.10 - 3.04 (m, 1H), 2.12 (br d, J = 12.4 Hz, 1H), 1.88 - 1.76 (m, 2H), 1.50 (br d, J = 3.6 Hz, 1H), 1.31 (br s, 3H), 1.17 - 1.09 (m, 1H), 1.05 (s, 3H) EXAMPLE 125. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-1-((4-FLUOROPHENYL)THIO)- 4-(3-METHOXYAZETIDIN-1-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)- 2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0447] Compound 1-11 (50.0 mg, 100 μmol) was obtained as yellow oil in 76.5% yield according to the general procedure of compound 1-8. HPLC: column: Xtimate C18 150*40mm*10um; mobile phase: [ water( HCl) - ACN]; gradient: 2% - 42% B over 36 min ¹ H NMR: (400 MHz, CD ₃ OD)δ 8.02 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 5.2, 8.8 Hz, 2H), 7.03 (dd, J = 8.8 Hz, 2H), 4.62 - 4.43 (m, 2H), 4.33 - 4.12 (m, 3H), 4.04 - 3.90 (m, 1H), 3.54 - 3.43 (m, 3H), 3.37 (br s, 3H), 3.14 (dd, J = 8.0, 14.4 Hz, 1H), 2.16 - 2.04 (m, 2H).

B. Step 2 [0448] (R)-N-((3-chloro-5-cyano-4-(((R)-1-((4-fluorophenyl)thio)-4- (3-methoxyazetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-p yran-2-carboxamide (8 mg, 12.71 μmol , 99.3% purity) was obtained as white solid in 25.4% yield according to the general procedure of (R)-N-((3-chloro-5-fluoro-4-(((R)-1-((4-fluorophenyl)thio)-4 -(3-methoxyazetidin- 1-yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H -pyran-2-carboxamide. HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; gradient: 8% -48% B over 32 min. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ = 7.84 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.26 - 7.08 (m, 4H), 6.07 (br d, J = 1.2 Hz, 1H), 4.38 - 4.21 (m, 1H), 4.18 - 3.93 (m, 3H), 3.63 - 3.46 (m, 3H), 3.32 - 3.29 (m, 3H), 3.21 (s, 3H), 3.17 (br dd, J = 8.0, 14.0 Hz, 2H), 2.13 (br d, J = 12.4 Hz, 1H), 1.97 - 1.81 (m, 2H), 1.50 (br d, J = 4.0 Hz, 1H), 1.30 (br s, 3H), 1.17 - 1.08 (m, 1H), 1.05 (s, 3H) EXAMPLE 126. (R)-N-((3-CYANO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-(4-FLUOROPHENOXY)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE

A. Step 1 [0449] Charge compound J-1 (2.50 g, 15.0 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1). Charge DCM (50.0 mL) to R1. Charge (4-methoxyphenyl)methyl 2,2,2-trichloroethanimidate (4.24 g, 15.0 mmol, 1.00 eq) to R1. Charge [(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1- yl]methanesulfonic acid;hydrate (375 mg, 1.50 mmol, 0.1 eq) to R1. R1 was stirred at 25 °C for 12 hrs. LCMS showed the starting material was consumed completely the desired compound (RT = 1.529 min) was detected. The reaction mixture was filtered and the filtrate washed with Sat. NaHCO ₃ solution (100 mL), the aqueous layer was extracted with DCM (3 *30 mL), the combined organic layers dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 97/3). Compound J-2 (2.76 g, 7.43 mmol, 49.5% yield, 77.2% purity) was obtained as a colorless liquid. LCMS: product: RT = 1.529 min, MS (ESI) m/z = 308.9 [M+23] ⁺ . ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.32 - 7.27 (m, 2H), 6.93 - 6.85 (m, 2H), 4.67 - 4.52 (m, 2H), 4.25 - 4.04 (m, 3H), 3.85 - 3.80 (m, 3H), 3.62 (t, J = 4.8 Hz, 2H), 2.78 - 2.70 (m, 1H), 2.69 - 2.57 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H). B. Step 2 [0450] Charge compound J-2 (2.46 g, 8.58 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1). Charge THF (30.0 mL) to R1. Charge LAH (651 mg, 17.1 mmol, 2.00 eq) to R1 at 0°C. R1 was stirred at 25 °C for 1 hr. TLC (Petroleum ether/Ethyl acetate = 2/1) indicated the starting material was consumed completely and one major new spot with larger polarity was detected. The reaction mixture was quenched by addition of H ₂ O (100 mL) at 0 °C, and then diluted with H ₂ O (100 mL), filtered and the filtrate was extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 85/15 to 75/1=25). Compound J-3 (1.61 g, 5.61 mmol, 65.3% yield, 85.2% purity) was obtained as a colorless liquid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.30 (br d, J = 8.4 Hz, 2H), 6.90 (br d, J = 8.4 Hz, 2H), 4.67 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.82 (s, 3H), 3.80 - 3.73 (m, 2H), 3.68 - 3.57 (m, 2H), 1.99 - 1.84 (m, 2H). [0451] Charge compound J-3 (1.61 g, 6.58 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1). Charge DCM (16.0 mL) to R1. Charge DHP (608 mg, 7.24 mmol, 661 μL, 1.10 eq) to R1. Charge PPTS (165 mg, 658 μmol, 0.100 eq) to R1 at 0 °C. R1 was stirred at 25 °C for 6 hrs. TLC (Petroleum ether/Ethyl acetate = 2/1) indicated that the starting material was consumed completely and one major new spot with lower polarity was detected. The reaction mixture was added TEA to pH = 7 and then diluted with H ₂ O (20 mL) and extracted with DCM (10 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 97/3 to 93/7). Compound J-4 (1.88 g, 4.86 mmol, 73.8% yield, 85.0% purity) was obtained as a colorless liquid. [0452] Charge compound J-4 (1.67 g, 5.08 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1). Charge DMF (17.0 mL) to R1. Charge compound J-4A (683 mg, 6.09 mmol, 1.20 eq) to R1. Charge KI (252 mg, 1.52 mmol, 0.300 eq) to R1. Charge K ₂ CO ₃ (1.40 g, 10.1 mmol, 2.00 eq) to R1. R1 was stirred at 140 °C for 12 hrs. LC-MS (EB11242-36-P1A2) showed the starting material was consumed completely and the desired compound (RT = 1.857 min) was detected. The reaction mixture was quenched by addition H ₂ O (100 mL), then diluted with H ₂ O (100 mL) and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 90/10). Compound J-5 (1.08 g, 1.93 mmol, 37.9% yield, 72.2% purity) was obtained as a yellow oil. LCMS: product: RT = 1.857 min, MS (ESI) m/z = 427.1 [M+23] ⁺ . ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.31 - 7.20 (m, 2H), 7.11 (br t, J = 8.8 Hz, 2H), 7.03 - 6.93 (m, 2H), 6.92 - 6.82 (m, 2H), 4.61 - 4.53 (m, 1H), 4.51 - 4.43 (m, 1H), 4.43 - 4.35 (m, 1H), 4.10 - 3.96 (m, 2H), 3.88 - 3.78 (m, 1H), 3.76 - 3.61 (m, 5H), 3.49 - 3.35 (m, 2H), 1.94 - 1.72 (m, 2H), 1.66 - 1.34 (m, 6H). E. Step 5 [0453] Charge compound J-5 (1.08 g, 2.67 mmol, 1.00 eq) to a 100 mL hydrogenation bottle (R1). Charge methanol (11.0 mL) to R1. Charge Pd(OH) ₂ (375 mg, 267 μmol, 10% purity, 0.100 eq) to R1 under argon atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (50 Psi) at 50 °C for 12 hrs. TLC (Petroleum ether/Ethyl acetate = 5/1) indicated the starting material was consumed completely and one major new spot with larger polarity was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Dichloromethane = 60/40 to 0/100). Compound J-6 (580 mg, 1.91 mmol, 71.4% yield, 93.5% purity) was obtained as a colorless oil F. Step 6 [0454] Charge NaH (59.0 mg, 1.48 mmol, 60% purity, 3.00 eq) in THF (2.00 mL) to a 10 mL round bottom flask (R1) equipped with N ₂ balloon. Charge compound J-6 (140 mg, 492 μmol, 1.00 eq) to R1 at 0°C. Stirred R1 at 25°C for 0.5 hrs. Charge a solution of S3 (118 mg, 541 μmol, 1.10 eq) in THF (1.00 mL) to R1 at 0°C. Stirred R1 at 25°C for 12 hrs. LCMS (Product RT = 1.683 min) indicated the starting material was consumed completely and desired product was formed. The reaction was quenched by addition of water (2 mL). The reaction mixture was transferred to a 120 mL separating funnel (R2). The aqueous phase was extracted with ethyl acetate (50.0 mL). The combined organic layer was washed with water (20.0 mL) and brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue to give a yellow oil. The yellow oil was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~22% Ethyl acetate/Petroleum ether gradient @ 30 mL/min). Compound 7-1 (138 mg, 260 μmol, 52.9% yield, 91.1% purity) was obtained as a colorless liquid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.92 (s, 1H), 7.87 (br d, J = 10.8 Hz, 1H), 6.95 (br t, J = 8.4 Hz, 2H), 6.71 - 6.62 (m, 2H), 5.27 - 5.18 (m, 1H), 5.07 - 4.98 (m, 2H), 4.61 (br d, J = 12.0 Hz, 1H), 4.31 - 4.09 (m, 3H), 3.93 - 3.76 (m, 1H), 3.72 - 3.64 (m, 1H), 3.58 - 3.47 (m, 1H), 2.31 - 2.11 (m, 2H), 1.90 - 1.68 (m, 3H), 1.60 - 1.46 (m, 4H) G. Step 7 [0455] Charge compound 7-1 (138 mg, 286 μmol, 1.00 eq) and Acid 9 (61.8 mg, 429 μmol, 1.50 eq) in ACN (1.00 mL) to a 8 mL round bottom flask (R1) at 25°C under N ₂ atmosphere. Charge EDCI (84.9 mg, 443 μmol, 1.55 eq) to R1 at 25°C. Charge DMAP (54.1 mg, 443 μmol, 1.55 eq) to R1 at 25°C. Stir R1 at 25°C for 12 hrs. LCMS (Product RT = 1.831 min) indicated reactant was consumed completely and desired product was formed. The mixture was quenched by addition of water (3 mL). The mixture was transferred to a 120 mL separate separating funnel (R2). The aqueous phase was extracted with dichloromethane (50.0 mL). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~5% DCM/MeOH gradient @ 45 mL/min). Compound 8-1 (185 mg, 242 μmol, 84.8% yield, 79.8% purity) was obtained as a yellow oil. H. Step 8 [0456] Charge compound 8-1 (180 mg, 295 μmol, 1.00 eq) in MeOH (1.00 mL) to a 8 mL flask (R1) under N ₂ atmosphere. Charge TsOH (50.9 mg, 295 μmol, 1.00 eq) to R1 at 25°C. Stir R1 at 25°C for 8 hrs. LCMS (Product RT = 1.677 min) indicated the starting material was consumed and desired product was formed. The reaction mixture was added pyridine to adjust pH = 7. The mixture was concentrated under reduced pressure to give crude product. The crude product was used for next step directly without purification. Compound 9-1 (155 mg, crude) was obtained as a yellow oil. LCMS: product: RT = 1.677 min, MS (ESI) m/z =547.2 [M+Na] ⁺ . I. Step 9 [0457] Charge compound 9-1 (155 mg, 295 μmol, 1.00 eq) in THF (1.00 mL) to 8 mL flask (R1) at 25°C. Charge Pyridine (46.7 mg, 591 μmol, 47.7 μL, 2.00 eq) and methyl sulfonyl methane sulfonate (77.2 mg, 443 μmol, 1.50 eq) to R1 at 0°C. Stir R1 at 25°C for 4 hrs. LCMS (Product RT = 1.748 min) indicated the starting material was consumed and desired product was formed. The mixture was transferred to a 120 mL separate separating funnel (R2). The reaction mixture was extracted with ethyl acetate (20.0 mL). The mixture was added to sat. NaHCO ₃ . The organic layer was washed with water (5.00 mL) and brine (5.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was used for next step without purification. Compound 10-1 (138 mg, 175 μmol, 59.2% yield, 76.5% purity) was obtained as a yellow oil. LCMS: product: RT = 1.746 min, MS (ESI) m/z =625.1 [M+Na] ⁺ . J. Step 10

[0458] Charge compound 10-1 (69.0 mg, 114 μmol, 1.00 eq) in THF (1.00 mL) to a 8 mL flask (R1) at 25°C under N ₂ atmosphere. Charge TEA (185 mg, 1.83 mmol, 254 μL, 16.0 eq) and 3- fluoroazetidine (127 mg, 1.14 mmol, 10.0 eq, HCl) to R1 at 25°C. Stir R1 at 40°C for 48 hrs. LCMS (Product RT = 4.112 min) indicated the starting material was consumed complete and desired product was formed. The reaction mixture was added MeOH (6.00 mL) and used for purification directly. The crude product was purified by reversed-phase HPLC (column: Welch Xtimate C18150*25mm*5um; mobile phase: [water (NH ₃ H ₂ O)-ACN]; gradient: 10%-50% B over 20 min). (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4- fluorophenoxy)butan-2-yl)oxy)phenyl)sulfonyl)-2-methyltetrah ydro-2H-pyran-2-carboxamide (12.0 mg, 19.8 μmol, 17.3% yield, 96.1% purity) was obtained as a white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.95 - 7.87 (m, 1H), 7.87 - 7.81 (m, 1H), 7.10 - 7.02 (m, 2H), 6.75 - 6.68 (m, 2H), 5.45 - 5.23 (m, 1H), 4.88 (br d, J = 6.0 Hz, 1H), 4.33 - 4.18 (m, 3H), 4.14 - 3.94 (m, 3H), 3.51 (br t, J = 10.4 Hz, 4H), 2.11 (br d, J = 12.8 Hz, 1H), 2.06 - 1.96 (m, 2H), 1.53 - 1.44 (m, 1H), 1.35 - 1.23 (m, 3H), 1.16 - 1.07 (m, 1H), 1.05 (s, 3H) EXAMPLE 127. (R)-N-((3-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-(4- FLUOROPHENOXY)BUTAN-2-YL)OXY)-5-FLUOROPHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0459] (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy )butan-2-yl)oxy)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide (25.0 mg, 97.5% purity) was obtained as colorless oil in 38.5% yield according to the general procedure of compound (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4-fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 9.65 - 9.12 (m, 1H), 7.93 - 7.85 (m, 1H), 7.84 - 7.79 (m, 1H), 7.13 - 7.03 (m, 2H), 6.78 - 6.67 (m, 2H), 4.90 - 4.81 (m, 1H), 4.29 - 4.21 (m, 1H), 4.18 - 4.09 (m, 1H), 3.64 - 3.53 (m, 1H), 3.51 - 3.34 (m, 3H), 2.82 (s, 6H), 2.26 - 2.12 (m, 3H), 1.49 (br d, J = 3.6 Hz, 1H), 1.36 - 1.24 (m, 3H), 1.15 - 1.06 (m, 1H), 1.04 (s, 3H) EXAMPLE 128. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-(4-FLUOROPHENOXY)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CHLORO-5- CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-(4-FLUOROPHENOXY)BUTAN-2- YL)OXY)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0460] Compound 7-2 (170 mg) was obtained as light yellow oil in 69.2% yield according to the general procedure of compound 7-1. [0461] Compound 8-2 (140 mg, 88.5% purity) was obtained as light yellow oil in 58.2% yield according to the general procedure of compound 8-1. C. Step 3 [0462] Compound 9-2 (100 mg, 83.3% purity) was obtained as light yellow oil in 68.8% yield according to the general procedure of compound 9-1. D. Step 4 [0463] Compound 10-2 (110 mg) was obtained as light yellow oil in 96.1% yield according to the general procedure of compound 10-1.

E. Step 5 [0464] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4-fluorophenoxy)butan- 2-yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (18.0 mg, 97.8% purity) was obtained as white solid in 30.3% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.29 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 6.94 (t, J = 8.8 Hz, 2H), 6.63 (dd, J = 4.0, 8.8 Hz, 2H), 5.45 - 5.22 (m, 1H), 5.20 - 5.10 (m, 1H), 4.38 - 4.14 (m, 4H), 4.13 - 3.96 (m, 2H), 3.74 - 3.61 (m, 2H), 3.47 (br d, J = 8.4 Hz, 2H), 2.26 - 2.10 (m, 3H), 1.66 - 1.56 (m, 1H), 1.54 - 1.25 (m, 5H), 1.20 (s, 3H) [0465] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(dimethylamino)-1-(4-fluo rophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide (13.0 mg, 99.0% purity) was obtained as white solid in 28.1% yield according to the general procedure of (R)-N-((3- cyano-4-(((R)-4-(dimethylamino)-1-(4-fluorophenoxy)butan-2-y l)oxy)-5-fluorophenyl)sulfonyl)- 2-methyltetrahydro-2H-pyran-2-carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.34 (br s, 1H), 8.26 - 8.07 (m, 2H), 6.95 (br d, J = 8.8 Hz, 2H), 6.69 - 6.59 (m, 2H), 5.16 (br d, J = 1.6 Hz, 1H), 4.33 - 4.14 (m, 2H), 3.68 (br d, J = 5.6 Hz, 4H), 2.98 (s, 6H), 2.51 - 2.32 (m, 2H), 2.19 (br d, J = 12.0 Hz, 1H), 1.64 - 1.56 (m, 1H), 1.53 - 1.24 (m, 5H), 1.20 (s, 3H) EXAMPLE 129.(R)-N-((3,5-DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1 -(4- FLUOROPHENOXY)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3,5- DICHLORO-4-(((R)-4-(DIMETHYLAMINO)-1-(4-FLUOROPHENOXY)BUTAN- 2- YL)OXY)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0466] Compound 7-3 (180 mg, 81.8% purity) was obtained as light yellow oil in 58.8% yield according to the general procedure of compound 7-1. [0467] Compound 8-3 (155 mg, 82.0% purity) was obtained as light yellow oil in 56.6% yield according to the general procedure of compound 8-1. C. Step 3 [0468] Compound 9-3 (126 mg, 77.0% purity) was obtained as light yellow oil in 72.2% yield according to the general procedure of compound 9-1. D. Step 4 [0469] Compound 10-3 (140 mg) was obtained as light yellow oil in 97.3% yield according to the general procedure of compound 10-1.

E. Step 5 [0470] (R)-N-((3,5-dichloro-4-(((R)-4-(dimethylamino)-1-(4-fluoroph enoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide(24.0 mg, 99.3% purity) was obtained as white solid in 43.2% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.89 (s, 2H), 6.95 (dd, J = 8.8 Hz, 2H), 6.66 (dd, J = 4.4, 9.2 Hz, 2H), 5.06 - 4.97 (m, 1H), 4.27 - 4.08 (m, 2H), 3.74 - 3.45 (m, 4H), 2.95 (s, 6H), 2.38 (br dd, J = 5.6, 10.0 Hz, 2H), 2.20 (br d, J = 12.8 Hz, 1H), 1.66 - 1.52 (m, 1H), 1.52 - 1.26 (m, 4H), 1.21 (s, 3H) [0471] (R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide (21.0 mg, 98.0% purity) was obtained as white solid in 26.2% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.91 (s, 2H), 6.94 (dd, J = 8.8 Hz, 2H), 6.68 - 6.58 (m, 2H), 5.42 - 5.15 (m, 1H), 5.04 - 4.97 (m, 1H), 4.30 - 4.09 (m, 4H), 4.03 - 3.87 (m, 2H), 3.76 - 3.59 (m, 2H), 3.49 - 3.33 (m, 2H), 2.22 - 2.07 (m, 3H), 1.66 - 1.56 (m, 1H), 1.54 - 1.27 (m, 5H), 1.22 (s, 3H) EXAMPLE 130. (R)-N-((3-CHLORO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1- YL)-1-(4-FLUOROPHENOXY)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CHLORO-4- (((R)-4-(DIMETHYLAMINO)-1-(4-FLUOROPHENOXY)BUTAN-2-YL)OXY)-5 - FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0472] Compound 7-4 (118 mg, 92.4% purity) was obtained as light yellow oil in 68.2% yield according to the general procedure of compound 7-1. [0473] Compound 8-4 (119 mg, 87.9% purity) was obtained as light yellow oil in 80.2% yield according to the general procedure of compound 8-1. C. Step 3 [0474] Compound 9-4 (92.0 mg, 86.9% purity) was obtained as light yellow oil in 89.4% yield according to the general procedure of compound 9-4. D. Step 4 [0475] Compound 10-4 (106 mg, 82.2% purity) was obtained as light yellow oil according to the general procedure of compound 10-1.

E. Step 5 [0476] (R)-N-((3-chloro-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)- 1-(4-fluorophenoxy)butan- 2-yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (10.0 mg, 85.8% purity) was obtained as white solid in 13.8% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.72 - 7.47 (m, 2H), 7.06 (br s, 2H), 6.74 (br s, 2H), 5.50 - 5.16 (m, 1H), 4.71 (br d, J = 1.4 Hz, 1H), 4.31 - 3.85 (m, 7H), 3.53 (br s, 3H), 2.14 - 1.95 (m, 3H), 1.56 - 1.45 (m, 1H), 1.31 (br s, 3H), 1.17 - 1.01 (m, 4H). [0477] (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-(4-fluorophenox y)butan-2-yl)oxy)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide (10.0 mg, 93.4% purity) was obtained as white solid in 24.2% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.66 - 7.43 (m, 2H), 7.07 (br t, J = 8.8 Hz, 2H), 6.82 - 6.65 (m, 2H), 4.67 (br d, J = 4.0 Hz, 1H), 4.23 - 4.14 (m, 1H), 4.13 - 4.05 (m, 1H), 3.64 - 3.45 (m, 4H), 2.80 (s, 6H), 2.27 - 2.09 (m, 3H), 1.47 (br s, 1H), 1.30 (br d, J = 7.6 Hz, 3H), 1.11 (br dd, J = 3.4, 11.8 Hz, 1H), 1.04 (s, 3H). EXAMPLE 131.(R)-N-((3-CYANO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-Y L)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CYANO-4- (((R)-4-(DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)O XY)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0478] Compound K-4 (373 mg, 748 μmol, 74.9% yield) was obtained as light yellow oil according to the general procedure of compound 7-1. LCMS: product: RT = 1.575 min, MS (ESI) m/z =520.9 [M+23] ⁺ . ¹ H NMR: (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.79 (dd, J = 2.0, 11.2 Hz, 1H), 7.37 - 7.28 (m, 2H), 6.98 (dt, J = 2.4, 8.6 Hz, 2H), 5.03 - 4.91 (m, 3H), 4.42 (br d, J = 1.6 Hz, 1H), 3.91 - 3.41 (m, 4H), 3.31 - 3.22 (m, 2H), 2.30 - 2.12 (m, 2H), 1.83 - 1.57 (m, 4H), 0.94 - 0.68 (m, 2H). B. Step 2 [0479] Compound K-5 (390 mg, 503 μmol, 67.2% yield, 80.6% purity) was obtained as light yellow oil according to the general procedure of compound 7-2. LCMS: product: RT = 1.771 min, MS (ESI) m/z =646.9 [M+23] ⁺ . ¹ H NMR: EB11242-10-P1A2H (400 MHz, CDCl ₃ ) δ 8.43 (d, J = 7.2 Hz, 1H), 8.12 - 7.56 (m, 2H), 7.29 (br d, J = 3.6 Hz, 1H), 7.03 - 6.90 (m, 2H), 6.66 (d, J = 7.2 Hz, 1H), 4.86 (br s, 1H), 4.62 - 4.43 (m, 1H), 4.04 - 3.34 (m, 8H), 3.24 (br t, J = 5.4 Hz, 2H), 3.18 (s, 3H), 2.29 - 2.09 (m, 2H), 1.72 - 1.43 (m, 10H). C. Step 3 [0480] Compound K-6 (325 mg, 601 μmol, 96.3% yield) was obtained as light yellow oil according to the general procedure of compound 7-3. LCMS: product: RT = 1.225 min, MS (ESI) m/z =557.0 [M+17] ⁺ . D. Step 4 [0481] Compound K-6 (140 mg, 226 μmol, 97.8% yield) was obtained as light yellow oil according to the general procedure of compound 7-4. LCMS: product: RT = 2.526 min, MS (ESI) m/z = 641.1[M+23] ⁺ . E. Step 5 [0482] (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)oxy)phenyl)sulfonyl)-2-methylte trahydro-2H-pyran-2-carboxamide (7.80 mg, 12.3 μmol, 10.9% yield, 94.7% purity) was obtained as white solid according to the general procedure of compound (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -(4- fluorophenoxy)butan-2-yl)oxy)phenyl)sulfonyl)-2-methyltetrah ydro-2H-pyran-2-carboxamide. LCMS: product: RT = 2.066 min, MS (ESI) m/z = 598.2 [M+H] ⁺ . ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 7.85 (br t, J = 5.0 Hz, 2H), 7.32 - 7.21 (m, 2H), 7.19 - 7.10 (m, 2H), 5.43 - 5.15 (m, 1H), 4.61 (br d, J = 4.8 Hz, 1H), 4.31 - 4.01 (m, 2H), 3.98 - 3.66 (m, 2H), 3.60 - 3.40 (m, 3H), 3.18 - 3.07 (m, 2H), 2.15 - 2.06 (m, 1H), 2.02 - 1.89 (m, 2H), 1.55 - 1.43 (m, 1H), 1.41 - 1.15 (m, 4H), 1.09 (br d, J = 11.8 Hz, 1H), 1.04 (s, 3H). [0483] (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl )thio)butan-2-yl)oxy)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide(24.7 mg, 97.9% purity) was obtained as white solid in 37.3% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-(4- fluorophenoxy)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide.Purification: HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:6%- 46% B over 32 min; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.83 (br t, J = 5.0 Hz, 2H), 7.30 - 7.20 (m, 2H), 7.19 - 7.10 (m, 2H), 4.56 (br s, 1H), 3.61 - 3.51 (m, 1H), 3.48 - 3.39 (m, 2H), 3.26 - 3.11 (m, 3H), 2.73 (s, 6H), 2.23 - 2.10 (m, 3H), 1.47 (br s, 1H), 1.29 (br d, J = 8.4 Hz, 3H), 1.15 - 1.06 (m, 1H), 1.03 (s, 3H). EXAMPLE 132. (R)-N-((3,5-DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3,5- DICHLORO-4-(((R)-4-(DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)B UTAN-2- YL)OXY)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

A. Step 1 [0484] Compound L-4 (390 mg, 96.9% purity) was obtained as colorless oil in 74.4% yield according to the general procedure of compound K-4. B. Step 2 [0485] Compound L-5 (410 mg, 94.9% purity) was obtained as yellow oil in 84.7% yield according to the general procedure of compound K-5. C. Step 3 [0486] Compound L-6 (256 mg, 90.0% purity) was obtained as yellow oil in 71.7% yield according to the general procedure of compound K-6.

[0487] Compound L-7 (256 mg) was obtained as yellow oil in 87.8% yield according to the general procedure of compound K-7. [0488] (R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide (28.5 mg, 98.9% purity) was obtained as white solid in 22.7% yield according to the general procedure of (R)-N-((3- cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluor ophenyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN];gradient:8%-48% B over 32 min; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.74 (s, 2H), 7.26 - 7.18 (m, 2H), 7.18 - 7.09 (m, 2H), 5.46 - 5.18 (m, 1H), 4.61 - 4.47 (m, 1H), 4.19 (br d, J = 12.0 Hz, 2H), 4.04 - 3.89 (m, 2H), 3.53 - 3.49 (m, 3H), 3.18 (br d, J = 5.6 Hz, 2H), 2.16 - 1.99 (m, 2H), 1.98 - 1.86 (m, 1H), 1.54 - 1.44 (m, 1H), 1.43 - 1.17 (m, 4H), 1.16 - 1.08 (m, 1H), 1.05 (s, 3H).LCMS: product: RT = 2.032 min, MS (ESI) m/z = 623.1 [M+H] ⁺ . [0489] (R)-N-((3,5-dichloro-4-(((R)-4-(dimethylamino)-1-((4-fluorop henyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide (43.7 mg, 98.8% purity) was obtained as white solid in 36.6% yield according to the general procedure of (R)-N-((3- cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4-fluor ophenyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN];gradient:8%-48% B over 32 min; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.71 (s, 2H), 7.28 - 7.08 (m, 4H), 4.50 (br d, J = 4.4 Hz, 1H), 3.55 (br t, J = 10.8 Hz, 1H), 3.43 (br d, J = 11.4 Hz, 2H), 3.26 - 3.12 (m, 3H), 2.76 (s, 6H), 2.33 - 2.22 (m, 1H), 2.20 - 2.09 (m, 2H), 1.47 (br s, 1H), 1.37 - 1.22 (m, 3H), 1.10 (br dd, J = 3.8, 7.8 Hz, 1H), 1.03 (s, 3H). LCMS: product: RT = 1.939 min, MS (ESI) m/z = 593.1 [M+H] ⁺ . EXAMPLE 133. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)OXY)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CHLORO-5- CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-((4-FLUOROPHENYL)THIO)BUTA N-2- YL)OXY)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

[0490] Compound M-4 (240 mg, 80.5% purity) was obtained as yellow oil in 46.6% yield according to the general procedure of compound K-4. [0491] Compound M-5 (350 mg, 77.8% purity) was obtained as yellow oil according to the general procedure of compound K-5. [0492] Compound M-6 (206 mg, 68.3% purity) was obtained as yellow oil in 67.7% yield according to the general procedure of compound K-6. D. Step 4 [0493] Compound M-7 (224 mg) was obtained as yellow oil in 95.3% yield according to the general procedure of compound K-7. E. Step 5 [0494] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)oxy)phenyl)sulfonyl)-2-methylte trahydro-2H-pyran-2-carboxamide (23.0 mg, 95.3% purity) was obtained as white solid in 20.2% yield according to the general procedure of compound (R)-N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)oxy)phenyl)sulfonyl)-2-methylte trahydro-2H-pyran-2- carboxamide. Purification: HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient:8%-48% B over 32 min; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.23 - 7.83 (m, 2H), 7.31 - 7.03 (m, 4H), 5.47 - 5.15 (m, 1H), 4.78 - 4.59 (m, 1H), 4.35 - 4.16 (m, 2H), 4.07 - 3.90 (m, 2H), 3.64 - 3.53 (m, 3H), 3.14 - 3.04 (m, 2H), 2.14 - 1.91 (m, 3H), 1.56 - 1.45 (m, 1H), 1.44 - 1.20 (m, 4H), 1.13 - 0.94 (m, 4H). LCMS: product: RT = 1.958 min, MS (ESI) m/z = 614.1 [M+H] ⁺ . [0495] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(dimethylamino)-1-((4-flu orophenyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide (38.4 mg, 96.8% purity) was obtained as white solid in 36.0% yield according to the general procedure of compound (R)- N-((3-cyano-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)oxy)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carbox amide. Purification: HPLC: column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN];gradient:8%- 48% B over 32 min; ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.08 - 7.91 (m, 2H), 7.26 - 7.11 (m, 4H), 4.70 - 4.60 (m, 1H), 3.66 - 3.44 (m, 3H), 3.29 - 3.22 (m, 3H), 2.77 (s, 6H), 2.34 - 2.11 (m, 3H), 1.48 (br d, J = 3.6 Hz, 1H), 1.28 (br d, J = 11.2 Hz, 3H), 1.09 (br dd, J = 8.8, 12.2 Hz, 1H), 1.03 (s, 3H). LCMS: product: RT = 1.881 min, MS (ESI) m/z = 584.1 [M+H] ⁺ . EXAMPLE 134. (R)-N-((3-CHLORO-4-(((R)-4-(3-(DIFLUOROMETHOXY)AZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE A. Step 1 [0496] Charge compound 1 (50.0 mg, 156 μmol, 1.00 eq) to 8 mL sealed tube (R1) at 25 °C. Charge DMSO (1.00 mL) to R1 at 25 °C. Charge sulfonamide 11 (35.5 mg, 156 μmol, 1.00 eq) to R1 at 25 °C. Charge DIEA (101 mg, 780 μmol, 136μL, 5.00 eq) to R1 at 25 °C. Stir R1 at 90 °C for 36 hrs. LCMS showed that the compound 1 was consumed and the desired mass (R _t = 1.138 min) was observed. Charge H ₂ O (50.0 mL) to 100 mL conical flask (R2). Charge R1 to R2 at 25 °C. The mixture was transferred to a 60.0 mL separating funnel (R3). EtOAc (100 mL) was added to R3, the organic layer was separated, the aqueous phase was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with H ₂ O (10.0 mL) and brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give crude product. The crude product was purified by pre-TLC (Dichloromethane / Methanol = 10 / 1) to give compound 2 (20.0 mg, 37.9 μmol, 24.3% yield) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.74 (ddd, J = 2.0, 5.8 Hz, 2H), 7.67 (ddd, J = 2.0, 6.8, 9.2 Hz, 2H), 7.30 (dd, J = 2.0, 12.8 Hz, 1H), 7.22 (dd, J = 5.2, 8.8 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.50 - 6.02 (m, 1H), 4.62 (br t, J = 6.0 Hz, 1H), 3.93 (br dd, J = 5.2, 7.6 Hz, 1H), 3.54 (q, J = 7.2 Hz, 2H), 3.05 - 2.94 (m, 3H), 2.55 - 2.50 (m, 1H), 1.78 - 1.52 (m, 2H)

B. Step 2 [0497] Charge Acid 9 (10.9 mg, 75.8 μmol, 2.00 eq) to 8 mL sealed tube (R1) at 25 °C. Charge ACN (1.00 mL) to R1 at 25 °C. Charge EDCI (14.5 mg, 75.8 μmol, 2.00 eq) to R1 at 25 °C. Charge DMAP (9.26 mg, 75.8 μmol, 2.00 eq) to R1 at 25 °C. Charge compound 2 (20.0 mg, 37.9 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs. LCMS showed that the compound 2 was consumed and the desired mass (R _t = 1.378 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ ) - ACN]; gradient: 14%-54% B over 32 min) to give (R)-N-((3-chloro-4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl )-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide (3.00 mg, 4.33 μmol, 11.4% yield, 94.4% purity) as a white solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.71 (s, 1H), 7.52 (dd, J = 1.2, 12.8 Hz, 1H), 7.29 (dd, J = 5.2, 8.8 Hz, 2H), 7.03 (dd, J = 8.8 Hz, 2H), 6.68 - 6.19 (m, 1H), 4.05 - 3.84 (m, 3H), 3.80 - 3.54 (m, 3H), 3.46 (br d, J = 1.6 Hz, 2H), 3.13 (d, J = 6.4 Hz, 2H), 2.98 - 2.80 (m, 2H), 2.15 (br dd, J = 4.0, 5.6 Hz, 1H), 1.90 (br dd, J = 2.4, 8.8 Hz, 1H), 1.83 - 1.70 (m, 1H), 1.70 - 1.55 (m, 2H), 1.56 - 1.39 (m, 3H), 1.40 - 1.37 (m, 1H), 1.55 - 1.29 (m, 3H), 1.29 - 1.17 (m, 3H)

EXAMPLE 135. (R)-N-((3-CHLORO-5-FLUORO-4-(((R)-4-(3-FLUOROAZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL )-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0498] Compound 8 (1.00 g, 2.08 mmol) was obtained as yellow oil in 56.7% yield according to the general procedure of compound 2.HPLC: column: Welch Xtimate C18250*50mm*10um; mobile phase: [ water( NH ₄ HCO ₃ ) - ACN]; gradient:15% - 55% B over 25 min. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.66 - 7.57 (m, 1H), 7.42 (dd, J = 2.0, 12.8 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 5.24 - 4.99 (m, 1H), 4.11 - 3.96 (m, 1H), 3.79 - 3.50 (m, 3H), 3.26 - 3.10 (m, 4H), 2.66 (t, J = 7.2 Hz, 2H), 1.94 - 1.69 (m, 2H)

^{ca bo a de} [0499] (R)-N-((3-chloro-5-fluoro-4-(((R)-4-(3-fluoroazetidin-1-yl)- 1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (700 mg, 1.15 mmol) was obtained as yellow solid in 73.7% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl )-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide. HPLC: column: Welch Xtimate C18250*50mm*10um; mobile phase: [ water ( NH ₄ HCO ₃ ) - ACN]; gradient: 10% - 45% B over 20 min. SFC: column: DAICEL CHIRALPAK IC (250mm*50mm, 10um); mobile phase: [CO ₂ -EtOH (0.1% NH ₃ H ₂ O)]; B%:40%, isocratic elution mode. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.73 (s, 1H), 7.54 (dd, J = 2.0, 12.4 Hz, 1H), 7.29 (dd, J = 5.2, 8.8 Hz, 2H), 7.03 (dd, J = 8.8 Hz, 2H), 5.26 - 5.11 (m, 1H), 4.07 - 3.85 (m, 3H), 3.80 - 3.72 (m, 1H), 3.65 - 3.53 (m, 3H), 3.14 (br d, J = 5.2 Hz, 2H), 3.03 - 2.80 (m, 2H), 2.22 - 2.10 (m, 1H), 1.97 - 1.86 (m, 1H), 1.84 - 1.71 (m, 1H), 1.69 - 1.58 (m, 1H), 1.53 - 1.39 (m, 3H), 1.34 - 1.29 (m, 1H), 1.22 (s, 3H)

EXAMPLE 136. (R)-N-((3-CHLORO-4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0500] Compound 10 (1.00 g, 2.08 mmol,) was obtained as yellow oil in 56.7% yield according to the general procedure of compound 2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.66 - 7.56 (m, 1H), 7.42 (dd, J = 2.0, 12.8 Hz, 1H), 7.38 - 7.29 (m, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 4.13 - 3.96 (m, 1H), 3.16 (d, J = 5.6 Hz, 2H), 2.55 - 2.39 (m, 2H), 2.25 (s, 6H), 2.06 - 1.94 (m, 1H), 1.86 - 1.74 (m, 1H)

B. Step 2 [0501] (R)-N-((3-chloro-4-(((R)-4-(dimethylamino)-1-((4-fluoropheny l)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide (0.95 g, 1.64 mmol) was obtained as white solid in 73.9% yield according to the general procedure of (R)-N- ((3-chloro-4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl)-1-(( 4-fluorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide. HPLC: column: Welch Xtimate C18250*50mm*10um; mobile phase: [ water( NH ₄ HCO ₃ ) -ACN]; gradient: 10% - 45% Bover 20 min. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.77 - 7.66 (m, 1H), 7.51 (dd, J = 2.0, 12.4 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.03 (dd, J = 8.8 Hz, 2H), 3.93 - 3.81 (m, 1H), 3.77 - 3.59 (m, 2H), 3.23 - 3.15 (m, 1H), 3.12 (d, J = 6.0 Hz, 2H), 3.09 - 2.98 (m, 1H), 2.26 (br d, J = 12.4 Hz, 1H), 2.14 (dq, J = 5.2, 9.2 Hz, 1H), 2.03 - 1.86 (m, 1H), 1.65 - 1.56 (m, 1H), 1.54 - 1.35 (m, 3H), 1.33 - 1.24 (m, 1H), 1.21 (s, 3H) EXAMPLE 137. (R)-N-((3,5-DICHLORO-4-(((R)-4-(3- (DIFLUOROMETHOXY)AZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTA N-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

[0502] Compound 12 (10 mg, crude) was obtained as a yellow oil in 29.4% yield according to the general procedure of compound 2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 0.86 - 0.92 (m, 1 H), 1.26 - 1.37 (m, 3 H), 1.69 (ddd, J = 12.00, 8.40, 8.40, 5.60 Hz, 1 H), 1.82 - 1.93 (m, 1 H), 2.58 - 2.64 (m, 1 H), 2.67 - 2.73 (m, 1 H), 3.08 (d, J = 6.40 Hz, 3 H), 3.59 - 3.67 (m, 2 H), 4.14 - 4.22 (m, 1 H), 4.72 (quin, J = 5.60 Hz, 1 H), 6.37 (t, J = 74.48 Hz, 1 H), 6.97 - 7.04 (m, 2 H), 7.24 - 7.30 (m, 2 H), 7.72 (s, 1 H), 7.96 (d, J = 6.40 Hz, 2 H). [0503] (R)-N-((3,5-dichloro-4-(((R)-4-(3-(difluoromethoxy)azetidin- 1-yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (10.0 mg, 97.8% purity) was obtained as a white solid in 87.6% yield according to the general procedure of (R)-N-((3-chloro-4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl )-1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 1.01 (s, 3 H), 1.04 - 1.11 (m, 1 H), 1.19 - 1.33 (m, 4 H), 1.45 (br d, J = 9.60 Hz, 1 H), 1.57 - 1.71 (m, 2 H), 2.11 (br d, J = 12.00 Hz, 1 H), 2.82 - 2.89 (m, 2 H), 3.05 (qd, J = 13.60, 6.40 Hz, 2 H), 3.37 - 3.52 (m, 5 H), 3.92 - 3.96 (m, 1 H), 4.60 (t, J = 5.60 Hz, 1 H), 6.40 - 6.79 (m, 1 H), 7.06 - 7.16 (m, 2 H), 7.19 - 7.28 (m, 2 H), 7.54 (s, 2 H). LCMS: product: RT = 1.986 min, (ESI) m/z 672.4 (M+H ⁺ ). EXAMPLE 138. (R)-N-((3-CHLORO-5-CYANO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYL-1,3-DIOXANE-2-CARBOXAMIDE [0504] (R)-N-((3-chloro-5-cyano-4-((4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan- 2-yl)amino)phenyl)sulfonyl)-2-methyl-1,3-dioxane-2-carboxami de (17.0 mg, 96.6% purity) was obtained as a white solid in 64.9% yield according to the general procedure of (R)-N-((3-chloro- 4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl)-1-((4-fluorophe nyl)thio)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide.1H NMR (400 MHz, CD ₃ OD) δ 8.04 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.01 (t, J = 8.8 Hz, 2H), 5.38 - 5.23 (m, 1H), 4.39 - 4.24 (m, 4H), 4.12 - 4.01 (m, 2H), 3.92 - 3.84 (m, 2H), 3.81 - 3.74 (m, 2H), 3.07 (dd, J = 7.6, 14.2 Hz, 1H), 2.04 - 1.89 (m, 3H), 1.31 - 1.25 (m, 6H) EXAMPLE 139. (R)-N-((3,5-DICHLORO-4-((4-(3-FLUOROAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2-METHYL - 1,3-DIOXANE-2-CARBOXAMIDE [0505] (R)-N-((3,5-dichloro-4-((4-(3-fluoroazetidin-1-yl)-1-((4-flu orophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyl-1,3-dioxane-2-carboxamide (22.8 mg, 99.1% purity) was obtained as a white solid in 89.7% yield according to the general procedure of (R)-N-((3-chloro- 4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl)-1-((4-fluorophe nyl)thio)butan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: (400 MHz, DMSO-d ₆ )δ 1.02 - 1.19 (m, 4 H), 1.56 - 1.82 (m, 3 H), 2.91 - 3.16 (m, 4 H), 3.39 - 3.65 (m, 4 H), 3.70 - 3.86 (m, 2 H), 3.90 - 4.07 (m, 1 H), 4.92 - 5.22 (m, 2 H), 7.03 - 7.29 (m, 7 H), 7.57 (s, 2 H). LCMS: product: RT = 1.704 min, (ESI) m/z = 624.1 (M+H ⁺ ). EXAMPLE 140.2-METHYL-1,3-DIOXANE-2-CARBOXYLIC ACID (ACID 18) [0506] Compound 1 (10.0 g, 114 mmol, 8.00 mL, 1.00 eq), compound 2 (13.0 g, 170 mmol, 12.3 mL, 1.50 eq) and Amberlite IR-120 (plus) resin (1.00 g, 11.4 mmol) was added to toluene (100 mL), the mixture were heated at reflux in a Dean-Stark apparatus for 16 hrs. After cooling to room temperature, the reaction mixture was filtered, the filtrate was concentrated and the resulting residue dissolved in 2 M aqueous NaOH (20.0 mL). The reaction mixture was then heated at reflux for 2 h, cooled to room temperature, acidified to pH = 1 with ice cold 6 M aqueous H ₃ PO ₄ (25 mL) and rapidly extracted with EtOAc (4 x 10.0 mL). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated and the resulting residue purified by triturated in solvent isopropyl ether (20.0 mL) at 25 °C to give Acid 18 (375 mg, 2.57 mmol, 2.26% yield) as a yellow solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ ppm 1.32 - 1.47 (m, 4 H) 1.91 - 2.12 (m, 1 H) 3.81 - 3.98 (m, 4 H). EXAMPLE 141. (R)-N-((4-(((R)-4-(BIS(METHYL-D3)AMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3-CYANO-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0507] Charge compound 5C (100 mg, 397 μmol, 1.00 eq, HCl) to a 8 mL sealed tube (R1) at 25 °C. Charge DMSO (2.00 mL) to R1 at 25 °C. Charge compound Sulfomamide 3 (86.7 mg, 397 μmol, 1.00 eq) to R1 at 25°C. Charge DIEA (257 mg, 1.99 mmol, 346 μL, 5.00 eq) to R1 at 25°C. Stir R1 at 90 °C for 12 hrs. LCMS (EB10876-25-IPCL5) showed that compound 5C was consumed and the desired mass (Rt = 0.961 min) was observed. Charge H2O (5.00 ml) to 250 mL conical flask (R2). Charge R1 to R2 at 25 °C. The mixture was transferred to a 60 mL separating funnel (R3). EtOAc (10.0 mL) was added to R3, the organic layer was separated and the aqueous phase was extracted with EtOAc (10.0 mL x5). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude product. The crude product (TLC: petroleum ether/EtOAc = 1: 1, R _f = 0.19) was purified by column chromatography on silica gel (Methanol: Dichloromethane = 0-10%) to give compound 2 (104 mg, 251 μmol, 63.3% yield) as a colorless oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.58 (dd, J = 1.6, 12.0 Hz, 1H), 7.32 (dd, J = 5.2, 8.4 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 4.59 (br s, 1H), 3.70 (t, J = 6.8 Hz, 2H), 3.34 (br d, J = 6.0 Hz, 1H), 3.19 (br d, J = 6.8 Hz, 1H), 2.12 - 1.80 (m, 2H) B. Step 2 [0508] Charge CH ₂ Cl ₂ (3.00 mL) and THF (1.00 mL) to a 100 mL round bottom flask (R1) equipped with a N ₂ balloon. Charge compound 2 (104 mg, 252 μmol, 1.00 eq) to R1 at 25 °C. Charge imidazole (25.7 mg, 377 μmol, 1.50 eq) to R1 at 25 °C. Charge TBSCl (56.9 mg, 377 μmol, 46.4 μL, 1.50 eq) to R1 at 25 °C. Stir R1 at 25 °C for 16 hr. TLC (Dichloromethane: Methanol = 20:1, Rf = 0.44) showed that compound 2 was consumed and a new major spot was observed. Charge H ₂ O (5.00 ml) to 50 mL conical flask (R2). Charge R1 to R2 at 25 °C. The mixture was transferred to a 60 mL separating funnel (R3). CH ₂ Cl ₂ (10.0 mL) was added to R3, the organic layer was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (10.0 mL x2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give crude product. The crude product was purified by pre-TLC (Dichloromethane: Methanol = 20:1, R _f = 0.44) to give a colorless oil. The colorless oil (TLC: Dichloromethane: Methanol = 20:1, R _f = 0.44) was purified by column chromatography on silica gel (EtOAc: petroleum ether = 0-12%) to give compound 2-1 (94.0 mg, 160 μmol, 63.7% yield, 89.9% purity) as a colorless oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.69 (dd, J = 1.2, 2.0 Hz, 1H), 7.57 (dd, J = 2.0, 12.0 Hz, 1H), 7.34 (dd, J = 5.6, 8.8 Hz, 2H), 6.98 (dd, J = 8.8 Hz, 2H), 4.69 - 4.61 (m, 1H), 3.77 (dd, J = 4.8, 7.2 Hz, 2H), 3.29 (d, J = 5.6 Hz, 1H), 3.24 - 3.16 (m, 1H), 2.08 - 1.99 (m, 1H), 1.92 - 1.83 (m, 1H), 0.86 (s, 9H), 0.01 (d, J = 13.2 Hz, 6H) C. Step 3 [0509] Charge Acid 9 (51.4 mg, 356 μmol, 2.00 eq) to a 40 mL sealed tube (R1) at 25 °C. Charge ACN (3.00 mL) to R1 at 25 °C. Charge EDCI (68.3 mg, 356 μmol, 2.00 eq) to R1 at 25 °C. Charge DMAP (43.5 mg, 356 μmol, 2.00 eq) to R1 at 25 °C. Charge compound 2-1 (94.0 mg, 178 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 25 °C for 16 hrs. LCMS showed that compound 2-1 was consumed and the desired mass (R _t = 0.795 min) was observed. Charge H ₂ O (10.0 ml) to 50 ml conical flask (R2). Charge R1 to R2 at 25 °C. The mixture was transferred to a 60 mL separating funnel (R3). EtOAc (10.0 mL) was added to R3, the organic layer was separated and the aqueous phase was extracted with EtOAc (10.0 mL x2). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give crude product. The crude product (TLC: Dichloromethane: Methanol = 20: 1, R _f = 0.33) was purified by column chromatography on silica gel (Methanol: Dichloromethane = 0-10%) to give compound 2-2 (100 mg, 143 μmol, 80.3% yield, 93.5% purity) as a colorless oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.85 (s, 1H), 7.69 (dd, J = 2.0, 12.0 Hz, 1H), 7.31 (dd, J = 5.2, 8.8 Hz, 2H), 6.98 (dd, J = 8.8 Hz, 2H), 4.74 - 4.63 (m, 1H), 3.87 - 3.71 (m, 3H), 3.46 - 3.37 (m, 1H), 3.24 - 3.15 (m, 1H), 2.09 - 1.97 (m, 2H), 1.89 (br dd, J = 4.8, 8.8 Hz, 2H), 1.70 - 1.24 (m, 8H), 1.22 (s, 3H), 0.84 (s, 9H), -0.01 (d, J = 14.4 Hz, 6H) D. Step 4 [0510] Charge THF (2.00 mL) to an 8 mL sealed tube (R1). Charge compound 2-2 to R1 at 25 °C. Charge TBAF (1.00 M, 306 μL, 2.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 2 hr. TLC (Dichloromethane: Methanol = 20: 1, R _f = 0.31) showed compound 2-2 was consumed and a new major spot was observed. The mixture was concentrated to give crude product. The crude product (TLC: Dichloromethane: Methanol = 20: 1, R _f = 0.31) was purified by column chromatography on silica gel (Methanol: Dichloromethane = 0-4%) to give compound 2-3 (74.0 mg, 137 μmol, 89.7% yield) as a colorless oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.83 (s, 1H), 7.69 (dd, J = 1.6, 12.0 Hz, 1H), 7.29 (dd, J = 5.2, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 4.64 - 4.58 (m, 1H), 3.74 (br s, 3H), 3.56 - 3.42 (m, 1H), 3.16 (dd, J = 7.6, 14.0 Hz, 1H), 2.12 - 1.90 (m, 4H), 1.71 - 1.43 (m, 6H), 1.22 (s, 3H) E. Step 5 [0511] Charge THF (1.00 mL) to a 2 mL sealed tube. Charge compound 2-3 (20.0 mg, 37.1 μmol, 1.00 eq) to R1 at 25 °C. Charge Pyridine (5.86 mg, 74.1 μmol, 5.98 μL, 2.00 eq) to R1 at 0 °C. Charge Ms ₂ O (9.68 mg, 55.6 μmol, 1.50 eq) to R1 at 0 °C. Stir R1 at 25 °C for 16 hrs. LCMS showed that compound 2-3 was consumed and the desired mass (R _t = 0.629 min) was observed. H ₂ O (2.00 mL) was added slowly to R1. The mixture in R1 was transferred to a 60 mL separating funnel (R2). EtOAc (2.00 mL) was added to R2, the organic layer was separated and the aqueous phase was extracted with EtOAc (2.00 mL x2). The combined organic layers were washed with NaHCO ₃ (1.00 mL x 2) and brine (2.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give compound 2-4 (34.0 mg, crude) as a light yellow oil. F. Step 6 [0512] Charge THF (1.00 mL) to a 8 mL sealed tube (R1) equipped with N ₂ . Charge compound 2-4 (34.0 mg, 55.0 μmol, 1.00 eq) to R1 at 25 °C. Charge 1,1,1-trideuterio-N- (trideuteriomethyl)methanamine;hydrochloride (48.2 mg, 550 μmol, 10.0 eq) to R1 at 25 °C. Charge TEA (89.1 mg, 881 μmol, 123 μL, 16.0 eq) to R1 at 25 °C. Stir R1 at 40 °C for 16 hr. LCMS showed that Compound 2-4 was consumed and the desired mass (R _t = 1.409 min) was observed. The mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 6%-46% B over 32 min) to give (R)-N-((4- (((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide (5.00 mg, 8.61 μmol, 15.6% yield, 98.6% purity) as a white solid. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.59 - 7.49 (m, 2H), 7.28 - 7.19 (m, 2H), 7.17 - 7.08 (m, 2H), 6.25 (br dd, J = 2.8, 5.6 Hz, 1H), 4.14 (br d, J = 2.4 Hz, 1H), 3.65 - 3.52 (m, 1H), 3.45 (br s, 1H), 3.27 (br d, J = 4.8 Hz, 1H), 3.22 - 3.12 (m, 2H), 3.02 - 2.81 (m, 2H), 2.14 (br d, J = 12.4 Hz, 1H), 1.98 (br d, J = 3.6 Hz, 2H), 1.47 (br d, J = 2.4 Hz, 1H), 1.41 - 0.92 (m, 8H). EXAMPLE 142. (R)-N-((3-CYANO-4-(((R)-4-(3-(DIFLUOROMETHYL)AZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0513] (R)-N-((3-cyano-4-(((R)-4-(3-(difluoromethyl)azetidin-1-yl)- 1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide (8.00 mg, 99.6% purity) was obtained as white solid in 28.1% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)s ulfonyl)-2-methyltetrahydro-2H- pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.65 - 7.43 (m, 2H), 7.25 (dd, J = 4.4, 12.6 Hz, 2H), 7.15 - 7.03 (m, 2H), 6.17 (dt, J = 5.2, 56.8 Hz, 1H), 4.23 (br d, J = 5.2 Hz, 1H), 3.61 - 3.51 (m, 2H), 3.36 (br s, 2H), 3.28 - 3.10 (m, 4H), 2.95 - 2.83 (m, 1H), 2.70 - 2.53 (m, 2H), 2.11 (br d, J = 11.6 Hz, 1H), 1.69 (br s, 2H), 1.47 (br d, J = 3.2 Hz, 1H), 1.28 (br s, 3H), 1.20 - 1.07 (m, 1H), 1.03 (s, 3H).

EXAMPLE 143. (R)-N-((3-CYANO-4-(((R)-4-(3-CYCLOPROPOXYAZETIDIN-1-YL)-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0514] (R)-N-((3-cyano-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-(( 4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide(7.20 mg, 96.7% purity) was obtained as white solid in 29.5% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)t hio)butan-2- yl)amino)-3-cyano-5-fluorophenyl)sulfonyl)-2-methyltetrahydr o-2H-pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.59 - 7.47 (m, 2H), 7.24 (dd, J = 5.6, 8.8 Hz, 2H), 7.16 - 7.05 (m, 2H), 4.30 - 4.10 (m, 2H), 3.99 - 3.69 (m, 2H), 3.63 - 3.49 (m, 2H), 3.25 (br dd, J = 4.8, 13.2 Hz, 3H), 3.18 - 3.10 (m, 1H), 2.97 - 2.69 (m, 2H), 2.12 (br d, J = 12.4 Hz, 1H), 1.76 (br d, J = 5.6 Hz, 2H), 1.47 (br d, J = 4.0 Hz, 1H), 1.37 - 0.98 (m, 8H), 0.50 - 0.38 (m, 4H). EXAMPLE 144. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3- CYCLOPROPOXYAZETIDIN-1-YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

A. Step 1 [0515] Compound 3 (99.0 mg) was obtained as light yellow solid in 57.9% yield according to the general procedure of compound 2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.96 - 7.77 (m, 2H), 7.37 - 7.20 (m, 2H), 6.98 (dd, J = 8.8 Hz, 2H), 4.82 - 4.70 (m, 1H), 3.72 (dd, J = 5.6, 7.2 Hz, 2H), 3.39 (dd, J = 5.2, 14.0 Hz, 1H), 3.22 (dd, J = 6.8, 14.0 Hz, 1H), 2.13 - 1.88 (m, 2H) B. Step 2 [0516] Compound 3-1 (75.0 mg) was obtained as colorless oil in 59.8% yield according to the general procedure of compound 2-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.96 - 7.78 (m, 2H), 7.32 (dd, J = 5.2, 8.8 Hz, 2H), 6.98 (dd, J = 8.8 Hz, 2H), 4.83 - 4.75 (m, 1H), 3.80 - 3.75 (m, 2H), 3.43 - 3.36 (m, 1H), 3.29 - 3.22 (m, 1H), 2.13 - 2.01 (m, 1H), 1.98 - 1.90 (m, 1H), 0.86 (s, 9H), 0.00 (d, J = 16.0 Hz, 6H) C. Step 3 [0517] Compound 3-2 (70.0 mg, 90.1% purity) was obtained as colorless oil in 68.2% yield according to the general procedure of compound 2-2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.10 - 7.94 (m, 2H), 7.29 (dd, J = 5.6, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 3.82 - 3.76 (m, 2H), 3.50 - 3.37 (m, 2H), 3.27 - 3.20 (m, 1H), 2.06 (ddd, J = 2.4, 5.2, 13.6 Hz, 2H), 1.70 - 1.42 (m, 4H), 1.39 - 1.27 (m, 4H), 1.22 (s, 3H), 0.85 (s, 9H), -0.01 (d, J = 16.4 Hz, 6H) D. Step 4 [0518] Compound 3-3 (30.0 mg, 94.3% purity) was obtained as colorless oil in 48.7% yield according to the general procedure of compound 2-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.06 - 7.94 (m, 2H), 7.26 (dd, J = 5.2, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 4.58 (br s, 2H), 3.85 - 3.76 (m, 1H), 3.72 (br d, J = 5.6 Hz, 2H), 3.41 (dd, J = 4.8, 14.0 Hz, 1H), 3.20 (dd, J = 7.6, 14.0 Hz, 1H), 2.11 - 1.92 (m, 3H), 1.73 - 1.41 (m, 5H), 1.37 - 1.29 (m, 3H), 1.22 (s, 3H) E. Step 5 [0519] Compound 3-4 (18.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4. F. Step 6 [0520] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-cyclopropoxyazetidin-1 -yl)-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (10.0 mg, 98.3% purity) was obtained as white solid in 53.2% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)s ulfonyl)-2-methyltetrahydro-2H- pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.78 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 5.6, 8.8 Hz, 2H), 7.15 - 7.05 (m, 2H), 4.37 (br t, J = 6.4 Hz, 1H), 4.08 (br t, J = 6.0 Hz, 1H), 3.60 - 3.51 (m, 2H), 3.45 - 3.39 (m, 1H), 3.29 (dd, J = 5.6, 13.6 Hz, 1H), 3.23 - 3.12 (m, 2H), 2.79 (br d, J = 7.6 Hz, 2H), 2.62 - 2.54 (m, 1H), 2.43 (br d, J = 10.8 Hz, 1H), 2.12 (br d, J = 12.0 Hz, 1H), 1.71 (br d, J = 6.8 Hz, 2H), 1.46 (br s, 1H), 1.39 - 1.11 (m, 4H), 1.12 - 0.98 (m, 4H), 0.47 - 0.33 (m, 4H) EXAMPLE 145. (R)-N-((3,5-DICHLORO-4-(((R)-4-(3-CYCLOPROPOXYAZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL )-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE A. Step 1 [0521] Compound 4 (70.0 mg) was obtained as yellow solid in 40.1% yield according to the general procedure of compound 2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.71 (s, 2H), 7.34 - 7.21 (m, 2H), 7.00 (dd, J = 8.8 Hz, 2H), 4.34 (br dd, J = 5.2, 8.0 Hz, 1H), 3.77 - 3.65 (m, 2H), 3.12 (dd, J = 2.8, 6.0 Hz, 2H), 2.06 (dtd, J = 4.8, 7.2, 14.0 Hz, 1H), 1.86 (tdd, J = 5.6, 8.0, 14.0 Hz, 1H) B. Step 2 [0522] Compound 4-1 (50.0 mg, 90.3% purity) was obtained as colorless oil in 51.2% yield according to the general procedure of compound 2-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.70 (s, 2H), 7.39 - 7.26 (m, 2H), 7.06 - 6.96 (m, 2H), 4.43 - 4.31 (m, 1H), 3.78 - 3.70 (m, 2H), 3.22 - 3.04 (m, 2H), 2.12 (dt, J = 5.2, 7.2 Hz, 1H), 1.84 - 1.73 (m, 1H), 0.85 (s, 9H), 0.05 - -0.10 (m, 6H) C. Step 3 [0523] Compound 4-2 (46.0 mg) was obtained as colorless oil in 74.9% yield according to the general procedure of compound 2-2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.82 (s, 2H), 7.31 - 7.24 (m, 2H), 7.04 - 6.97 (m, 2H), 3.85 - 3.75 (m, 2H), 3.14 (d, J = 6.4 Hz, 2H), 2.16 - 1.99 (m, 2H), 1.84 - 1.75 (m, 1H), 1.67 - 1.43 (m, 4H), 1.38 - 1.26 (m, 4H), 1.19 (s, 3H), 0.84 (s, 9H), 0.04 - - 0.10 (m, 6H) D. Step 4 [0524] Compound 4-3 (22.0 mg, 89.3% purity) was obtained as colorless oil in 51.3% yield according to the general procedure of compound 2-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.82 (s, 2H), 7.23 (dd, J = 5.2, 8.8 Hz, 2H), 7.01 (dd, J = 8.8 Hz, 2H), 3.84 - 3.70 (m, 3H), 3.53 - 3.38 (m, 1H), 3.19 - 3.03 (m, 2H), 2.05 (dq, J = 4.0, 6.8 Hz, 2H), 1.93 - 1.86 (m, 1H), 1.62 (br dd, J = 4.0, 8.8 Hz, 2H), 1.53 - 1.43 (m, 2H), 1.38 - 1.31 (m, 2H), 1.19 (s, 3H) E. Step 5 [0525] Compound 4-4 (13.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4. F. Step 6 [0526] (R)-N-((3,5-dichloro-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl) -1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (65.0 mg, 98.3% purity) was obtained as white solid in 47.9% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)s ulfonyl)-2-methyltetrahydro-2H- pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.55 (s, 2H), 7.25 - 7.16 (m, 2H), 7.16 - 7.08 (m, 2H), 4.15 (br d, J = 5.2 Hz, 1H), 3.89 (br d, J = 4.0 Hz, 1H), 3.80 - 3.64 (m, 1H), 3.60 - 3.52 (m, 1H), 3.28 - 3.20 (m, 1H), 3.13 - 2.96 (m, 3H), 2.83 - 2.62 (m, 2H), 2.13 (br d, J = 11.6 Hz, 1H), 1.83 - 1.60 (m, 2H), 1.52 - 1.39 (m, 1H), 1.34 - 1.21 (m, 4H), 1.02 (s, 4H), 0.51 - 0.35 (m, 4H) EXAMPLE 146. (R)-N-((3-CHLORO-4-(((R)-4-(3-CYCLOPROPOXYAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE A. Step 1 [0527] Compound 5 (210 mg) was obtained as colorless oil in 41.7% yield according to the general procedure of compound 2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.59 (dd, J = 0.8, 2.0 Hz, 1H), 7.46 - 7.28 (m, 3H), 6.99 (dd, J = 8.8 Hz, 2H), 4.25 - 4.15 (m, 1H), 3.70 (t, J = 5.6 Hz, 2H), 3.16 (d, J = 6.0 Hz, 2H), 2.01 - 1.96 (m, 1H), 1.91 - 1.79 (m, 1H) B. Step 2 [0528] Compound 5-1 (222 mg, 95.5% purity) was obtained as colorless oil in 59.6% yield according to the general procedure of compound 2-1. ¹ H NMR:(400 MHz, CD ₃ OD) δ 7.66 - 7.51 (m, 1H), 7.45 - 7.26 (m, 3H), 6.99 (dd, J = 8.8 Hz, 2H), 4.36 - 4.12 (m, 1H), 3.84 - 3.69 (m, 2H), 3.23 - 3.05 (m, 2H), 2.14 - 1.97 (m, 1H), 1.78 (dtd, J = 1.6, 4.0, 14.0 Hz, 1H), 0.85 (s, 9H), -0.01 (d, J = 18.8 Hz, 6H) C. Step 3 [0529] Compound 5-2 (248 mg, 84.2% purity) was obtained as colorless oil in 76.1% yield according to the general procedure of compound 2-2. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.71 (s, 1H), 7.52 (dd, J = 1.6, 12.8 Hz, 1H), 7.32 (dd, J = 5.2, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 4.35 - 4.24 (m, 1H), 3.86 - 3.70 (m, 3H), 3.50 - 3.38 (m, 1H), 3.16 (d, J = 6.0 Hz, 2H), 2.10 - 2.02 (m, 2H), 1.84 - 1.72 (m, 1H), 1.69 - 1.22 (m, 8H), 1.21 (s, 3H), 0.83 (s, 9H), 0.08 - -0.15 (m, 6H) D. Step 4 [0530] Compound 5-3 (200 mg, 95.1% purity) was obtained as colorless oil in 92.7% yield according to the general procedure of compound 2-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.76 - 7.68 (m, 1H), 7.53 (dd, J = 2.0, 12.8 Hz, 1H), 7.29 (dd, J = 5.2, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 4.30 - 4.19 (m, 1H), 3.87 - 3.75 (m, 1H), 3.69 (dd, J = 5.6, 6.8 Hz, 2H), 3.47 - 3.36 (m, 1H), 3.25 - 3.08 (m, 2H), 2.09 - 1.93 (m, 2H), 1.92 - 1.78 (m, 1H), 1.71 - 1.22 (m, 6H), 1.20 (s, 3H) E. Step 5 [0531] Compound 5-4 (10.0 mg, crude) was obtained as light yellow oil according to the general procedure of compound 2-4. F. Step 6 [0532] (R)-N-((3-chloro-4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-( (4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide (5.80 mg, 98.2% purity) was obtained as white solid in 55.4% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4- fluorophenyl)thio)butan-2-yl)amino)-3-cyano-5-fluorophenyl)s ulfonyl)-2-methyltetrahydro-2H- pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.42 (s, 1H), 7.34 - 7.20 (m, 3H), 7.13 (dd, J = 8.8 Hz, 2H), 4.07 (t, J = 5.6 Hz, 1H), 3.90 - 3.78 (m, 1H), 3.60 - 3.48 (m, 4H), 3.19 (td, J = 2.8, 5.6 Hz, 1H), 3.10 (br d, J = 6.4 Hz, 2H), 2.72 (br s, 2H), 2.45 - 2.39 (m, 1H), 2.12 (br d, J = 12.0 Hz, 1H), 1.69 - 1.56 (m, 2H), 1.45 (br d, J = 4.4 Hz, 1H), 1.25 (br d, J = 17.6 Hz, 4H), 1.10 - 0.99 (m, 4H), 0.40 (br d, J = 15.6 Hz, 4H) EXAMPLE 147. (R)-N-((3-CHLORO-4-(((R)-4-(3-(DIFLUOROMETHYL)AZETIDIN-1- YL)-1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0533] (R)-N-((3-chloro-4-(((R)-4-(3-(difluoromethyl)azetidin-1-yl) -1-((4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide(9.00 mg, 100% purity) was obtained as white solid in 28.1% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)t hio)butan-2- yl)amino)-3-cyano-5-fluorophenyl)sulfonyl)-2-methyltetrahydr o-2H-pyran-2-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.44 (s, 1H), 7.34 - 7.19 (m, 3H), 7.16 - 7.05 (m, 2H), 6.17 (dt, J = 4.4, 56.8 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.47 (br s, 5H), 3.10 (br d, J = 5.2 Hz, 2H), 2.99 - 2.86 (m, 1H), 2.82 - 2.59 (m, 2H), 2.09 (br d, J = 12.4 Hz, 1H), 1.77 - 1.58 (m, 2H), 1.47 (br d, J = 3.6 Hz, 1H), 1.35 - 1.06 (m, 5H), 1.03 (s, 3H)

EXAMPLE 148. (R)-N-((4-(((R)-4-(BIS(METHYL-D3)AMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3-CHLORO-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0534] (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)t hio)butan-2-yl)amino)-3- chloro-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran- 2-carboxamide(8.13 mg, 97.9% purity) was obtained as white solid in 38.9% yield according to the general procedure of (R)-N- ((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)thio)bu tan-2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.44 (s, 1H), 7.34 - 7.19 (m, 3H), 7.18 - 7.07 (m, 2H), 3.84 - 3.71 (m, 1H), 3.64 - 3.52 (m, 1H), 3.13 (br d, J = 5.6 Hz, 2H), 2.85 - 2.64 (m, 2H), 2.12 (br d, J = 12.4 Hz, 1H), 2.02 - 1.78 (m, 2H), 1.46 (br s, 1H), 1.39 - 0.94 (m, 8H) EXAMPLE 149. (R)-N-((4-(((R)-4-(3-(DIFLUOROMETHOXY)AZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE A. Step 1 [0535] Charge compound 5C (500 mg, 2.32 mmol, 1.00 eq) to a 40 ml microwave tube (R1). Charge NMP (10 mL) to R1 at 25°C. Charge DIEA (1.50 g, 11.6 mmol, 2.02 mL, 5.00 eq) and Sulfomamide 2 (490 mg, 2.32 mmol, 1.00 eq) to R1 at 25°C. Stir R1 at 100°C for 2 hrs in microwave. Stir R1 at 100 °C for 4 hrs in microwave. Stir R1 at 120 °C for 5 hrs in microwave. LCMS (EB11004-18-IPCL5) showed that the compound 5C was consumed and the desired mass (Rt = 1.803 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um;mobile phase: [water(NH ₄ HCO ₃ )-ACN];gradient:16%-56% B over 32 min) to give compound 1 (77 mg, 189.45 μmol, 8.16% yield) (confirmed by HNMR: EB11004-18-P1N1) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.36 - 7.25 (m, 4H), 6.99 (dd, J = 8.4 Hz, 2H), 4.16 - 4.04 (m, 1H), 3.71 - 3.65 (m, 2H), 3.13 (d, J = 6.4 Hz, 2H), 2.22 (s, 1H), 1.99 (ddd, J = 4.4, 6.8, 11.6 Hz, 1H), 1.83 - 1.73 (m, 1H), 1.40 (s, 1H) B. Step 2 [0536] Compound 1-1 (78 mg) was obtained as yellow oil in 76.1% yield according to the general procedure of compound 2-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.39 - 7.24 (m, 4H), 7.03 - 6.95 (m, 2H), 6.92 (s, 1H), 4.21 - 4.12 (m, 1H), 3.81 - 3.69 (m, 2H), 3.19 - 3.02 (m, 2H), 2.08 - 2.01 (m, 1H), 1.83 - 1.69 (m, 1H), 0.86 (s, 9H), 0.00 (d, J = 2.0 Hz, 6H) C. Step 3 [0537] Compound 1-2 (22 mg) was obtained as yellow solid according to the general procedure of compound 2-2. D. Step 4 [0538] Compound 1-3 (62 mg) was obtained as yellow oil in 75.3% yield according to the general procedure of compound 2-3. ¹ H NMR: EB11178-26-P1N1, (400 MHz, CD ₃ OD) δ 7.44 (br dd, J = 10.0 Hz, 2H), 7.30 (dd, J = 5.2, 8.8 Hz, 2H), 6.99 (dd, J = 8.8 Hz, 2H), 6.92 (s, 1H), 4.19 - 4.12 (m, 1H), 3.79 (td, J = 3.2, 12.0 Hz, 1H), 3.68 (dd, J = 5.6, 6.4 Hz, 2H), 3.46 - 3.36 (m, 1H), 3.21 - 3.05 (m, 2H), 2.08 - 2.03 (m, 1H), 2.00 - 1.92 (m, 1H), 1.87 - 1.76 (m, 1H), 1.67 - 1.60 (m, 1H), 1.53 - 1.43 (m, 2H), 1.39 - 1.27 (m, 4H), 1.20 (s, 3H) E. Step 5

[0539] Compound 1-4(10.0 mg) was obtained as yellow oil according to the general procedure of compound 2-4. F. Step 6 [0540] (R)-N-((4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl)-1-((4-f luorophenyl)thio)butan-2- yl)amino)-3,5-difluorophenyl)sulfonyl)-2-methyltetrahydro-2H -pyran-2-carboxamide (2.20 mg, 92.0% purity) was obtained as white solid in 19.4% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)t hio)butan-2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: EB11178-17- P1N2, (400 MHz, CD ₃ OD) δ 7.47 (br dd, J = 9.6 Hz, 2H), 7.31 - 7.18 (m, 2H), 7.01 (dd, J = 8.8 Hz, 2H), 6.50 (dd, J = 73.2 Hz, 1H), 5.00 (br s, 1H), 4.29 (br d, J = 7.2 Hz, 2H), 4.02 - 3.87 (m, 3H), 3.79 (br d, J = 11.2 Hz, 1H), 3.51 - 3.46 (m, 1H), 3.27 - 3.02 (m, 4H), 2.07 - 1.92 (m, 2H), 1.87 - 1.76 (m, 1H), 1.66 - 1.59 (m, 1H), 1.42 - 1.28 (m, 4H), 1.21 (s, 3H)

EXAMPLE 150. (R)-N-((4-(((R)-4-(3-(DIFLUOROMETHYL)AZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0541] (R)-N-((4-(((R)-4-(3-(difluoromethyl)azetidin-1-yl)-1-((4-fl uorophenyl)thio)butan-2- yl)amino)-3,5-difluorophenyl)sulfonyl)-2-methyltetrahydro-2H -pyran-2-carboxamide(3.00 mg) was obtained as white solid in 29.5% yield according to the general procedure of (R)-N-((4- (((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.41 (br dd, J = 9.6 Hz, 2H), 7.28 (dd, J = 4.4, 8.4 Hz, 2H), 7.01 (dd, J = 8.4 Hz, 2H), 6.27 - 5.81 (m, 1H), 3.86 (br dd, J = 3.2, 8.8 Hz, 1H), 3.74 - 3.50 (m, 6H), 3.15 - 3.00 (m, 3H), 2.96 - 2.77 (m, 2H), 2.16 (br d, J = 12.4 Hz, 1H), 1.94 - 1.81 (m, 1H), 1.71 - 1.58 (m, 2H), 1.44 (br s, 3H), 1.36 - 1.26 (m, 2H), 1.20 (s, 3H)

EXAMPLE 151. (R)-N-((4-(((R)-4-(3-CYCLOPROPOXYAZETIDIN-1-YL)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-3,5- DIFLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0542] (R)-N-((4-(((R)-4-(3-cyclopropoxyazetidin-1-yl)-1-((4-fluoro phenyl)thio)butan-2- yl)amino)-3,5-difluorophenyl)sulfonyl)-2-methyltetrahydro-2H -pyran-2-carboxamide (2.50 mg, 94.1% purity) was obtained as white solid in 22.9% yield according to the general procedure of (R)-N-((4-(((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)t hio)butan-2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.40 (br dd, J = 9.6 Hz, 2H), 7.27 (dd, J = 5.2, 8.8 Hz, 2H), 7.01 (dd, J = 8.8 Hz, 2H), 4.35 (quin, J = 6.0 Hz, 1H), 4.00 (br t, J = 8.8 Hz, 2H), 3.86 - 3.76 (m, 1H), 3.66 (br s, 2H), 3.58 - 3.46 (m, 2H), 3.35 - 3.32 (m, 2H), 3.15 - 2.91 (m, 4H), 2.22 (br d, J = 12.0 Hz, 1H), 1.99 - 1.86 (m, 1H), 1.78 - 1.65 (m, 1H), 1.63 - 1.53 (m, 1H), 1.51 - 1.37 (m, 3H), 1.31 - 1.26 (m, 1H), 1.20 (s, 3H), 0.58 - 0.45 (m, 4H).

EXAMPLE 152. (R)-N-((3,5-DIFLUORO-4-(((R)-1-((4-FLUOROPHENYL)THIO)-4-(3- METHOXYAZETIDIN-1-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0543] (R)-N-((3,5-difluoro-4-(((R)-1-((4-fluorophenyl)thio)-4-(3-m ethoxyazetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-p yran-2-carboxamide (2.10 mg) was obtained as white solid in 9.27% yield according to the general procedure of (R)-N-((4- (((R)-4-(bis(methyl-d3)amino)-1-((4-fluorophenyl)thio)butan- 2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.40 (m, 2H), 7.31 - 7.19 (m, 2H), 7.11 - 6.88 (m, 2H), 4.25 - 3.99 (m, 5H), 3.86 - 3.56 (m, 7H), 3.11 - 3.04 (m, 3H), 2.24 - 2.18 (m, 1H), 1.99 - 1.92 (m, 1H), 1.78 - 1.70 (m, 1H), 1.62 - 1.56 (m, 1H), 1.54 - 1.37 (m, 4H), 1.34 - 1.24 (m, 2H), 1.20 (s, 3H)

EXAMPLE 153. (S)-N-((3,5-DIFLUORO-4-(((S)-1-(3-FLUOROAZETIDIN-1-YL)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3,5- DIFLUORO-4-(((S)-1-(3-FLUOROAZETIDIN-1-YL)-5-(4-FLUOROPHENYL )PENTAN- 3-YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0544] A mixture was prepared according to the general procedure of (S)-N-((3-cyano-4-((1- (dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3- yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . The product was purified by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm 10um); mobile phase: [0.1%NH ₃ H ₂ O MEOH]; B%: 20%-20% 12min). (S)-N-((3,5-difluoro-4-(((S)-1-(3-fluoroazetidin-1-yl)-5-(4- fluorophenyl)pentan-3-yl)amino)phenyl)sulfonyl)-2-methyltetr ahydro-2H-pyran-2-carboxamide (5.96 mg, 98.0% purity) was obtained as a white solid in 7.59% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3-yl)pentan- 3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-c arboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.42 (m, 2H), 7.02-7.08 (m, 2H), 6.96-6.92 (m, 2H), 5.16-5.12 (m, 1H), 3.76-3.60 (m, 3H), 3.49-3.48 (m, 1H), 2.83-2.66 (m, 2H), 2.26-2.15 (m, 1H), 1.84-1.82 (m, 2H), 1.76-1.55 (m, 4H), 1.45-1.41 (m, 4H), 1.30-1.29 (m, 4H), 1.20 (s, 4H), 0.97-0.84 (m, 1H). LCMS (ESI) m/z 572.2 (M+H ⁺ ). Chiral SFC e.e.% = 97.1%. (R)-N-((3,5-difluoro-4-(((S)-1-(3- fluoroazetidin-1-yl)-5-(4-fluorophenyl)pentan-3-yl)amino)phe nyl)sulfonyl)-2-methyltetrahydro- 2H-pyran-2-carboxamide(6.20 mg, 96.8% purity) was obtained as a white solid in 7.80% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6- (trifluoromethyl)pyridin-3-yl)pentan-3-yl)amino)-5-fluorophe nyl)sulfonyl)-1-fluorocyclohexane- 1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ7.45 (d, J = 2.0 Hz, 2H),, 7.12-7.08 (m, 2H), 6.96-6.92 (m, 2H), 5.28-5.20 (m, 1H), 3.90-3.78 (m, 2H), 3.78-3.64 (m, 1H), 2.93-2.54 (m, 2H), 2.23-2.10 (m, 1H), 2.01-1.86 (m, 2H), 1.80-1.70 (m, 2H), 1.69-1.50 (m, 2H), 1.49-1.44 (m, 4H), 1.42-1.28 (m, 3H), 1.19 (s, 3H), 1.01-0.63(m, 2H). LCMS (ESI) m/z 572.2 (M+H ⁺ ). Chiral SFC e.e.% = 95.4%.

EXAMPLE 154. (S)-N-((3-CYANO-5-FLUORO-4-(((S)-1-(3-FLUOROAZETIDIN-1-YL)- 5-(4-FLUOROPHENYL)PENTAN-3-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE AND (R)-N-((3-CYANO-5- FLUORO-4-(((S)-1-(3-FLUOROAZETIDIN-1-YL)-5-(4-FLUOROPHENYL)P ENTAN-3- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0545] A mixture was prepared according to the general procedure of (S)-N-((3-cyano-4-((1- (dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentan-3- yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . The product was purified by SFC (column: DAICEL CHIRALCEL OZ 250*25 mm I.D. 10um; mobile phase: [0.1%NH ₃ H ₂ O IPA]; B%: 40%-40%, 9min). (S)-N-((3-cyano-5-fluoro-4-(((S)-1-(3-fluoroazetidin-1-yl)-5 -(4- fluorophenyl)pentan-3-yl)amino)phenyl)sulfonyl)-2-methyltetr ahydro-2H-pyran-2- carboxamide(mg, 97.8% purity) was obtained as a white solid in 14.4% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3- yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclo hexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.84 (s, 1H), 7.75-7.72 (m, 1H), 7.14-7.10 (m, 2H), 6.97-6.92 (m, 2H), 5.26 (s, 1H), 5.11 (s, 1H), 4.02-3.81 (m, 2H), 3.77-3.71 (m, 1H), 3.58-3.50 (m, 2H), 2.96- 2.78(m, 2H), 2.76-2.54 (m, 2H), 2.20-2.03 (m, 1H), 1.94-1.92 (m, 2H), 1.86-1.70 (m, 2H), 1.63- 1.50 (m, 1H), 1.49-1.42 (m, 4H), 1.30-1.20 (m, 2H), 1.18 (s, 3H). LCMS (ESI) m/z 579.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%. (R)-N-((3-cyano-5-fluoro-4-(((S)-1-(3-fluoroazetidin-1-yl)- 5-(4-fluorophenyl)pentan-3-yl)amino)phenyl)sulfonyl)-2-methy ltetrahydro-2H-pyran-2- carboxamide (7.67 mg, 98.7% purity) was obtained as a white solid in 8.46% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin- 3-yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyc lohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.86 (s, 1H), 7.76-7.72 (m, 1H), 7.13-7.09 (m, 2H), 6.97-6.92 (m, 2H), 5.28 (s, 1H), 5.13 (s, 1H), 4.36-4.22 (m, 1H), 4.13-3.86 (m, 2H), 3.76-3.73 (m, 1H),3.66- 3.54 (m, 3H), 3.05-2.84 (m, 1H), 2.73-2.64 (m, 1H), 2.18-2.07 (m, 1H), 2.03-1.95 (m, 2H), 1.93- 1.62 (m, 2H), 1.70-1.57 (m, 1H), 1.45-1.39 (m, 4H), 1.38-1.26 (m, 3H), 1.20 (s, 3H). LCMS (ESI) m/z 579.3 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 155. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOPENTANE-1-CARBOXAMIDE [0546] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamide (20.5 mg, 100% purity) was obtained as a white solid in 31.6% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.74-7.71 (m, 1H), 7.11-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.18 (s, 1H), 3.21-3.15 (m, 1H), 3.13 (s, 4H), 2.80 (s, 6H), 2.77-2.68 (m, 1H), 2.07-1.99 (m, 2H), 1.99-1.88 (m, 4H), 1.84-1.74 (m, 2H), 1.69-1.60 (m, 4H). LCMS (ESI) m/z 549.3 (M+H ⁺ ). EXAMPLE 156. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0547] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide(11 .3 mg, 100% purity) was obtained as a white solid in 21.3% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80 (s, 1H), 7.73-7.70 (m, 1H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.18 (s, 1H), 3.16-3.13 (m, 2H), 3.11 (s, 3H), 2.78 (s, 6H), 2.74-2.59 (m, 2H), 2.07-1.99 (m, 2H), 1.99-1.92 (m, 2H), 1.79-1.71 (m, 2H), 1.70-1.62 (m, 2H), 1.56-1.42 (m, 6H). LCMS (ESI) m/z 563.3 (M+H ⁺ ).

EXAMPLE 157. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-4- METHYL-2-OXABICYCLO[2.1.1]HEXANE-1-CARBOXAMIDE [0548] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-4-methyl-2-oxabicyclo[2.1.1]hexane-1- carboxamide(17.6 mg, 100% purity) was obtained as a white solid in 34.0% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.81-7.73 (m, 2H), 7.11-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.18 (s, 1H), 3.54 (s, H), 3.26-3.18 (m, 2H), 2.84 (s, 6H), 2.80-2.71 (m, 1H), 2.69-2.60(m, 2H), 2.14-2.04 (m, 2H), 1.97-1.95 (m, 2H), 1.86-1.82 (m, 2H), 1.66-1.58 (m, 2H), 1.29 (s, 3H). LCMS (ESI) m/z 547.2 (M+H ⁺ ).

EXAMPLE 158. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOPENTANE-1- CARBOXAMIDE [0549] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-1-methoxycyclopentane-1-carboxamide (45.5 mg, 97.5% purity) was obtained as a white solid in 67.6% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.79-7.70 (m, 2H), 7.21-7.08 (m, 5H), 4.20-4.15 (m, 1H), 3.31-2.74 (m, 13H), 2.04-1.18 (m, 12H). LCMS (ESI) m/z 531.2 (M+H ⁺ ).

EXAMPLE 159. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1- CARBOXAMIDE [0550] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide(31 .4 mg, 96.7% purity) was obtained as a white solid in 45.1% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.79-7.70 (m, 2H), 7.23-7.08 (m, 5H), 4.20-4.16 (m, 1H), 3.18-2.59 (m, 13H), 2.02-1.96 (m, 4H), 1.72-1.21 (m, 11H). LCMS (ESI) m/z 545.2 (M+H ⁺ ). EXAMPLE 160. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-4-METHYL-2- OXABICYCLO[2.2.2]OCTANE-1-CARBOXAMIDE

[0551] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-4-methyl-2-oxabicyclo[2.2.2]octane-1- carboxamide (35.9 mg, 95.9% purity) was obtained as a white solid in 50.0% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.78-7.69 (m, 2H), 7.22-7.08 (m, 5H), 4.19-4.16 (m, 1H), 3.59 (s, 2H), 3.15-2.63 (m, 10H), 2.03- 1.49 (m, 12H), 0.79-0.75 (m, 3H). LCMS (ESI) m/z 557.3 (M+H ⁺ ). EXAMPLE 161. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-PHENYLPENTAN-3- YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-4-METHYL-2- OXABICYCLO[2.1.1]HEXANE-1-CARBOXAMIDE [0552] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-phenylpentan-3-yl)am ino)-5- fluorophenyl)sulfonyl)-4-methyl-2-oxabicyclo[2.1.1]hexane-1- carboxamide (49.1 mg, 96.4% purity) was obtained as a white solid in 72.4% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80-7.72 (m, 2H), 7.23-7.08 (m, 5H), 4.20-4.16 (m, 1H), 3.54-3.22 (m, 2H), 3.21-2.66 (m, 10H), 2.05-1.96 (m, 8H), 1.90-1.29 (m, 3H). LCMS (ET60464-206-P1E2) (ESI) m/z 529.2 (M+H ⁺ ). EXAMPLE 162. (S)-N-((3-CYANO-4-((1-(DIMETHYLAMINO)-5-(4- FLUOROPHENYL)PENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-4- METHYL-2-OXABICYCLO[2.2.2]OCTANE-1-CARBOXAMIDE [0553] (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(4-fluorophenyl)pent an-3-yl)amino)-5- fluorophenyl)sulfonyl)-4-methyl-2-oxabicyclo[2.2.2]octane-1- carboxamide(36.1 mg, 98.7% purity) was obtained as a white solid in 52.5% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ7.79 (s, 1H), 7.73-7.70 (m, 1H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 4.18-4.18 (m, 1H), 3.60 (s, 2H), 3.15-3.13 (m, 2H), 2.79 (s, 6H), 2.75-2.65 (m, 1H), 2.03-1.98 (m, 6H), 1.96-1.83 (m, 2H), 1.56-1.52 (m, 4H), 1.52-1.49 (m, 1H), 0.75 (s, 3H). LCMS (ESI) m/z 575.3 (M+H ⁺ ). EXAMPLE 163. (R)-3-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUORO-N-((4- METHYLCYCLOHEXYL)SULFONYL)BENZAMIDE

A. Step 1 [0554] Compound D1-5 (380 mg, crude) was obtained as yellow oil according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.83 (s, 1H), 7.69-7.65 (m, 1H), 7.35-7.33 (m, 2H), 7.00-6.96 (m, 2H), 4.46-4.43 (m,1H), 4.36-4.30 (m, 2H),3.31-3.29 (m, 1H), 3.26-3.18 ^m, 1H ^, 2.50-2.43 (m, 2H), 2.24 (s, 6H), 2.01-1.87 (m, 2H), 1.39-1.35 (m, 3H). LCMS (ESI) m/z 434.2 (M+H ⁺ ). B. Step 2 [0555] To a solution of D1-5 (0.4 g, 922.69 μmol) in 1,4-dioxane (2 mL) saturated with NH ₃ .H ₂ O (3.64 g, 25.96 mmol, 4.00 mL, 25% purity)was stirred under 15 Psi at 60°C for 12 hrs in a 30 mL of autoclave. LCMS (RT = 1.584min) showed the starting material was consumed completely. The mixture was cooled to 20 °C and concentrated in reduced pressure. The residue was purified by prep-HPLC: column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water( NH4HCO3)-ACN];B%: 25%-55%,8min to give compound D1-5A (50.0 mg, 13.1% yield, 97.8% purity) as yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.81-7.80 (m, 1H), 7.71-7.67 (m,1 H), 7.36-7.32 (m, 2H), 7.02-6.98 (m, 2H), 3.32-3.19 (m, 3H), 2.52-2.47 (m, 2H), 2.26 (s, 6H), 2.01-1.99 (m, 1H), 1.90-1.88 (m, 1H). LCMS (ESI) m/z 405.1 (M+H ⁺ ). C. Step 3 [0556] To a solution of D1-5A (10 mg, 24.72 μmol) in THF (0.5 mL) saturated with LiHMDS (1 M, 49.45 μL) was stirred at -70°C for 2 hrs. The mixture was added 4- methylcyclohexanesulfonyl chloride (6.32 mg, 32.14 μmol) and stirred at 20°C for 12 hrs. LCMS (RT = 1.692 min) showed ~34.2% of D1-5A (RT = 1.572 min) was remained, and ~37.0% of desired product was detected. The residue was poured into saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (5 mLx3). The combined organic phase was washed with brine (10 mLx2), dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum. The residue was purified by prep-HPLC: column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [water(NH4HCO3)-ACN];B%: 35%-55%,8 min to give (R)-3-cyano-4-((4-(dimethylamino)-1-((4-fluorophenyl)thio)bu tan-2-yl)amino)-5-fluoro-N-((4- methylcyclohexyl)sulfonyl)benzamide (4.1 mg, 29.1% yield, 99.1% purity) as a white solid. ¹ H NMR: (400 MHz, MeOD) δ 7.91-7.79 (m, 2H), 7.28-7.22 (m, 2H), 7.01-6.97 (m, 2H), 4.20-4.17 (m, 1H), 3.55-3.47 (m, 2H), 3.22-3.12 (m, 2H), 2.86 (s, 6H), 2.17-1.82 (m, 7H), 1.65-1.59 (m, 3H), 1.02-1.00 (m, 1H), 0.99-0.90 (m, 3H), 0.89-0.88 (m, 2H). LCMS (ESI) m/z 565.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 164.3-CHLORO-5-CYANO-4-FLUOROBENZENESULFONAMIDE (SULFONAMIDE 7) A. Step 1 [0557] To a solution of compound 1A (1.00 g, 4.59 mmol), in dioxane (10.0 mL) was added Pd ₂ (dba) ₃ (104 mg, 114 μmol) and Xantphos (119 mg, 205 μmol) and DIEA (1.19 g, 9.17 mmol), phenylmethanethiol (672 mg, 5.41 mmol). The mixture was stirred at 100 °C for 12 hrs. TLC (petroleum ether/ethyl acetate = 20/1, compound 1A Rf = 0.51, compound 2A Rf = 0.43) indicated compound 1A was consumed completely. The reaction mixture was quenched by ice H ₂ O (15.0 mL). The combined organic layers were washed with EtOAc (10.0 mL), and extracted with EtOAc (20.0 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 200/1 to 0/1) to give compound 2A (0.66 g, 51.8% yield) as a yellow oil. B. Step 2 [0558] To a solution of compound 2A (1.15 g, 4.14 mmol) in H ₂ O (0.50 mL) and MeCN (27.0 mL) was added AcOH (248 mg, 4.14 mmol) and compound A-2 (1.22 g, 6.21 mmol). The mixture was stirred at -10 °C for 6 hrs. LCMS (compound 3A RT = 1.939 min) showed no compound 2A remained. Several new peaks were shown on LCMS and 41.0% of compound 3A was detected. The reaction mixture was diluted with H ₂ O (10.0 mL) and washed with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 0/1; TLC: petroleum ether/ethyl acetate = 5/1, product R _f = 0.55) to give compound 3A (1.20 g, 57.1% yield) as a light-yellow oil. [0559] To a solution of compound 3A (100 mg, 393 μmol) in THF (2.00 mL) was added NH ₃ .H ₂ O (275 mg, 1.97 mmol). The mixture was stirred at 0 °C for 2 hrs. LCMS (compound 3A RT = 1.370 min) showed no compound 3A remained. The reaction mixture was adjusted pH=2 with 2 mol HCL. The combined organic layers were washed with EtOAc (5.00 mL) and extracted with EtOAc (150 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2, petroleum ether/ethyl acetate =20 /1 to give compound Sulfonamide 7 (40.0 mg, 43.4% yield) as white oil. EXAMPLE 165. (R)-N-((3-CHLORO-5-CYANO-4-((4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0560] Compound D2-1 (80.0 mg) was obtained as a yellow solid in 29.4% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD-d ₆ ) δ 7.91 (m, 1H), 7.91-7.80 (m, 1H), 7.29-7.26 (m, 2H), 7.01-6.96 (m, 2H), 4.59 (m, 1H) 3.36-3.32 (m, 2H), 3.19- 3.14 (m, 1H), 2.55-2.44 (m, 2H), 2.24 (s, 6H), 2.00-1.72 (m, 2H). B. Step 2 [0561] (R)-N-((3-chloro-5-cyano-4-((4-(dimethylamino)-1-((4-fluorop henyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (23.0 mg, 94.6% purity) was obtained as a white solid in 44.0% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 8.04-8.02 ( m, 1H), 7.91-7.90 (m, 1H), 7.20-7.17 (m, 2H), 7.05-7.00 (m, 2H), 4.33-4.29 (m, 1H), 3.31-3.12 (m, 2H), 3.11-3.06 (m, 5H), 2.81 (s, 6H), 2.17-2.14 (m, 2 H), 1.75-1.51 (m, 5H), 1.51- 1.46 (m, 6H). LCMS (ESI) m/z 597.1 (M+H ⁺ ). EXAMPLE 166. (R)-N-((3-CYANO-4-(((S)-1-(DIMETHYLAMINO)-5-PHENYLPENTAN- 3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H- PYRAN-2-CARBOXAMIDE AND (S)-N-((3-CYANO-4-(((S)-1-(DIMETHYLAMINO)-5- PHENYLPENTAN-3-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0562] (R)-N-((3-cyano-4-(((S)-1-(dimethylamino)-5-phenylpentan-3-y l)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide(45.7 mg, 100% purity) was obtained as a white solid in 38.1% yield according to the general procedure of (S)-N-((3-cyano- 4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pen tan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.80-7.71 (m, 2H), 7.23-7.08 (m, 5H), 4.20-3.66 (m, 1H), 3.21-3.17 (m, 2H), 2.82-2.64 (m, 2H), 2.20-1.96 (m, 13H), 1.94-1.91 (m, 8H). LCMS (ESI) m/z 531.3 (M+H ⁺ ). Chiral SFC e.e.% = 99.6%. [0563] (S)-N-((3-cyano-4-(((S)-1-(dimethylamino)-5-phenylpentan-3-y l)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide(44.8 mg, 99.3% purity) was obtained as a white solid in 37.0% yield according to the general procedure of (S)-N-((3- cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridin-3- yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.81-7.71 (m, 2H), 7.23-7.08 (m, 5H), 4.20-3.65 (m, 1H), 3.19-3.15 (m, 2H), 2.79-2.01 (m, 15H), 1.99-1.18 (m, 9H). LCMS (ESI) m/z 531.2 (M+H ⁺ ). Chiral SFC e.e.% = 97.6%. EXAMPLE 167. TERT-BUTYL (R)-(4-(DIMETHYLAMINO)-1-HYDROXYBUTAN-2- YL)CARBAMATE A. Step 1 [0564] Charge compound 1 (45.0 g, 191 mmol, 1.00 eq) to a 1000 mL round bottom flask(R1). Charge Me ₂ NH (2.00 M, 450 mL, 4.70 eq) to R1 at 25 °C. Stir R1 at 60 °C for 16 hrs. LCMS showed that the compound 1 was consumed and the desired mass (Rt = 1.178 min) was observed. The mixture was concentrated to give compound 2 (54.0 g, crude) (confirmed by HNMR: EB10792-14-P1N1) as a yellow solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.50 - 7.17 (m, 5H), 5.17 - 4.95 (m, 2H), 4.05 (quin, J = 5.6 Hz, 1H), 3.63 - 3.51 (m, 2H), 3.11 - 2.99 (m, 3H), 2.89 (s, 3H), 2.72 - 2.49 (m, 2H) B. Step 2 [0565] Charge compound 2 (21.4 g, 76.3 mmol, 1.00 eq) to a 500 mL Hydrogenation bottle (R1) equipped with H ₂ (15.0 psi) balloon. Charge MeOH (150 mL) to R1 at 25 °C. Charge Pd/C (2.00 g, 1.88 mmol, 10% purity, 2.46e ^-2 eq) to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs. LCMS showed that the compound 2 was consumed and the desired mass (Rt = 0.13 min) was observed. The mixture was filtered and the filtrate was concentrated to give compound 3 (11.0 g, crude) as yellow liquid in MeOH (100 mL). C. Step 3 [0566] Charge compound 3 (11.0 g, 75.3 mmol, 1.00 eq) to a 100 mL three-neck bottle (R1) equipped with a N ₂ balloon. Charge MeOH (10.0 mL) to R1 at 25 °C. Charge DIEA (14.6 g, 113 mmol, 20.0 mL, 1.50 eq) slowly to R1 at 25 °C. Charge (Boc) ₂ O (19.7 g, 90.3 mmol, 20.7 mL, 1.20 eq) slowly to R1 at 25 °C. Stir R1 at 25 °C for 1 h. LCMS showed that compound 3 was consumed and the desired mass (Rt = 0.469 min) was observed. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product (Dichloromethane: Methanol = 10 : 1, R _f = 0.20) was purified by column chromatography on silicagel (Methanol: Dichloromethane = 0-10%) to give compound 4 (13.6 g, 55.2 mmol, 73.4% yield) (confirmed by HNMR: EB10792-79-P1N1) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 4.07 - 3.88 (m, 1H), 3.55 (t, J = 6.4 Hz, 2H), 3.09 (s, 3H), 2.92 (s, 3H), 2.70 - 2.44 (m, 2H), 1.43 (s, 9H) D. Step 4 [0567] Charge compound 4 (8.60 g, 34.9 mmol, 1.00 eq) to a 500 mL three-neck bottle (R1) equipped with a N ₂ balloon. Charge THF (86.0 mL) to R1 at 25 °C. Charge LAH (2.65 g, 69.8 mmol, 2.00 eq) slowly to R1 at 0 °C. Stir R1 at 0 °C for 1 h. Stir R1 at 25 °C for 2 hrs. TLC (Dichloromethane : Methanol = 10 : 1) showed compound 4 was consumed and a new major spot was observed. The reaction mixture was added Na ₂ SO ₄ ·10H ₂ O (8.00 g) slowly at 0 °C and stir R1 at 25 °C for 0.5 h. The mixture was filtered, the filtrate were concentrated under reduced pressure to give compound 5 (6.30 g, 27.1 mmol, 77.7% yield) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 3.59 - 3.41 (m, 3H), 2.50 - 2.29 (m, 2H), 2.25 (s, 6H), 1.79 (ddd, J = 4.8, 9.2, 14.4 Hz, 1H), 1.65 - 1.50 (m, 1H), 1.44 (s, 9H) EXAMPLE 168. (R)-N-((9-CYANO-2-((CYCLOHEXYLTHIO)METHYL)-5-METHYL- 2,3,4,5-TETRAHYDRO-1H-BENZO[B][1,4]DIAZEPIN-7-YL)SULFONYL)-1 - METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0568] Charge compound 5 (500 mg, 2.15 mmol, 1.00 eq) to a 40 ml sealed tube (R1). Charge toluene (5.00 mL) to R1 at 25 °C. Charge cyclohexanethiol (250 mg, 2.15 mmol, 263 μL, 1.00 eq) to R1 at 25 °C. Charge CMBP (935 mg, 3.87 mmol, 1.80 eq) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS showed that the compound 5 was consumed and the desired mass (Rt = 1.786 min) was observed. The mixture was concentrated to give crude product. Sat. citric acid solution (100 mL) was added to R1. The mixture was back-extracted with EtOAc (30.0 mL), the organic layer was discarded. The aqueous phase was adjusted to pH = ~ 8 with Sat. K ₂ CO ₃ solution, the mixture was extracted with EtOAc (10.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give a crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 42%-82% B over 32 min) to give two compounds as yellow oil. The first compound was lyophilized to give compound 1-1 (120 mg, crude) as a yellow oil. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 6.70 (br d, J = 8.4 Hz, 1H), 3.49 (br d, J = 4.8 Hz, 1H), 2.71 - 2.61 (m, 1H), 2.21 - 2.13 (m, 2H), 2.08 (s, 6H), 1.89 (br d, J = 10.4 Hz, 2H), 1.72 - 1.50 (m, 4H), 1.48 - 1.14 (m, 15H), 0.92 - 0.85 (m, 1H) B. Step 2 [0569] Charge compound 1-1 (120 mg, 363 μmol, 1.00 eq) to a 10mL round bottom flask(R1). Charge HCl/dioxane (6.00 mL) to R1 at 25 °C. Stir R1 at 25 °C for 1 h. LCMS (EB11176-62- IPCL1) showed that the compound 1-1 was consumed and the desired mass (R _t = 0.358 min) was observed. The mixture was concentrated to give compound 1-2 (90.0 mg, crude) as a yellow oil. C. Step 3

[0570] Charge compound 1-2 (10.0 mg, 43.4 μmol, 1.00 eq) to a 4.00 mL round bottom flask (R1). Charge NMP (0.50 mL) to R1 at 25 °C. Charge DIEA (28.1 mg, 217 μmol, 37.8 μL, 5.00 eq) to R1 at 25 °C. Charge S3 (9.47 mg, 43.4 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 150 °C for 3 hrs. Stir R1 at 145 °C for 72 hrs. LCMS (EB11176-83-IPCL4) showed that the compound 1-2 was consumed and the desired mass (R _t = 0.969 min) was observed. The mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₃ H ₂ O)-ACN]; gradient: 40%-80% B over 20 min) to give compound 1-3 (8.00 mg, 19.8 μmol, 45.5% yield, 97.4% purity) as a yellow solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.45 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 3.92 - 3.78 (m, 1H), 3.44 (ddd, J = 5.2, 8.0, 13.2 Hz, 1H), 3.20 - 3.12 (m, 1H), 3.01 (dd, J = 4.8, 13.6 Hz, 1H), 2.88 (s, 3H), 2.78 - 2.58 (m, 2H), 2.14 - 1.95 (m, 3H), 1.79 - 1.58 (m, 4H), 1.45 - 1.19 (m, 6H) D. Step 4 [0571] Charge compound 1-3 (8.00 mg, 20.3 μmol, 1.00 eq) to a 4.00 ml sealed tube(R1). Charge ACN (0.50 mL) to R1 at 25 °C. Charge DMAP (4.95 mg, 40.6 μmol, 2.00 eq) to R1 at 25 °C. Charge Acid 7 (6.42 mg, 40.6 μmol, 2.00 eq) to R1 at 25 °C. Charge EDCI (7.77 mg, 40.6 μmol, 2.00 eq) to R1 at 25 °C. Stir R1 at 25 °C for 12 hrs. LCMS showed that the compound 1-3 was consumed and the desired mass (R _t = 0.735 min) was observed. The mixture was concentrated to give crude product. The combined crude product was purified by pre-HPLC (column: Welch Xtimate C1840*200mm 7um; mobile phase: [water (FA)-ACN]; gradient: 50%-60% B over 25 min) to give (R)-N-((9-cyano-2-((cyclohexylthio)methyl)-5-methyl-2,3,4,5- tetrahydro-1H-benzo[b][1,4]diazepin-7-yl)sulfonyl)-1-methoxy cyclohexane-1-carboxamide (2.55 mg, 4.54 μmol, 22.4% yield, 95.2% purity) as a light yellow solid. (400 MHz, CD ₃ OD) δ 7.58 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 3.94 (tt, J = 4.4, 8.9 Hz, 1H), 3.42 (ddd, J = 5.6, 7.8, 13.2 Hz, 1H), 3.22 - 3.15 (m, 1H), 3.11 (s, 3H), 3.01 (dd, J = 4.8, 13.6 Hz, 1H), 2.87 (s, 3H), 2.77 - 2.62 (m, 2H), 2.18 - 1.94 (m, 3H), 1.80 - 1.22 (m, 19H) EXAMPLE 169. (R)-N-((8-CYANO-2-(2-(CYCLOHEXYLTHIO)ETHYL)-4-METHYL- 1,2,3,4-TETRAHYDROQUINOXALIN-6-YL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0572] Charge compound 5 (500 mg, 2.15 mmol, 1.00 eq) to a 40 ml sealed tube (R1). Charge toluene (5.00 mL) to R1 at 25 °C. Charge cyclohexanethiol (250 mg, 2.15 mmol, 263 μL, 1.00 eq) to R1 at 25 °C. Charge CMBP (935 mg, 3.87 mmol, 1.80 eq) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS showed that the compound 5 was consumed and the desired mass (Rt = 1.786 min) was observed. The mixture was concentrated to give crude product. Sat. citric acid solution (100 mL) was added to R1. The mixture was back-extracted with EtOAc (30.0 mL), the organic layer was discarded. The aqueous phase was adjusted to pH = ~ 8 with Sat. K ₂ CO ₃ solution, the mixture was extracted with EtOAc (10.0 mL x 2). The combined organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 42%-82% B over 32 min) to give two compounds as yellow oil. The second compound was lyophilized to give compound 2-1 (60.0 mg, crude) as a yellow oil. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 6.59 (br d, J = 8.4 Hz, 1H), 6.35 - 5.99 (m, 1H), 3.56 (br s, 1H), 2.69 - 2.58 (m, 1H), 2.46 - 2.36 (m, 1H), 2.20 - 2.01 (m, 8H), 1.87 (br d, J = 4.4 Hz, 2H), 1.78 - 1.59 (m, 3H), 1.58 - 1.04 (m, 15H) B. Step 2 [0573] Compound 2-2 (40.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2. C. Step 3 [0574] Charge compound 2-2 (40.0 mg, 174 μmol, 1.00 eq) to a 4.00 mL round bottom flask(R1). Charge DMSO (0.50 mL) to R1 at 25 °C. Charge DIEA (112 mg, 868 μmol, 151 μL, 5.00 eq) to R1 at 25 °C. Charge S3 (37.9 mg, 174 μmol, 1.00 eq) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS showed that compound 2-2 was consumed and the desired mass (R _t =1.478 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (HCl)- ACN]; gradient: 32%-72% B over 36 min) give compound 2-3 (25.0 mg, 63.4 μmol, 36.5% yield) as a white solid. ¹ H NMR: (400 MHz, DMSO-d6) δ 7.15 (d, J = 2.0 Hz, 1H), 7.08 (s, 3H), 6.92 (d, J = 1.6 Hz, 1H), 3.65 (br d, J = 2.4 Hz, 1H), 3.19 (dd, J = 3.6, 11.5 Hz, 1H), 3.05 (dd, J = 4.8, 11.2 Hz, 1H), 2.87 (s, 3H), 2.77 - 2.54 (m, 3H), 1.98 - 1.78 (m, 3H), 1.76 - 1.61 (m, 3H), 1.56 (br d, J = 8.4 Hz, 1H), 1.36 - 1.12 (m, 5H)

[0575] (R)-N-((8-cyano-2-(2-(cyclohexylthio)ethyl)-4-methyl-1,2,3,4 -tetrahydroquinoxalin-6- yl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (7.00 mg, 12.7 μmol, 97.2 % purity) was obtained as white solid in 25.1% yield according to the general procedure of (R)-N-((9-cyano-2- ((cyclohexylthio)methyl)-5-methyl-2,3,4,5-tetrahydro-1H-benz o[b][1,4]diazepin-7-yl)sulfonyl)- 1-methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 7.42 (d, J = 1.6 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 3.82 - 3.72 (m, 1H), 3.25 (dd, J = 3.6, 11.4 Hz, 1H), 3.11 (s, 4H), 2.94 (s, 3H), 2.68 (br d, J = 6.0 Hz, 3H), 2.03 - 1.69 (m, 8H), 1.67 - 1.45 (m, 8H), 1.41 - 1.18 (m, 7H) EXAMPLE 170. (R)-N-((3-CYANO-4-((1-(CYCLOHEXYLTHIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0576] Compound 3-1 (60.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 3.77 (br dd, J = 4.4, 7.6 Hz, 1H), 2.75 - 2.21 (m, 11H), 2.08 - 1.18 (m, 21H) B. Step 2 [0577] Compound 3-2 (60.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2. C. Step 3 [0578] Charge compound 4 (10.0 mg, 27.9 μmol, 1.00 eq) to a 2.00 mL sealed bottle (R1). Charge DMSO (0.30 mL) to R1 at 25 °C. Charge DIEA (18.0 mg, 140 μmol, 24.3 μL, 5.00 eq) to R1 at 25 °C. Charge compound 3-2 (7.45 mg, 27.9 μmol, 1.00 eq, HCl) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS showed that the compound 4 was consumed and the desired mass (R _t = 1.334min) was observed. The mixture was purified by pre-HPLC (column: Xtimate C18 150*40mm*10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 12%-52% B over 32 min) to give (R)-N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (3.27 mg, 5.58 μmol, 20.0 % yield, 97.0% purity) as a white solid. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.87 (s, 1H), 7.79 (dd, J = 1.6, 12.0 Hz, 1H), 4.71 - 4.66 (m, 1H), 3.27 - 3.15 (m, 2H), 3.11 (s, 3H), 2.83 (br s, 6H), 2.64 - 2.47 (m, 3H), 1.91 - 1.81 (m, 4H), 1.78 - 1.46 (m, 13H), 1.34 - 1.18 (m, 7H) EXAMPLE 171. (R)-N-((3-CYANO-4-((4-(CYCLOHEXYLTHIO)-1- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0579] Compound 4-1 (30.0 mg) was obtained as yellow oil in 4.22% yield according to the general procedure of compound 1-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 3.88 - 3.67 (m, 1H), 2.71 - 2.31 (m, 4H), 2.04 - 1.90 (m, 2H), 1.85 - 1.71 (m, 3H), 1.67 - 1.51 (m, 1H), 1.45 (s, 9H), 1.39 - 1.19 (m, 5H). B. Step 2 [0580] Compound 4-2 (28.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2.

C. Step 3 [0581] (R)-N-((3-cyano-4-((4-(cyclohexylthio)-1-(dimethylamino)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (5.00 mg, 8.36 μmol, 95.1% purity) was obtained as white solid in 6.88% yield according to the general procedure of (R)-N- ((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)butan-2-yl )amino)-5-fluorophenyl)sulfonyl)- 1-methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.01 (s, 1H), 7.90 (dd, J = 2.0, 12.0 Hz, 1H), 3.52 - 3.41 (m, 2H), 3.12 (s, 3H), 3.01 (br d, J = 14.4 Hz, 6H), 2.64 (td, J = 6.4, 13.2 Hz, 1H), 2.58 - 2.45 (m, 2H), 2.01 - 1.46 (m, 17H), 1.31 - 1.14 (m, 6H) EXAMPLE 172. (R)-N-((3-CYANO-4-((1-(CYCLOHEPTYLTHIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE AND (R)-N-((3-CYANO-4-((4- (CYCLOHEPTYLTHIO)-1-(DIMETHYLAMINO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE

[0582] A mixture of compound 5-1 and 5-1A (30.0 mg, 87.1 μmol) were obtained as yellow oil in 40.5% yield according to the general procedure of compound 1-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 3.82 - 3.55 (m, 1H), 2.96 - 2.82 (m, 1H), 2.58 - 2.32 (m, 3H), 2.24 (s, 6H), 2.07 - 1.93 (m, 2H), 1.90 - 1.64 (m, 4H), 1.63 - 1.48 (m, 9H), 1.45 (s, 9H)

[0583] Compound 5-2 and 5-2A (20.0 mg, 81.8 μmol) was obtained as black brown oil in 94.0% yield according to the general procedure of compound 1-2. [0584] Compound 5-3 and 5-3A (12.0 mg, 27.1 μmol) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (HCl)-ACN]; gradient:%-46% B over 36 min ) as yellow oil in 33.1% yield according to the general procedure of compound 2-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.91 - 7.66 (m, 2H), 3.59 - 3.34 (m, 2H), 3.10 - 2.90 (m, 6H), 2.88 - 2.69 (m, 2H), 2.63 - 2.49 (m, 1H), 2.35 - 2.08 (m, 1H), 1.94 - 1.88 (m, 2H), 1.67 - 1.36 (m, 10H) [0585] (R)-N-((3-cyano-4-((4-(cycloheptylthio)-1-(dimethylamino)but an-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (10.0 mg, 17.2 μmol) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (FA)- ACN]; gradient: 20%-60% B over 25 min) as white solid in 63.3% yield according to the general procedure of compound (R)-N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)buta n-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.87 (s, 1H), 7.77 (dd, J = 2.0, 12.0 Hz, 1H), 4.74 - 4.65 (m, 1H), 3.28 - 3.18 (m, 2H), 3.11 (s, 3H), 2.93 - 2.78 (m, 6H), 2.77 - 2.70 (m, 1H), 2.62 - 2.46 (m, 2H), 2.01 - 1.13 (m, 25H) [0586] (R)-N-((3-cyano-4-((1-(cycloheptylthio)-4-(dimethylamino)but an-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (3.88 mg, 6.66 μmol) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (FA)- ACN]; gradient: 20%-60% B over 25 min) as white solid in 24.6% yield according to the general procedure of compound (R)-N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)buta n-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.50 (br s, 1H), 7.83 (s, 1H), 7.74 (dd, J = 2.0, 12.0 Hz, 1H), 4.43 - 4.33 (m, 1H), 3.18 (br t, J = 7.6 Hz, 2H), 3.12 (s, 3H), 2.90 - 2.72 (m, 8H), 2.24 - 2.11 (m, 1H), 2.11 - 2.11 (m, 1H), 2.06 - 1.85 (m, 3H), 1.77 - 1.61 (m, 6H), 1.60 - 1.40 (m, 13H), 1.31 - 1.22 (m, 1H) EXAMPLE 173. N-((3-CYANO-4-(((2R)-4-(DIMETHYLAMINO)-1-((TETRAHYDRO- 2H-PYRAN-3-YL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL )-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0587] Compound 6-1 (10.0 mg, crude) was obtained by pre-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water NH ₄ HCO ₃ )-ACN]; radient: 18%-58% B over 32 min) as yellow oil according to the general procedure of compound 1-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 3.99 (br d, J = 11.2 Hz, 1H), 3.82 (br d, J = 11.6 Hz, 1H), 3.58 (br d, J = 5.6 Hz, 1H), 3.48 - 3.34 (m, 1H), 3.24 (t, J = 10.8 Hz, 1H), 2.87 - 2.54 (m, 3H), 2.39 (td, J = 6.8, 10.0 Hz, 2H), 2.25 (s, 6H), 2.14 - 2.05 (m, 1H), 1.93 - 1.41 (m, 15H) B. Step 2 [0588] Compound 6-1 (10 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2. C. Step 3 [0589] N-((3-cyano-4-(((2R)-4-(dimethylamino)-1-((tetrahydro-2H-pyr an-3-yl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide (1.10 mg, 1.93 μmol, 100% purity) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (HCl)-ACN]; gradient: 2%-42% B over 36 min) as light yellow solid in 36.7% yield according to the general procedure of compound (R)-N-((3-cyano-4-((1-(cyclohexylthio)-4- (dimethylamino)butan-2-yl)amino)-5-fluorophenyl)sulfonyl)-1- methoxycyclohexane-1- carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.43 (br s, 2H), 7.85 (s, 1H), 7.75 (dd, J = 2.0, 12.0 Hz, 1H), 4.00 - 3.70 (m, 2H), 3.37 (br dd, J = 3.2, 10.8 Hz, 1H), 3.26 - 3.16 (m, 3H), 3.12 (s, 3H), 2.92 - 2.64 (m, 9H), 2.24 - 2.11 (m, 1H), 2.07 - 1.92 (m, 2H), 1.77 - 1.22 (m, 14H) EXAMPLE 174. (R)-N-((4-((1-((4-CHLOROPHENYL)THIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-3-CYANO-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0590] Charge compound 5 (90.0 mg, 387 μmol, 1.00 eq) to a 4.00 mL sealed tube (R1). Charge THF (2.00 mL) to R1 at 25 °C. Charge PBu ₃ (118 mg, 581 μmol, 143 μL, 1.50 eq) to R1 at 25 °C. Charge 4-chlorobenzenethiol (84.0 mg, 581 μmol, 1.50 eq) to R1 at 25 °C. Charge DIAD (118 mg, 581 μmol, 113 μL, 1.50 eq) to R1 at 0 °C. Stir R1 at 25 °C for 12 hrs. LCMS showed that the compound 5 was consumed and the desired mass (Rt = 1.402 min) was observed. The mixture was concentrated to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )- ACN]; gradient: 44%-84% Bover 32 min ) to give compound 7-1 (30.0 mg, 83.6 μmol, 21.6% yield) as a yellow oil. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.45 - 7.35 (m, 2H), 7.32 - 7.27 (m, 2H), 3.69 - 3.57 (m, 1H), 3.12 - 2.92 (m, 2H), 2.54 - 2.38 (m, 2H), 2.32 (s, 6H), 1.96 - 1.85 (m, 1H), 1.67 - 1.58 (m, 1H), 1.42 (s, 9H) B. Step 2 [0591] Compound 7-2 (20.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 1-2. C. Step 3 [0592] Compound 7-3 (10.0 mg, 21.9 μmol) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (HCl) - ACN]; gradient: 2%-42% B over 36 min) as yellow solid in 28.3 % yield according to the general procedure of compound 2-3. D. Step 4

[0593] (R)-N-((4-((1-((4-chlorophenyl)thio)-4-(dimethylamino)butan- 2-yl)amino)-3-cyano-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide (3.11 mg, 5.01 μmol, 96.2% purity) was obtained by pre-HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₃ H ₂ O+NH ₄ HCO ₃ )-ACN]; gradient: 10%-50% B over 32 min) as white solid in 22.9 % yield according to the general procedure of compound (R)-N-((3-cyano-4-((1- (cyclohexylthio)-4-(dimethylamino)butan-2-yl)amino)-5-fluoro phenyl)sulfonyl)-1- methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.77 (s, 1H), 7.70 (dd, J = 2.0, 11.9 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.20 - 7.14 (m, 2H), 4.32 - 4.23 (m, 1H), 3.18 - 3.14 (m, 2H), 3.12 (s, 3H), 2.76 (br s, 5H), 2.20 - 2.00 (m, 2H), 1.78 - 1.23 (m, 12H) EXAMPLE 175. (R)-N-((3-CYANO-4-((1-((2,4-DIFLUOROPHENYL)THIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0594] Compound 8-1 (55.0 mg) was obtained as yellow oil in 17.7% yield according to the general procedure of compound 7-1. B. Step 2 [0595] Compound 8-2 (76.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 7-2. C. Step 3 [0596] Compound 8-3 (21.0 mg, 85.5% purity) was obtained as light yellow solid in 13.4 % yield according to the general procedure of compound 7-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.69 (s, 1H), 7.60 (dd, J = 2.0, 12.0 Hz, 1H), 7.37 (dt, J = 6.4, 8.4 Hz, 1H), 6.99 - 6.83 (m, 2H), 4.37 (br t, J = 5.2 Hz, 1H), 3.29 - 3.21 (m, 1H), 3.18 - 3.08 (m, 1H), 2.73 - 2.57 (m, 2H), 2.11 - 2.00 (m, 1H), 1.98 - 1.88 (m, 1H)

D. Step 4 [0597] (R)-N-((3-cyano-4-((1-((2,4-difluorophenyl)thio)-4-(dimethyl amino)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-ca rboxamide (10.0 mg, 98.9% purity) was obtained as white solid in 33.5 % yield according to the general procedure of compound (R)-N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)buta n-2-yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.57 - 7.47 (m, 2H), 7.37 - 7.18 (m, 2H), 7.05 (br d, J = 2.0 Hz, 1H), 4.22 - 4.09 (m, 1H), 3.25 - 3.10 (m, 3H), 2.92 (s, 3H), 2.80 - 2.62 (m, 2H), 2.40 (s, 6H), 2.03 - 1.81 (m, 2H), 1.66 - 1.44 (m, 4H), 1.43 - 1.26 (m, 5H), 1.24 - 1.07 (m, 1H). EXAMPLE 176. (R)-N-((4-((1-((2-CHLORO-4-FLUOROPHENYL)THIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-3-CYANO-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE

[0598] Compound 9-1 (45.0 mg, 64.8% purity) was obtained as yellow oil in 8.99% yield according to the general procedure of compound 7-1. [0599] Compound 9-2 (46.0 mg, crude) was obtained as yellow oil according to the general procedure of compound 7-2. [0600] Compound 9-3 (26.0 mg, 84.4% purity) was obtained as light yellow solid in 31.5 % yield according to the general procedure of compound 7-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.70 - 7.66 (m, 1H), 7.60 (dd, J = 2.0, 12.0 Hz, 1H), 7.48 (dd, J = 6.0, 8.8 Hz, 1H), 7.22 (dd, J = 2.8, 8.8 Hz, 1H), 7.03 (dt, J = 2.8, 8.4 Hz, 1H), 4.49 - 4.37 (m, 1H), 3.38 - 3.32 (m, 1H), 3.19 (dd, J = 7.6, 14.0 Hz, 1H), 2.77 - 2.62 (m, 2H), 2.40 (s, 6H), 2.13 - 2.04 (m, 1H), 1.95 (dt, J = 4.0, 9.2 Hz, 1H) D. Step 4 [0601] (R)-N-((4-((1-((2-chloro-4-fluorophenyl)thio)-4-(dimethylami no)butan-2-yl)amino)-3- cyano-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carbox amide (10.0 mg, 97.6% purity) was obtained as white solid in 29.0 % yield according to the general procedure of compound (R)- N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)butan-2- yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.59 - 7.49 (m, 2H), 7.47 - 7.33 (m, 2H), 7.20 (dt, J = 2.8, 8.8 Hz, 1H), 4.22 (br d, J = 5.2 Hz, 1H), 3.31 - 3.22 (m, 2H), 2.93 (s, 5H), 2.55 (br s, 6H), 2.09 - 1.95 (m, 2H), 1.64 - 1.49 (m, 5H), 1.34 (br d, J = 4.8 Hz, 5H), 1.24 - 1.11 (m, 1H) EXAMPLE 177. (R)-N-((4-((1-((4-CHLORO-2-FLUOROPHENYL)THIO)-4- (DIMETHYLAMINO)BUTAN-2-YL)AMINO)-3-CYANO-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE

A. Step 1 [0602] Compound 10-1 (3.00 mg, 85.0% purity) was obtained as white solid in 1.57% yield according to the general procedure of compound 7-1. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.50 (s, 1H), 7.52 (dd, J = 8.0 Hz, 1H), 7.21 (dd, J = 9.2 Hz, 2H), 3.63 (br d, J = 6.0 Hz, 1H), 3.05 (br d, J = 6.4 Hz, 2H), 2.96 (br t, J = 7.2 Hz, 2H), 2.72 (br s, 6H), 2.13 - 1.98 (m, 1H), 1.84 - 1.70 (m, 1H), 1.43 (s, 10H) B. Step 2 [0603] Compound 10-2 (4.00 mg, crude) was obtained as light yellow solid according to the general procedure of compound 7-2. C. Step 3

[0604] Compound 10-3 (6.00 mg, 93.1% purity) was obtained as light yellow solid in 92.1 % yield according to the general procedure of compound 7-3. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.69 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 2.0, 12.0 Hz, 1H), 7.32 (dd, J = 8.0 Hz, 1H), 7.14 (ddd, J = 2.0, 8.8, 16.8 Hz, 2H), 4.48 - 4.33 (m, 1H), 3.37 - 3.33 (m, 1H), 3.18 (dd, J = 7.6, 14.0 Hz, 1H), 2.95 - 2.79 (m, 2H), 2.54 (s, 6H), 2.20 - 2.07 (m, 1H), 2.02 (ddd, J = 4.8, 9.6, 14.4 Hz, 1H) D. Step 4 [0605] (R)-N-((4-((1-((4-chloro-2-fluorophenyl)thio)-4-(dimethylami no)butan-2-yl)amino)-3- cyano-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carbox amide (6.00 mg, 97.8% purity) was obtained as white solid in 70.3 % yield according to the general procedure of compound (R)- N-((3-cyano-4-((1-(cyclohexylthio)-4-(dimethylamino)butan-2- yl)amino)-5- fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxamide. ¹ H NMR: (400 MHz, CD ₃ OD) δ 8.47 (br s, 3H), 7.84 - 7.64 (m, 2H), 7.26 - 7.09 (m, 3H), 4.32 - 4.19 (m, 1H), 3.26 (d, J = 5.2 Hz, 1H), 3.20 - 3.08 (m, 6H), 2.75 (s, 6H), 2.26 - 1.96 (m, 2H), 1.81 - 1.61 (m, 4H), 1.58 - 1.41 (m, 5H), 1.38 - 1.19 (m, 2H)

EXAMPLE 178. (R)-N-((3-CYANO-4-(((2R,3S)-4-(DIMETHYLAMINO)-3-FLUORO-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0606] Charge LiHMDS (1 M, 53.1 mL, 2.50 eq) to a 250 mL three neck bottle (R1) at 25°C. Charge compound 1 (5.00 g, 21.3 mmol, 1.00 eq) in THF (50 mL) to R1 at -60°C. Charge NFSI (8.71 g, 27.6 mmol, 1.30 eq) in THF (50 mL) to R1 at -60°C. Stir R1 at -60°C for 30 min. TLC (Petroleum ether : Ethyl acetate = 1:1) showed that the starting material was consumed and two new spot was observed. The reaction mixture was quenched with Sat. NH ₄ Cl (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 100/1 to 10/1) to give a mixture of compound 2-1 and 2-2 (1.91 g, 7.54 mmol, 35.5% yield) as white solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ 8.24 - 7.72 (m, 1H), 7.43 - 7.15 (m, 5H), 5.22 - 4.81 (m, 3H), 4.70 - 4.50 (m, 1H), 4.15 - 3.98 (m, 1H), 3.44 - 3.35 (m, 1H) B. Step 2 [0607] Charge compound 2-1 and 2-2 (1.81 g, 7.15 mmol, 1.00 eq) to a 40 mL sealed tube (R1) at 25 °C. Charge N-methylmethanamine (2 M, 16.8 mL, 4.70 eq) to R1. Stir R1 at 60 °C for 12 hrs. TLC (Dichloromethane : Methanol = 20 : 1) showed the starting material was consumed and two new spot was observed. LCMS showed the desired mass (RT = 1.40 min, 1.53 min) was detected. The reaction mixture was purified by pre-HPLC (column: Welch Xtimate C18 250*50mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:0%-40% B over 20 min) to give P1 and P2. Compound 3-1 (0.69 g, 2.31 mmol, 32.4% yield) was obtained as white solid; ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.42 - 7.31 (m, 5H), 5.61 - 5.37 (m, 2H), 5.15 - 5.07 (m, 2H), 4.24 - 4.10 (m, 1H), 4.03 (br d, J = 11.0 Hz, 1H), 3.79 - 3.67 (m, 1H), 3.38 - 3.28 (m, 1H), 3.06 (s, 3H), 2.99 - 2.94 (m, 3H). Compound 3-2 (0.47 g, 1.58 mmol, 22.0% yield) was obtained as a white solid; ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.44 - 7.31 (m, 5H), 5.78 (br d, J = 7.9 Hz, 1H), 5.55 - 5.35 (m, 1H), 5.18 - 5.07 (m, 2H), 4.26 - 4.08 (m, 1H), 3.94 - 3.86 (m, 1H), 3.85 - 3.77 (m, 1H), 3.14 (s, 3H), 2.99 (s, 3H), 2.83 - 2.53 (m, 1H) C. Step 3 [0608] Charge compound 3-1 (0.77 g, 2.58 mmol, 1.00 eq) to a 50 mL single bottle (R1) at 25 °C. Charge MeOH (8.00 mL) to R1. Charge Pd/C (70.0 mg, 65.8 μmol, 10% purity, 2.55e-2 eq) to R1^^Stir R1 under H ₂ balloon (15 psi) at 25 °C for 1 hr. TLC (Dichloromethane/Methanol = 10/1) showed the starting material was consumed and one major spot was observed. The reaction mixture was filtered. Charge Boc ₂ O (676 mg, 3.10 mmol, 711 μL, 1.20 eq) to the filtrate. Stir R1 at 25 °C for 1 hr. TLC (Dichloromethane/Methanol = 10/1) showed starting material was consumed and one major spot was observed. The reaction mixture was concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Dichloromethane/Methanol = 100/1 to 10/1) to give compound 4-1 (554 mg, 2.10 mmol, 81.2% yield) as white solid. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 5.59 - 5.37 (m, 1H), 5.33 - 5.19 (m, 1H), 4.19 - 3.95 (m, 2H), 3.79 - 3.61 (m, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 1.45 (s, 9H) [0609] Charge compound 4-1 (200 mg, 756 μmol, 1.00 eq) to a 8 mL sealed tube (R1) at 25 °C. Charge THF (4.00 mL) to R1. Charge 4-fluorobenzenethiol (242 mg, 1.89 mmol, 2.50 eq) to R1. Charge tributylphosphane (459 mg, 2.27 mmol, 560 μL, 3.00 eq) to R1. Charge DIAD (459 mg, 2.27 mmol, 440 μL, 3.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 12 hrs. TLC (Petroleum ether/Ethyl acetate = 1/1) showed that the starting material was consumed and two new spot was observed. The reaction mixture was concentrated to give crude product. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=100/1 to 10/1) to give compound 5-1 (289 mg, crude) as colorless oil. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.45 (br dd, J = 5.3, 8.3 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 5.67 - 5.43 (m, 1H), 5.13 (br d, J = 9.0 Hz, 1H), 4.25 - 4.08 (m, 1H), 3.33 (br dd, J = 6.4, 14.1 Hz, 1H), 3.09 (br dd, J = 8.1, 14.0 Hz, 1H), 2.93 (br d, J = 6.3 Hz, 6H), 1.44 (s, 10H) E. Step 5 [0610] Charge compound 5-1 (179 mg, 478 μmol, 1.00 eq) to a 50 mL single bottle (R1) at 25 °C. Charge THF (3.00 mL) to R1. Charge BH ₃ .THF (1 M, 1.91 mL, 4.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 12 hr. LCMS showed the desired mass was detected (RT = 1.381 min). The reaction mixture was quenched with MeOH (2 mL). The mixture was concentrated under reduced pressure to give crude product. The crude product was purified by pre-HPLC (column: Xtimate C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:32%-72% B over 32 min) to give compound 6-1 (43.0 mg, 119.29 μmol, 24.95% yield) as white solid. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.51 - 7.37 (m, 2H), 7.02 (t, J = 8.6 Hz, 2H), 5.05 - 4.75 (m, 2H), 4.00 - 3.67 (m, 1H), 3.18 - 2.95 (m, 2H), 2.73 - 2.54 (m, 1H), 2.53 - 2.35 (m, 1H), 2.28 (s, 7H), 1.46 (s, 9H) F. Step 6 [0611] Charge compound 6-1 (43 mg, 119 μmol, 1.00 eq) to a 50 mL single bottle (R1). Charge HCl/dioxane (4 M, 596 μL, 20.0 eq) to R1^^Stir R1 at 25 °C for 1h. LCMS showed the desired mass was detected (RT = 0.834 min). The reaction mixture was concentrated to give crude product. The crude product was used directly in next step. Compound 7-1 (35.0 mg, 117.92 μmol, 98.85% yield, HCl) was obtained as yellow solid;

[0612] Charge compound 7-1 (20 mg, 67.4 μmol, 1.00 eq, HCl) to a 10 mL sealed tube (R1) at 25°C. Charge NMP (2.00 mL) to R1. Charge 3-cyano-4,5-difluoro-benzenesulfonamide (14.7 mg, 67.4 μmol, 1.00 eq) to R1. Charge DIEA (43.5 mg, 336 μmol, 58.7 μL, 5.00 eq) to R1^^Stir R1 at 90°C for 12 hr. LCMS showed the desired mass (RT = 1.234 min) was detected. The reaction mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:24%-64% B over 32 min) to give compound 8-1 (6.00 mg, 13.09 μmol, 19.42% yield) (confirmed by HNMR: EB11173-60-P1N1) as yellow soild. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.74 (s, 1H), 7.67 (dd, J = 1.9, 11.9 Hz, 1H), 7.34 (dd, J = 5.3, 8.6 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.09 - 4.95 (m, 1H), 4.64 - 4.42 (m, 1H), 3.42 (dd, J = 5.4, 14.3 Hz, 1H), 3.25 (dd, J = 8.4, 14.2 Hz, 1H), 2.86 - 2.57 (m, 2H), 2.29 (s, 7H) [0613] Charge Acid 9 (3.77 mg, 26.2 μmol, 2.00 eq) to a 8 mL sealed tube (R1) at 25° C. Charge CH ₃ CN (1.00 mL) to R1. Charge EDCI (5.02 mg, 26.2 μmol, 2.00 eq) to R1. Charge DMAP (3.20 mg, 26.2 μmol, 2.00 eq) to R1. Charge compound 8-1 (6.00 mg, 13.1 μmol, 1.00 eq) to R1. Stir R1 at 25 °C for 12 hrs. LCMS showed the desired mass (RT = 1.26 min) was detected. The reaction mixture was purified by pre-HPLC (column: Xtimate C18 150*40mm*10um;mobile phase: [water(FA)-ACN];gradient:2%-42% B over 25 min) to give (R)-N-((3-cyano-4-(((2R,3S)-4-(dimethylamino)-3-fluoro-1-((4 -fluorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide (2.40 mg, 4.10 μmol, 31.37% yield) (confirmed by HNMR: EB11173-65-P1N1; LCMS: EB11173-65-P1L2; SFC: EB11173-65-P1S1) as white solid. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.87 (s, 1H), 7.80 (dd, J = 1.9, 12.1 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.06 (dd, J = 8.7 Hz, 2H), 5.30 - 5.14 (m, 1H), 4.51 - 4.33 (m, 1H), 3.82 - 3.69 (m, 1H), 3.68 - 3.57 (m, 1H), 3.53 - 3.40 (m, 2H), 3.27 - 3.08 (m, 2H), 2.70 (s, 6H), 2.24 - 2.12 (m, 1H), 1.63 (br dd, J = 4.6, 9.2 Hz, 1H), 1.55 - 1.39 (m, 3H), 1.37 - 1.30 (m, 1H), 1.22 (s, 3H) EXAMPLE 179. (R)-N-((3-CHLORO-5-CYANO-4-(((2R,3S)-4-(DIMETHYLAMINO)-3- FLUORO-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE A. Step 1 [0614] Charge DMSO (1.00 mL) to an 8 mL seal tube(R1). Charge Compound 7-1 (33.0 mg, 111 μmol, 1.00 eq, HCl) to R1 at 25 °C. Charge Compound S7 (39.1 mg, 167 μmol, 1.50 eq) to R1 at 25 °C. Charge DIEA (71.8 mg, 556 μmol, 96.8 μL, 5.00 eq) to R1 at 25 °C. Stir R1 at 90 °C for 12 hrs. LCMS showed that compound 7-1 was consumed and the desired mass (R _t = 1.226 min) was observed. The crude product was purified by pre-HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 26%-66% B over 32 min) to give Compound 8-2 (18.0 mg, 27.7 μmol, 24.9% yield, 73.0% purity) as a light yellow solid. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.99 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.35 - 7.23 (m, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 5.13 (dt, J = 4.4, 7.2 Hz, 1H), 4.74 - 4.67 (m, 1H), 3.44 (br dd, J = 5.6, 14.0 Hz, 2H), 3.28 (br s, 2H), 2.83 - 2.61 (m, 2H), 2.28 (s, 6H). B. Step 2 [0615] (R)-N-((3-chloro-5-cyano-4-(((2R,3S)-4-(dimethylamino)-3-flu oro-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (8.00 mg, 97.3% purity) was obtained as white solid in 34.2% yield according to the general procedure of (R)-N-((3-cyano-4-(((2R,3S)-4-(dimethylamino)-3-fluoro-1-((4 - fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide. ¹ HNMR: (400 MHz, CD ₃ OD) δ 8.43 (s, 2H), 8.08 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.30 - 5.12 (m, 2H), 3.69 (br s, 2H), 3.45 (dd, J = 5.6, 14.4 Hz, 1H), 3.21 (dd, J = 8.4, 14.4 Hz, 2H), 3.15 - 2.99 (m, 1H), 2.58 (s, 6H), 2.23 - 2.11 (m, 1H), 1.67 - 1.57 (m, 1H), 1.53 - 1.26 (m, 5H), 1.22 (s, 3H) EXAMPLE 180. (R)-N-((3-CYANO-4-(((2R,3R)-4-(DIMETHYLAMINO)-3-FLUORO-1- ((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0616] Compound 4-2 (255 mg) was obtained as white solid according to the general procedure of compound 4-1. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 5.57 - 5.35 (m, 2H), 4.12 - 4.00 (m, 1H), 3.96 - 3.63 (m, 2H), 3.16 (d, J = 0.8 Hz, 3H), 3.01 (s, 3H), 1.47 (s, 8H) [0617] Compound 5-2 (896 mg) was obtained as colorless oil according to the general procedure of compound 5-1. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.42 (dd, J = 5.2, 8.7 Hz, 2H), 7.03 (dd, J = 8.6 Hz, 2H), 5.47 - 5.38 (m, 1H), 4.14 (q, J = 7.2 Hz, 1H), 3.22 (br dd, J = 5.6, 14.3 Hz, 1H), 3.14 - 3.04 (m, 1H), 3.02 (s, 3H), 2.93 (s, 3H), 1.46 (s, 9H) C. Step 3 [0618] Compound 6-2 (46.0 mg) was obtained as yellow oil according to the general procedure of compound 6-1. D. Step 4 [0619] Compound 7-2 (60.0 mg) was obtained as colorless according to the general procedure of compound 7-1. E. Step 5

[0620] Compound 8-3 (24.0 mg, 87.1% purity) was obtained as light yellow solid in 45.1% yield according to the general procedure of compound 8-2. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.74 - 7.58 (m, 2H), 7.28 (dd, J = 5.2, 8.8 Hz, 2H), 7.00 (dd, J = 8.8 Hz, 2H), 4.57 (br d, J = 3.6 Hz, 1H), 3.46 (dd, J = 3.2, 14.4 Hz, 1H), 3.19 (dd, J = 9.2, 14.4 Hz, 1H), 2.94 - 2.61 (m, 2H), 2.33 (s, 6H) F. Step 6 [0621] (R)-N-((3-cyano-4-(((2R,3R)-4-(dimethylamino)-3-fluoro-1-((4 - fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide(7.20 mg, 98.9% purity) was obtained as white solid in 23.3% yield according to the general procedure of (R)-N-((3-cyano-4-(((2R,3S)-4-(dimethylamino)-3-fluoro-1-((4 - fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -2-methyltetrahydro-2H-pyran-2- carboxamide. ¹ HNMR: (400 MHz, CD ₃ OD) δ 8.37 (s, 1H), 7.89 - 7.68 (m, 2H), 7.21 (dd, J = 5.2, 8.4 Hz, 2H), 7.03 (dd, J = 8.8 Hz, 2H), 5.14 - 5.06 (m, 1H), 4.52 - 4.39 (m, 1H), 3.78 - 3.68 (m, 1H), 3.66 - 3.57 (m, 1H), 3.55 - 3.47 (m, 1H), 3.26 (br s, 1H), 3.16 (br dd, J = 9.2, 14.4 Hz, 2H), 2.67 (s, 6H), 2.22 - 2.09 (m, 1H), 1.68 - 1.58 (m, 1H), 1.54 - 1.26 (m, 5H), 1.22 (s, 3H)

EXAMPLE 181. (R)-N-((3-CHLORO-5-CYANO-4-(((2R,3R)-4-(DIMETHYLAMINO)-3- FLUORO-1-((4-FLUOROPHENYL)THIO)BUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE [0622] Compound 8-4 (15.0 mg, 90.3% purity) was obtained as light yellow solid in 28.2% yield according to the general procedure of compound 8-2. ¹ HNMR: (400 MHz, CD ₃ OD) δ 8.07 - 7.71 (m, 2H), 7.24 (dd, J = 5.2, 8.8 Hz, 2H), 7.00 (dd, J = 8.8 Hz, 2H), 5.00 - 4.95 (m, 1H), 4.81 - 4.76 (m, 1H), 3.51 (dd, J = 3.2, 14.4 Hz, 1H), 3.22 (dd, J = 8.8, 14.4 Hz, 1H), 2.91 - 2.76 (m, 1H), 2.75 - 2.59 (m, 1H), 2.30 (s, 6H)

B. Step 2 [0623] (R)-N-((3-chloro-5-cyano-4-(((2R,3R)-4-(dimethylamino)-3-flu oro-1-((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide (5.00 mg, 96.9% purity) was obtained as white solid in 25.5% yield. ¹ HNMR: (400 MHz, CD ₃ OD) δ 8.42 (br s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 5.2, 8.8 Hz, 2H), 7.02 (dd, J = 8.8 Hz, 2H), 5.14 - 4.96 (m, 2H), 3.76 - 3.60 (m, 2H), 3.58 - 3.44 (m, 1H), 3.17 (br dd, J = 9.2, 14.4 Hz, 2H), 3.12 - 2.97 (m, 1H), 2.56 (s, 6H), 2.22 - 2.12 (m, 1H), 1.66 - 1.56 (m, 1H), 1.54 - 1.26 (m, 5H), 1.22 (s, 3H) EXAMPLE 182. (R)-N-((3-CYANO-4-(((2R,3S)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)-3-METHOXYBUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

[0624] Charge NaHMDS (1 M, 85.0 mL, 2.50 eq) to a 500 mL three neck bottle (R1) at 25 °C. Charge compound 1 (8 g, 34.0 mmol, 1.00 eq) in THF (40 mL) to R1 at -60 °C. Charge 2- (benzenesulfonyl)-3-phenyl-oxaziridine (17.7 g, 68.0 mmol, 2.00 eq) in THF (40 mL) to R1 at - 60 °C. Stir R1 at -60 °C for 30 min. TLC (Petroleum ether : Ethyl acetate = 1 : 1) showed the starting material was consumed and four new spot was observed. The reaction mixture was quenched with Sat. NH ₄ Cl (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 100/1 to 10/1) to give compound 1-1 (534 mg, 2.13 mmol, 6.25% yield) as white solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ = 7.88 - 7.72 (m, 2H), 7.63 - 7.51 (m, 2H), 7.40 - 7.29 (m, 6H), 6.17 (d, J = 7.0 Hz, 1H), 5.03 (s, 2H), 4.39 (t, J = 8.2 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.19 - 4.08 (m, 1H), 3.84 (t, J = 8.8 Hz, 1H). [0625] Charge compound 1-1 (1.20 g, 4.78 mmol, 1.00 eq) to a 40 mL sealed tube (R1) at 25 °C. Charge CH ₃ CN (20 mL) to R1. Charge MeI (3.46 g, 24.4 mmol, 1.52 mL, 5.10 eq) to R1. Charge Ag ₂ O (1.27 g, 5.49 mmol, 1.15 eq) to R1. Stir R1 at 25 °C under N ₂ without light for 12 hrs. TLC (Petroleum ether : Ethyl acetate = 1 : 1) showed the starting material was consumed and one major spot was observed. The reaction mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 10/1) to give compound 1-2 (0.53 g, 2.00 mmol, 41.8% yield) as yellow solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ = 7.94 (br d, J = 6.8 Hz, 1H), 7.45 - 7.27 (m, 5H), 5.06 (s, 2H), 4.50 - 4.41 (m, 1H), 4.29 (quin, J = 8.0 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.93 (t, J = 8.4 Hz, 1H), 3.47 (s, 3H). C. Step 3 [0626] Charge compound 1-2 (530 mg, 2.00 mmol, 1.00 eq) to a 40 mL sealed tube (R1) at 25°C. Charge N-methylmethanamine (2 M, 4.70 mL, 4.70 eq) to R1. Stir R1 at 60 °C for 12 hrs. TLC (Petroleum ether : Ethyl acetate = 1 : 1) showed that the starting material was consumed and one new spot was observed. The reaction mixture was concentrated to give Compound 1-3 (629 mg, crude) as yellow oil. ¹ HNMR: EB11173-21-P1N1 (400 MHz, DMSO-d ₆ ) δ = 7.47 - 7.23 (m, 5H), 6.87 (d, J = 9.1 Hz, 1H), 5.00 (q, J = 12.8 Hz, 2H), 4.83 (t, J = 5.6 Hz, 1H), 4.30 (d, J = 4.8 Hz, 1H), 3.91 - 3.78 (m, 1H), 3.51 - 3.38 (m, 1H), 3.31 (br d, J = 5.4 Hz, 1H), 3.19 (s, 3H), 3.02 (s, 3H), 2.80 (s, 3H) D. Step 4 [0627] Charge compound 1-3 (629 mg, 2.03 mmol, 1.00 eq) to a 50 mL single bottle (R1) at 25 °C. Charge MeOH (6 mL) to R1. Charge Pd/C (63.0 mg, 59.2 μmol, 10% purity, 2.92e-2 eq) to R1. Stir R1 under H ₂ ballon (15 psi) at 25°C for 1 hr. TLC (Dichloromethane : Methanol = 10:1) showed that the starting material was consumed and one major spot was observed. The reaction mixture was filtered. Charge Boc ₂ O (530 mg, 2.43 mmol, 558 μL, 1.20 eq) to the filtrate. Stir R1 at 25 °C for 1 hr. TLC (Dichloromethane : Methanol = 10:1) showed the starting material was consumed and one major spot was observed. The reaction mixture was concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Dichloromethane: Methanol = 100/1 to 10/1) to give compound 1-4 (502 mg, 1.82 mmol, 89.6% yield) as white solid. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 5.40 - 5.32 (m, 1H), 4.46 (br d, J = 4.3 Hz, 1H), 4.05 - 3.93 (m, 2H), 3.63 (dd, J = 5.3, 11.3 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H), 3.01 (s, 3H), 2.55 - 2.33 (m, 1H), 1.44 (s, 10H). E. Step 5 [0628] Charge compound 1-4 (200 mg, 723 μmol, 1.00 eq) to a 8 mL sealed tube (R1) at 25 °C. Charge THF (4 mL) to R1. Charge 4-fluorobenzenethiol (185 mg, 1.45 mmol, 155 μL, 2.00 eq) to R1. Charge tributylphosphane (293 mg, 1.45 mmol, 357 μL, 2.00 eq) to R1. Charge DIAD (293 mg, 1.45 mmol, 281 μL, 2.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 12 hrs. TLC (Petroleum ether : Ethyl acetate= 1 : 1) showed the starting material was consumed and three new spot was observed. The reaction mixture was concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 100/1 to 10/1) to give compound 1-5 (254 mg, 657 μmol, 90.8% yield) as yellow oil. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.44 (br dd, J = 5.6, 7.6 Hz, 2H), 7.03 (t, J = 8.8 Hz, 2H), 5.21 (br d, J = 8.8 Hz, 1H), 4.44 (s, 1H), 4.07 - 3.93 (m, 1H), 3.36 - 3.21 (m, 4H), 3.10 (br dd, J = 9.2, 13.6 Hz, 1H), 2.90 (br d, J = 4.0 Hz, 7H), 1.41 (s, 10H). F. Step 6

[0629] Charge compound 1-5 (254 mg, 657 μmol, 1.00 eq) to a 50 mL single bottle (R1) at 25 °C. Charge THF (6 mL) to R1. Charge LAH (2.5 M, 262 μL, 1.00 eq) to R1 at 0 °C. Stir R1 at 25 °C for 1 hr. TLC (Dichloromethane : Methanol = 10 : 1) showed that the starting material was consumed and one new spot was observed. The reaction mixture was added Na ₂ SO ₄ ·10H ₂ O (100 mg) slowly at 0 °C and stirred at 25 °C for 0.5 h. The mixture was filtered, the filtrate was concentrated under reduced pressure to give crude product. The crude product was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10 : 1) to give compound 1-6 (140 mg, 375 μmol, 57.2% yield) as yellow oil. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.43 - 7.29 (m, 2H), 6.99 - 6.87 (m, 2H), 5.04 (br d, J = 9.2 Hz, 1H), 3.84 (q, J = 7.6 Hz, 1H), 3.54 (br t, J = 5.6 Hz, 1H), 3.29 (s, 3H), 3.04 - 2.86 (m, 2H), 2.38 - 2.21 (m, 2H), 2.16 (s, 6H), 1.37 (s, 8H). G. Step 7 [0630] Charge compound 1-6 (140 mg, 375 μmol, 1.00 eq) to a 50 mL single bottle (R1), Charge HCl/dioxane (4 M, 1.88 mL, 20.0 eq) to R1, Stir R1 at 25 °C for 1hr. TLC (Dichloromethane : Methanol = 10 : 1) showed that the starting material was consumed and one new spot was observed. LCMS showed the desired mass (RT = 1.52 min) was detected. The reaction mixture was concentrated to give crude product. The crude product was used directly in next step. Compound 1-7 (147 mg, crude, HCl) was obtained as yellow solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ = 10.61 - 10.02 (m, 1H), 8.57 (br s, 3H), 7.61 (dd, J = 5.3, 8.7 Hz, 2H), 7.30 (t, J = 8.8 Hz, 2H), 4.22 - 4.03 (m, 1H), 3.60 - 3.49 (m, 2H), 3.41 (s, 4H), 3.33 - 3.21 (m, 2H), 2.82 (s, 6H) H. Step 8 [0631] Charge compound 1-7 (20.0 mg, 64.7 μmol, 1.00 eq, HCl) to a 8 mL sealed tube (R1) at 25 °C. Charge DMSO (0.5 mL) to R1. Charge 3-cyano-4,5-difluoro-benzenesulfonamide (21.0 mg, 96.2 μmol, 1.49 eq) to R1^^Charge DIEA (41.8 mg, 323.8 μmol, 56.4 μL, 5.00 eq) to R1^^ Stir R1 at 90 °C for 48 hrs. LCMS showed the desired mass (RT= 1.374min) was detected. The reaction mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:30%-70% B over 32 min) to give compound 1-8 (20 mg, 42.5 μmol, 65.6% yield) as yellow solid. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.73 (s, 1H), 7.64 (dd, J = 1.9, 12.3 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.09 - 7.00 (m, 2H), 4.65 - 4.52 (m, 1H), 3.83 - 3.70 (m, 1H), 3.42 (s, 3H), 3.40 - 3.35 (m, 1H), 3.20 (dd, J = 7.9, 14.0 Hz, 1H), 2.59 - 2.41 (m, 2H), 2.23 (s, 7H) I. Step 9 [0632] Charge Acid 9 (12.3mg, 85.0 μmol, 2.00 eq) to an 8 mL sealed tube (R1) at 25 °C. Charge CH3CN (1 mL) to R1. Charge EDCI (16.3 mg, 85.0 μmol, 2.00 eq) to R1. Charge DMAP (10.4 mg, 85.0 μmol, 2.00 eq) to R1. Charge compound 1-8 (20.0 mg, 42.5 μmol, 1.00 eq) to R1. Stir R1 at 25 °C for 12 hrs. LCMS (Eb11173-67-IPCL2) showed the desired mass (RT = 1.27 min) was detected. The reaction mixture was purified by pre-HPLC (column: Xtimate C18150*40mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];gradient:10%-50% B over 32 min) to give (R)-N-((3-cyano-4-(((2R,3S)-4-(dimethylamino)-1-((4-fluoroph enyl)thio)-3- methoxybutan-2-yl)amino)-5-fluorophenyl)sulfonyl)-2-methylte trahydro-2H-pyran-2- carboxamide (6.60 mg, 11.1 μmol, 26.0% yield) as white solid. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.81 (s, 1H), 7.74 (dd, J = 1.8, 11.8 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.05 (t, J = 8.8 Hz, 2H), 4.29 (td, J = 3.7, 9.6 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.68 (br d, J = 5.8 Hz, 2H), 3.45 - 3.37 (m, 4H), 3.27 (br d, J = 2.8 Hz, 1H), 3.24 - 3.14 (m, 1H), 3.05 (dd, J = 9.9, 14.1 Hz, 1H), 2.80 (s, 6H), 2.21 (br d, J = 12.5 Hz, 1H), 1.66 - 1.55 (m, 1H), 1.54 - 1.38 (m, 3H), 1.30 (br d, J = 8.4 Hz, 1H), 1.20 (s, 3H) EXAMPLE 183. (R)-N-((3-CHLORO-5-CYANO-4-(((2R,3S)-4-(DIMETHYLAMINO)-1- ((4-FLUOROPHENYL)THIO)-3-METHOXYBUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE A. Step 1 [0633] Compound 1-8-1 (20.0 mg) was obtained as yellow solid according to the general procedure of compound 1-8. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.94 (d, J = 2.1 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.39 - 7.30 (m, 2H), 7.03 (t, J = 8.8 Hz, 2H), 3.79 (dt, J = 2.4, 6.7 Hz, 1H), 3.45 - 3.36 (m, 4H), 3.24 (dd, J = 7.5, 14.0 Hz, 1H), 2.49 (br d, J = 6.8 Hz, 2H), 2.23 (s, 7H) B. Step 2 [0634] (R)-N-((3-chloro-5-cyano-4-(((2R,3S)-4-(dimethylamino)-1-((4 -fluorophenyl)thio)-3- methoxybutan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro- 2H-pyran-2-carboxamide(10.9 mg) was obtained as white solid according to the general procedure of (R)-N-((3-cyano-4- (((2R,3S)-4-(dimethylamino)-1-((4-fluorophenyl)thio)-3-metho xybutan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 8.02 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 5.3, 8.6 Hz, 2H), 7.06 (t, J = 8.7 Hz, 2H), 4.71 (br t, J = 5.6 Hz, 1H), 3.81 (dt, J = 2.2, 6.5 Hz, 1H), 3.74 - 3.63 (m, 2H), 3.41 (s, 3H), 3.39 - 3.34 (m, 1H), 3.18 (dd, J = 7.4, 13.9 Hz, 1H), 2.54 (d, J = 6.6 Hz, 2H), 2.25 (s, 7H), 1.61 (br d, J = 4.5 Hz, 1H), 1.52 - 1.39 (m, 3H), 1.33 - 1.23 (m, 2H), 1.21 (s, 3H). EXAMPLE 184. (R)-N-((3-CYANO-4-(((2R,3R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)-3-METHOXYBUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

A. Step 1 [0635] Charge compound 1-1 (1.46 g, 5.81 mmol, 1.00 eq) to a 40 mL sealed tube (R1) at 25 °C. Charge THF (12 mL) to R1. Charge 4-nitrobenzoic acid (2.82 g, 16.8 mmol, 2.90 eq) to R1. Charge PPh ₃ (5.41 g, 20.6 mmol, 3.55 eq) to R1. Charge DEAD (3.95 g, 22.6 mmol, 4.12 mL, 3.90 eq) to R1 at 0 °C. Stir R1 at 25 °C for 12 hrs. TLC (Petroleum ether : Ethyl acetate = 1:1) showed that the starting material was consumed and five new spot was observed. The reaction mixture was concentrated to give crude product. The crude product was purified by column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 1:1 ) to give colorless oil. The colorless oil was purified by pre-HPLC (column: Welch Xtimate C18250*50mm*10um;mobile phase: [water(HCl)-ACN];gradient:20%-60% B over 20 min) to give compound 2-1 (984 mg, 2.33 mmol, 40.0% yield, 94.6% purity) was obtained as white solid. ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ = 8.34 (br d, J = 8.4 Hz, 2H), 8.22 - 8.09 (m, 3H), 7.35 - 7.14 (m, 5H), 6.02 (d, J = 7.1 Hz, 1H), 4.94 (s, 2H), 4.75 - 4.55 (m, 2H), 4.33 (d, J = 9.5 Hz, 1H) B. Step 2 [0636] Charge compound 2-1 (840 mg, 2.0 mmol, 1.00 eq) to a 40 mL sealed tube (R1) at 25 °C. Charge DCM (8 mL) and MeOH (8 mL) to R1. Charge NaOMe (5.4 M, 37.0 μL, 0.10 eq) to R1 at -20 °C. Stir R1 at -20 °C for 1 min. TLC (Petroleum ether : Ethyl acetate = 1 : 1) showed that the starting material was consumed and four new spot was observed. The reaction mixture was poured into sat critic (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers was washed with brine, (30 mL), dried over Na2SO4, filtered, and concentrated to give crude product. The reaction mixture was purified by column chromatography (SiO ₂ , Petroleum ether : Ethyl acetate = 100/1 to 10/1) to give compound 3-1 (190 mg, 756 μmol, 37.8% yield) as white solid; ¹ HNMR: (400 MHz, DMSO-d ₆ ) δ = 7.48 (br d, J = 6.4 Hz, 1H), 7.40 - 7.28 (m, 4H), 6.08 (br d, J = 6.4 Hz, 1H), 5.05 (s, 2H), 4.49 (t, J = 6.8 Hz, 1H), 4.42 - 4.36 (m, 1H), 4.35 - 4.28 (m, 1H), 4.10 (dd, J = 1.6, 9.6 Hz, 1H) C. Step 3 [0637] Compound 4-1 (143 mg) was obtained as yellow solid according to the general procedure of compound 1-2. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.45 - 7.31 (m, 5H), 5.43 (br s, 1H), 5.13 (s, 2H), 4.52 (br d, J = 4.4 Hz, 1H), 4.39 (br d, J = 4.0 Hz, 2H), 4.02 (br d, J = 6.0 Hz, 1H), 3.61 (s, 3H). D. Step 4 [0638] Compound 5-1 (184 mg) was obtained as yellow oil according to the general procedure of compound 1-3. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.38 - 7.21 (m, 4H), 5.77 (br d, J = 8.0 Hz, 1H), 5.18 - 4.94 (m, 2H), 4.32 (d, J = 2.8 Hz, 1H), 3.91 - 3.75 (m, 2H), 3.65 - 3.49 (m, 1H), 3.28 (s, 3H), 3.10 (s, 3H), 2.92 (s, 3H). [0639] Compound 6-1 (72.0 mg) was obtained as yellow oil according to the general procedure of compound 1-4. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 5.54 (br d, J = 7.1 Hz, 1H), 4.39 (br s, 1H), 3.94 - 3.78 (m, 2H), 3.66 (br dd, J = 1.4, 6.0 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 3H), 3.01 (s, 3H), 2.81 - 2.67 (m, 1H), 1.48 (s, 10H). [0640] Compound 7-1 (62.0 mg) was obtained as yellow oil according to the general procedure of compound 1-5. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.40 (dd, J = 5.3, 8.5 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.34 (br d, J = 8.9 Hz, 1H), 4.21 (d, J = 4.4 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.31 (s, 3H), 3.14 - 3.06 (m, 2H), 3.02 (s, 3H), 2.90 (s, 3H), 1.44 (s, 10H) [0641] Compound 8-1 (30.0 mg) was obtained as yellow oil according to the general procedure of compound 1-6. ¹ HNMR: (400 MHz, CDCl ₃ ) δ = 7.34 (br dd, J = 5.4, 8.2 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H), 5.46 (br s, 1H), 3.92 - 3.77 (m, 1H), 3.41 (br d, J = 5.0 Hz, 1H), 3.28 (s, 3H), 3.02 (br d, J = 4.8 Hz, 2H), 2.46 - 2.28 (m, 3H), 2.20 (s, 7H), 1.36 (s, 10H) H. Step 8 [0642] Compound 9-1 (36.0 mg) was obtained as yellow solid according to the general procedure of compound 1-7. I. Step 9 [0643] Compound 10-1 (14.0 mg) was obtained as yellow solid according to the general procedure of compound 1-8. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.60 (d, J = 0.8 Hz, 1H), 7.51 (dd, J = 2.0, 12.5 Hz, 1H), 7.26 (dd, J = 5.1, 8.8 Hz, 2H), 6.92 (t, J = 8.8 Hz, 2H), 4.57 - 4.52 (m, 1H), 3.54 (q, J = 4.8 Hz, 1H), 3.32 (s, 3H), 3.30 - 3.25 (m, 1H), 3.18 - 3.08 (m, 1H), 2.61 - 2.42 (m, 2H), 2.21 (s, 6H). J. Step 10 [0644] (R)-N-((3-cyano-4-(((2R,3R)-4-(dimethylamino)-1-((4-fluoroph enyl)thio)-3- methoxybutan-2-yl)amino)-5-fluorophenyl)sulfonyl)-2-methylte trahydro-2H-pyran-2- carboxamide (7.82 mg) was obtained as white solid according to the general procedure of (R)-N- ((3-cyano-4-(((2R,3S)-4-(dimethylamino)-1-((4-fluorophenyl)t hio)-3-methoxybutan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 8.37 (br s, 1H), 7.84 (s, 1H), 7.76 (dd, J = 2.0, 12.0 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.11 - 6.97 (m, 2H), 4.37 (td, J = 4.4, 9.0 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.77 - 3.67 (m, 1H), 3.66 - 3.56 (m, 1H), 3.47 (s, 3H), 3.40 - 3.34 (m, 1H), 3.28 - 3.17 (m, 2H), 2.85 (s, 6H), 2.16 (br d, J = 13.4 Hz, 1H), 1.66 - 1.57 (m, 1H), 1.53 - 1.39 (m, 3H), 1.37 - 1.25 (m, 2H), 1.20 (s, 3H). EXAMPLE 185. (R)-N-((3-CHLORO-5-CYANO-4-(((2R,3R)-4-(DIMETHYLAMINO)-1- ((4-FLUOROPHENYL)THIO)-3-METHOXYBUTAN-2- YL)AMINO)PHENYL)SULFONYL)-2-METHYLTETRAHYDRO-2H-PYRAN-2- CARBOXAMIDE

A. Step 1 [0645] Compound 10-1-1 (8.00 mg) was obtained as yellow solid according to the general procedure of compound 1-8. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 7.82 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 5.2, 8.4 Hz, 2H), 6.91 (t, J = 8.4 Hz, 2H), 4.85 (br d, J = 4.0 Hz, 1H), 3.58 (q, J = 4.8 Hz, 1H), 3.37 - 3.30 (m, 4H), 3.15 (dd, J = 8.1, 14.3 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.52 - 2.44 (m, 1H), 2.22 (s, 6H). B. Step 2 [0646] (R)-N-((3-chloro-5-cyano-4-(((2R,3R)-4-(dimethylamino)-1-((4 -fluorophenyl)thio)-3- methoxybutan-2-yl)amino)phenyl)sulfonyl)-2-methyltetrahydro- 2H-pyran-2-carboxamide (6.51 mg) was obtained as white solid according to the general procedure of (R)-N-((3-cyano-4- (((2R,3S)-4-(dimethylamino)-1-((4-fluorophenyl)thio)-3-metho xybutan-2-yl)amino)-5- fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carboxa mide. ¹ HNMR: (400 MHz, CD ₃ OD) δ = 8.05 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.08 - 7.01 (m, 2H), 4.52 (td, J = 4.3, 8.6 Hz, 1H), 4.13 - 3.95 (m, 1H), 3.73 - 3.59 (m, 2H), 3.46 (s, 3H), 3.40 (dd, J = 4.5, 14.3 Hz, 1H), 3.24 (dd, J = 5.5, 8.8 Hz, 1H), 2.80 (s, 6H), 2.25 - 2.12 (m, 1H), 1.67 - 1.54 (m, 1H), 1.51 - 1.41 (m, 3H), 1.36 - 1.29 (m, 1H), 1.19 (s, 3H). EXAMPLE 186. (S)-N-((3-CYANO-5-FLUORO-4-(4-METHYL-2- PHENETHYLPIPERAZIN-1-YL)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE AND (R)-N-((3-CYANO-5-FLUORO- 4-(4-METHYL-2-PHENETHYLPIPERAZIN-1-YL)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0647] To a solution of compound 1 (5.00 g, 53.1 mmol, 4.85 mL) in THF (25.0 mL) was added LDA (2 M, 26.6 mL) at -78 °C, and compound A (9.09 g, 53.1 mmol, 6.31 mL) in THF (22.2 g, 308 mmol, 25.0 mL) was added to the mixture at -20 °C. The mixture was stirred at 0 °C for 1 hr, and 25 °C for 1 hr. LCMS (compound 2: RT = 1.580 min) showed compound 1 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by NH ₄ OAc 10.0 mL. The combined organic layers were extracted with DCM 45.0 mL, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1000/1 to 1/1, petroleum ether/ethyl acetate = 2:1) to give compound 2 (3.78 g, 38.6% yield) as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.52-8.35 (m, 3H), 7.29-7.16 (m, 5H), 3.14-3.07 (m, 4H). B. Step 2 [0648] To a solution of compound 2 (3.00 g, 16.2 mmol) in EtOH (60.0 mL) was added Pd/C (1.80 g, 16.2 mmol, 10% purity) and H ₂ (50 Psi). The mixture was stirred at 25 °C for 8 hrs. LCMS (compound 3: RT = 0.286 min) showed compound 2 was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give compound 3 (2.80 g, 90.3% yield) was obtained as yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.36-7.24 (m, 5H), 3.07-2.50 (m, 9H), 2.00-1.72 (m, 2H), 1.71-1.69 (m, 2H). C. Step 3 [0649] To a solution of compound 3 (1.90 g, 9.99 mmol) in DCM (14.0 mL) was added Boc ₂ O (2.18 g, 9.99 mmol, 2.29 mL) and TEA (1.11 g, 10.9 mmol, 1.53 mL). The mixture was stirred at 0 °C for 1 hr. LCMS (compound Amine 19: RT = 0.512 min) showed compound 3 was consumed completely and one main peak with desired mass was detected. The reaction mixture was quenched by H ₂ O 25.0 mL. The combined organic layers were extracted with DCM 60.0 mL, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1000/1 to 10/1) to give compound Amine 19 (1.58 g, 54.4% yield) as yellow oil. ¹ H NMR: (400 MHz, MeOD) δ 7.28-7.16 (m, 5H), 3.98-3.86 (m, 2H), 2.94-2.63 (m, 7H), 1.71-1.68 (m, 2H), 1.67-1.45 (m, 9H). D. Step 4 [0650] Compound 19-3 (100 mg) was obtained as white solid in 11.2% yield according to the general procedure of compound D6-3. E. Step 5 [0651] Compound 19-4 (90.0 mg) was obtained as yellow oil in 69.9% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin-3- yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyclo hexane-1-carboxamide .

F. Step 6 [0652] Compound 19-4 (80.0 mg, 127 μmol) was for further purification. The residue was purified by prep-HPLC (column: (s, s) WHELK-O1 (250 mm x 30 mm, 5 um); mobile phase: [Heptane-EtOH (0.1% TFA)]; B%: 40%, isocratic elution mode) to give compound 19-5 (30.0 mg, 37.5% yield) and compound 19-6 (35.0 mg, 43.7% yield) were obtained as white solid. LCMS (ESI) m/z 573.4 (M+H ⁺ ). Chiral SFC e.e.% = 96.9%. LCMS (ESI) m/z 573.5 (M+H ⁺ ). Chiral SFC e.e.% = 100%.

G. Step 7 [0653] Compound 19-7 (12.0 mg, HCl) was obtained as yellow oil in 71.3% yield according to the general procedure of compound Amine 4. Compound 19-8 (12.0 mg, HCl) was obtained as yellow oil in 71.3% yield according to the general procedure of compound Amine 4.

H. Step 8 [0654] (S)-N-((3-cyano-5-fluoro-4-(4-methyl-2-phenethylpiperazin-1- yl)phenyl)sulfonyl)-1- methoxycyclohexane-1-carboxamide (9.74 mg, 99.3% purity) was obtained as white solid in 77.8% yield according to the general procedure of compound 24-4. ¹ H NMR: (400 MHz, MeOD) δ 7.94-7.80 (m, 2H), 7.19-6.95 (m, 5H), 3.65-3.25 (m, 2H), 3.24-3.23 (m, 1H), 3.06 (s, 3H), 2.54-2.49 (m, 6H), 2.33 (s, 3H), 1.73-1.24 (m, 13H). LCMS (ESI) m/z 543.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. 2D NMR [0655] (R)-N-((3-cyano-5-fluoro-4-(4-methyl-2-phenethylpiperazin-1- yl)phenyl)sulfonyl)-1- methoxycyclohexane-1-carboxamide (9.36 mg, 98.0% purity) was obtained as white solid in 75.3% yield according to the general procedure of compound 24-4. ¹ H NMR: (400 MHz, MeOD) δ 8.00-7.86 (m, 2H), 7.20-6.95 (m, 5H), 3.72-3.35 (m, 4H), 3.07-2.70 (m, 4H), 2.56-2.52 (m, 5H), 1.74-1.23 (m, 13H). LCMS (ESI) m/z 543.2 (M+H ⁺ ). Chiral SFC e.e.% = 100%. EXAMPLE 187. (R)-N-((3-CYANO-4-((4-(3-(DIFLUOROMETHOXY)AZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0656] To a solution of compound 5 (100 mg, 286.19 μmol) in THF (1 mL) was added MsCl (49.18 mg, 429.28 μmol, 33.23 μL) and TEA (144.80 mg, 1.43 mmol, 199.17 μL) at 0 °C was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 3 hrs under N ₂ atmosphere . LCMS showed one main peak with desired mass was detected. The solution of compound 6 (122.35 mg, crude) as colorless oil in THF (1 mL) was obtained and the solution was used into the next step without further purification. B. Step 2

[0657] To a solution of compound 6 (122.35 mg, 286.19 μmol) in THF (1 mL) was added TEA (144.80 mg, 1.43 mmol, 199.17 μL) and compound C1 (84.15 mg, 429.29 μmol, HCl) at 0 °C was degassed and purged with N ₂ for 3 times, and then the mixture was heated to 40°C and stirred for 72 hrs under N ₂ atmosphere. LCMS (compound 7-C1 RT = 2.320min) showed the starting material was consumed completely. The mixture was cooled to 20°C and concentrated in reduced pressure. The residue was poured into ice-water (20 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered, and concentrated in vacuum. The residue was compound 7-C1 (135 mg, crude) as colorless oil. C. Step 3 [0658] To a solution of compound 7-C1 (135 mg, 297.03 μmol) in DCM (1 mL) was added Me ₂ S (92.28 mg, 1.49 mmol, 109.07 μL) followed by addition of BF _3• Et ₂ O (421.56 mg, 2.97 mmol, 365.31 μL) at 0°C and the mixture was stirred at 20°C for 12 hours. LCMS (compound 8-P1 RT = 0.925 min) showed the starting material was consumed completely. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC: column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-17% B over 8.0 min to give compound 8-C1 (35 mg, 36.78% yield, 95.1% purity) as yellow oil.

D. Step 4 [0659] Compound 9-C1 (40 mg, 91.1% purity) was obtained as yellow oil in 60.4% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.68-7.60 (m, 3H), 7.59-7.56 (m, 3H), 7.02-6.97 (m, 3H), 6.55-6.18 (m, 1H), 5.49 (s, 1H), 3.67 (s,1H), 4.74 (m,1H), 3.68-3.67 (m, 2H), 3.16-3.14 (m, 2H), 3.12-3.09 (m.5H), 2.204 (s, 2H), 1.864 (s, 1H), 1.29-1.24 ^m, 2H). LCMS (ET65480-64-P1A7) (ESI) m/z 519.2 (M+H ⁺ ). E. Step 5 [0660] (R)-N-((3-cyano-4-((4-(3-(difluoromethoxy)azetidin-1-yl)-1-( (4- fluorophenyl)thio)butan-2-yl)amino)-5-fluorophenyl)sulfonyl) -1-methoxycyclohexane-1- carboxamide (2.28 mg, 90.2% purity) was obtained as a white solid in 59.8% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin- 3-yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyc lohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.81 (s, 1H), 7.71-7.68 (m, 1H), 7.27-7.24 (m, 2H), 7.03-6.99 (m, 2H), 6.61-6.24 (m, 1H), 5.17 (s, 1H), 4.58 (s, 1H), 4.38 (s, 1H), 3.57-3.39 (m.6H), 3.26 (m, 1H), 3.13-3.11 (m, 5H), 1.90-1.58 (m, 4H), 1.54-1.50 (m, 8H), 1.29-1.23 (m, 4H), LCMS (ESI) m/z 659.2 (M+H ⁺ ). EXAMPLE 188. N-((3-CYANO-4-((2R,4R)-2-(2-(DIMETHYLAMINO)ETHYL)-4- PHENYLPYRROLIDIN-1-YL)-5-FLUOROPHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE [0661] To a solution of compound 1A (900 mg, 3.09 mmol) in THF (6.30 mL) was added BH ₃ .THF (1 M, 6.18 mL) at 15 °C and the mixture was stirred at 80 °C for 0.5 hr. TLC (Petroleum ether/Ethyl acetate = 1/1, product R _f = 0.37) showed the compound 1A was consumed and one new spot formed. The mixture was cooled to -10-0°C. The reaction mixture was quenched by addition MeOH (10.0 mL), the mixture was stirred at -10-0 °C for 0.5 hr, at 60°C for 0.5 hr, and the mixture was poured into H ₂ O (10.0 mL) and extracted with EtOAc (10.0 mL x 3). The combined organic layers were washed with brine (40.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a compound 2A (790 mg, 2.16 mmol, 69.9% yield, 75.9% purity) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.35-7.31 (m, 2H), 7.27-7.21 (m, 3H), 4.23 (d, J = 11.2 Hz, 1H), 3.80-3.71 (m, 3H), 1.31 (d, J = 6.0 Hz, 18H), 3.45 (d, J = 13.6 Hz, 2H), 2.28-2.15 (m, 1H), 2.05-2.01 (m, 1H), 1.49 (s, 9H) B. Step 2 [0662] To a solution of compound 2A (690 mg, 2.49 mmol) in DCM (4.8 mL) was added at MsCl (598 mg, 5.22 mmol, 404.36 μL) and TEA (780 mg, 7.71 mmol) at 0 °C and the mixture was stirred at 15 °C for 1 hr. LCMS (product RT = 0.808 min) showed the compound 2A was consumed and one new peak with desired mass detected. The reaction mixture was quenched by addition H ₂ O (30.0 mL) and extracted with MTBE (30.0 mL x 3). The combined organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give compound 3A (1.05 g, 1.70 mmol, 68.4% yield, 89.6% purity) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.35-7.31 (m, 2H), 7.27-7.23 (m, 3H), 4.41-4.37 (m, 2H), 4.23- 4.18 (m, 1H), 3.82-3.78 (m, 1H), 3.55-3.51 (m, 3H), 2.78 (s, 3H), 2.35-2.34 (m, 1H), 2.22-2.18 (m, 1H), 1.46 (s, 9H). C. Step 3 [0663] To a solution of compound 3A (1.05 g, 2.95 mmol) in DMF (7.00 mL) was added NaCN (217 mg, 4.43 mmol) and TEA (597 mg, 5.91 mmol, 822 μL) at 15 °C and the mixture was stirred at 90 °C for 4 hrs. TLC (petroleum ether/ethyl acetate=1/1, product Rf = 0.60) showed the compound 3A was consumed and one new spot formed. The reaction mixture was quenched by addition NaHCO3 (50.00 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50.00 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 to 1/1) to give compound 4A (523 mg, 1.74 mmol, 58.8% yield, 95.2% purity) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.36-7.32 (m, 2H), 7.28-7.23 (m, 3H), 4.22-4.10 (m, 1H), 3.89-3.86 (m, 1H), 3.84-3.67 (m, 1H), 3.39-3.37 (m, 1H), 2.89-2.81 (m, 2H), 2.34-2.30 (m, 2H), 1.47 (s, 9H). D. Step 4 [0664] To a solution of Raney-Ni (448 mg, 5.24 mmol) in THF (5.00 mL) and MeOH (5.00 mL) was added compound 4A (500 mg, 1.75 mmol) at 15 °C and the mixture was stirred at 50 °C for 12 hrs under H ₂ atmosphere. TLC (Petroleum ether/Ethyl acetate = 2/1, product R _f = 0.7) showed the reaction 1 was consumed and one new spot formed. Filtered the reaction mixture and the reaction mixture was concentrated in vacuum to remove solvent to give compound 5A (413 mg, 1.31 mmol, 74.9% yield, 92.0% purity) as a white solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.34-7.27 (m, 2H), 7.24-7.23 (m, 3H), 4.12-4.00 (m, 1H), 3.75-3.73 (m, 1H), 3.47-3.45 (m, 2H), 3.30-3.27 (m, 1H), 2.95-2.71 (m, 2H), 2.14-2.02 (m, 3H), 1.49 (s, 9H). E. Step 5 [0665] To a solution of compound 5A (363 mg, 1.25 mmol) in MeOH (5 mL) was added HCHO (608.64 mg, 7.50 mmol) and NaBH3CN (392.76 mg, 6.25 mmol) at 15 °C and the mixture was stirred at 15 °C for 12 hrs. LCMS (ET72814-36-P1A, product RT = 0.624 min) showed the reaction 1 was consumed and one new peak with desired mass was detected. The reaction mixture quenched with water (10 mL) and extracted by DCM (15 mL x 3). The solution was dried with Na ₂ SO ₄ and filtered. The reaction mixture was concentrated in vacuum to remove solvent. The reaction mixture was purified by prep-HPLC: (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 35%-65% B over 8.0 min) to give compound 6A (142 mg, 440 μmol, 35.2% yield, 98.8% purity) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 2H), 7.27-7.21 (m, 3H), 4.01-3.74 (m, 2H), 3.48-3.29 (m, 2H), 2.35-2.25 (m, 8H), 2.12-2.07 (m, 3H), 1.51-1.49 (m, 10H). F. Step 6 [0666] A solution of compound 6A (122 mg, 383 μmol) in HCl/MeOH (1.5 mL) was stirred at 15 °C for 1 hrs. LCMS (product RT = 0.395 min) showed the reaction 1 was consumed and one new peak with desired mass was detected. The reaction mixture was concentrated in vacuum to remove solvent to give Amine 25C (118 mg, 93.9% yield) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.30-7.25 (m, 5H), 4.56 (s, 1H), 4.09 (s, 1H), 3.84-3.78 (m, 3H), 3.65-3.47 (m, 1H), 3.00 (s, 6H), 2.75-2.74 (m, 1H), 2.35 (s, 3H).

G. Step 7 [0667] To a solution of Amine 25C (118 mg, 540 μmol) in DMSO (2.00 mL) was added sulfonamide 3 (141 mg, 648 μmol) and DIEA (349 mg, 2.70 mmol) at 15 °C and the mixture was stirred at 90 °C for 12 hrs. LCMS (product RT = 0.521 min) showed the reaction 1 was consumed and one new peak with desired mass was detected. The reaction mixture was quenched by H ₂ O (2.0 mL).The combined organic layers were extracted with DCM (20 mL x 3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give compound 7A (152 mg, 176 μmol, 32.7% yield, 48.5% purity) as a yellow solid. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.61-7.60 (m, 1H), 7.32-7.18 (m, 5H), 4.69-4.68 (m, 1H), 4.59-4.55 (m, 1H), 4.15-4.10 (m, 2H), 3.64-3.60 (m, 2H), 2.36-2.33 (m, 3H), 2.21 (s, 6H), 2.16-2.05 (m, 1H), 1.59-1.56 (m, 1H).

H. Step 8 [0668] To a solution of compound 7A (100 mg, 240 μmol) in ACN (2.00 mL) was added Acid 7 (56.9 mg, 360 μmol),EDCI (69.0 mg, 360 μmol) and DMAP (44.0 mg, 360.1 μmol) at 15 °C and the mixture was stirred at 15 °C for 12 hrs. LCMS (product RT = 1.707 min) showed the reaction 1 was consumed and one new peak with desired mass was detected. The reaction mixture diluted with water (5 mL) and extracted by ethyl acetate (10 mL x 3). The solution was dried with Na2SO4 and filtered. The reaction mixture was concentrated in vacuum to remove solvent. The combined crude product was purified by prep-HPLC: (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H ₂ O (10mM NH ₄ HCO ₃ )-ACN]; gradient: 30%-55% B over 8.0 min) to give N-((3-cyano-4-((2R,4R)-2-(2-(dimethylamino)ethyl)-4- phenylpyrrolidin-1-yl)-5-fluorophenyl)sulfonyl)-1-methoxycyc lohexane-1-carboxamide (35.8 mg, 61.6 μmol, 25.6% yield, 95.8% purity) as a white solid. (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.90-7.78 (m, 1H), 7.30-7.19 (m, 5H), 4.50-4.39 (m, 1H), 4.38-4.36 (m, 1H), 3.66-3.54 (m, 2H), 3.51-3.31 (m, 2H), 3.16-3.10 (m, 5H), 2.36-2.23 (m, 3H), 1.17-1.65 (m, 5H), 1.53-1.47 (m, 5H), 1.26-1.22 (m, 1H). EXAMPLE 189. (R)-N-((3-CHLORO-5-CYANO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)- 1-((4-FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0669] (R)-N-((3-chloro-5-cyano-4-(((R)-4-(3-fluoroazetidin-1-yl)-1 -((4- fluorophenyl)thio)butan-2-yl)amino)phenyl)sulfonyl)-2-methyl tetrahydro-2H-pyran-2- carboxamide(38.28 mg, 99.% purity) was obtained as a white solid in 46.4% yield according to the general procedure of (S)-N-((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl) pyridin- 3-yl)pentan-3-yl)amino)-5-fluorophenyl)sulfonyl)-1-fluorocyc lohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.95-7.83 (m, 2H), 7.14-7.11 (m, 2H), 6.94-6.89 (m, 2H), 5.24-4.99 (m, 1H), 4.46-4.33 (m, 2H), 3.94-3.78 (m, 4H), 3.65-3.48 (m, 1H), 3.24-3.23 (m, 1H), 2.96-2.77 (m, 2H), 2.05-2.01 (s, 1H), 1.89-1.74 (m, 2H), 1.54-1.51 (m, 1H), 1.42-1.29 (m, 3H), 1.27-1.17 (m, 1H), 1.10 (s, 3H). LCMS (ET55012-574-P1D1), (ESI) m/z 613.0 (M+H ⁺ ). EXAMPLE 190. (R)-N-((3-CYANO-5-FLUORO-4-((1-((4-FLUOROPHENYL)THIO)-4-(3- METHOXYAZETIDIN-1-YL)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-1- METHOXYCYCLOHEXANE-1-CARBOXAMIDE A. Step 1 [0670] Compound 7-A1 (180 mg, 72.1% purity) was obtained as yellow oil in 44.1% yield according to the general procedure of compound 7-P1. ¹ H NMR: (400 MHz, MeOD) δ 7.45-7.31 (m, 7H), 7.05-7.02 (m, 2H), 5.08-5.04 (m, 2H), 4.01-3.98 (m, 1H), 3.67-3.66 (m, 1H), 3.54-3.53 (m, 2H), 3.24-3.22 (m, 3H), 3.00-2.92 (m, 4H), 2.49-2.47 (m, 2H) , 1.73-1.70 (m, 1H), 1.51-1.48 (m, 1H). LCMS (ET60921-357-P1E1) (ESI) m/z 419.2 (M+H ⁺ ). B. Step 2 [0671] Compound 8-A1 (80 mg, crude) was obtained as yellow oil according to the general procedure of compound 8-P1. Compound 8-A1 (80 mg, crude) was further analysis. ¹ H NMR: ET60921-363-P1F1 (400 MHz, MeOD) δ 7.54-7.50 (m, 2H), 7.14-7.09 (m, 2H), 4.08-4.05 (m, 1H), 3.72-3.70 (m, 2H), 3.27 (s, 3H), 3.17-3.16 (m, 4H), 3.14-3.00 (m, 1H), 2.78-2.76 (m, 2H), 1.84-1.80 (m, 1H), 1.60-1.55 (m, 1H). LCMS (ET60921-363-P1E1) (ESI) m/z 285.3 (M+H ⁺ ).

[0672] Compound 9-A1 (50 mg, 85.7% purity) was obtained as yellow oil in 50.5% yield according to the general procedure of compound D6-3. ¹ H NMR: (400 MHz, MeOD) δ 7.68-7.57 (m, 2H), 7.33-7.29 (m, 2H), 7.02-6.98 (m, 2H), 4.41 (s, 1H), 4.04-4.03 (m, 1H), 3.60-3.59 (m, 2H), 3.28 (s, 3H), 3.25-3.14 (m, 1H), 2.94-2.68 (m, 2H), 2.66 (s, 6H), 1.82-1.76 (m, 2H). LCMS (ET60921-365-P1E1) (ESI) m/z 483.3 (M+H ⁺ ). [0673] (R)-N-((3-cyano-5-fluoro-4-((1-((4-fluorophenyl)thio)-4-(3-m ethoxyazetidin-1- yl)butan-2-yl)amino)phenyl)sulfonyl)-1-methoxycyclohexane-1- carboxamide (17.3 mg, 95.7% purity) was obtained as a white solid in 25.6% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.77-7.68 (m, 2H), 7.26-7.23 (m, 2H), 7.04-6.99 (m, 2H), 4.25-4.09 (m, 4H), 3.67-3.66 (m, 2H), 3.26-3.11 (m, 8H), 2.82-2.79 (m, 1H), 1.87--1.50 (m, 13H), 1.49 -1.17 (m, 2H). LCMS (ET60921-370-P1E1) (ESI) m/z 623.0 (M+H ⁺ ). EXAMPLE 191. (R)-N-((3,5-DICHLORO-4-(((R)-4-(3-FLUOROAZETIDIN-1-YL)-1-((4 - FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)PHENYL)SULFONYL)-2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0674] (R)-N-((3,5-dichloro-4-(((R)-4-(3-fluoroazetidin-1-yl)-1-((4 -fluorophenyl)thio)butan-2- yl)amino)phenyl)sulfonyl)-2-methyltetrahydro-2H-pyran-2-carb oxamide (34.2 mg, 99.0% purity) was obtained as a white solid in 24.5% yield according to the general procedure of (S)-N- ((3-cyano-4-((1-(dimethylamino)-5-(6-(trifluoromethyl)pyridi n-3-yl)pentan-3-yl)amino)-5- fluorophenyl)sulfonyl)-1-fluorocyclohexane-1-carboxamide . ¹ H NMR: (400 MHz, MeOD) δ 7.82 (s, 2H), 7.20-7.16 (m, 2H), 7.03-6.99 (m, 2H), 5.22 (dd, J = 56 Hz, 1H), 4.10-4.03 (m, 3H), 3.74-3.70 (m, 2H), 3.63-3.57 (m, 1H), 3.06-3.04 (m, 3H), 2.15-2.12 (m, 1H), 2.08-1.96 (m, 1H), 1.86-1.71 (m, 1H), 1.67-1.54 (m, 1H), 1.51-1.37 (m, 3H),1.35-1.25 (m, 3H), 1.18 (s, 3H). LCMS (ET61932-311-P1C1) (ESI) m/z 622.0 (M+H ⁺ ).

EXAMPLE 192. (R)-N-((3-CYANO-4-(((R)-4-(DIMETHYLAMINO)-1-((4- FLUOROPHENYL)THIO)BUTAN-2-YL)AMINO)-5-FLUOROPHENYL)SULFONYL) -2- METHYLTETRAHYDRO-2H-PYRAN-2-CARBOXAMIDE [0675] Compound 4 (1.10 g, 2.50 mmol) was obtained as yellow oil in 60.5% yield according to the general procedure of compound 2.HPLC: column: Welch Xtimate C18250*50mm*10um; mobile phase: [water ( NH ₄ HCO ₃ ) - ACN]; gradient: 10%-50% B over 25 min. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.68 (dd, J = 1.2, 2.0 Hz, 1H), 7.59 (dd, J = 2.0, 12.0 Hz, 1H), 7.31 (dd, J = 5.2, 8.8 Hz, 2H), 7.00 (dd, J = 8.8 Hz, 2H), 4.42 (br s, 1H), 3.29 - 3.24 (m, 1H), 3.19 - 3.09 (m, 1H), 2.57 - 2.35 (m, 2H), 2.24 (s, 6H), 2.08 - 1.92 (m, 1H), 1.86 - 1.80 (m, 1H)

B. Step 2 [0676] (R)-N-((3-cyano-4-(((R)-4-(dimethylamino)-1-((4-fluorophenyl )thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide (1.05 g, 1.84 mmol) was obtained as white solid in 73.8% yield according to the general procedure of (R)-N- ((3-chloro-4-(((R)-4-(3-(difluoromethoxy)azetidin-1-yl)-1-(( 4-fluorophenyl)thio)butan-2- yl)amino)-5-fluorophenyl)sulfonyl)-2-methyltetrahydro-2H-pyr an-2-carboxamide. HPLC: column: Welch Xtimate C18250 *50mm*10 um; mobile phase: [ water ( NH ₄ HCO ₃ ) - ACN]; gradient:10% - 55% B over 20 min. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.80 (s, 1H), 7.73 (dd, J = 2.0, 11.6 Hz, 1H), 7.31 - 7.17 (m, 2H), 7.04 (dd, J = 8.8 Hz, 2H), 4.24 (td, J = 4.4, 8.0 Hz, 1H), 3.78 - 3.63 (m, 2H), 3.30 - 3.20 (m, 3H), 3.13 (dd, J = 7.6, 14.0 Hz, 1H), 2.83 (s, 6H), 2.28 - 2.00 (m, 3H), 1.68 - 1.55 (m, 1H), 1.53 - 1.37 (m, 3H), 1.37 - 1.24 (m, 1H), 1.21 (s, 3H) EXAMPLE 193. N-((3-CYANO-4-(4-(DIMETHYLAMINO)-2-(((4- FLUOROPHENYL)THIO)METHYL)PIPERIDIN-1-YL)-5- FLUOROPHENYL)SULFONYL)-1-METHOXYCYCLOHEXANE-1-CARBOXAMIDE

[0677] Charge compound J-1 (10.0 g, 38.8 mmol, 1.00 eq) to a 250 ml three neck flask (R1). Charge THF (100 mL) to R1 at 25 °C. Charge NaBH ₄ (3.09 g, 81.6 mmol, 2.10 eq) to R1 at 0°C. Stir R1 at 0 °C for 1 hr. TLC (petroleum ether/EtOAc = 1/1) showed that the starting material was consumed and a new major spot was observed. The mixture was quenched by addition of Sat. NH ₄ Cl (200 mL) and extracted with ethyl acetate (250 mL x 2), the combined organic layers were washed with brine (250 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give compound J-2 (9.00 g, crude) as a yellow oil was used directly for next step without further purification. [0678] Charge compound J-2 (9.00 g, 34.7 mmol, 1.00 eq) to a 250 ml single neck flask (R1). Charge HCl/dioxane (4.00 M, 49.9 mL, 5.76 eq) slowly to R1 at 25°C. Stirred R1 at 25°C for 1 hr. TLC (petroleum ether/ethyl acetate = 1/1) indicated that the starting material was consumed and a new major spot was observed. The reaction mixture was concentrated under reduced pressure to give compound J-3 (5.00 g, crude, HCl) as a yellow gum and used for next step directly. C. Step 3 [0679] Charge compound J-3 (5.00 g, 25.5 mmol, 1.00 eq, HCl) to a 250 ml single neck flask (R1). Charge THF (50.0 mL) to R1 at 25°C. Charge imidazole (8.70 g, 127 mmol, 5.00 eq) and TBDPSCl (14.0 g, 51.1 mmol, 13.0 mL, 2.00 eq) to R1 at 25°C. Stirred R1 at 25°C for 2 hrs. LCMS (Product RT = 1.473 min) indicated starting material was consumed completely and desired product was formed. Charge H ₂ O (50.0 mL) to R1 at 0°C and extracted with ethyl acetate (3*100 mL), then the organic phase was dried by Na ₂ SO ₄ , filtered and concentrated to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 20+20 g SepaFlash® Silica Flash Column, Eluent of 0~6% methanol/dichloromethane gradient @ 50 mL/min) to give compound J-4 (2.82 g, 6.39 mmol, 90.1% purity) as a yellow oil. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.66 - 7.52 (m, 4H), 7.40 - 7.24 (m, 6H), 3.87 - 3.79 (m, 1H), 3.69 - 3.63 (m, 1H), 3.63 - 3.58 (m, 3H), 3.16 - 2.97 (m, 1H), 2.84 - 2.72 (m, 1H), 2.38 - 2.30 (m, 1H), 2.11 - 2.04 (m, 1H), 1.92 - 1.76 (m, 2H), 1.64 - 1.50 (m, 1H), 1.47 - 1.32 (m, 2H), 0.98 (s, 9H). LCMS: product: RT =0.567 min, MS (ESI) m/z = 398.7 [M+H] ⁺ . D. Step 4 [0680] Charge compound J-4 (2.30 g, 5.78 mmol, 1.00 eq) to a 250 ml three neck flask (R1). Charge THF (20.0 mL) to R1 at 25°C. Charge LAH (219 mg, 5.78 mmol, 1.00 eq) to R1 at 0°C. Stirred R1 at 25°C for 1 hr. LCMS (Product RT = 0.618 min) indicated the starting material was consumed completely and desired mass was formed. The mixture was quenched by Na ₂ SO ₄ ·10H ₂ O (2.00 g), then the mixture was filtered and the filtrate was concentrated to give crude product compound J-5 (1.76 g, 3.81 mmol, 80.1% purity) as a yellow gum. LCMS: product: RT =0.548 min, MS (ESI) m/z = 370.2 [M+H] ⁺ . ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.63 - 7.54 (m, 4H), 7.35 - 7.25 (m, 6H), 4.13 - 4.05 (m, 1H), 3.71 - 3.65 (m, 1H), 3.48 - 3.38 (m, 1H), 3.33 - 3.08 (m, 2H), 2.95 - 2.87 (m, 1H), 2.80 - 2.70 (m, 1H), 2.45 - 2.25 (m, 1H), 1.72 - 1.58 (m, 1H), 1.53 - 1.32 (m, 2H), 1.21 - 1.08 (m, 1H), 1.02 - 0.95 (m, 10H) E. Step 5 [0681] Charge J-5 (1.76 g, 4.76 mmol, 1.00 eq) to a 100 ml single neck flask (R1). Charge THF (15.0 mL) to R1 at 25°C. Charge 5a (671 mg, 5.24 mmol, 560 μL, 1.10 eq) to R1 at 0°C. Charge Bu ₃ P (1.35 g, 6.67 mmol, 1.64 mL, 1.40 eq) to R1 at 0°C. Charge DIAD (1.35 g, 6.67 mmol, 1.29 mL, 1.40 eq) to R1 at 0°C. Stir R1 at 25°C for 8 hrs. LCMS (Product RT˙0.644 min) indicated starting material J-5 was consumed completely and desired MS was formed. Charge H ₂ O (50.0 mL) to R1 at 0°C and extracted with dichloromethane (3*20.0 mL), then the organic layer was washed with water (20 mL) and brine (20 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (ISCO®; 12+12 g SepaFlash® Silica Flash Column, Eluent of 0~6% methanol/dichloromethane gradient @ 50 mL/min) to give product compound J-6 (4.00 g, crude) as a yellow oil. LCMS: EB11241-29-P1CDOWN, product: RT =0.665 min, MS (ESI) m/z =480.3 [M+H] ⁺ .

[0682] Charge J-6 (4.00 g, 8.34 mmol, 1.00 eq) to a 100 ml single neck flask (R1). Charge THF (5.00 mL) to R1 at 25°C. Charge TBAF (1.00 M, 16.6 mL, 2.00 eq) to R1 at 25°C. Stirred R1 at 25°C for 2 hrs. LCMS (Product RT = 0.503 min) showed starting material was consumed completely and desired MS was formed. The reaction mixture was added HCl (1.00 M) to adjust pH = 7, then water phase was washed with petroleum ether (2*50.0 mL). The water phase was purified by reversed-phase HPLC (column: Welch Xtimate C18250*50mm*10um; mobile phase: [water (HCl)-ACN]; gradient: 0%-30% B over 20 min) to give product compound J-7 (5.50 g, crude) as a yellow liquid. LCMS: product: RT = 0.353 min, MS (ESI) m/z =242.1 [M+H] ⁺ . [0683] Charge J-7 (4.50 g, 18.6 mmol, 1.00 eq) to a 100 ml single neck flask (R1). Charge MeOH (5.00 mL) to R1 at 25°C. Charge TEA (4.81 g, 47.5 mmol, 6.62 mL, 2.55 eq) to R1 at 25°C. Charge Boc ₂ O (8.14 g, 37.2 mmol, 8.57 mL, 2.00 eq) to R1 at 25°C. Stirred R1 at 25°C for 12 hrs. LCMS (Product RT = 0.629 min) showed starting material was consumed completely and desired MS was formed. The reaction mixture was diluted with ethyl acetate (100 mL), the organic layer was washed with brine (20.0 mL), dried over Na ₂ SO ₄ , concentrated to give the residue. The residue was purified by flash silica gel chromatography (ISCO®; 12+12 g SepaFlash® Silica Flash Column, Eluent of 0~45% Ethyl acetate/Petroleum ether gradient @ 50 mL/min) to give compound J-8 (457 mg, 1.31 mmol, 97.8% purity) was obtained as a colorless oil. LCMS: product: RT = 0.629 min, MS (ESI) m/z =242.1 [M-Boc+H] ⁺ . H. Step 8 [0684] Charge Compound J-8 (457 mg, 1.34 mmol, 1.00 eq) to a 100 mL single neck flask (R1). Charge dioxane (1.00 mL) to R1 at 25°C. Charge HCl/dioxane (4 M, 4.02 mL, 12.0 eq) to R1 at 25°C. Stirred R1 at 25°C for 1 hr. LCMS (Product RT = 0.256, 0.964 min) indicated starting material was consumed completely and desired MS was formed. The reaction mixture was concentrated under rescued pressure to give compound J-9 (530 mg, crude, HCl) was obtained as a colorless liquid and used for next step directly. LCMS: product: RT = 0.629 min, MS (ESI) m/z =242.1 [M+H] ⁺ .

I. Step 9 [0685] Charge compound J-9 (525 mg, 2.18 mmol, 1.00 eq) to a 20.0 mL microwave tube (R1). Charge DMSO (5.00 mL) to R1 at 25°C. Charge sulfonamide 3 (474 mg, 2.18 mmol, 1.00 eq) to R1 at 25°C. Charge DIEA (2.81 g, 21.7 mmol, 3.79 mL, 10.0 eq) to R1 at 25°C. Stirred R1 at 90°C for 12 hrs. LCMS (Product RT = 5.266, 5.400 min) indicated starting material J-9 remained and desired MS was formed. The crude product was purified by reversed-phase HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water ( NH ₄ HCO ₃ )-ACN]; gradient:14%-54% B over 32 min) and lyophilized to give the product J-10 (60.0 mg, 72.59 μmol, 3.34% yield, 99.7% purity) as a white solid. LCMS: product: RT = 0.633 min, MS (ESI) m/z =440.1 [M+H] ⁺ . ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.86 - 7.83 (m, 1H), 7.71 - 7.66 (m, 1H), 7.14 - 7.08 (m, 2H), 6.96 - 6.90 (m, 2H), 4.97 - 4.88 (m, 2H), 4.10 - 4.00 (m, 2H), 3.68 - 3.58 (m, 1H), 3.44 - 3.35 (m, 1H), 3.19 - 3.07 (m, 2H), 2.23 - 2.08 (m, 2H), 2.04 - 1.91 (m, 1H) J. Step 10

[0686] Charge Compound J-10 (60.0 mg, 72.8 μmol, 1.00 eq) to a 10.0 ml single neck flask (R1). Charge DCM (1.00 mL) to R1 at 25°C. Charge DMP (60.0 mg, 72.8 μmol, 22.5 μL, 1.00 eq) to R1 at 0°C. Stirred R1 at 25°C for 3 hrs. LCMS (EB11241-39-P1R2, Product RT = 1.551 min) indicated that the starting material was consumed completely and desired MS was formed. The reaction mixture was quenched with NaHSO ₃ (1.00 mL) and NaHCO ₃ (1.00 mL), the mixture was extracted with dichloromethane (3*3.00 mL), the combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , concentrated to give the crude product. The crude product was purified by reversed-phase HPLC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO ₂ -EtOH (0.1%NH ₃ H ₂ O)]; B%:20%, isocratic elution mode) to give residue. The residue was further purified by prep-TLC (DCM/MeOH = 20/1) to give product P1 and P2. Compound 12-1 (17.5 mg, 36.5 μmol, 50.2% yield, 91.4% purity) was obtained as a white solid, purity = 91.4% was from LCMS. LCMS: product: RT = 1.547 min, MS (ESI) m/z =460.1 [M+Na] ⁺ . [0687] Charge compound 12-1 (17.0 mg, 38.8 μmol, 1.00 eq) to a 100 ml single neck flask (R1). Charge DMAc (1.00 mL) to R1 at 25°C. Charge N-methylmethanamine (44.3 mg, 544 μmol, 49.8 μL, 14.0 eq, HCl) to R1 at 25°C. Charge NaBH(OAc) ₃ (41.1 mg, 194 μmol, 5.00 eq) to R1 at 25°C. Stirred R1 at 40°C for 12 hrs. LCMS (Product RT = 0.483 min) indicated starting material was consumed completely and desired MS was formed. The organic layers were diluted with acetonitrile (10.0 mL) and filtered, then the organic layer was used for purification directly. The crude product was purified by reversed-phase HPLC (column: Xtimate C18 150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 24%-64% B over 32 min) to give compound 13-1 (14.3 mg, 25.8 μmol, 66.4% yield, 84.2% purity) was obtained as a white solid, purity = 84.2% was from LCMS. LCMS: product: RT = 1.227 min, MS (ESI) m/z =467.2 [M+H] ⁺ . L. Step 12 [0688] Charge compound 13-1 (14.3 mg, 30.6 μmol, 1.00 eq) to a 10.0 ml single neck flask (R1). Charge ACN (1.00 mL) to R1 at 25°C. Charge acid 7 (7.27 mg, 45.9 μmol, 1.50 eq) to R1 at 25°C. Charge EDCI (8.81 mg, 45.9 μmol, 1.50 eq) and DMAP (5.62 mg, 45.9 μmol, 1.50 eq) to R1 at 25°C. Stirred R1 at 25°C for 8 hrs. LCMS (Product RT = 0.676 min) indicated starting material was consumed and desired MS was formed. The mixture was filtered and used for purification directly. The crude product was purified by reversed-phase HPLC (column: Xtimate C18150*40mm*10um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; gradient: 10%-50% B over 32 min). Further purification was conducted by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: [CO ₂ -MeOH (0.1%NH ₃ H ₂ O)]; B%:30%, isocratic elution mode). N-((3-cyano-4-(4-(dimethylamino)-2-(((4-fluorophenyl)thio)me thyl)piperidin-1- yl)-5-fluorophenyl)sulfonyl)-1-methoxycyclohexane-1-carboxam ide (3.24 mg, 4.86 μmol, 15.85% yield, 91.0% purity) was obtained as a colorless solid, the structure was confirmed by HNMR, purity = 91.0% was from LCMS, ee% = 97.8% was from SFC. ¹ H NMR: (400 MHz, CD ₃ OD) δ 7.91 - 7.86 (m, 1H), 7.85 - 7.79 (m, 1H), 7.06 - 6.97 (m, 4H), 4.03 - 3.95 (m, 1H), 3.76 (br t, J = 12.6 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.50 (br d, J = 12.0 Hz, 1H), 3.13 (s, 3H), 2.88 (s, 6H), 2.35 - 2.27 (m, 1H), 2.22 - 2.17 (m, 1H), 2.13 - 2.07 (m, 1H), 2.07 - 2.00 (m, 1H), 1.76 (br s, 1H), 1.62 (br d, J = 10.4 Hz, 2H), 1.53 - 1.46 (m, 4H), 1.33 (br d, J = 6.8 Hz, 4H). [0689] All technical and scientific terms used herein, unless otherwise defined below, are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations on those techniques and/or substitutions of equivalent techniques that would be apparent to one of skill in the art. While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject. [0690] All patents, patent publications, patent applications, journal articles, books, technical references, and the like discussed in the instant disclosure are incorporated herein by reference in their entirety for all purposes. [0691] It is to be understood that the figures and descriptions of the disclosure have been simplified to illustrate elements that are relevant for a clear understanding of the disclosure. It should be appreciated that the figures are presented for illustrative purposes and not as construction drawings. Omitted details and modifications or alternative embodiments are within the purview of persons of ordinary skill in the art. [0692] It can be appreciated that, in certain aspects of the disclosure, a single component may be replaced by multiple components, and multiple components may be replaced by a single component, to provide an element or structure or to perform a given function or functions. Except where such substitution would not be operative to practice certain embodiments of the disclosure, such substitution is considered within the scope of the disclosure. [0693] The examples presented herein are intended to illustrate potential and specific implementations of the disclosure. It can be appreciated that the examples are intended primarily for purposes of illustration of the disclosure for those skilled in the art. There may be variations to these diagrams or the operations described herein without departing from the spirit of the disclosure. For instance, in certain cases, method steps or operations may be performed or executed in differing order, or operations may be added, deleted or modified. [0694] Where a range of values is provided, it is understood that each intervening value, to the smallest fraction of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Any narrower range between any stated values or unstated intervening values in a stated range and any other stated or intervening value in that stated range is encompassed. The upper and lower limits of those smaller ranges may independently be included or excluded in the range, and each range where either, neither, or both limits are included in the smaller ranges is also encompassed within the technology, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included. [0695] In the foregoing description, numerous specific details are set forth to provide a more thorough understanding of the present invention. However, it will be apparent to one of skill in the art that the invention described in this disclosure may be practiced without one or more of these specific details. In other instances, well-known features and procedures well known to those skilled in the art have not been described in order to avoid obscuring the invention. Embodiments of the disclosure have been described for illustrative and not restrictive purposes. Although the present invention is described primarily with reference to specific embodiments, it is also envisioned that other embodiments will become apparent to those skilled in the art upon reading the present disclosure, and it is intended that such embodiments be contained within the present inventive methods. Accordingly, the present disclosure is not limited to the embodiments described above or depicted in the drawings, and various embodiments and modifications can be made without departing from the scope of the claims below.