Acylsulfonamide KAT6A inhibitors

Abstract

The present disclosure describes acyl sulfonamide compounds of Formula (J) and pharmaceutically acceptable salts, compositions, methods, and uses thereof. Such compounds are believed to be therapeutically useful as KAT6A inhibitors, in particular for the treatment and / or prevention of diseases and conditions mediated by KAT6A in a subject.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of Indian Application No. 202311018002 filed March 16, 2023; the specification of which is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present disclosure relates to acyl sulfonamide compounds of Formula (J) or a pharmaceutically acceptable salt thereof, which are believed to be useful as KAT6A inhibitors for the treatment of diseases or conditions mediated by KAT6A. Methods of making the compounds and pharmaceutical compositions comprising the compounds are also described. BACKGROUND

[0004] The MYST family of histone acetyltransferases (HATs) is named after its four founding members MOZ, Ybf2 (Sas3), Sas2, and Tip60. The presence of zinc fingers and chromatin-structuring domains is a typical feature of these HATs. MYST acetylates lysine residues on histones H2A, H3, and H4. Several MYST family proteins contain zinc fingers as well as a highly conserved motif A found in GNATs that facilitates acetyl-CoA binding. MYST HATs are involved in several key nuclear processes and play a key role in gene-specific transcriptional regulation, DNA damage response, repair, and replication. Aberrant activity of these HATs or their associated complexes can easily lead to severe cellular malfunction, resulting in cell death or uncontrolled growth and malignancy. In fact, MYST family HATs are associated with several forms of human cancer. (Avvakumov, N, et al., “The MYST family of histone acetyltransferases and their intimate links to cancer.” Oncogene 26.37 (2007): 5395-5407.)

[0005] MOZ (monocytic leukemia zinc finger protein) is believed to be an oncogene in humans. MOZ plays a key role as a transcriptional co-activator and epigenetic regulator in the proliferation and differentiation processes of hematopoietic progenitor and stem cells. An in-depth understanding of the dysregulation of these processes indicates that MOZ fusion proteins are associated with the formation of leukemic stem cells and interfere with the activity of key proteins such as transcription factors, which makes MOZ a promising target for acute myeloid leukemia therapy. Targeting MOZ by small molecules would bring hope for acute myeloid leukemia therapy. (Zhou C. et al., “MOZ / KAT6A: a promising target for acute myeloid leukaemia therapy.” (2020): 759-761).

[0006] Cellular senescence plays a key role in limiting tumor growth. KAT6A has been shown to inhibit cellular senescence in mouse embryonic fibroblasts (MEFs) without affecting apoptosis or DNA damage. MOZ was thought to directly bind to genes that suppress senescence, including Cdc6, E2f2, Ezh2, and Melk, and in its absence, H3K9ac and H3K27ac at the TSS of these loci was reduced. (Sheikh, B. N., et al., "MOZ (MYST3, KAT6A) inhibits senescence via the INK4A-ARF pathway." Oncogene 34.47 (2015): 5807-5820).

[0007] Histone acetyltransferase KAT6A was thought to be important for cell proliferation and tumor growth in glioma through upregulation of PI3K / AKT signaling via TRIM24 binding. KAT6A has been shown to promote H3K23 acetylation and association with TRIM24, leading to increased PIK3CA expression and activation of PI3K / Akt signaling, thereby enhancing tumorigenesis of glioma. Thus, KAT6A was thought to play an oncogenic role in glioma. (Lv, D., et al., "Histone acetyltransferase KAT6A upregulates PI3K / AKT signalling through TRIM24 binding." Cancer research 77.22 (2017): 6190-6201).

[0008] A number of publications disclose small molecule compounds and derivatives thereof capable of targeting KAT target proteins. Because there are currently no FDA-approved targeted therapies for specific KAT6A or KAT6B target proteins, there is a need to develop compounds, compositions, and methods for treating KAT6A- or KAT6B-activated proliferative disorders and autoimmune diseases. SUMMARY

[0009] In some embodiments, the compounds of the disclosure are represented by formula (J):

[0010]

[0011] or a pharmaceutically acceptable salt thereof,

[0012] wherein

[0013] X is O or NR 4 ;

[0014] Ring A is phenyl or heteroaryl;

[0015] Ring B is phenyl or heteroaryl;

[0016] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e ;

[0017] each R 1a and R 1b is independently hydrogen or C1-C6 alkyl;

[0018] each R 1cindependently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 1c1 R 1c2 , OH, or -CN;

[0019] each R 1c1 and R 1c2 are independently hydrogen or C1-C6alkyl;

[0020] each R 1d is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl;

[0021] each R 1e is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, OH, or -CN;

[0022] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4alkyl, OH, or -CN;

[0023] L is -C1-C4alkylene-, -(C1-C4alkylene)-O-, or -O-;

[0024] R 2 is heteroaryl, substituted with 0, 1, 2, 3, or 4 R 2a ;

[0025] each R 2a is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b , -C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b , -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2;

[0026] each R 2b and R 2cindependently hydrogen or C1-C6alkyl;

[0027] each R 3 independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8cycloalkyl, (C1-C3alkyl)(C3-C8cycloalkyl), -O-(C3-C8cycloalkyl), heterocycloalkyl, (C1-C3alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or,

[0028] two R 3 on the same carbon atom together represent oxo;

[0029] each R 3a and R 3b are independently hydrogen or C1-C6alkyl;

[0030] each R3c independently C1-C6alkyl, halogen, C1-C6haloalkyl, or C1-C6haloalkoxy; 3c1 R 3c2 , OH, or -CN;

[0031] each R 3c1 and R 3c2 is independently hydrogen or C1-C6alkyl;

[0032] each R 3d is independently C3-C8cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl;

[0033] each R 3e is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, or C1-C6haloalkoxy;

[0034] R 4 is hydrogen or C1-C6alkyl;

[0035] the subscript n is 0, 1, 2, 3, or 4; and

[0036] the subscript q is 0, 1, 2, 3, or 4;

[0037] wherein

[0038] each heterocycloalkyl is a 3- to 8-membered ring comprising 1-4 heteroatoms each independently N, O, or S; and

[0039] each heteroaryl is a 5- to 6-membered ring comprising 1-4 heteroatoms each independently N, O, or S.

[0040] In some embodiments, the compositions of the present application are pharmaceutical compositions comprising a compound of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the compounds of the present application are compounds or pharmaceutically acceptable salts thereof for use as a medicament. In some embodiments, the compounds of the present application are compounds for use in treating a disease or disorder mediated by KAT6A. In some embodiments, the methods of the present application are methods of modulating KAT6A in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the methods of the present application are methods of treating a disease or disorder mediated by KAT6A in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 Synergy scores for Compound 282 in combination with everolimus at various concentrations are provided.

[0043] Figure 2 Synergy scores for each concentration of Compound 282 in combination with inavolisib are provided.

[0044] Figure 3 Synergy scores for each concentration of Compound 282 in combination with alpelisib are provided. DETAILED DESCRIPTION

[0045] I. GENERAL

[0046] The present disclosure provides, inter alia, acyl sulfonamide compounds represented by Formula (J) and pharmaceutically acceptable salts thereof. Also described herein are pharmaceutical compositions comprising a compound that is believed to be useful as a KAT6A inhibitor for the treatment of a disease or disorder that depends on or is mediated by KAT6A. The present disclosure also includes formulations of a compound of Formula (J) or a pharmaceutically acceptable salt thereof.

[0047] II. DEFINITIONS

[0048] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. The following terms are intended to have the meanings presented, unless a different meaning is clearly intended by the context of their use.

[0049] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0050] "Alkyl" means a monovalent saturated aliphatic radical including, but not limited to, C1-C 10 straight-chain alkyl or C3-C 10 branched-chain alkyl. In some embodiments, alkyl is C1-C6straight-chain alkyl or C3-C8branched-chain alkyl. In some embodiments, alkyl refers to C1-C4straight-chain alkyl or C3-C6branched-chain alkyl. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neopentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl, and 4-octyl. "Alkyl" can be optionally substituted.

[0051] "Alkylene" means a divalent saturated aliphatic radical including, but not limited to, C1-C 10 straight-chain alkylene or C3-C 10branched alkylene. In some embodiments, alkylene refers to a C1-C6 straight chain alkylene or a C3-C8 branched chain alkylene. In some embodiments, alkylene refers to a C1-C4 straight chain alkylene or a C3-C6 branched chain alkylene. Examples of alkylene include, but are not limited to, methylene, ethylene, 1 -propylene, 2-propylene, isopropylene, n-butylene, and sec-butylene. An "alkylene" can be further optionally substituted.

[0052] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. An alkenyl group can comprise any number of carbons, such as C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 , and C6. An alkenyl group can 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, or 1,3,5-hexatrienyl. An alkenyl group can be substituted or unsubstituted.

[0053] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. An alkynyl group can comprise any number of carbons, such as C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6and C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1 -butynyl, 2-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. Alkynyl groups can be substituted or unsubstituted.

[0054] “Alkoxy” refers to the group -O-alkyl, wherein alkyl is as defined above. In some embodiments, alkoxy refers to C1-C6 straight chain alkoxy or C3-C8 branched chain alkoxy. In some embodiments, alkoxy refers to C1-C4 straight chain alkoxy or C3-C6 branched chain alkoxy. Exemplary C1-C4 straight chain alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, and n-butyloxy. Exemplary C3-C6 branched chain alkoxy groups include, but are not limited to, isopropyloxy, isobutyloxy, sec-butyloxy, and t-butyloxy. 10 Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, n-butyloxy, and t-butyloxy. Alkoxy groups can be optionally substituted with one or more suitable groups as described herein.

[0055] “Alkoxyalkyl” refers to an alkyl group substituted with one or more alkoxy groups, wherein the definitions of alkyl and alkoxy are as defined above. In some embodiments, alkoxyalkyl represents (C1-C6)alkyl(C1-C6)alkoxy or (C1-C4)alkyl(C1-C4)alkoxy. Exemplary alkoxyalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, and ethoxyethyl.

[0056] The term “halo” or “halogen,” alone or in combination, means fluoro, chloro, bromo, or iodo.

[0057] “Haloalkyl” refers to an alkyl group substituted with one or more halogen atoms, wherein “halogen” and “alkyl” are as defined above. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0058] “Haloalkoxy” refers to an alkoxy group (i.e., halo-C 1-8 alkoxy) substituted with one or more halogen atoms. Examples of haloalkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and 1-bromoethoxy.

[0059] “Amino” refers to the -NH2 group.

[0060] “Hydroxy / ” or “hydroxyl,” alone or in combination, means -OH.

[0061] “Hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxyl groups.

[0062] "Cycloalkyl" refers to a single saturated or partially unsaturated all-carbocyclic ring (i.e., C 3-20 Cycloalkyl also includes multiple condensed, saturated and partially unsaturated all-carbocyclic ring systems (e.g., ring systems comprising 2, 3, or 4 carbocyclic rings). Thus, cycloalkyl includes polycyclic carbocyclic rings, such as bicyclic carbocyclic rings (e.g., bicyclic carbocyclic rings having about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to about 20 ring carbon atoms). The rings of a multiply condensed ring system can be linked to one another by fused, spiro, and bridged linkages, as valence permits. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

[0063] "Heteroatom" as used herein indicates a sulfur, nitrogen, or oxygen atom.

[0064] "Heterocycloalkyl" refers to a 3- to 15-membered non-aromatic, saturated or partially saturated, bridged bicyclic, monocyclic, or polycyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)2, NH, or C(O), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur, unless the size of the ring is specifically mentioned. Heterocycloalkyl also refers to a bridged bicyclic ring system having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(0)2, NH, or C(O). Examples of heterocycloalkyl include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinomethyl, isoindolinyl, oxoisoindolinyl, dioxoisoindolinyl, azabicyclooctanyl, diazabicyclooctanyl, azocinyl, chromanyl, isochromanyl, and xanthenyl. The attachment of a heterocycloalkyl substituent can be via a carbon atom or a heteroatom. A heterocycloalkyl group can be optionally substituted with one or more suitable groups. In some embodiments, heterocycloalkyl refers to a 4- to 6-membered ring (unless the size of the ring is specifically mentioned) selected from the group consisting of azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl. A heterocycloalkyl group is optionally substituted with one or more groups described herein.

[0065] "Aryl" is an optionally substituted monocyclic, bicyclic, or polycyclic aromatic ring system having about 6 to 14 carbon atoms. In some embodiments, aryl includes 6- to 10-membered aromatic ring systems. C6-C 14 Examples of aryl include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenenyl, and acenaphthyl. An aryl group can be optionally substituted with one or more suitable groups described herein.

[0066] "Heteroaryl" refers to a fully unsaturated and aromatic ring system containing a total of 5 to 14 ring atoms, unless the size of the ring is specifically mentioned. At least one of the ring atoms is a heteroatom (i.e., O, N, or S), with the remaining ring atoms / groups independently selected from C, N, O, or S. The heteroaryl group can be a single ring (monocyclic) or multiple rings (bicyclic, tricyclic, or polycyclic) that are fused together or covalently linked. In some embodiments, the heteroaryl group is a 5- to 6-membered ring. The ring can contain 1 to 4 heteroatoms selected from N, O, and S, wherein the N atom is optionally quaternized. Any suitable ring position of the heteroaryl moiety can be covalently linked to the defined chemical structure. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl, isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl / pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl, pteridinyl, 9H-carbazolyl, a-carbolinyl, indolizinyl, benzisothiazolyl, benzoxazolyl, pyrrolopyridinyl, purinyl, benzothiadiazolyl, benzoxadiazolyl, benzotriazolyl, benzothiadiazolyl, carbazolyl, dibenzothiophenyl, acridinyl, and the like. The heteroaryl group can be further substituted.

[0067] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical applications.

[0068] "Pharmaceutically acceptable salt" refers to a product produced by the reaction of a compound of the present application with a suitable acid or base. In some cases, the agent can exist in the form of a pharmaceutically acceptable salt. In some cases, the pharmaceutically acceptable salt can be a salt as described in Berge et al., J. Pharm. Sci, 1977. In some cases, the pharmaceutically acceptable salt can include those derived from mineral, organic acid or inorganic base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include, for example, nontoxic salts of the parent compound which are formed, for example, from non-toxic inorganic or organic acids.

[0069] The pharmaceutically acceptable salts of the present application can be prepared from the basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base, such as the hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K, and the like, or by reacting free base forms of these compounds with an appropriate acid, in a stoichiometric amount. Such reactions typically are carried out in water or in an organic solvent, or in a mixture of both. Generally, use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, is desirable, where feasible. Lists of additional suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in Stahl and Wermuth's “Handbook of Pharmaceutical Salts: Properties, Selection and Use” (Wiley-VCH, Weinheim, Germany, 2002).

[0070] “Composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. “Pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0071] “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluting, preservative, dye / colorant, flavoring, surfactant, wetting, dispersing, suspending, stabilizing, isotonic, solvent, surface active or emulsifying agent, that has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0072] “Administer,” “administering” and / or “administration” as used herein mean the direct application of one or more disclosed compounds or a pharmaceutically acceptable salt of one or more disclosed compounds or a composition comprising one or more disclosed compounds to a subject, or the application of an analog of the compound or a pharmaceutically acceptable salt of the compound or a composition to the subject, which can form an equivalent amount of the active compound in the subject.

[0073] “Carrier” encompasses carriers, excipients, and diluents, and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.

[0074] “Treat,” “treating” and / or “treatment” refer to a method of alleviating or abrogating a disease and / or one or more symptoms associated with the disease.

[0075] “Prevent,” “preventing” and / or “prevention” refer to a method of preventing the onset of a disease and / or its attendant symptoms or impeding a subject from acquiring a disease. “Prevent,” “preventing” and “prevention” also include delaying the onset of a disease and / or one or more symptoms associated with the disease and reducing the risk that a subject will acquire the disease.

[0076] “Subject” or “patient” refers to an animal, such as a mammal, for example, a human. In some embodiments, the subject is a mammal, such as a mouse, rat, dog, cat, another veterinary animal, such as a goat, pig, horse, cow, or donkey; or a primate, such as a non-human primate, for example, a cynomolgus monkey, rhesus monkey, or chimpanzee, or a human. In some embodiments, the subject is a human.

[0077] “Therapeutically effective amount” refers to the amount of a compound of Formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof; or a composition comprising a compound of Formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof; that is effective in producing the desired therapeutic response in a particular patient suffering from a disease or condition, particularly their use in a disease or condition associated with cancer. A therapeutically effective amount encompasses the amount of a compound of Formula (J), or a pharmaceutically acceptable salt or stereoisomer or tautomer thereof, that when administered induces a positive change in the disease or condition to be treated, or is sufficient to prevent the development of, or to alleviate to some extent, one or more symptoms of the disease or condition being treated in a subject. In terms of the amount of a compound used to treat a subject, an amount of the compound that is low enough to avoid adverse or severe side effects, within the scope of sound medical judgment, is also contemplated. The therapeutically effective amount of a compound or composition will vary with the particular condition being treated, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the age and physical condition of the end user, the particular compound or composition used, and the particular pharmaceutically acceptable carrier used.

[0078] III. Compounds

[0079] In some embodiments, the compounds of the present disclosure are represented by formula (J):

[0080]

[0081] or a pharmaceutically acceptable salt thereof,

[0082] wherein

[0083] X is O or NR 4 ;

[0084] Ring A is phenyl or heteroaryl;

[0085] Ring B is phenyl or heteroaryl;

[0086] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c substituted, each alkyl and alkenyl is substituted with 0, 1, 2, or 3 R 1d substituted, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e substituted;

[0087] each R 1a and R 1b are independently hydrogen or C1-C6 alkyl;

[0088] each R 1c is independently C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NR 1c1 R 1c2 , OH, or -CN;

[0089] each R 1c1 and R 1c2 are independently hydrogen or C1-C6 alkyl;

[0090] each R 1d is independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl;

[0091] each R 1e is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN;

[0092] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN;

[0093] L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-;

[0094] R 2 is heteroaryl, substituted with 0, 1, 2, 3, or 4 R 2a ;

[0095] each R 2a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b-C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2;

[0096] Each R 2b and R 2c Independently hydrogen or C1-C6 alkyl;

[0097] Each R 3 Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a -C(O)OR 3a -OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a (R) 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R) 3a (R) 3b -S(O)(NH)R 3a -S(O)(NH)N(R) 3a (R) 3b ), -N(R 3a (R) 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R...3c substituted, each alkyl is substituted with 0, 1, 2, or 3 R 3d substituted, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e substituted; or,

[0098] two R 3 together represent oxo;

[0099] each R 3a and R 3b are independently hydrogen or C1-C6alkyl;

[0100] each R 3c are independently C1-C6alkoxy, halogen, C1-C6haloalkoxy, -NR 3c1 R 3c2 , OH, or -CN;

[0101] each R 3c1 and R 3c2 are independently hydrogen or C1-C6alkyl;

[0102] each R 3d are independently C3-C8cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl;

[0103] each R 3e are independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, or C1-C6haloalkoxy;

[0104] R 4 is hydrogen or C1-C6alkyl;

[0105] the subscript n is 0, 1, 2, 3, or 4; and

[0106] the subscript q is 0, 1, 2, 3, or 4;

[0107] wherein

[0108] each heterocycloalkyl is a 3- to 8-membered ring including 1 to 4 heteroatoms each independently N, O, or S; and

[0109] each heteroaryl is a 5- to 6-membered ring including 1 to 4 heteroatoms each independently N, O, or S.

[0110] In some embodiments, X is O. In some embodiments, X is NH.

[0111] In some embodiments, ring B is heteroaryl. In some embodiments, ring B is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring B is pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl. In some embodiments, ring B is pyridyl or pyrimidinyl. In some embodiments, ring B is phenyl.

[0112] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), (II), (III), or (IV):

[0113]

[0114] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , R 4 and n are each as described in Classes and Subclasses herein, both singly and in combination, and Y is N, CH, or CR 3 .

[0115] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I):

[0116]

[0117] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 and n are each as described in Classes and Subclasses herein, both singly and in combination.

[0118] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is a compound of Formula (II):

[0119]

[0120] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 and n are each as described in Classes and Subclasses herein, both singly and in combination, and Y is N, CH, or CR 3 .

[0121] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is a compound of Formula (III):

[0122]

[0123] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , R 4 , and n are each as described in classes and subclasses herein, both singly and in combination.

[0124] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is a compound of Formula (IV):

[0125]

[0126] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , R 4 , and n are each as described in classes and subclasses herein, both singly and in combination, and Y is N, CH, or CR 3 .

[0127] In some embodiments, the compound of Formula (J), or a pharmaceutically acceptable salt thereof, is represented by Formula (I):

[0128]

[0129] or a pharmaceutically acceptable salt thereof, wherein:

[0130] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b , -N(R 1a )(R1b OH, -CN, -NO2, C3-C8cycloalkyl, (C1-C3alkyl)(C3-C8cycloalkyl), -O-(C3-C8cycloalkyl), heterocycloalkyl, (C1-C3alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10aryl, (C1-C3alkyl)(C6-C10aryl), -O-(C6-C10aryl), heteroaryl, (C1-C3alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 10 substituents, each alkoxyl and alkynyl is substituted with 0, 1, 2, or 3 R 10 substituents, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 10 substituents; 1c 1d 1e

[0131] each R 1a and R 1b are independently hydrogen or C1-C6alkyl;

[0132] each R 1c is independently C1-C6alkoxy, halogen, C1-C6haloalkyl, -NR 1c1 R 1c2 , OH, or -CN;

[0133] each R 1c1 and R 1c2 are independently hydrogen or C1-C6alkyl;

[0134] each R 1d is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10

[0135] each R 1e is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, OH, or -CN;

[0136] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4alkyl, OH, or -CN;

[0137] L is -C1-C4alkylene-, -(C1-C4alkylene)-O-, or -O-;

[0138] R 2 is heteroaryl, substituted with 0, 1, 2, 3, or 4 R 2a substituents; ​​​​

[0139] Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2;

[0140] Each R 2b and R 2c Independently hydrogen or C1-C6 alkyl;

[0141] Each R 3 Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a -C(O)OR 3a -OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a (R) 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R) 3a (R) 3b -S(O)(NH)R 3a -S(O)(NH)N(R) 3a (R) 3b ), -N(R 3a (R) 3b), OH, -CN, -NO2, C3-C8cycloalkyl, (C1-C3alkyl)(C3-C8cycloalkyl), -O-(C3-C8cycloalkyl), heterocycloalkyl, (C1-C3alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10aryl, (C1-C3alkyl)(C6-C10aryl), -O-(C6-C10aryl), heteroaryl, (C1-C3alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 10 , each alkoxy is substituted with 0, 1, 2, or 3 R 10 , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 10 ; or, 3c ; or, 3d ; or, 3e ; or, ; or,

[0142] two R 3 on the same carbon atom, together represent oxo; ; or,

[0143] each R 3a and R 3b are independently hydrogen or C1-C6alkyl; ; or,

[0144] each R 3c is independently C1-C6alkoxy, halogen, C1-C6haloalkyl, -NR 3c1 R 3c2 , OH, or -CN; ; or,

[0145] each R 3c1 and R 3c2 are independently hydrogen or C1-C6alkyl; ; or,

[0146] each R 3d is independently C3-C8cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl; ; or,

[0147] each R 3e is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, or C1-C6haloalkoxy; ; or,

[0148] the subscript n is 0, 1, 2, 3, or 4; and ; or,

[0149] the subscript q is 0, 1, 2, 3, or 4; ; or,

[0150] wherein ; or,

[0151] each heterocycloalkyl is a 3- to 8-membered ring comprising 1 to 4 heteroatoms each independently N, O, or S; and ; or,

[0152] each heteroaryl is a 5- to 6-membered ring comprising 1 to 4 heteroatoms each independently N, O, or S.

[0153] In some embodiments, a compound of Formula (J), Formula (I), or a pharmaceutically acceptable salt thereof, is represented by Formula (la):

[0154]

[0155] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 and n are as described in classes and subclasses herein, both singly and in combination.

[0156] In some embodiments, a compound of Formula (J), (I), and / or (la), or a pharmaceutically acceptable salt thereof, is represented by Formula (lb):

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, and R 3 are as described in classes and subclasses herein, both singly and in combination.

[0159] In some embodiments, a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof:

[0160] group has the structure:

[0161]

[0162] or wherein R 1 is as described in classes and subclasses herein, wherein R 1 is as described in classes and subclasses herein.

[0163] In some embodiments, a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof: 1 independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 10 independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C1c substituted, and each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d substituted; or alternatively, two R 1 , together with the atom to which they are attached, combine to form a C5-C8 cycloalkyl or heterocycloalkyl.

[0164] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salt thereof, is a compound of the following formula, or pharmaceutically acceptable salt thereof: 1 independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is substituted with 0, 1, 2, or 3 R 10 independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is substituted with 0, 1, 2, or 3 R 1c independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is substituted with 0, 1, 2, or 3 R 1d independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is substituted with 0, 1, 2, or 3 R 1 independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, or heterocycloalkyl, wherein each alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is substituted with 0, 1, 2, or 3 R

[0165] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salt thereof, is a compound of the following formula, or pharmaceutically acceptable salt thereof: 1a and R 1b independently hydrogen or C1-C4 alkyl.

[0166] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salt thereof, is a compound of the following formula, or pharmaceutically acceptable salt thereof: 1c is halogen, -NR 1c1 R 1c2 , OH, or -CN.

[0167] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salt thereof, is a compound of the following formula, or pharmaceutically acceptable salt thereof: 1d independently heteroaryl.

[0168] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib), or pharmaceutically acceptable salt thereof, is a compound of the following formula, or pharmaceutically acceptable salt thereof: 1e independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0169] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 1 independently CH3, CH2CH3, -C(CH3)3, OCH3, CH2CH3, -OCH(CH3)2, OCH2-pyridyl, C(CH3)2OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, pyrazolyl, or

[0170] or alternatively, two R 1 together with the atom to which they are attached combine to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxolene, dihydro-1,3-oxazine, difluorodihydrofuran, or methyldihydrofuran. In some embodiments, two R 1 combine to form:

[0171]

[0172] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -O-, or -CH2O-.

[0173] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.

[0174] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazyl, pyrimidyl, or pyrazyl, each of which is substituted with 0, 1, or 2 R 2a .

[0175] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 2a is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0176] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 2b and R 2c are independently hydrogen or Ci-C4alkyl.

[0177] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0178]

[0179] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 2 is

[0180]

[0181] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently Ci-C6alkyl, Ci-C6alkoxy, Ci-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, Ci-C6haloalkyl, Ci-C6haloalkoxy, -C(0)R 3a , -C(0)OR 3a , -OC(0)R 3a , -C(0)N(R 3a )(R 3b ), -N(R 3a )C(0)(R 3b ), -S(0)2R 3a , -S(0)2N(R 3a )(R 3b ), OH, -CN, C3-C8cycloalkyl, or heterocycloalkyl.

[0182] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein two R 3 together on the same carbon atom represent oxo.

[0183] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b is independently hydrogen or C1-C4 alkyl.

[0184] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3c is halogen, -NR 3c1 R 3c2 , OH, or -CN.

[0185] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3d is independently heteroaryl.

[0186] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3e is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

[0187] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0188] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0189] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently Me, OMe, OEt, CHF2, CF3, OCHF2, OCF3, F, Br, CN, or cyclopropyl.

[0190] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, wherein subscript q is 1, 2, or 3.

[0191] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, wherein subscript n is 1 or 2.

[0192] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, having the structure of a compound shown in Table 1.

[0193] Table 1. Compounds

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound, wherein the compound has the structure:

[0203]

[0204] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb) is a compound, wherein the compound has the structure:

[0205]

[0206] In some embodiments, the compound of Formula (J), (I), (la), and / or (lb), or a pharmaceutically acceptable salt thereof, is a compound, wherein the compound has the structure:

[0207]

[0208] In some embodiments, the compound of Formula (J), (I), (Ia), and / or (Ib) is a compound, wherein the compound has the structure:

[0209]

[0210] In some embodiments, the compound of Formula (J) is represented by Formula (II):

[0211]

[0212] or a pharmaceutically acceptable salt thereof, wherein

[0213] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or –O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R1d substituted, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e substituents;

[0214] each R 1a and R 1b is independently hydrogen or C1-C6alkyl;

[0215] each R 1c is independently C1-C6alkoxy, halogen, C1-C6haloalkoxy, -NR 1c1 R 1c2 , OH, or -CN;

[0216] each R 1c1 and R 1c2 is independently hydrogen or C1-C6alkyl;

[0217] each R 1d is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C 10 aryl, or heteroaryl;

[0218] each R 1e is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, OH, or -CN;

[0219] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4alkyl, OH, or -CN;

[0220] L is -C1-C4alkylene-, -(C1-C4alkylene)-O-, or -O-;

[0221] R 2 is heteroaryl, substituted with 0, 1, 2, 3, or 4 R 2a substituents;

[0222] each R 2a is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b , -C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2;

[0223] Each R 2b and R 2c Independently hydrogen or C1-C6 alkyl;

[0224] Y represents CH and CR. 3 Or N;

[0225] Each R 3 Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a -C(O)OR 3a -OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a (R) 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R) 3a (R) 3b -S(O)(NH)R 3a -S(O)(NH)N(R) 3a (R) 3b ), -N(R 3a (R) 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R... 3c Substitution, each alkoxy group via 0, 1, 2 or 3 R... 3dsubstituted, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e substituted; or,

[0226] two R 3 together represent oxo;

[0227] each R 3a and R 3b are independently hydrogen or C1-C6alkyl;

[0228] each R 3c are independently C1-C6alkoxy, halogen, C1-C6haloalkoxy, -NR 3c1 R 3c2 , OH, or -CN;

[0229] each R 3c1 and R 3c2 are independently hydrogen or C1-C6alkyl;

[0230] each R 3d are independently C3-C8cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl;

[0231] each R 3e are independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, or C1-C6haloalkoxy;

[0232] the subscript n is 0, 1, 2, 3, or 4; and

[0233] the subscript q is 0, 1, 2, 3, or 4;

[0234] wherein

[0235] each heterocycloalkyl is a 3- to 8-membered ring including 1 to 4 heteroatoms each independently N, O, or S; and

[0236] each heteroaryl is a 5- to 6-membered ring including 1 to 4 heteroatoms each independently N, O, or S.

[0237] In some embodiments of Formula (II), Y is N. In some embodiments, Y is CR 3 . In some embodiments, Y is CH.

[0238] In some embodiments, the compound of Formula (J), Formula (II), or a pharmaceutically acceptable salt thereof, is represented by Formula (IIa):

[0239]

[0240] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2, L, R 3 and n, singly and in combination, are as described in the classes and subclasses herein, and Y is N, CH, or CR 3 .

[0241] In some embodiments, the compound of Formula (J), (II), and / or (IIa), or a pharmaceutically acceptable salt thereof, is represented by Formula (IIb):

[0242]

[0243] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, and R 3 and n, singly and in combination, are as described in the classes and subclasses herein, and Y is N, CH, or CR 3 .

[0244] In some embodiments, the compound of Formula (J), (II), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments, Y is CR 3 . In some embodiments, Y is CH.

[0245] In some embodiments, the compound of Formula (J), (II), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, is represented by Formula (IIc):

[0246]

[0247] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, and R 3 and n, singly and in combination, are as described in the classes and subclasses herein.

[0248] In some embodiments, the compound of Formula (J), (II), (IIa), (IIb), and / or (IIc), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, wherein

[0249] group having the structure: or a pharmaceutically acceptable salt thereof, wherein R 1 and n, singly and in combination, are as described in the classes and subclasses herein.

[0250] In some embodiments, the compound of Formula (J), (II), (IIa), (IIb), and / or (IIc), or a pharmaceutically acceptable salt thereof, is a compound, or a pharmaceutically acceptable salt thereof, wherein each R 1Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl or heteroaryl, wherein each alkyl group is derived from 0, 1, 2 or 3 R groups. 1c Substitution, and each alkoxy and alkynyl group is substituted with 0, 1, 2 or 3 R groups. 1d Replace; or alternatively, replace the two Rs adjacent to the carbon. 1 Together with the atoms they are attached to, they form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0251] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc) or their pharmaceutically acceptable salts are the following compounds or their pharmaceutically acceptable salts, wherein each R 1 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 aryl or heteroaryl, wherein each alkyl group is derived from 0 or 1 R 1c Substitution, and each alkoxy and alkynyl group is via 0 or 1 R 1d Replace; or alternatively, replace the two Rs adjacent to the carbon. 1 Together with the atoms they are attached to, they form C5-C8 cycloalkyl or heterocycloalkyl groups.

[0252] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc) or their pharmaceutically acceptable salts are the following compounds or their pharmaceutically acceptable salts, wherein each R 1a and R 1b It is independently hydrogen or C1-C3 alkyl.

[0253] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc), or pharmaceutically acceptable salts thereof, are the following compounds or pharmaceutically acceptable salts thereof, wherein each R 1c Halogen, -NR 1c1 R 1c2 ,OH or -CN.

[0254] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 1d independently is heteroaryl.

[0255] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 1e independently is C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0256] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 1 independently is -CH3, -CH2CH3, -C(CH3)3, -OCH3, -OCD3, -C(CH3)2OCH3, -C(CH3)2CH2OH, -CH2CH3, -OCH(CH3)2, -C(CH3)2OH, -C(CH3)(CH2CH3)OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, cyclopropyl, cyclopropyloxy, cyclobutyloxy,

[0257]

[0258] two R 1 independently are C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN. 1 independently are C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0259]

[0260] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CH2O-, or -O-.

[0261] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.

[0262] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with 0, 1, or 2 R 2a substituents.

[0263] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 2a is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0264] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 2b and R 2c are independently hydrogen or C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0266]

[0267] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein R 2 is

[0268]

[0269] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a, -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), OH, -CN, C3-C8cycloalkyl, or heterocycloalkyl.

[0270] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein two R 3 groups on the same carbon atom together represent oxo.

[0271] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b is independently hydrogen or C1-C4alkyl.

[0272] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein each R 3c is halogen, -NR 3c1 R 3c2 , OH, or -CN.

[0273] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein each R 3d is independently heteroaryl.

[0274] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein each R 3e is independently C1-C4alkyl, C1-C4alkoxy, halogen, or C1-C4haloalkyl.

[0275] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie), or a pharmaceutically acceptable salt thereof, is a compound of the following formula, or a pharmaceutically acceptable salt thereof, wherein each R3 It is independently a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0276] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc), or pharmaceutically acceptable salts thereof, are the following compounds or pharmaceutically acceptable salts thereof, wherein each R 3 It is independently a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0277] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc), or pharmaceutically acceptable salts thereof, are the following compounds or pharmaceutically acceptable salts thereof, wherein each R 3 It can be independently Me, Ome, CHF2, CF3, OCHF2, OCF3 or cyclopropyl.

[0278] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc) or pharmaceutically acceptable salts thereof are compounds in which the subscript q is 1, 2 or 3, or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc) or their pharmaceutically acceptable salts are the following compounds or their pharmaceutically acceptable salts, wherein the subscript n is 0 or 1.

[0280] In some embodiments, the compounds of formulas (J), (II), (IIa), (IIb) and / or (IIc) or their pharmaceutically acceptable salts are compounds having the structures of the compounds shown in Table 2 or their pharmaceutically acceptable salts.

[0281] Table 2. Compounds

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) or pharmaceutically acceptable salt thereof is a compound, wherein the compound has the structure:

[0292]

[0293] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) is a compound, wherein the compound has the structure:

[0294]

[0295] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) or pharmaceutically acceptable salt thereof is a compound, wherein the compound has the structure:

[0296]

[0297] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) is a compound, wherein the compound has the structure:

[0298]

[0299] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) or pharmaceutically acceptable salt thereof is a compound, wherein the compound has the structure:

[0300]

[0301] In some embodiments, the compound of Formula (J), (II), (Ila), (lib), and / or (lie) is a compound, wherein the compound has the structure:

[0302]

[0303] In some embodiments, the compound of Formula (J) or pharmaceutically acceptable salt thereof is represented by Formula (III):

[0304]

[0305] or a pharmaceutically acceptable salt thereof, wherein

[0306] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or –O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e ;

[0307] each R 1a and R 1b is independently hydrogen or C1-C6 alkyl;

[0308] each R 1c is independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, -NR 1c1 R1c2 OH or -CN;

[0309] each R 1c1 and R 1c2 is independently hydrogen or Ci-C6alkyl;

[0310] each R 1d is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C 10 aryl or heteroaryl;

[0311] each R 1e is independently Ci-C6alkyl, Ci-C6alkoxy, halogen, Ci-C6haloalkyl, Ci-C6haloalkoxy, OH or -CN;

[0312] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5 or 6 halogen, Ci-C4alkyl, OH or -CN;

[0313] L is -Ci-C4alkylene-, -(Ci-C4alkylene)-0- or -0-;

[0314] R 2 is heteroaryl, substituted with 0, 1, 2, 3 or 4 R 2a ;

[0315] each R 2a is independently Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, Ci-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, Ci-C6haloalkyl, Ci-C6haloalkoxy, -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b , -C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b , -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN or -NO2;

[0316] each R 2b and R 2c is independently hydrogen or Ci-C6alkyl;

[0317] each R 3independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8cycloalkyl, (C1-C3alkyl)(C3-C8cycloalkyl), -O-(C3-C8cycloalkyl), heterocycloalkyl, (C1-C3alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or,

[0318] two R 3 on the same carbon atom together represent oxo;

[0319] each R 3a and R 3b is independently hydrogen or C1-C6alkyl;

[0320] each R 3c is independently C1-C6alkoxy, halogen, C1-C6haloalkoxy, -NR 3c1 R3c2 OH or -CN;

[0321] each R 3c1 and R 3c2 is independently hydrogen or Ci-C6alkyl;

[0322] each R 3d is independently C3-C8cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl;

[0323] each R 3e is independently Ci-C6alkyl, Ci-C6alkoxy, halogen, Ci-C6haloalkyl, or Ci-C6haloalkoxy;

[0324] R 4 is hydrogen or Ci-C6alkyl;

[0325] the subscript n is 0, 1, 2, 3, or 4; and

[0326] the subscript q is 0, 1, 2, 3, or 4;

[0327] wherein

[0328] each heterocycloalkyl is a 3- to 8-membered ring comprising 1-4 heteroatoms each independently N, O, or S; and

[0329] each heteroaryl is a 5- to 6-membered ring comprising 1-4 heteroatoms each independently N, O, or S.

[0330] In some embodiments, the compound of Formula (J) or Formula (III) is represented by Formula (Ilia):

[0331]

[0332] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , n, and R 4 are described, individually and in combination, in the classes and subclasses herein.

[0333] In some embodiments, the compound of Formula (J), (III), and / or (Ilia) or a pharmaceutically acceptable salt thereof is represented by Formula (Illb):

[0334]

[0335] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , and R 4 are described, individually and in combination, in the classes and subclasses herein.

[0336] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof,

[0337] group having the structure:

[0338]

[0339] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 10 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 1c is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 1d are taken together with the atom to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl. 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R

[0340] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 10 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 1c is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 1d are taken together with the atom to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl. 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R

[0341] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1a and R 1b are independently hydrogen or C1-C4 alkyl.

[0342] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1c is halogen, -NR 1c1 R 1c2 , OH, or -CN.

[0343] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1d is independently heteroaryl.

[0344] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1e is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0345] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 1 is independently -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CH2CH3, -OCH(CH3)2, -OCH2-pyridyl, -C(CH3)2OH, F, Cl, Br, -CF3, -OCHF2, -OCF3, -OCH2CF3, -C(CH3)2CH2OH, -OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, or pyrazolyl; or alternatively, two R 1 on adjacent carbon atoms combine, together with the atoms to which they are attached, to form cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxolyl, dihydro-1,3-oxazinyl, or methyldihydrofuran. In some embodiments, two R 1 combine to form:

[0346]

[0347] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, L is -CH2-, -CH2O-, or -O-.

[0348] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, L is -CH2-.

[0349] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with 0, 1, or 2 R 2a substituents.

[0350] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 2a is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0351] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 2b and R 2c are independently hydrogen or C1-C4 alkyl.

[0352] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, R 2 is

[0353]

[0354] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, R 2 is

[0355]

[0356] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b , -N(R 3a )C(O)(R 3b), -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), OH, -CN, C3-C8cycloalkyl, or heterocycloalkyl.

[0357] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3 together represent oxo.

[0358] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3a and R 3b are independently hydrogen or C1-C4alkyl.

[0359] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3c is halogen, -NR 3c1 R 3c2 , OH, or -CN.

[0360] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3d is independently heteroaryl.

[0361] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3e is independently C1-C4alkyl, C1-C4alkoxy, halogen, or C1-C4haloalkyl.

[0362] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3 is independently C1-C6alkyl, C1-C6alkoxy, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -CN, or C3-C8cycloalkyl.

[0363] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3 is independently C1-C4alkyl, C1-C4alkoxy, halogen, C1-C4haloalkyl, C1-C4haloalkoxy, -CN, or C3-C6cycloalkyl.

[0364] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, each R 3 is independently Me, OMe, OEt, CHF2, CF3, OCHF2, OCF3, F, Br, CN, or cyclopropyl.

[0365] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is Me, Et, or iPr. In some embodiments, R 4 is hydrogen.

[0366] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, subscript q is 1, 2, or 3.

[0367] In some embodiments of the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, subscript n is 1 or 2.

[0368] In some embodiments, the compound of Formula (J), (III), (Ilia), and / or (Illb), or a pharmaceutically acceptable salt thereof, is a compound of Formula (J), (III), (Ilia), and / or (Illb) as set forth in Table 3, or a pharmaceutically acceptable salt thereof.

[0369] Table 3. Compounds

[0370]

[0371]

[0372]

[0373] In some embodiments, the compound of Formula (J) is represented by Formula (IV):

[0374]

[0375] or a pharmaceutically acceptable salt thereof, wherein

[0376] each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR1a -OC(O)R 1a -C(O)N(R) 1a (R) 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a (R) 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R) 1a (R) 1b -S(O)(NH)R 1a -S(O)(NH)N(R) 1a (R) 1b ), -N(R 1a (R) 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R... 1c Substitution, with each alkoxy and alkynyl group via 0, 1, 2, or 3 R groups. 1d Substitution, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is determined by 0, 1, 2, or 3 R groups. 1e replace;

[0377] Each R 1a and R 1b Independently hydrogen or C1-C6 alkyl;

[0378] Each R 1c Independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, -NR 1c1 R 1c2 OH or -CN;

[0379] Each R 1c1 and R 1c2 Independently hydrogen or C1-C6 alkyl;

[0380] Each R 1d Independently deuterium, C3-C8 cycloalkyl, heterocycloalkyl, C6-C 10aryl or heteroaryl;

[0381] each R 1e is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN;

[0382] alternatively, two R 1 groups on adjacent carbons, together with the atoms to which they are attached, combine to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN;

[0383] L is -C1-C4 alkylene-, -(C1-C4 alkylene)-O-, or -O-;

[0384] R 2 is heteroaryl, substituted with 0, 1, 2, 3, or 4 R 2a ;

[0385] each R 2a is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b , -C(O)OR 2b , -OC(O)R 2b , -C(O)N(R 2b )(R 2c ), -N(R 2b )C(O)(R 2c ), -S(O)2R 2b , -S(O)2N(R 2b )(R 2c ), -N(R 2b )(R 2c ), OH, -CN, or -NO2;

[0386] each R 2b and R 2c are independently hydrogen or C1-C6 alkyl;

[0387] Y is CH, CR 3 , or N;

[0388] each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a ;-OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a (R) 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a -S(O)2R 3a -S(O)2N(R) 3a (R) 3b -S(O)(NH)R 3a -S(O)(NH)N(R) 3a (R) 3b ), -N(R 3a (R) 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R... 3c Substitution, each alkoxy group via 0, 1, 2 or 3 R... 3d Substitution, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is determined by 0, 1, 2, or 3 R groups. 3e Replace; or,

[0389] Two Rs on the same carbon atom 3 Together they represent oxygen groups;

[0390] Each R 3a and R 3b Independently hydrogen or C1-C6 alkyl;

[0391] Each R 3c Independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, -NR 3c1 R 3c2 OH or -CN;

[0392] Each R 3c1 and R 3c2 Independently hydrogen or C1-C6 alkyl;

[0393] Each R3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group;

[0394] Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0395] R 4 It is hydrogen or C1-C6 alkyl;

[0396] The subscript n is 0, 1, 2, 3, or 4; and

[0397] The subscript q is 0, 1, 2, 3, or 4;

[0398] in

[0399] Each heterocyclic alkyl group is a 3- to 8-membered ring, comprising 1 to 4 heteroatoms, each independently of N, O, or S; and

[0400] Each heteroaryl group is a 5- to 6-membered ring, comprising 1 to 4 heteroatoms, each of which is independently N, O, or S.

[0401] In some embodiments, compounds of formula (J) or formula (IV), or pharmaceutically acceptable salts thereof, are represented by formula (IVa):

[0402]

[0403] Or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 L, R 3 , n and R 4 Individually and in combination as described in the categories and subclasses of this document, and Y is N, CH, or CR. 3 .

[0404] In some embodiments, compounds of formula (J), (IV) and / or (IVa) or pharmaceutically acceptable salts thereof are represented by formula (IVb):

[0405]

[0406] Or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 L, R 3 and R 4 Individually and in combination as described in the categories and subclasses of this document, and Y is N, CH, or CR. 3 .

[0407] In some embodiments of a compound of Formula (J), (IV), (IVa), and / or (IVb), or a pharmaceutically acceptable salt thereof, Y is N. In some embodiments, Y is CR 3 In some embodiments, Y is CH.

[0408] In some embodiments, a compound of Formula (J), (IV), (IVa), and / or (IVb) is represented by Formula (IVc):

[0409]

[0410] or a pharmaceutically acceptable salt thereof, wherein R 1 , q, R 2 , L, R 3 , and R 4 are each independently as described in classes and subclasses herein, both singly and in combination.

[0411] In some embodiments of a compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof,

[0412] the group has the structure:

[0413] wherein R 1 are each independently as described in classes and subclasses herein, both singly and in combination.

[0414] In some embodiments of a compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C10 aryl, or heteroaryl, wherein each alkyl is substituted with 0, 1, 2, or 3 R 10 , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1c ; or alternatively, two R 1d on adjacent carbons combine, along with the atom to which they are attached, to form a C5-C8 cycloalkyl or heterocycloalkyl. 1

[0415] ​In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C10 aryl, heteroaryl, heterocycloalkyl, -CN, -NR 10 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 1c is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 1d is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 1 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C

[0416] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1a and R 1b is independently hydrogen or C1-C3 alkyl.

[0417] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1c is halogen, -NR 1c1 R 1c2 , OH, or -CN.

[0418] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1d is independently heteroaryl.

[0419] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1e is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, or -CN.

[0420] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 1independently -CH3, -CH2CH3, -C(CH3)3, -OCH3, -CH2CH3, -OCH(CH3)2, -C(CH3)2OH, -C(CH3)(CH2CH3)OH, F, Cl, Br, -CF3, -OCHF2, -OCF3, -OCH2CF3, cyclopropyl, cyclopropyloxy, cyclobutyloxy,

[0421]

[0422] two R 1 combined with the atom to which they are attached form a cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxolyl, dihydro-1,3-oxazinyl, or methyldihydrofuran. In some embodiments, two R 1 combined to form:

[0423]

[0424] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, L is -CH2-, -CH2O-, or -O-.

[0425] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, L is -CH2-.

[0426] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with 0, 1, or 2 R 2a substituents.

[0427] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 2a is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN.

[0428] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R2b and R 2c independently hydrogen or C1-C4alkyl.

[0429] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 2 is

[0430]

[0431] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 2 is

[0432]

[0433] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3 independently C1-C6alkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkoxyalkyl, halogen, C1-C6haloalkyl, C1-C6haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), OH, -CN, C3-C8cycloalkyl, or heterocycloalkyl.

[0434] In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: 3 together represent oxo.

[0435] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3a and R 3b independently hydrogen or C1-C4alkyl.

[0436] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3c is halogen, -NR 3c1 R 3c2 , OH, or -CN.

[0437] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3d is independently heteroaryl.

[0438] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3e is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

[0439] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3 is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

[0440] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3 is independently C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

[0441] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, each R 3 is independently Me, Ome, CHF2, CF3, OCHF2, OCF3, or cyclopropyl.

[0442] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, R 4 is hydrogen or C1-C4 alkyl. In some embodiments, R 4 is Me, Et, or iPr. In some embodiments, R 4 is hydrogen.

[0443] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, subscript q is 1, 2, or 3.

[0444] In some embodiments of the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, subscript n is 0 or 1.

[0445] In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), or (IVc), wherein the compound is a compound of Formula (I), (II), (III), (IIIa), (IIIb), (IIIc), (IV), (IVa), (IVb), or (IVc) as depicted in Table 4, or a pharmaceutically acceptable salt thereof.

[0446] Table 4. Compounds

[0447]

[0448]

[0449]

[0450]

[0451] In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

[0452] 4-((1H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3-methoxybenzamide (14) e

[0453] 4-((1H-pyrazol-1-yl)methyl)-3-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)benzamide

[0454] 4-((1H-pyrazol-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide (67),

[0455] 5-((1H-pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide (203),

[0456] 5-((1H-pyrazol-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide (204),

[0457] 5-((lH-Pyrazol-l-yl)methyl)-6-methoxy-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide (229),

[0458] 5-((lH-Pyrazol-l-yl)methyl)-6-methoxy-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide (229),

[0459] 5-((lH-Pyrazol-l-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (241),

[0460] 5-((lH-Pyrazol-l-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide (285),

[0461] 4-((lH-Pyrazol-l-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7- yl)sulfonyl)benzamide (314),

[0462] and pharmaceutically acceptable salts thereof.

[0463] In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 4-((lH-pyrazol-l-yl)methyl)-N-((2,6- dimethoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 4-((lH-pyrazol-l-yl)methyl)-3-methoxy-N-((2,4,6- trimethoxyphenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 4-((lH-pyrazol-l-yl)methyl)-N-((2-ethoxy-6- methoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-N-((2,6- dimethoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-N-((5-ethyl-2- methoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6- trimethoxyphenyl)sulfonyl)pyridinecarboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-6-cyclopropyl-N-((2,6- dimethoxyphenyl)sulfonyl)pyridinecarboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-N-((3-chloro-2,6- dimethoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 5-((lH-pyrazol-l-yl)methyl)-N-((4- bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (J), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, is 4-((lH-pyrazol-l-yl)methyl)-3- methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0464] IV. Compositions

[0465] In some embodiments, the pharmaceutical composition of the present application comprises a compound of the present application, e.g., a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0466] The compounds of the present application can be used as a sole drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable excipients.

[0467] The compounds of the present application are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well-known in the pharmaceutical art, and comprise at least one compound of the present application. The pharmaceutical compositions of the present patent application comprise one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by a regulatory agency or are generally recognized as safe for human or animal use. Pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickening agents, and solvents.

[0468] The pharmaceutical compositions can be administered by oral, parenteral, or inhalation routes. Examples of parenteral administration include injection administration, transdermal administration, transmucosal administration, nasal administration, and pulmonary administration.

[0469] Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, low -alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.

[0470] The pharmaceutical composition can also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preservatives, buffers, sweeteners, flavoring agents, colorants, or any combination of the foregoing.

[0471] The pharmaceutical composition can be in conventional form, for example, tablet, capsule, solution, suspension, injection, or product for topical application. In addition, the pharmaceutical composition of the present application can be formulated to provide a desired release profile.

[0472] Administration of the compounds of the present application, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the acceptable pharmaceutical administration routes. The administration route can be any route that is effective for transporting the active compounds of the present patent application to the appropriate or desired site of action. Suitable administration routes include, but are not limited to, oral, nasal, buccal, transdermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.

[0473] Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), sugar-coated pills (containing active ingredients in the form of powder or pellets), lozenges, and buccal tablets.

[0474] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.

[0475] Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, impregnated dressings, and can contain appropriate conventional additives such as preservatives, solvents to help drug penetration.

[0476] The pharmaceutical composition of the present patent application can be prepared by conventional techniques known in the literature.

[0477] The appropriate dose of the compound for treating the diseases or disorders described herein can be determined by a person skilled in the relevant field. The therapeutic dose is usually determined by human dose range study based on preliminary evidence from animal studies. The dose must be sufficient to produce the desired therapeutic benefit without causing undesirable side effects. The person skilled in the art can also well use and adjust the administration mode, dosage form and suitable pharmaceutical excipients. All changes and modifications are within the scope of the present patent application.

[0478] In some embodiments, the pharmaceutical compositions of the present application are pharmaceutical compositions comprising a compound of Formula (J) or a pharmaceutically acceptable salt thereof as described herein and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of at least one compound described herein. The compounds described herein can be associated with, or diluted or encapsulated in, a carrier that can be in the form of a capsule, sachet, paper, or other container, with a pharmaceutically acceptable excipient, such as a carrier or diluent.

[0479] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, baby oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0480] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0481] In order to prolong the effect of a drug, it is often desirable to slow its absorption from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0482] Compositions for rectal or vaginal administration can be presented as a suppository, which can be prepared from a mixture of the compound of the present application with one or more suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which is solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0483] Solid compositions of a similar type can also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for such compositions include lactose or milk sugar and high molecular weight polyethylene glycols.

[0484] The active compounds can also be in micro-encapsulated form, with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings and other coatings known to those in the art. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, including but not limited to, binders such as magnesium aluminum, stearate and other stearate, microcrystalline cellulose, and lubricants such as sodium oleate, sodium stearate, magnesium stearate, glycine, sodium chloride, and the like. In the case of capsules, tablets and pills, the dosage forms can also comprise buffering agents.

[0485] Dosage forms for the topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active component is admixed with a pharmaceutical carrier, which can comprise

[0486] Ointments, pastes, creams and gels can contain, in addition to compound of the present application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0487] Sprays and powders can contain, in addition to compound of the present application, excipients such as lactose, talc, aluminim hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbon.

[0488] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0489] Administration of the disclosed compounds and pharmaceutical compositions can be achieved via any mode of administration of the therapeutic agent. These modes include systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or local modes of administration.

[0490] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions can be in solid, semi-solid, or liquid dosage form, for example, injectables, tablets, suppositories, pills, time release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, etc., sometimes in unit dosage form and consistent with conventional pharmaceutical practice. Likewise, they can be administered intravenously (bolus and infusion), intraperitoneally, subcutaneously, or intramuscularly, and all using forms well known to those skilled in the pharmaceutical arts.

[0491] Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) diluents, e.g., purified water; triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil; fish oils, such as EPA or DHA or esters or triglycerides thereof or mixtures thereof; omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; also for tablets; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweetener, natural and synthetic gum such as acacia, tragacanth, or sodium alginate, waxes, and / or polyvinylpyrrolidone, if desired; d) disintegrants, e.g., starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors, and sweeteners; f) emulsifiers or dispersing agents such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS, or other acceptable emulsifiers; and / or g) agents that enhance the absorption of compounds such as cyclodextrins, hydroxypropyl-cyclodextrins, PEG 400, PEG 200.

[0492] Liquid compositions, particularly injectable compositions, can be prepared, for example, by dissolving, dispersing, etc. For example, one or more of the disclosed compounds are dissolved or mixed with a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerol, ethanol, or the like, to which can be added suitable protein, such as albumin, chylomicron, or serum proteins, to form injectable isotonic solutions or suspensions. Proteins such as albumin, chylomicron, or serum proteins can be used to solubilize the disclosed compounds.

[0493] One or more of the disclosed compounds or compositions can be delivered by parenteral administration. Parenteral injectable solutions are typically used for subcutaneous, intramuscular, or intravenous injection and infusion. The injectable solutions can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolving in liquid prior to injection.

[0494] In some embodiments, the pharmaceutical compositions of the present application comprise a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.

[0495] In some embodiments, the pharmaceutical compositions of the present application comprising a compound of the present application, e.g., a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, are used as a medicament.

[0496] In some embodiments, the pharmaceutical compositions of the present application comprising a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, are used to treat a disease or condition that depends on or is mediated by KAT6A.

[0497] V. Administration

[0498] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for a desired period of time or duration, such as at least about one week, at least about two weeks, at least about three weeks, one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more. In one variation, the compounds are administered on a daily or intermittent schedule for the desired duration, until the lifetime of the individual.

[0499] The dosage or frequency of administration of the compounds of the disclosure can be adjusted according to the judgment of the attending medical practitioner.

[0500] An effective amount of the compound can be administered to an individual (e.g., a human).

[0501] The compounds of the present application can be administered by any useful route and means, for example, by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound of the present application is from about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, for example, from about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or for example, from about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, from about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or for example, from about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day.

[0502] A therapeutically effective amount of a compound of the present application is from about 0.01 mg per dose to about 1000 mg per dose, for example, from about 0.01 mg per dose to about 100 mg per dose, or for example, from about 0.1 mg per dose to about 100 mg per dose, or for example, from about 1 mg per dose to about 100 mg per dose, or for example, from about 1 mg per dose to about 10 mg per dose. Other therapeutically effective amounts of a compound of the present application are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of a compound of the present application are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose. A single dose can be administered once per hour, per day, or per week. For example, a single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once per week. A single dose can also be administered once per month.

[0503] VI. Methods and / or Uses

[0504] In some embodiments, the method of the application is a method of treating a disease or disorder, comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0505] In some embodiments, the use of the application is the use of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a disease or condition (e.g., cancer).

[0506] In some embodiments, the compound for use in the application is a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder mediated by KAT6A.

[0507] In some embodiments, the method of the application is a method of inhibiting KAT6A in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0508] In some embodiments, the method of the application is a method for treating a disease or disorder mediated by KAT6A in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0509] In some embodiments, a compound for use in the application is a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0510] In some embodiments, a method of the application is a method of modulating KAT6A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof.

[0511] In some embodiments, a use of the application is the use of a pharmaceutical composition comprising a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a disease or disorder mediated by KAT6A. In some embodiments, the use of the pharmaceutical composition comprises a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a cancer mediated by KAT6A.

[0512] In some embodiments, a use of the application is the use of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder mediated by KAT6A.

[0513] In some embodiments, the disease or disorder mediated by or dependent on KAT6A is a cancer.

[0514] In some embodiments, the cancer is selected from brain glioma, glioblastoma, astrocytoma, spongioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastocytic large cell leukemia, mantle cell leukemia, multiple myeloma, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erytholeukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and virus-associated cancer.

[0515] In some embodiments, the use of the present application is the use of a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cancer selected from brain glioma, glioblastoma, astrocytoma, spongioblastoma, Sanfilippo syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal carcinoma, buccal cancer, oral cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and virus-associated cancer.

[0516] In some embodiments, the compound for use in the present application is a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder mediated by KAT6A.

[0517] In some embodiments, the compound for use in the application is a compound of Formula (J), (I), (la), (lb), (II), (Ila), (lib), (lie), (III), (Ilia), (Illb), (IV), (IVa), (IVb), and / or (IVc), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a cancer selected from the group consisting of brain glioma, glioblastoma, astrocytoma, glioblastoma multiforme, Prader-Willi syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblast large cell leukemia, mantle cell leukemia, multiple myeloma, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and a virus-associated cancer.

[0518] In some embodiments, the present disclosure provides compounds for use in combination with other compounds or biological entities for the treatment of a disease or disorder. Suitable combinations of compounds and dosages for combination therapy to treat the diseases or disorders described herein can be determined by one of skill in the relevant art. Combination therapy with the compounds of the present disclosure can be used to treat a disease or disorder. In some embodiments, the disease or disorder is a cancer.

[0519] In some embodiments, the present disclosure provides a compound for use in a method of treating a disease or disorder in a subject, the method comprising administering the compound to the subject in combination or alternation with an estrogen receptor antagonist or an estrogen receptor partial antagonist. As described herein, an estrogen receptor "partial" antagonist refers to an estrogen receptor antagonist that exhibits antagonist activity in an estrogen receptor antagonist assay, but also exhibits detectable estrogen receptor agonist activity in an estrogen receptor agonist assay.

[0520] In some embodiments, the present disclosure provides a compound for use in a method of treating a disease or condition in a subject, the method comprising administering the compound to the subject in combination or alternation with a selective estrogen receptor modulator (SERM). In some embodiments, the SERM is tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, elacestrant, or bazedoxifene.

[0521] In some embodiments, the present disclosure provides a compound for use in a method of treating a disease or condition in a subject, the method comprising administering the compound to the subject in combination or alternation with a selective estrogen receptor degrader. In some embodiments, the SERD is fulvestrant, camizestrant, patuximab, imlunestrant, elacestrant, or giredestrant.

[0522] In some embodiments, the present disclosure provides a compound for use in a method of treating a disease or condition in a subject, the method comprising administering the compound to the subject in combination or alternation with a complete estrogen receptor antagonist (CERAN). In some embodiments, the CERAN is fulvestrant or patuximab. In some embodiments, the CERAN is fulvestrant. In some embodiments, the CERAN is patuximab.

[0523] In some embodiments, the present disclosure provides a compound for use in a method of treating a disease or condition in a subject, the method comprising administering the compound to the subject in combination or alternation with an additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is selected from a HER2 inhibitor, an mTOR inhibitor, a CDK4 / 6 inhibitor, a CDK2 selective inhibitor, a CDK4 selective inhibitor, a PI3 kinase inhibitor, a PIK3CA inhibitor, an aromatase inhibitor, an antibody or inhibitor of PD-1, PD-L1, or CTLA-4, an antibody or inhibitor of EGFR, PGFR, or IGFR, a USP1 inhibitor, or an AKT inhibitor.

[0524] In some embodiments, the additional anti-cancer agent is a CDK2 inhibitor. In some embodiments, the CDK2 inhibitor is PF-07104091 (talacotisib).

[0525] In some embodiments, the additional anti-cancer agent is a HER2 inhibitor. In some embodiments, the HER2 inhibitor is selected from tucatinib, trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, lapatinib, and neratinib.

[0526] In some embodiments, the additional anti-cancer agent is an mTOR inhibitor. In some embodiments, the mTOR inhibitor is selected from the group consisting of everolimus, sirolimus, temsirolimus, and LY3023414.

[0527] In some embodiments, the additional anti-cancer agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, reloxaliib, trilaciclib, and SHR6390.

[0528] In some embodiments, the additional anti-cancer agent is a CDK4-selective inhibitor. In some embodiments, the CDK-4 selective inhibitor is PF-07220060 (atexakinib).

[0529] In some embodiments, the additional anti-cancer agent is a PI3 kinase inhibitor. In some embodiments, the PI3 kinase inhibitor is selected from the group consisting of perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

[0530] In some embodiments, the PI3 kinase inhibitor is a PIK3CA inhibitor. In some embodiments, the PIK3CA inhibitor is selected from the group consisting of alpelisib, taselisib, LY3023414, iniparib, STX-478, RLY-2608, LOXO-783, OKI-219, and TOS-358.

[0531] In some embodiments, the additional anti-cancer agent is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from the group consisting of aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, formestane, fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatriene-3,17-dione, and 4-androstene-3,6,17-trione.

[0532] In some embodiments, the additional anti-cancer agent is an antibody or inhibitor of PD-1, PD-L1, or CTLA-4.

[0533] In some embodiments, the additional anti-cancer agent is an antibody or inhibitor of EGFR, PGFR, or IGFR. In some embodiments, the anti-cancer agent is erlotinib or gefitinib.

[0534] In some embodiments, the additional anti-cancer agent is a USP1 inhibitor.

[0535] In some embodiments, the additional anti-cancer agent is an AKT inhibitor. In some embodiments, the additional anti-cancer agent is capivasatinib.

[0536] VII. EXAMPLES

[0537] While specific embodiments of the application have been discussed, the above specification is illustrative and not restrictive. Many variations of the application will become apparent to those skilled in the art upon review of the specification and claims below. The full scope of the application should be determined by reference to the claims below, along with their full scope of equivalents, and the specification, along with such variations.

[0538] The following abbreviations refer to the following definitions, respectively:

[0539] DMSO - dimethyl sulfoxide;

[0540] THF - tetrahydrofuran;

[0541] DCM - dichloromethane;

[0542] LiHMDS - lithium bis(trimethylsilyl)amide;

[0543] Pd(Amphos)Cl2 - bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)palladium(II) chloride;

[0544] NH4CI - ammonium chloride;

[0545] Na2SO4 - sodium sulfate;

[0546] BPO - benzoyl peroxide;

[0547] br - broad;

[0548] °C - degrees Celsius;

[0549] DMSO-d6 - deuterated dimethyl sulfoxide;

[0550] DMF - N,N-dimethylformamide;

[0551] Et - ethyl;

[0552] g - grams;

[0553] h - hours;

[0554] 1 H - proton;

[0555] iPr - isopropyl;

[0556] LC - MS - liquid chromatography-mass spectrometry;

[0557] Me - methyl;

[0558] Mhz - megahertz (frequency);

[0559] MS - mass spectrometry;

[0560] Ms - methanesulfonyl;

[0561] M - mole;

[0562] mmol - millimole;

[0563] mL - milliliter;

[0564] min - minute;

[0565] mol - mole;

[0566] M + / - - molecular ion; m / z - mass to charge ratio;

[0567] NBS - N-bromosuccinimide;

[0568] NMR - nuclear magnetic resonance;

[0569] ppm - parts per million;

[0570] rt or RT - room temperature;

[0571] RM - reaction mixture;

[0572] br - broad;

[0573] s - singlet;

[0574] d - doublet;

[0575] t - triplet;

[0576] q - quartet;

[0577] m - multiplet;

[0578] dd - doublet of doublets;

[0579] TLC - thin layer chromatography;

[0580] % - percent; and

[0581] delta.

[0582] a) Sulfonylamide Intermediates

[0583] Intermediate 15: 2-methoxy-4-(1H-pyrazol-1-yl)benzenesulfonamide

[0584]

[0585] Step 1: 1-(3-methoxyphenyl)-1H-pyrazole

[0586] To a degassed solution of 1-iodo-3-methoxybenzene (10 g, 42.7 mmol) in 1,4-dioxane (100 mL) at RT was added 1H-pyrazole (3.49 g, 51.2 mmol), CuI (0.81 g, 4.2 mmol) and K3PO4 (18.1 g, 85.4 mmol). The reaction mixture was then heated to 90 °C for 16 h. The reaction mixture was allowed to cool to RT and water was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude compound. The crude compound was purified by combi flash chromatography using 20% ethyl acetate in hexane to give the title compound (6.5 g, 87.3%). LC-MS: 175.1 [M+H] + .

[0587] Step 2: 2-Methoxy-4-(1H-pyrazol-1-yl)benzenesulfonyl chloride

[0588] To a solution of 1-(3-methoxyphenyl)-1H-pyrazole (2 g, 11.4 mmol) in chlorosulfonic acid (13.3 g, 114.8 mmol) was added dropwise thionyl chloride (1.6 g, 13.7 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with ice water and extracted with DCM. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated to give the title compound (1.2 g). LC-MS: 273.0 [M+H] + .

[0589] Step 3: 2-Methoxy-4-(1H-pyrazol-1-yl)benzenesulfonamide

[0590] To a solution of 2-methoxy-4-(1H-pyrazol-1-yl)benzenesulfonyl chloride (1.2 g, 4.4 mmol) in DCM (10 mL) was added dropwise 7 M methanolic ammonia at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated aq. NaHCO3, dried over Na2SO4, and concentrated to give the title compound (0.3 g). LC-MS: 254.0 [M+H] + .

[0591] Intermediate 16

[0592] The following intermediate 16 listed below was prepared following similar procedures as described above for intermediate 15 using appropriate reagents known to those skilled in the art with suitable modifications.

[0593]

[0594] Intermediate 17: 4-(tert-butyl)-2-methoxybenzenesulfonamide

[0595]

[0596] Step 1: 4-(tert-butyl)-2-methoxybenzenesulfonic acid

[0597] To a solution of 1-(tert-butyl)-3-methoxybenzene (6 g, 36.5 mmol) in dry DCM (90 mL) was added chlorosulfonic acid (5.1 g, 43.8 mmol) dropwise at 0 °C over 15 min. The reaction mixture was then allowed to warm to room temperature gradually and stirred overnight. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was washed with saturated Aq. NaHCO3, dried over Na2SO4, and concentrated to give the title compound (5 g). LC-MS: 243.0 [M-H] - .

[0598] Step 2: 4-(tert-butyl)-2-methoxybenzenesulfonyl chloride

[0599] To a solution of 4-(tert-butyl)-2-methoxybenzenesulfonic acid (5 g, 20.4 mmol) in 1,2-DCE (75 mL) was added PCl5(8.5 g, 40.9 mmol) portion wise at 0 °C. After the addition was complete, the reaction mixture was heated to 80 °C for 16 h. The reaction mixture was then allowed to cool to RT and concentrated to give the crude compound. The crude compound was purified by combi flash chromatography using 50% EtOAc in hexanes to give the title compound (6.3 g, 74.3%).

[0600] Step 3: 4-(tert-butyl)-2-methoxybenzenesulfonamide

[0601] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using the appropriate reagents with suitable modifications. LC-MS: 244.1 [M+H] + .

[0602] Intermediate 18: 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide

[0603]

[0604] Step 1: 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride

[0605] To a stirred solution of 6-methoxy-1,2,3,4-tetrahydronaphthalene (0.5 g, 3.08 mmol) in DCM (15 mL) was added chlorosulfonic acid (1.07 g, 9.2 mmol) drop wise at 0 °C. The reaction mixture was allowed to warm to RT gradually and stirred at RT for 1 h. The reaction mixture was then poured into ice cold water and extracted with DCM. The organic layer was washed with aqueous NaHC03solution, dried over Na2S04and concentrated to get the title compound (0.52 g, 65%).

[0606] Step 2: 3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonamide

[0607] The title compound was prepared using a similar procedure as described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 241.9 [M+H] + .

[0608] Intermediate 19 to 26f

[0609] The following intermediates in Table 5 were prepared following a similar procedure as described above for Intermediate 18 using appropriate reagents known to those skilled in the art with suitable modifications. In some cases, the procedure started with a commercially available sulfonyl chloride building block.

[0610] Table 5. Intermediates

[0611]

[0612]

[0613] Intermediate 50: 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0614]

[0615] Step 1 : 6-methoxybenzofuran-3(2H)-one

[0616] To a solution of 6-hydroxybenzofuran-3(2H)-one (7.2 g 48.62 mmol) in DMF (80 mL) was added K2C03(13.44 g, 97.25 mmol) and Mel (1 1.45 g, 80.71 mmol) at 0 °C. The reaction mixture was allowed to warm to RT slowly and stirred for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to get the crude compound which was used for the next step without further purification (6.10 g, 88.60%). 1H NMR (DMSO-d6, 400 MHz): δ 7.53 (d, 1H), 6.83 (d, 1H), 6.71 (dd, 1H), 4.77 (s, 2H), 3.87 (s, 3H).

[0617] Step 2: 6-methoxy-2,3-dihydrobenzofuran-3-ol

[0618] To a solution of 6-methoxybenzofuran-3(2H)-one (7.0 g, 42.64 mmol) in MeOH (80 mL) was added NaBH4(3.22 g, 85.27 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to RT and stirred for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to obtain the title compound (6.20 g, 84.80 %). 1 H NMR (DMSO-d6, 400 MHz): δ 7.23 (d, 1H), 6.46 (dd, 1H), 6.41 (s, 1H), 5.43 (d, 1H), 5.21-5.16 (m, 1H), 4.52-4.48 (m, 1H), 4.25-4.21 (m, 1H), 3.72 (s, 3H).

[0619] Step 3: 6-methoxy-2,3-dihydrobenzofuran

[0620] To a solution of 6-methoxy-2,3-dihydrobenzofuran-3-ol (6.0 g, 48.62 mmol) in TFA (8.22 g, 72.21 mmol) was added triethylsilane (4.1 g, 36.10 mmol) at 0 °C followed by heating at 70 °C for 12 h. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over solid sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as eluent to obtain the pure compound (1.40 g, 25.8 %). 1 H NMR (DMSO-d6, 400 MHz): δ 7.23 (d, 1H), 6.46 (dd, 1H), 6.41 (s, 1H), 5.43 (d, 1H), 5.21-5.16 (m, 1H), 4.52-4.48 (m, 1H), 4.25-4.21 (m, 1H), 3.72 (s, 3H).

[0621] Step 4: 6-methoxy-2,3-dihydrobenzofuran-7-thiol

[0622] To a solution of 6-methoxy-2,3-dihydrobenzofuran (1.40 g, 9.32 mmol) in THF (14 mL) was added n-BuLi (5.59 mL, 13.99 mmol) and TMEDA (0.10 g, 0.93 mmol) slowly drop wise successively at 0 °C. The reaction mixture was allowed to warm up to RT slowly and stirred at the same temperature for 20 min. A solution of sulfur powder (0.28 g, 8.39 mmol) in toluene (4 mL) was added to the reaction mixture at 0 °C. The reaction mixture was stirred at RT for 12 h. The reaction was quenched with 1 N HCI solution and extracted with ethyl acetate. The combined organic layers were dried over solid sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 15% ethyl acetate in hexane as eluent to obtain the title compound (1.0 g, 58.86%). LC-MS: 181.0 [M-H] - .

[0623] Step 5: 7-(Benzylthio)-6-methoxy-2,3-dihydrobenzofuran

[0624] To a solution of 6-methoxy-2,3-dihydrobenzofuran-7-thiol (1.0 g, 5.48 mmol) in THF (10 mL) was added potassium tert-butoxide (0.739 g, 6.58 mmol) and benzyl chloride (0.69 g, 5.48 mmol) successively at 0 °C. The reaction mixture was allowed to warm up to RT slowly and stirred for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 5-15% ethyl acetate in hexane as eluent to obtain the title compound (0.45 g, 30.11%). LC-MS: 273.0 [M+H] + .

[0625] Step 6: 6-Methoxy-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0626] To a solution of 7-(benzylthio)-6-methoxy-2,3-dihydrobenzofuran (0.25 g, 0.98 mmol) in acetonitrile (3 mL), acetic acid (2 mL), and water (1 mL) was added DCDMH (0.21 g, 1.10 mmol) at 0 °C and stirred for 15 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 15-20% ethyl acetate in hexane as eluent to obtain the title compound (0.17 g, 74.5%). 1H NMR (DMSO-d6, 400 MHz): δ 7.09 (d, 1H), 6.39 (d, 1H), 4.47 (t, 2H), 3.69 (s, 3H), 3.06 (t, 2H).

[0627] Step 7: 6-methoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0628] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-d6, 400 MHz): δ

[0629] 7.31 (d, 1H), 6.96 (s, 2H), 6.56 (d, 1H), 4.59 (t, 2H), 3.81 (s, 3H), 3.11 (t, 2H).

[0630] Intermediate 51 : 2-methoxy-6-(1H-pyrazol-1-yl)benzenesulfonamide

[0631]

[0632] Step 1: 2-methoxy-6-(lH-pyrazol-l-yl)benzenethiol

[0633] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (CDC13, 400 MHz): δ 7.62 (d, 1H), 7.32 (t, 1H), 6.97 - 6.90 (m, 3H), 6.50 (d, 1H), 3.86 (s, 1H), 3.82 (s, 3H)

[0634] Step 2: l-(2-(benzylthio)-3-methoxyphenyl)-lH-pyrazole

[0635] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 297.1.1 [M+H] + .

[0636] Step 3: 2-methoxy-6-(lH-pyrazol-l-yl)benzenesulfonyl chloride

[0637] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications: LC-MS: 273.0 [M+H] + .

[0638] Step 4: 2-methoxy-6-(lH-pyrazol-l-yl)benzenesulfonamide

[0639] The title compound was prepared using a similar procedure described in step 3 of Intermediate 15 using appropriate reagents with suitable modifications: LC-MS: 254.0 [M+H]+.

[0640] Intermediate 52: 2-(pyridin-2-ylmethoxy)benzenesulfonamide

[0641]

[0642] Step 1: 2-((2-bromophenoxymethyl)pyridine

[0643] To a solution of 2-bromophenol (2 g, 11.56 mmol) and K2CO3(3.19 g 23.12 mmol) in acetonitrile (ACN, 20 mL) was added 2-(chloromethyl)pyridine (1.17 g, 13.87 mmol) and stirred at 90 °C for 12 h. The reaction mixture was allowed to cool to RT, diluted with EtOAc, washed with 2 N NaOH solution (10 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude. The crude was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as eluent to get the title compound (2.8 g, 91.7%). LC-MS: 264.8 [M+H] +

[0644] Step 2: 2-((2-(benzylthio)phenoxy)methyl)pyridine

[0645] To a degassed solution of 2-((2-bromophenoxy methyl)pyridine (2.8 g, 10.60 mmol) and benzyl mercaptan (1.31 g, 10.60 mmol), N,N-diisopropylethylamine (2.74 g, 21.20 mmol) and XantPhos (1.22 g, 2.22 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3(1.94 gm 2.12 mmol) and stirred at 80 °C for 2 h. The reaction mixture was passed through celite and washed with ethyl acetate. The filtrate was concentrated to get the crude which was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as eluent to get the title compound (2.5 g, 76.7%). LC-MS: 306.1 [M-H] -

[0646] Step 3: 2-(pyridin-2-ylmethoxy)benzenesulfonyl chloride

[0647] To a solution of 2-((2-(phenylsulfanyl)phenoxy)methyl)pyridine (1.5 g, 4.87 mmol) in acetonitrile (12 mL), acetic acid (6 mL) and water (3 mL) was added sulfuryl chloride (1.31 g, 9.75 mmol) at 0 °C and stirred at same temperature for 15 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 3-5% ethyl acetate in hexane as eluent to get the title compound (0.35 g, 25.3%). LC-MS: 281.9 [M-H] -

[0648] Step 4: 2-(pyridin-2-ylmethoxy)benzenesulfonamide

[0649] The title compound was prepared using similar procedure described in step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 263.0 [M-H] - .

[0650] Intermediate 53: 5-methoxy-1-methyl-1H-indazole-4-sulfonamide

[0651]

[0652] Step 1: 4-bromo-5-methoxy-1-methyl-1H-indazole

[0653] To a solution of 4-bromo-5-methoxy-1H-indazole (0.8 g 3.52 mmol) in THF (40 mL) was added KO t Bu (0.59 g, 5.28 mmol) and Mel (5 g, 35.2 mmol) at 0 °C. The reaction mixture was allowed to warm to RT slowly and stirred for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 40-50% ethyl acetate in hexane as eluent to get the title compound (0.8 g, 94.1%). LC-MS: 240.7 [M+H] + .

[0654] Step 2: 4-(phenylsulfanyl)-5-methoxy-1-methyl-1H-indazole

[0655] To a degassed solution of 4-bromo-5-methoxy-l-methyl-lH-indazole (0.86 g, 3.57 mmol) and benzyl mercaptan (0.443 g, 3.57 mmol) in toluene (15 mL) at RT was added Pd2(dba)3(0.326 gm 0.35 mmol), N,N-diisopropylethylamine (0.922 g, 7.13 mmol) and XantPhos (0.413 g, 0.71 mmol) to make the reaction mixture. The reaction mixture was heated at 100 °C for 12 h. After completion of the reaction, the mixture was passed through celite and washed with ethyl acetate and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 30-40% EtOAc in hexane as eluent to get the title compound (0.65 g, 64.05%); LC-MS: 285.1 [M+H] + .

[0656] Step 3: 5-Methoxy-l-methyl-lH-indazole-4-sulfonyl chloride

[0657] The title compound was prepared using similar procedure described in step 6 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 261.0 [M+H] + .

[0658] Step 4: 5-Methoxy-l-methyl-lH-indazole-4-sulfonamide

[0659] The title compound was prepared using similar procedure described in step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 242.1 [M+H] + .

[0660] Intermediate 54: 5-(2-Hydroxypropan-2-yl)-2-methoxybenzenesulfonamide

[0661]

[0662] Step 1: Methyl 3-(chlorosulfonyl)-4-methoxybenzoate

[0663] The title compound was prepared using similar procedure described in step 1 of Intermediate 18 using appropriate reagents with suitable modifications. LC-MS: 264.1 [M+H] + .

[0664] Step 2: Methyl 4-methoxy-3-sulfamoylbenzoate

[0665] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 246.1 [M+H] + .

[0666] Step 3: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfonamide

[0667] To a solution of methyl 4-methoxy-3-sulfamoylbenzoate (0.1 g, 0.408 mmol) in THF (2 mL) was added MeMgBr (1.2 mL, 1.22 mmol, 1 M in THF) at 0 °C followed by stirring at rt for 2 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude material. The crude compound was purified by silica gel flash column chromatography using 80% EtOAc in hexane to get the title compound (0.075 g, 75%). LC-MS: 246.0 [M+H] + .

[0668] Intermediate 55: 2-isopropoxy-6-methoxybenzenesulfonamide

[0669]

[0670] Step 1: 2-isopropoxy-6-methoxyphenyl sulfenamide

[0671] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (CDC13, 400 MHz): δ 7.20 (t, 1H), 6.50 (d, 1H), 6.48 (d, 1H), 4.40-4.37 (m, 1H), 3.90 (s, 3H), 1.21 (d, 6H).

[0672] Step 2: benzyl (2-isopropoxy-6-methoxyphenyl) sulfane

[0673] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (CDC13, 400 MHz): δ 7.28-7.16 (m, 6H), 6.55 (d, 1H), 6.50 (d, 1H), 4.54-4.51 (m, 1H), 4.03 (s, 2H), 3.84 (s, 3H), 1.36 (d, 6H).

[0674] Step 3: 2-isopropoxy-6-methoxybenzenesulfonyl chloride

[0675] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 264.9 [M+H] + .

[0676] Step 4: 2-Isopropoxy-6-methoxybenzenesulfonamide

[0677] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-d6, 400 MHz): δ

[0678] 7.38 (t, 1H), 7.15 (d, 1H), 6.82 (s, 2H), 6.68 (d, 1H), 4.61-4.58 (m, 1H), 3.82 (s, 3H), 1.28 (d, 6H).

[0679] Intermediate 56: 5-methoxy-2,3-dihydro-1H-indene-4-sulfonamide

[0680]

[0681] Step 1: 4-Bromo-5-methoxy-2,3-dihydro-lH-inden-l-one

[0682] To a solution of 5-methoxy-2,3-dihydro-lH-inden-l-one (10 g, 61.65 mmol) in water (120 mL) was added NBS (10.97 g, 61.65 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude material. The crude compound was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane as eluent to get the title compound (12 g, 80.7%). LC-MS: 240.7 [M+H] + .

[0683] Step 2: 4-Bromo-5-methoxy-2,3-dihydro-lH-indene

[0684] To a solution of 4-bromo-5-methoxy-2,3-dihydro-lH-inden-l-one (10 g, 41.47 mmol) in TFA (60 mL) was added triethylsilane (2.39 g, 20.74 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to RT followed by stirring at reflux for 16 h. The reaction was diluted with ice water, quenched with aqueous NaHC03solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to get crude material. The crude compound was purified by silica gel flash column chromatography using hexane as eluent to get the title compound (6 g, 63.7%). LC-MS: 227.9 [M+H] + .

[0685] Step 3: 5-Methoxy-2,3-dihydro-lH-indene-4-sulfonamide

[0686] To a solution of 4-bromo-5-methoxy-2,3-dihydro-lH-indene (0.2 g, 0.88 mmol) in THF (7 mL) was added n-BuLi (1.65 mL, 2.64 mmol) at -78 °C and stirred at same temperature for 1 h. SO2gas was then bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm slowly to RT and stirred for 1 h. The reaction mixture was concentrated to get solid mass. The solid mass was dissolved in DCM and NCS (0.35 g, 2.64 mmol) was added to it at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to get crude material. The crude compound was dissolved in DCM and 7 N methanolic ammonia (5 mL) was added to it at RT. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to get crude compound. The crude compound was purified by silica gel flash column chromatography using 50% ethyl acetate in hexane as eluent to get the title compound (6 g, 63.7%). LC-MS: 228.1 [M+H] + .

[0687] Intermediate 57: 2-methoxy-5,6,7,8-tetrahydronaphthalene-1-sulfonamide

[0688]

[0689] Step 1: l-Bromo-5,6,7,8-tetrahydronaphthalen-2-ol

[0690] To a solution of 5,6,7,8-tetrahydronaphthalen-2-ol (5 g, 33.73 mmol) in DMF (60 mL) was added NBS (6 g, 33.73 mmol) at 0 °C. The reaction mixture was allowed to warm up to RT slowly and stirred for 18 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 5% EtOAc in hexane as eluent to get the title compound (6 g, 78.32%). 1 H NMR (CDC13, 400 MHz): δ 6.95 (d, 1H), 6.85 (d, 1H), 5.54 (s, 1H), 2.75-2.68 (m, 4H), 1.88-1.83 (m, 2H), 1.79-1.73 (m, 2H).

[0691] Step 2: 5-Bromo-6-methoxy-1,2,3,4-tetrahydronaphthalene

[0692] To a solution of 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol (6 g, 26.42 mmol) and K2CO3 (7.9 g, 57.24 mmol) in acetone (60 mL) was added Mel (12.2 g, 85.86 mmol) and stirred at RT for 16 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane to get the title compound (4.5 g, 70.64%). 1 H NMR (CDC13, 400 MHz): δ 7.00 (d, 1H), 6.73 (d, 1H), 3.88 (s, 3H), 2.80-2.71 (m, 4H), 1.86-1.79 (m, 2H), 1.78-1.72 (m, 2H).

[0693] Step 3: 2-Methoxy-5,6,7,8-tetrahydronaphthalen-1-sulfonamide

[0694] The title compound was prepared using similar procedure as described in Step 3 of Intermediate 56 using appropriate reagents with suitable modifications. LC-MS: 242.1 [M+H] + .

[0695] Intermediate 58: 2-ethoxy-6-methoxybenzenesulfonamide

[0696]

[0697] Step 1: 2-(phenylmethylthio)-3-methoxyphenol

[0698] To a degassed solution of 2-bromo-3-methoxyphenol (2 g, 9.84 mmol) and phenylmethanethiol (1.22 g, 9.84 mmol), N,N-diisopropylethylamine (3.42 mL, 19.7 mmol) and Xantphos (1.14 g, 0.1.97 mmol) in toluene (30 mL) was added Pd2(dba)3(0.901 gm 0.98 mmol) and stirred at 100 °C for 16 h. The reaction mixture was allowed to cool to RT, passed through a pad of celite, washed with ethyl acetate and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 30-40% EtOAc in hexane as eluent to get the title compound (0.4 g, 16.5%); LC-MS: 245.0 [M+H] + .

[0699] Step 2: Benzyl (2-ethoxy-6-methoxyphenyl)sulfane

[0700] This compound was prepared using a similar procedure as described in Step 1 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 275.1 [M+H] + .

[0701] Step 3: 2-Ethoxy-6-methoxybenzenesulfonyl chloride

[0702] The title compound was prepared using a similar procedure as described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-d6, 400 MHz): δ

[0703] 7.25 (t, 1H), 6.64 (d, 1H), 6.63 (d, 1H), 4.00 (q, 2H), 3.72 (s, 3H), 1.28 (t, 3H).

[0704] Step 4: 2-Ethoxy-6-methoxybenzenesulfonamide

[0705] The title compound was prepared using a similar procedure as described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 232.0 [M+H] + .

[0706] Intermediate 59: 2-cyclobutoxy-6-methoxybenzenesulfonamide

[0707]

[0708] Step 1: Benzyl (2-cyclobutoxy-6-methoxyphenyl)sulfane

[0709] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 53 using appropriate reagents with suitable modifications. LC-MS: 301.1 [M-H] -

[0710] Step 2: 2-Cyclobutoxy-6-methoxybenzenesulfonyl chloride

[0711] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-d6, 400 MHz): δ

[0712] 7.50 (t, 1H), 6.62 (d, 1H), 6.49 (d, 1H), 4.81 - 4.73 (m, 1H), 3.99 (s, 3H), 2.25 - 2.21 (m, 2H), 1.92 - 1.87 (m, 2H), 1.51 - 1.46 (m, 2H).

[0713] Step 3: 2-Cyclobutoxy-6-methoxybenzenesulfonamide

[0714] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 256.0 [M-H] - .

[0715] Intermediate 63: 2-(difluoromethoxy)-6-methoxybenzenesulfonamide

[0716]

[0717] Step 1: 2-(Benzylthio)-3-methoxyphenol

[0718] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 52 using appropriate reagents with suitable modifications. LC-MS: 245.1 [M-H] - .

[0719] Step 2: Benzyl(2-(difluoromethoxy)-6-methoxyphenyl)sulfane

[0720] To a solution of 2-(phenylsulfanyl)-3-methoxyphenol (0.3 g, 1.217 mmol) and diethyl (bromodifluoromethyl)phosphonate (0.650 g, 2.43 mmol) in acetonitrile (20 mL) was added potassium hydroxide (0.342 g, 6.09 mmol) at 0 °C. The reaction mixture was then allowed to warm to RT slowly and stirred for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to get crude material. The crude material was purified by silica gel flash column chromatography using 0-20% ethyl acetate in hexane as eluent to afford the title compound (0.2 g, 55.41%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.48 - 7.15 (m, 6H), 7.00 (dd, 1H), 6.79 (t, 1H), 6.76 (dd, 1H), 4.03 (s, 2H), 3.85 (s, 3H).

[0721] Step 3: 2-(Difluoromethoxy)-6-methoxybenzenesulfonyl chloride

[0722] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 270.8 [M-H] - .

[0723] Step 4: 2-(Difluoromethoxy)-6-methoxybenzenesulfonamide

[0724] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 252.0 [M-H] - .

[0725] Intermediate 64: 3-ethyl-2,6-dimethoxybenzenesulfonamide

[0726]

[0727] Step 1: 2,4-Dimethoxy-1-vinylbenzene

[0728] To a degassed solution of 1-bromo-2,4-dimethoxybenzene (3.0 g, 13.82 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.25 g, 27.64 mmol) and K2CO3(5.73 g, 41.46 mmol) in 1,4-dioxane (50 mL), water (10 mL) was added Pd(Amphos)Cl2(0.97 g, 1.38 mmol) and stirred at 100 °C for 12 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with 10% methanol in DCM. The organic layer was dried over Na2SO4, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane to get the title compound (2.0 g, 88.14%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.42 (d, 1H), 6.85 (dd, 1H), 6.55-6.50 (m, 2H), 5.63 (dd, 1H), 5.09 (d, 1H), 3.80 (s, 3H), 3.77 (s, 3H).

[0729] Step 2: 1-ethyl-2,4-dimethoxybenzene

[0730] A mixture of 1-ethyl-2,4-dimethoxybenzene (1.9 g, 11.57 mmol) and Pd-C (1.84 g, 17.35 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) was stirred under hydrogen positive pressure using a balloon for 6 h. The reaction mixture was filtered through a pad of celite and washed with 5% methanol in DCM. The filtrate was concentrated to get the crude compound which was carried to the next step without purification (1.85 g). 1 H NMR (DMSO-D6, 400 MHz): δ 7.01 (d, 1H), 6.51 (s, 1H), 6.43 (dd, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 2.49 (q, 2H), 1.18 (t, 3H).

[0731] Step 3: 3-ethyl-2,6-dimethoxybenzenesulfonamide

[0732] To a solution of 1 -ethyl-2,4-dimethoxybenzene (1.8 g, 10.82 mmol) in THF (20 mL) was added TMEDA (2.13 g, 18.4 mmol), n-BuLi (0.73 mL, 18.4 mmol) at 0 °C and stirred at same temperature for 1 h. Then SO2gas was bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm up to 0 °C slowly and stirred for 1 h. The reaction mixture was concentrated to get a solid mass. The solid mass was dissolved in DCM and NCS (2.26 g, 16.93 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with ice cold water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to get the crude material. The crude compound was dissolved in DCM (10 mL) and 7 N methanolic ammonia (10 mL) was added to the reaction mixture and stirred at RT for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 50% ethyl acetate in hexane as eluent to get the title compound (0.6 g). LC-MS: 244.0 [M-H] - .

[0733] Intermediate 65: 2,6-dimethoxy-3-methylbenzenesulfonamide

[0734]

[0735] Step 1 : 2,4-Dimethoxy-1 -methylbenzene

[0736] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 64 using appropriate reagents with suitable modifications. 1 H NMR, CDC13, 400 MHz): δ 7.40 (d, 1 H), 6.46 (d, 1 H), 6.42 (dd, 1 H), 3.83 (s, 3H), 3.82 (s, 3H), 2.17 (S, 3H).

[0737] Step 2: 2,6-Dimethoxy-3-methylbenzenesulfonamide

[0738] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 64 using appropriate reagents with suitable modifications. LC-MS: 230.0 [M-H] - .

[0739] Intermediate 66: 3-cyclopropyl-2,6-dimethoxybenzenesulfonamide

[0740]

[0741] Step 1 : 1 -cyclopropyl-2,4-dimethoxybenzene

[0742] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 64 using appropriate reagents with suitable modifications. LC-MS: 179.1 [M+H] + .

[0743] Step 2: 3-cyclopropyl-2,6-dimethoxybenzenesulfonamide

[0744] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 64 using appropriate reagents with suitable modifications. LC-MS: 256.1 [M-H] - .

[0745] Intermediate 67: 5-cyclopropyl-2-methoxybenzenesulfonamide

[0746]

[0747] Step 1 : ((5-bromo-2-methoxyphenyl)sulfonyl)carbamic acid tert-butyl ester

[0748] To a solution of 5-bromo-2-methoxybenzenesulfonamide (10 g, 37.57 mmol) in DCM (100 mL) was added DIPEA (15.36 mL, 112.73 mmol), DMAP (0.46 g, 3.75 mmol) followed by (Boc)20 (12.3 g, 56.36 mmol) at 0 °C. The reaction mixture was allowed to warm slowly to rt and stirred at rt for 12 h. The reaction was quenched with ice cold water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 30-50% ethyl acetate in hexane as eluent to get the title compound (6.5 g, 47.23%). LC-MS: 363.9 [M-H] - .

[0749] Step 2: ((5-cyclopropyl-2-methoxyphenyl)sulfonyl)carbamic acid tert-butyl ester

[0750] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 35 using appropriate reagents with suitable modifications. LC-MS: 326.0 [M-H] - .

[0751] Step 3: 5-cyclopropyl-2-methoxybenzenesulfonamide

[0752] To a solution of tert-butyl ((5-cyclopropyl-2-methoxyphenyl)sulfonyl)carbamate (0.8 g, 2.44 mmol) in DCM (10 mL) was added TFA (1.12 mL, 14.65 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mass was quenched with saturated NaHC03solution and extracted with DCM. The organic layer was washed with water, brine, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 40-50% ethyl acetate in hexane as eluent to obtain the title compound (0.25 g, 45%). LC-MS: 226.0 [M-H] - .

[0753] Intermediate 68: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonamide

[0754]

[0755] Step 1: 2-(Benzylsulfanyl)-3-methoxyphenol

[0756] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 53 using appropriate reagents with suitable modifications. LC-MS: 245.1 [M-H] - .

[0757] Step 2: Benzyl (2-methoxy-6-(2,2,2-trifluoroethoxy)phenyl)sulfane

[0758] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 52 using appropriate reagents with suitable modifications. LC-MS: 327.1 [M-H] - .

[0759] Step 3: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonyl chloride

[0760] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 50 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-D6, 400 MHz): δ

[0761] 7.23 (t, 1H), 6.79 (d, 1H), 6.63 (d, 1H), 4.55 (q, 2H), 3.72 (s, 3H).

[0762] Step 4: 2-Methoxy-6-(2,2,2-trifluoroethoxy)benzenesulfonamide

[0763] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 284.0 [M-H] - .

[0764] Intermediate 69: 2-(Cyclopropylmethoxy)-6-methoxybenzenesulfonamide

[0765]

[0766] Step 1: 1-(Cyclopropylmethoxy)-3-methoxybenzene

[0767] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 50 using appropriate reagents with suitable modifications. LC-MS: 179.1 [M+H] + .

[0768] Step 2: 2-(Cyclopropylmethoxy)-6-methoxybenzenesulfonamide

[0769] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 64 using appropriate reagents with suitable modifications. LC-MS: 256.0 [M-H] - .

[0770] Intermediate 73: 2-Methoxy-6-(trifluoromethyl)benzenesulfonamide

[0771]

[0772] Step 1: 2-Methoxy-6-(trifluoromethyl)benzenesulfonamide

[0773] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-D6, 400 MHz): δ

[0774] 7.64 (dd, 1H), 7.38 (s, 2H), 7.28 (d, 1H), 7.03 (d, 1H), 3.95 (s, 3H).

[0775] Intermediate 74: 5-(1-Cyclopropyl-1-hydroxyethyl)-2-methoxybenzenesulfonamide

[0776]

[0777] Step 1: 5-Acetyl-2-methoxybenzenesulfonyl chloride

[0778] To a stirred solution of chlorosulfonic acid (13.96 g, 119.85 mmol) and SOCl2(4.75 g, 39.95 mmol) was added 1-(4-methoxyphenyl)ethan-1-one (3.0 g, 19.97 mmol) drop wise at 0 °C. The reaction mixture was allowed to warm to RT gradually and stirred at RT for 16 h. The reaction mixture was then poured into ice cold water to get a precipitate. The precipitate was filtered and dried under vacuum to get the title compound (4.0 g, 81.6 %). LC-MS: 249.0 [M+H] + .

[0779] Step 2: 5-acetyl-2-methoxybenzenesulfonamide

[0780] The title compound was prepared using a similar procedure as described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 230.0 [M+H] + .

[0781] Step 3: 5-(1-cyclopropyl-1-hydroxyethyl)-2-methoxybenzenesulfonamide

[0782] To a solution of 5-acetyl-2-methoxybenzenesulfonamide (0.3 g, 1.30 mmol) in THF (3 mL) was added cyclopropyl magnesium bromide (2.61 mL, 7.84 mmol, 3 M in THF) at -78 °C followed by stirring at rt for 16 h. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 5% methanol in DCM as eluent to get the title compound (0.30 g, 45 %). LC-MS: 270.0 [M-H] - .

[0783] Intermediate 75: 5-(2-hydroxybutan-2-yl)-2-methoxybenzenesulfonamide

[0784]

[0785] The title compound was prepared using a similar procedure as described in Step 3 of Intermediate 74 using appropriate reagents with suitable modifications. LC-MS: 258.1 [M-H] - .

[0786] Intermediate 78: 3-chloro-2,6-dimethoxybenzenesulfonamide

[0787]

[0788] Step 1: 3-chloro-2,6-dimethoxybenzenesulfonamide

[0789] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 15 using appropriate reagents with suitable modifications. LC-MS: 250.0 [M-H] - .

[0790] Intermediate 79: 4,6-dimethoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0791]

[0792] Step 1: 2,6-Dibromo-3,5-dimethoxyphenol

[0793] To a solution of 3,5-dimethoxyphenol (1.0 g, 6.48 mmol) in DCM (30 mL) was added bromine (2.07 g, 12.97 mmol) at 0 °C and stirred for 1 h. The reaction mixture was then allowed to warm to RT and quenched with aqueous sodium thiosulfate solution and extracted with DCM. The organic layer was washed with water, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude was purified by silica gel flash column chromatography using 0-20% ethyl acetate in hexane as eluent to get the title compound (2.2 g, 90.5%). LC-MS: 312.9 [M+H] + .

[0794] Step 2: 2,4-Dibromo-3-(2-bromoethoxy)-1,5-dimethoxybenzene

[0795] To a stirred solution of 2,6-dibromo-3,5-dimethoxyphenol (1.0 g, 3.20 mmol) and 1,2-dibromoethane (2.40 g, 12.82 mmol) in acetone was added K2C03(1.32 g, 9.61 mmol) and stirred at 80 °C for 12 h. The reaction mixture was concentrated, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent to get the title compound (1.1 g, 81.9%). 1 H NMR (DMSO-D6, 400 MHz): δ 6.72 (s, 1H), 4.24 (t, 2H), 3.91 (s, 6H), 3.84 (t, 2H).

[0796] Step 3: 4,6-Dimethoxy-2,3-dihydrobenzofuran-7-sulfonamide

[0797] To a solution of 2,4-dibromo-3-(2-bromoethoxy)-l,5-dimethoxybenzene (0.2 g, 0.47 mmol) in THF (7 mL) was added n-BuLi (1.48 mL, 2.38 mmol) at -78 °C and stirred at same temperature for 1 h. Then SO2 gas was bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm up to RT and stirred for 1 h. The reaction mixture was concentrated to get a solid mass. The solid mass was dissolved in DCM and NCS (0.19 g, 1.43 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude material. The crude material was dissolved in DCM and 7 N methanolic ammonia (8 mL) was added to the reaction mixture at RT. The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude compound. The crude compound was washed with 50% diethyl ether in n-pentane to get the title compound. (0.07 g, 32.6%). LC-MS: 258.0 [M-H]-

[0798] Intermediate 88: 6-ethoxy-3-ethyl-2-methoxybenzenesulfonamide

[0799]

[0800] Step 1: 4-Ethoxy-2-methoxy-l-vinylbenzene

[0801] To a degassed solution of l-bromo-4-ethoxy-2-methoxybenzene (1.8 g, 7.79 mmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (2.4 g, 15.58 mmol) and K2CO3(3.23 g, 23.36 mmol) in 1,4-dioxane (20 mL), water (4 mL) was added Pd(Amphos)Cl2(0.55 g, 0.77 mmol) and stirred at 100 °C for 12 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to get crude. The crude compound was purified by silica gel flash column chromatography using 5-7% ethyl acetate in hexane to get the title compound (1.1 g, 79.24%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.08 (d, 1H), 6.95-6.88 (m, 2H), 6.68-6.61 (m, 1H), 5.72 (dd, 1H), 5.13 (dd, 1H), 4.00 (q, 2H), 3.79 (s, 3H), 1.32 (t, 3H).

[0802] Step 2: 4-Ethoxy-1-ethyl-2-methoxybenzene

[0803] A mixture of 4-ethoxy-2-methoxy-1-vinylbenzene (2.0 g, 11.22 mmol) and Pd-C (1.79 g, 16.83 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) was stirred under hydrogen positive pressure using a balloon for 12 h. The reaction mixture was filtered through a pad of celite and washed with 5% methanol in DCM. The filtrate was concentrated to get the crude compound which was carried to the next step without purification (2.0 g). LC-MS: 181.1.0 [M+H] + .

[0804] Step 3: 6-Ethoxy-3-ethyl-2-methoxybenzenesulfonamide

[0805] To a solution of 4-ethoxy-1-ethyl-2-methoxybenzene (0.3 g, 1.66 mmol) in THF (4 mL) was added TMEDA (0.58 g, 4.99 mmol), n-BuLi (3.1 mL, 4.99 mmol) at 0 °C and stirred at same temperature for 1 h. Then SO2 gas was bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm up to 0 °C slowly and stirred for 1 h. The reaction mixture was concentrated to get a solid mass. The solid mass was dissolved in DCM (10 mL) and NCS (0.4 g, 2.99 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude compound was dissolved in DCM (2 mL) and 7 N methanolic ammonia (10 mL) was added to the reaction mixture and stirred at RT for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude. The crude compound was re-crystallized using 50% EtOAc in pentane to get the title compound (0.11 g, 59.16%). LC-MS: 260.1 [M+H] + .

[0806] Intermediate 89: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0807]

[0808] Step 1: 2,6-dibromo-4-(trifluoromethyl)phenol

[0809] Sulfuric acid (0.22 mL, 4.15 mmol) was added dropwise to a solution of 2-bromo-4- (trifluoromethyl)phenol (1.0 g, 4.15 mmol) in ACN (10 mL) and stirred at RT for 10 min, followed by the addition of N-bromosuccinimide (0.775 g, 4.35 mmol). The reaction mixture was stirred at RT for 12 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 0-10% ethyl acetate in hexane as eluent to obtain the title compound. (1.2 g, 60.3%). LC-MS: 318.8 [M+H] + .

[0810] Step 2: 1,3-Dibromo-2-(2-bromoethoxy)-5-(trifluoromethyl)benzene

[0811] To a solution of 2,6-dibromo-4-(trifluoromethyl)phenol (0.8 g, 2.50 mmol) and K2CO3 (1.04 g, 7.50 mmol) in ACN (20 mL) was added 1,2-dibromoethane (1.88 g, 10.00 mmol) and stirred at 90 °C for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 1-3% ethyl acetate in hexane as eluent to get the title compound (0.7 g, 65.6%). 1 H NMR (DMSO-d6, 400 MHz): δ 8.14 (s, 2H), 4.38 (t, 2H), 3.88 (t, 2H).

[0812] Step 3: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0813] To a solution of 1,3-dibromo-2-(2-bromoethoxy)-5-(trifluoromethyl)benzene (0.5 g, 1.17 mmol) in THF (10 mL) was added n-BuLi (4.39 mL, 7.02 mmol) at -78 °C and stirred at the same temperature for 1 h. Then SO2 gas was bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm up to RT and stirred for 1 h. The reaction mixture was concentrated to get a solid mass. The solid mass was dissolved in DCM and NCS (0.47 g, 3.51 mmol) was added to it at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude title compound (0.5 g). 1H NMR (DMSO-d6, 400 MHz): δ

[0814] 7.65 (s, 1H), 7.54 (s, 1H), 4.62 (m, 2H), 3.69 (t, 2H).

[0815] Step 4: 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0816] To a stirred solution of 5-(trifluoromethyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride (0.5 g, 1.74 mmol) in DCM (7 mL) was added 7 M methanolic ammonia (7 mL) drop wise at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated aq. NaHC03, dried over Na2S04and concentrated to get the title compound (0.3 g). LC-MS: 265.9 [M-H] - .

[0817] Intermediate 90: 5-(tert-butyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0818]

[0819] Step 1: 1-(tert-butyl)-4-(2,2-dimethoxyethoxy)benzene

[0820] To a stirred solution of 4-(tert-butyl)phenol (2.0 g, 13.31 mmol) in DMF (75 mL) was added NaH (1.02 g, 26.62 mmol) at 0 °C and stirred for 30 min followed by addition of 2-bromo-l,l-dimethoxyethane (2.7 g, 15.98 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred at 110 °C for 12 h. The reaction mixture was added to ice water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2S04and concentrated to get the crude title compound (3.5 g). 1 H NMR (CDC13, 400 MHz): δ 7.30 (d, 2H), 6.88 (d, 2H), 4.72 (t, 1H), 4.01 (d, 2H), 3.45 (s, 6H), 1.30 (s, 9H).

[0821] Step 2: 5-(tert-butyl)benzofuran

[0822] To a solution of 1-(tert-butyl)-4-(2,2-dimethoxyethoxy)benzene (2.0 g, 8.39 mmol) in toluene (25 mL) was added polyphosphoric acid (2.18 g, 10.07 mmol) and stirred at 110 °C for 5 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to get the crude title compound (1.5 g). 1 H NMR (CDCI3, 400 MHz): δ 7.63-7.61 (m, 2H), 7.46 (d, 1H), 7.39 (d, 1H), 6.77 (d, 1H), 1.41 (s, 9H).

[0823] Step 3: 5-(tert-Butyl)-2,3-dihydrobenzofuran-7-ol

[0824] The title compound was prepared using similar procedure as described in Step 2 of Intermediate 88 using appropriate reagents with suitable modifications (0.36 g). LC-MS: 177.2 [M+H] + .

[0825] Step 4: 5-(tert-Butyl)-2,3-dihydrobenzofuran-7-sulfonyl chloride

[0826] To a stirred solution of 5-(tert-butyl)-2,3-dihydrobenzofuran (0.2 g, 1.14 mmol) in DCM (40 mL) was added chlorosulfonic acid (0.66 g, 5.67 mmol) drop wise at 0 °C. The reaction mixture was allowed to warm to RT gradually and stirred at RT for 30 min. The reaction mixture was then poured into ice cold water quenched with NaHC03solution, extracted with DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude title compound (0.15 g). 1 H NMR (DMSO-d6, 400 MHz): δ 7.36 (d, 1H), 7.20 (d, 1H), 4.46 (t, 2H), 3.11 (t, 2H), 1.23 (s, 9H).

[0827] Step 5: 5-(tert-Butyl)-2,3-dihydrobenzofuran-7-sulfonamide

[0828] The title compound was prepared using similar procedure as described in Step 4 of Intermediate 89 using appropriate reagents with suitable modifications. LC-MS: 256.1 [M+H] + .

[0829] The following compounds listed in Table 6 were prepared following similar procedures as described above in Step 4 and Step 5 of Intermediate 90 using appropriate reagents with suitable modifications known to a person skilled in the art.

[0830] Table 6. Intermediates

[0831]

[0832] Intermediate 97: 5-methoxybenzo[d][1,3]dioxol-4-sulfonamide

[0833]

[0834] Step 1: 5-methoxybenzo[d][l,3]dioxole-4-sulfonyl chloride

[0835] To a solution of 5-methoxybenzo[d][l,3]dioxole (0.2 g, 1.31 mmol) in THF (4 mL) at 0 °C was added TMEDA (0.305 g, 2.62 mmol), n-BuLi (2.46 mL, 3.94 mmol) and stirred at same temperature for 1 h. Then SO2gas was bubbled into the reaction mixture at -78 °C for 30 min. The reaction mixture was allowed to warm up to 0 °C slowly and stirred for 2 h. The reaction mixture was concentrated to get a solid mass. This solid mass was dissolved in DCM (5 mL) and NCS (0.526 g, 3.94 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm up to RT and stirred for 1 h. The reaction was quenched with ice cold water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated to get crude material (0.3 g). 1 H NMR (DMSO-d6, 400 MHz): δ 6.75 (d, 1H), 6.33 (d, 1H), 5.90 (s, 2H), 3.65 (s, 3H).

[0836] Step 2: 5-methoxybenzo[d][l,3]dioxole-4-sulfonamide

[0837] The title compound was prepared using similar procedure as described in step 4 of Intermediate 89 using appropriate reagents with suitable modifications. LC-MS: 232.0 [M+H] + .

[0838] Intermediate 98: 2,6-dimethoxy-4-methylbenzenesulfonamide

[0839]

[0840] Step 1: 2,6-dimethoxy-4-methylbenzenesulfonyl chloride

[0841] The title compound was prepared using similar procedure as described in step 1 of Intermediate 97 using appropriate reagents (1 g) with suitable modifications. 1H NMR (DMSO-D6, 400 MHz): δ 6.49 (s, 2H), 3.72 (s, 6H), 2.57 (s, 3H).

[0842] Step 2: 2,6-Dimethoxy-4-methylbenzenesulfonamide

[0843] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 89 using appropriate reagents with suitable modifications. LC-MS: 232.0 [M+H] + .

[0844] Intermediate 107: 2-cyclopropoxy-6-methoxybenzenesulfonamide

[0845]

[0846] Step 1: 2-Cyclopropoxy-6-methoxybenzenesulfonamide

[0847] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 102g of Example 16 using appropriate reagents with suitable modifications. LC-MS: 244.0 [M+H] + .

[0848] Intermediate 108: 3-chloro-2,6-dimethoxybenzenesulfinamide

[0849]

[0850] Step 1: 3-Chloro-2,6-dimethoxybenzenesulfonamide

[0851] To a solution of 3-chloro-2,6-dimethoxybenzenesulfonyl chloride (3.8 g, 14.06 mmol) in water (50 mL) was added NaHC03(2.35 g, 28.03 mmol) and Na2S03(7.06 g, 28.03 mmol) at rt, followed by stirring at 100 °C for 12 h. The reaction mixture was concentrated, then diluted with EtOH (80 mL) and stirred for 10 min. The inorganic salts were filtered and the filtrate was concentrated to get the crude compound. The crude was dissolved in toluene (50 mL) and oxalyl chloride (1.42 mL, 16.82 mmol) was added to it at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was concentrated to get the crude compound. The crude was dissolved in EtOAc (30 mL) and aqueous NH4OH (30 mL) was added to it at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was washed with 50% diethyl ether in pentane to get the title compound (0.5 g, 34.5%). LC-MS: 236.0 [M+H]+ .

[0852] Intermediate 109 to 117

[0853] The following intermediates in Table 7 were prepared following a similar procedure as described above for Intermediate 108 using appropriate reagents known to those skilled in the art with suitable modifications. In some cases, the procedure started with a commercially available sulfonyl chloride building block.

[0854] Table 7. Intermediates

[0855]

[0856]

[0857] Intermediate 118: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfinamide

[0858]

[0859] Step 1: 5-acetyl-2-methoxybenzenesulfonyl chloride

[0860] A mixture of chlorosulfonic acid (3.32 mL, 49.93 mmol) and thionyl chloride (5.0 mL) was stirred in an ice bath for 30 min. Then, 1-(4-methoxyphenyl)ethan-1-one (5.0 g, 33.29 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 16 h. The reaction mixture was quenched slowly with ice water to get a precipitate. The precipitate was filtered and washed with water to get the title compound (10.0 g). LC-MS: 249.0 [M+H] + .

[0861] Step 2: 5-acetyl-2-methoxybenzenesulfinamide

[0862] The title compound was prepared using a similar procedure as described in Step 1 for Intermediate 108 using appropriate reagents with suitable modifications (0.50 g); LC-MS: 214.0 [M+H] + .

[0863] Step 3: 5-(2-hydroxypropan-2-yl)-2-methoxybenzenesulfinamide

[0864] To a stirred solution of 5-acetyl-2-methoxybenzenesulfinamide (0.30 g, 1.30 mmol) in THF (12 mL) was added MeMgBr (3.49 mL, 10.47 mmol, 3M in ethyl ether) at -78 °C and stirred at same temperature for 30 min. The reaction mixture was then allowed to warm to RT and stirred for 16 h. The reaction mixture was cooled, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 5% methanol in DCM as eluent to get the title compound (0.250 g, 83.35%). LC-MS: 230.0 [M+H] + .

[0865] b) Benzoic acid intermediate

[0866] Intermediate 1 : 4-((1H-pyrazol-1-yl)methyl)-2-methoxybenzoic acid

[0867]

[0868] Step 1: Methyl 2-methoxy-4-methylbenzoate

[0869] A stirred solution of 2-hydroxy-4-methylbenzoic acid (5 g, 32.8 mmol) in DMF (50 mL) was cooled to 0 °C and NaH (1.97 g, 82.1 mmol) and iodomethane (5.6 g, 49.2 mmol) were added sequentially at 0 °C. The reaction mixture was allowed to warm to RT and stirred at RT for 2 h. The reaction mixture was added to ice water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2S04and concentrated to get the crude compound. The crude compound was purified by combi flash chromatography using 0-10% ethyl acetate in hexane to get the title compound (3 g, 50.6%). LC-MS: 181.1 [M+H] + .

[0870] Step 2: Methyl 4-(bromomethyl)-2-methoxybenzoate

[0871] To a solution of methyl 2-methoxy-4-methylbenzoate (2.6 g, 14.4 mmol) in CC14(30 mL) was added N-bromosuccinimide (NBS, 2.5 g, 14.4 mmol) and benzoyl peroxide (BPO, 0.035 g, 0.14 mmol) and heated to reflux overnight. The reaction mixture was then allowed to cool to RT and diluted with DCM and washed with water. The organic layer was dried over Na2S04and concentrated to give the crude compound. The crude compound was purified by combi flash chromatography using 0-20% ethyl acetate in hexane to give the title compound (2.5 g, 66.8%). LC-MS: 261.0 [M+H] + .

[0872] Step 3: Methyl 4-((lH-pyrazol-l-yl)methyl)-2-methoxybenzoate

[0873] To a stirred solution of methyl 4-(bromomethyl)-2-methoxybenzoate (2.5 g, 9.6 mmol), 1H-pyrazole (0.98 g, 14.4 mmol) in DMF was added K2C03(4 g, 28.4 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04and concentrated to give the crude compound. The crude compound was purified by combiflash chromatography using 40% ethyl acetate in hexane to give the title compound (2 g, 84.1%). LC-MS: 247.1 [M+H] + .

[0874] Step 4: 4-((lH-pyrazol-l-yl)methyl)-2-methoxybenzoic acid

[0875] To a stirred solution of methyl 4-((lH-pyrazol-l-yl)methyl)-2-methoxybenzoate (0.8 g, 3.2 mmol) in THF (6 mL) and water (2 mL) was added LiOH.H20 (0.38 g, 16.2 mmol) and stirred at room temperature for 12 h. The reaction mixture was diluted with ice cold water, pH was adjusted to 5 using Aq. citric acid and extracted with 20% methanol in DCM. The organic layer was dried over Na2S04and concentrated to give the title compound (0.6 g). LC-MS: 233.1 [M+H] + .

[0876] Intermediate 2 to 7, 9 and 10

[0877] The following intermediates of intermediates 2 to 10 listed in Table 8 were prepared following similar procedures as described above for intermediate 1 using appropriate reagents known to those skilled in the art with suitable modifications.

[0878] Table 8. Intermediates.

[0879]

[0880] Intermediate 2a: 3-methoxy-4-(pyrazol-l-ylmethyl)benzamide

[0881]

[0882] Dissolve 3-methoxy-4-(pyrazol-l-ylmethyl)benzoic acid (1.00 eq, 125 mg, 0.538 mmol) and CDI (1.50 eq, 131 mg, 0.807 mmol) in THF (3 mL) and stir for 1 h. Add 7 N ammonium hydroxide solution (10.00 eq, 0.770 mL) and stir for 16 h. Dilute the solution with water, neutralize with 1 N HC1, and extract with EtOAc. Wash the organics with 1 N HC1, water, and brine solution. Then dry the organics over sodium sulfate, filter, and dry in vacuo to give the title compound (120 mg, 96% yield). LC-MS: m / z = 232.1 [M+H] +

[0883] Intermediate 11: 4-((lH-pyrazol-l-yl)methyl)-3-cyclopropylbenzoic acid

[0884]

[0885] Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate

[0886] The title compound is prepared using a similar procedure described in Step 2 of Intermediate 1 using the appropriate reagents with suitable modifications.

[0887] Step 2: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-bromobenzoate

[0888] The title compound is prepared using a similar procedure described in Step 3 of Intermediate 1 using the appropriate reagents with suitable modifications. LC-MS: 295.0 [M+H] + .

[0889] Step 3: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-cyclopropylbenzoate

[0890] To a degassed solution of methyl 4-((lH-pyrazol-l-yl)methyl)-3- bromobenzoate (0.4 g, 1.35 mmol), cyclopropylboronic acid (0.466 g, 5.41 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added Pd(Amphos)Cl2(0.096 g, 0.13 mmol) and K3PO4(0.86 g, 4 mmol). The reaction mixture was heated to 90 °C for 16 h. The reaction mass was allowed to cool to RT, diluted with water and used for 10% methanol extraction in DCM. The organic layer was dried over Na2SO4, filtered and concentrated to get the crude compound. The crude compound was purified by combi flash chromatography using 20-25% ethyl acetate in hexane to get the title compound. LC-MS: 257.1 [M+H] + .

[0891] Step 4: 4-((lH-pyrazol-l-yl)methyl)-3-cyclopropylbenzoic acid

[0892] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 243.1 [M+H] + .

[0893] Intermediate 12

[0894] The following Intermediate 12 shown below was prepared following a similar procedure described above for Intermediate 11 using appropriate reagents known to those skilled in the art with suitable modifications.

[0895]

[0896] Intermediate 13: 4-((1H-pyrazol-1-yl)methyl)-3-cyanobenzoic acid

[0897]

[0898] Step 1: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-cyanobenzoate

[0899] To a degassed solution of 4-((lH-pyrazol-l-yl)methyl)-3-bromobenzoic acid methyl ester (0.3 g, 1.01 mmol), Zn(CN)2(0.14 g, 1.21 mmol) in DMF (4 mL) was added Pd(PPh3)4and stirred at 100 °C for 1 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2S04and concentrated to get the crude compound. The crude compound was purified by combi flash chromatography using 0-25% ethyl acetate in hexane to get the title compound (0.18 g). LC-MS: 242.1 [M+H] + .

[0900] Step 2: 4-((lH-pyrazol-l-yl)methyl)-3-cyanobenzoic acid

[0901] The title compound was prepared using a similar procedure described in step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 228.0 [M+H] + .

[0902] Intermediate 14: 4-((1H-pyrazol-1-yl)methyl)-3-(trifluoromethyl)benzoic acid

[0903]

[0904] Step 1: 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)benzoic acid methyl ester

[0905] To a stirred solution of 4-((lH-pyrazol-l-yl)methyl)-3-bromobenzoic acid methyl ester (0.15 g, 0.5 mmol) in DMF (2 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (0.48 g, 2.54 mmol) and Cul (0.19 g, 1 mmol) sequentially at RT. The mixture was heated at 100 °C for 16 h. The reaction mass was allowed to cool to RT, quenched with ice cold water and washed with brine solution. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound (0.15 g) which was used for the next step without purification. LC-MS: 285.1 [M+H] + .

[0906] Step 2: 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethyl)benzoic acid

[0907] The title compound was prepared using a similar procedure described in step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 271.1 [M+H] + .

[0908] Intermediate 31 : 4-((1H-pyrazol-1-yl)methyl)-3-trifluoromethoxy)benzoic acid perfluorophenyl ester

[0909]

[0910] Step 1: 4-Bromo-2-(trifluoromethoxy)benzoic acid (isobutyl carbonate) anhydride

[0911] To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (3.0 g, 10.52 mmol) in THF (45 mL) was added Et3N (1.6 g, 15.78 mmol) and isobutyl chloroformate (1.8 g, 13.16 mmol) sequentially at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to obtain the title compound (3.8 g, 95%). 1 H NMR (DMSO-d6, 400 MHz): d 7.94 (d, 1H), 7.61 (d, 1H), 7.60 (s, 1H), 4.15 (d, 2H), 2.11-2.06 (m, 1H), 1.01 (d, 6H).

[0912] Step 2: (4-Bromo-2-(trifluoromethoxy)phenyl)methanol

[0913] To a stirred solution of methyl 4-bromo-2-(trifluoromethoxy)benzoic acid (isobutyl carbonate) anhydride (3.8 g, 9.90 mmol) in THF (45 mL) was added LiBH4(1.76 g, 11.8 mmol) at 0 °C and stirred at 70 °C for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to obtain the title compound (2.8 g, 90%). 1 H NMR (DMSO-d6, 400 MHz): d 7.48 (d, 1H), 7.47 (s, 1H), 7.42 (d, 1H), 4.75 (s, 2H).

[0914] Step 3: 1-(4-Bromo-2-(trifluoromethoxy)benzyl)-1H-pyrazole

[0915] To a solution of (4-bromo-2-(trifluoromethoxy)phenyl)methanol (1.5 g, 5.53 mmol) and l-(methylsulfonyl)-lH-pyrazole (0.97 g, 6.64 mmol) in acetonitrile (15 mL) was added Cs2CO3(2.16 g, 6.64 mmol) and stirred at 70 °C for 2 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to get crude compound which was further purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluent to get the title compound (1.5 g, 84.4%). LC-MS: 322.9 [M+H]+.

[0916] Step 4: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethoxy)benzoate

[0917] To a degassed solution of l-(4-bromo-2-(trifluoromethoxy)benzyl)-lH-pyrazole (1.5 g, 4.67 mmol), triethylamine (1.41 g, 14.01 mmol) in methanol (60 mL) was added Pd(dppf)Cl2-DCM (0.38 g, 0.46 mmol). The reaction mixture was heated to 80 °C in a pressure vessel with 80 PSI carbon monoxide pressure for 16 h. The reaction mixture was allowed to cool to RT, filtered through a pad of celite and concentrated to get the title compound (1.0 g, 71.3%). LC-MS: 301.0 [M+H]+.

[0918] Step 5: 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethoxy)benzoic acid

[0919] To a stirred solution of methyl 4-((lH-pyrazol-l-yl)methyl)-3- (trifluoromethoxy)benzoate (0.5 g, 1.66 mmol) in THF (5 mL), methanol (3 mL) and water (2 mL) was added lithium hydroxide hydrate (0.15 g, 6.66 mmol) and stirred at room temperature for 12 h. The reaction mixture was diluted with ice cold water, pH was adjusted to 5 using IN HC1 and extracted with 20% methanol in DCM. The organic layer was dried over Na2SO4and concentrated to get the title compound (0.4 g, 83.9%). LC-MS: 287.0 [M+H]+.

[0920] Step 6: Perfluorophenyl 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethoxy)benzoate

[0921] To a solution of 4-((lH-pyrazol-l-yl)methyl)-3-(trifluoromethoxy)benzoic acid (0.2 g, 0.69 mmol), 2,3,4,5,6-pentafluorophenol (0.15 g, 0.84 mmol) and DMAP (0.017 g, 0.14 mmol) in DCM (20 mL) was added EDC.HC1 (0.201 g, 1.04 mmol) at 0 °C and then the solution was stirred at RT for 12 h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated to get crude compound which was further purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as eluent to afford the title compound (0.27 g, 85.4%). LC-MS: 453.0 [M+H]+. 1 H NMR (DMSO-d6, 400 MHz): δ 8.19 (d, 1H), 8.06 (s, 1H), 7.91 (d, 1H), 7.54 (d, 1H), 7.28 (d, 1H), 6.35 (t, 1H), 5.59 (s, 2H).

[0922] Intermediate 35: 4-((1H-pyrazol-1-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid perfluorophenyl ester

[0923]

[0924] Step 1: Methyl 2-amino-4-bromo-3-fluorobenzoate

[0925] To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (5.0 g, 21.36 mmol) in DMF was added potassium carbonate (4.42 g, 32.04 mmol) and iodomethane (3.63 g, 25.63 mmol) successively and stirred at RT for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04and concentrated to get crude compound. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as eluent to afford the title compound (4.8 g). LC-MS: 248.9 [M+H] + .

[0926] Step 2: (2-amino-4-bromo-3-fluorophenyl)methanol

[0927] The title compound was prepared using similar procedure described in Step 2 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 221.0 [M+H] + .

[0928] Step 3: 6-((lH-pyrazol-l-yl)methyl)-3-bromo-2-fluoroaniline

[0929] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 272.0 [M+H] + .

[0930] Step 4: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-amino-2-fluorobenzoate

[0931] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 250.0 [M+H] + .

[0932] Step 5: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-bromo-2-fluorobenzoate

[0933] To a solution of methyl 4-((lH-pyrazol-l-yl)methyl)-3-amino-2-fluorobenzoate (0.9 g, 3.61 mmol) and copper(I) bromide (0.80 g, 3.61 mmol) in acetonitrile (10 mL) was added tert-butyl nitrile (0.41 g, 3.97 mmol) and stirred at 60 °C for 10 min. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2S04, filtered and concentrated under reduced pressure to afford the title compound (0.6 g, 53.07 %). LC-MS: 314.0 [M+H] + .

[0934] Step 6: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-cyclopropyl-2-fluorobenzoate

[0935] To a degassed solution of methyl 4-((lH-pyrazol-l-yl)methyl)-3-bromo-2-fluorobenzoate (0.3 g, 0.95 mmol), cyclopropylboronic acid (0.32 g, 3.83 mmol) and K3P04 (0.610 g, 2.87 mmol) in 1,4-dioxane (2.7 mL) and water (0.3 mL) was added Pd(Amphos)Cl2 (0.068 g, 0.090 mmol) and stirred at 100 °C for 12 h. The reaction mixture was allowed to cool to RT, filtered through celite and used for 10% methanol wash in DCM. The filtrate was washed with aqueous NaHC03, dried over anhydrous Na2S04, filtered and concentrated and purified by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent to afford the title compound (0.150 g, 57 %). LC-MS: 275.1 [M+H] + .

[0936] Step 7: 4-((lH-Pyrazol-l-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid

[0937] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 261.0 [M+H] + .

[0938] Step 8: 4-((lH-Pyrazol-l-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid perfluorophenyl ester

[0939] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 427.0 [M+H] + .

[0940] Intermediate 36: 4-((1H-pyrazol-1-yl)methyl)-2,3-dimethoxybenzoic acid perfluorophenyl ester

[0941]

[0942] Step 1: Methyl 4-bromo-2,3-dihydroxybenzoate

[0943] Methyl 2,3-dihydroxybenzoate (3.0 g, 17.84 mmol) in DCM was added dropwise to a pre-mixed solution of 2-methylpropan-2-amine (2.61 g, 35.68 mmol) and bromine (2.85 g, 35.68 mmol) in toluene and DCM at -78 °C and stirred at the same temperature for 30 min. The reaction mixture was allowed to warm up to RT slowly and stirred for 16 h. The reaction mixture was diluted with EtOAc, washed with 1 M HC1. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under vacuum to get crude material. The crude material was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as eluent to get the title compound (1.80 g, 40.8%). LC-MS: 246.9 [M-H] - .

[0944] Step 2: Methyl 4-bromo-2,3-dimethoxybenzoate

[0945] To a solution of methyl 4-bromo-2,3-dihydroxybenzoate (1.8 g, 7.28 mmol) and K2CO3(3.0 g, 21.85 mmol) in acetone was added iodomethane (10.34 g, 72.86 mmol) and stirred at 50 °C for 5 h. The mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude compound which was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent to get the title compound (1.75 g, 87.3%). LC-MS: 275.0 [M+H] + .

[0946] Step 3: (4-bromo-2,3-dimethoxyphenyl)methanol

[0947] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 31 using appropriate reagents with suitable modifications. 1 H NMR, DMSO-d6, 400 MHz): δ

[0948] 7.35 (d, 1H), 7.11 (d, 1H), 5.18 (t, 1H), 4.49 (d, 2H), 3.79 (s, 3H), 3.78 (s, 3H).

[0949] Step 4: methyl l-(4-bromo-2,3-dimethoxybenzyl)-lH-pyrazole

[0950] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 277.0 [M+H] + .

[0951] Step 5: methyl 4-((lH-pyrazol-l-yl)methyl)-2,3-dimethoxybenzoate

[0952] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 277.0 [M+H] + .

[0953] Step 6: 4-((lH-pyrazol-l-yl)methyl)-2,3-dimethoxybenzoic acid

[0954] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 263.1 [M+H] + .

[0955] Step 7: 4-((lH-Pyrazol-l-yl)methyl)-2,3-dimethoxybenzoic acid perfluorophenyl ester

[0956] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 429.0 [M+H] + .

[0957] Intermediate 37: 4-((1H-pyrazol-1-yl)methyl)-2,5-dimethoxybenzoic acid perfluorophenyl ester

[0958]

[0959] Step 1: (4-Bromo-2,5-dimethoxyphenyl)methanol

[0960] To a solution of 4-bromo-2,5-dimethoxybenzaldehyde (1.0 g, 4.08 mmol) in EtOH (10 mL) was added NaBH4(0.67 g, 16.32 mmol) at 0 °C. The mixture was warmed to RT and stirred for 4 h. The reaction mass was quenched with water at RT, extracted with ethyl acetate, washed with water, brine solution, dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (1.0 g). 1 H NMR, DMSO-d6, 400 MHz): δ 1H NMR, DMSO-d6, 400 MHz): δ 7.15 (s, 1H), 7.14 (s, 1H), 5.16 (t, 1H), 4.45 (d, 2H), 3.80 (s, 3H), 3.74 (s, 3H).

[0961] Step 2: l-(4-Bromo-2,5-dimethoxybenzyl)-lH-pyrazole

[0962] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 299.0 [M+H] + .

[0963] Step 3: Methyl 4-((lH-pyrazol-l-yl)methyl)-2,5-dimethoxybenzoate

[0964] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 277.1 [M+H] + .

[0965] Step 4: 4-((lH-Pyrazol-l-yl)methyl)-2,5-dimethoxybenzoic acid

[0966] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 263.1 [M+H] + .

[0967] Step 5: 4-((lH-Pyrazol-l-yl)methyl)-2,5-dimethoxybenzoic acid perfluorophenyl ester

[0968] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 429.1 [M+H] + .

[0969] Intermediate 39: 4-((lH-Pyrazol-l-yl)methyl)-3-bromo-2-fluorobenzoic acid

[0970]

[0971] Step 1: 4-((lH-Pyrazol-l-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid

[0972] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 301.0 [M+H] + .

[0973] Intermediate 60: 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid perfluorophenyl ester

[0974]

[0975] Step 1: 4-((lH-Pyrazol-l-yl)methyl)-3-cyclopropyl-2-fluorobenzoic acid

[0976] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 399.1 [M+H] + .

[0977] Intermediate 62: 4-((1H-pyrazol-1-yl)methyl)-3-(difluoromethoxy)benzoic acid perfluorophenyl ester

[0978]

[0979] Step 1: 3-(Difluoromethoxy)-4-methylbenzoic acid methyl ester

[0980] To a solution of methyl 3-hydroxy-4-methylbenzoate (2 g, 12.03 mmol) in ACN (80 mL) was added 5 N KOH solution (10 mL, 60.17 mmol) and (bromodifluoromethyl)diethyl phosphate (6.42 g, 24.07 mmol) successively at 0 °C. The reaction mixture was allowed to warm up to RT slowly and stirred for 16 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 10-20% ethyl acetate in hexane as eluent to get the title compound (0.85 g, 32.7%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.76 (dd, 1H), 7.67 (s, 1H), 7.49 (d, 1H), 7.31 (t, 1H), 3.86 (s, 3H), 2.31 (s, 3H).

[0981] Step 2: Methyl 4-(bromomethyl)-3-(difluoromethoxy)benzoate

[0982] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 1 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-d6, 400 MHz): δ

[0983] 7.83 (dd, 1H), 7.74 - 7.22 (m, 2H), 7.44 (t, 1H), 4.71 (s, 2H), 3.90 (s, 3H).

[0984] Step 3: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-(difluoromethoxy)benzoate

[0985] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 283.0 [M+H] + .

[0986] Step 4: 4-((lH-pyrazol-l-yl)methyl)-3-(difluoromethoxy)benzoic acid

[0987] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 269.1 [M+H] + .

[0988] Step 5: Perfluorophenyl 4-((lH-pyrazol-l-yl)methyl)-3-(difluoromethoxy)benzoate

[0989] The title compound was prepared using a similar procedure described in Step 6 of Intermediate 31 using the appropriate reagents with suitable modifications. LC-MS: 445.0 [M+H] + .

[0990] Intermediate 70: 3-Methoxy-4-(pyrimidin-2-yloxymethyl)benzoic acid

[0991]

[0992] Step 1: Methyl 3-methoxy-4-(pyrimidin-2-yloxymethyl)benzoate

[0993] To a mixture of methyl 4-(hydroxymethyl)-3-methoxybenzoate (1.50 eq, 154 mg, 0.786 mmol) and tetrahydrofuran (12.0 mL) was added sodium hydride (1.50 eq, 19 mg, 0.786 mmol) in portions. After 10 min, 2-chloropyrimidine (1.00 eq, 60 mg, 0.524 mmol) was added and the mixture was stirred at room temperature over the weekend. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (153 mg, 0.556 mmol, 106.13%). LC-MS: 275 [M+H] + .

[0994] Step 2: 3-Methoxy-4-(pyrimidin-2-yloxymethyl)benzoic acid

[0995] A mixture of methyl 3-methoxy-4-(pyrimidin-2-yloxymethyl)benzoate (150 mg, 0.5469 mmol) and 3N NaOH solution (1.4 mL, 4.3751 mmol) was stirred in 1 mL EtOH and 1 mL THF at ambient temperature overnight. The reaction was diluted with EtOAc, acidified with 1N HCI (to pH 5) and extracted with EtOAc. The organics were washed with brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (110 mg, 0.423 mmol, 77%). LC-MS: 261 [M+H] + .

[0996] Intermediate 71 and 72

[0997] The following intermediates listed in Table 9 were prepared following a similar procedure described above for Intermediate 70 using appropriate reagents known to those skilled in the art with suitable modifications.

[0998] Table 9. Intermediates

[0999]

[1000] c) Pyridine- and pyrimidine-carboxyl intermediates

[1001] Intermediate 8: 5-((1H-Pyrazol-1-yl)methyl)picolinic acid

[1002]

[1003] Step 1: 5-(bromomethyl)pyridinecarboxylic acid ethyl ester

[1004] To a solution of 5-methylpyridinecarboxylic acid ethyl ester (2.0 g, 12.10 mmol) in CC14(15 mL) was added NBS (2.15 g, 12.10 mmol) and peroxide (0.293 g, 1.21 mmol) and stirred at 75 °C for 12 h. The reaction mixture was then cooled to RT and diluted with DCM and washed with water. The organic layer was dried over Na2S04and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 15-20% ethyl acetate in hexane to get the title compound (1.8 g, 60.9%). LC-MS: 244.0 [M+H] + .

[1005] Step 2: 5-((lH-pyrazol-l-yl)methyl)pyridinecarboxylic acid ethyl ester

[1006] To a stirred solution of 5-(bromomethyl)pyridinecarboxylic acid ethyl ester (1.8 g, 7.37 mmol), lH-pyrazole (0.653 g, 9.58 mmol) in DMF (15 mL) was added K2C03(3.05 g, 22.11 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane to get the title compound (0.8 g, 46.9%). LC-MS: 232.1 [M+H] + .

[1007] Step 3: 5-((lH-pyrazol-l-yl)methyl)pyridinecarboxylic acid

[1008] To a stirred solution of ethyl 5-((lH-pyrazol-l-yl)methyl)picolinic acid (0.2 g, 3.2 mmol) in THF (4 mL), EtOH (3 mL) and water (2 mL) was added LiOH.H2O (0.104 g, 4.32 mmol) and stirred at room temperature for 12 h. The reaction mixture was evaporated and diluted with ice cold water and pH was adjusted to 5 using aqueous citric acid to get the solid mass. The solid mass was filtered, washed with ice cold water and dried under vacuum to get the title compound (0.16 g, 91%). LC-MS: 204.1 [M+H] + .

[1009] Intermediate 29: 6-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-5- methoxypicolinamide Nicotinamide

[1010]

[1011] Step 1: 5-bromo-3-methoxypyridin-2-yl)methanol

[1012] To a stirred solution of methyl 5-bromo-3-methoxypyridine-2-carboxylate (3 g, 12.19 mmol) in EtOH (30 mL) was added NaBH4(1.38 g, 36.57 mmol) at 0 °C and stirred at RT for 4 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound which was further purified by silica gel column chromatography using 20% ethyl acetate in hexane as eluent to get the title compound (1.4 g, 53%). LC-MS: 220.0 [M+H] + .

[1013] Step 2: 2-((lH-pyrazol-l-yl)methyl)-5-bromo-3-methoxypyridine

[1014] To a solution of (5-bromo-3-methoxypyridin-2-yl)methanol (1.5 g, 6.87 mmol) and l-(methylsulfonyl)-lH-pyrazole (1.20.8.25 mmol) in acetonitrile (15 mL) was added Cs2C03(2.69 g, 8.25 mmol) and stirred at 70 °C for 1 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound which was further purified by silica gel column chromatography using 30% ethyl acetate in hexane as eluent to get the title compound (1.5 g, 81%). LC-MS: 270.0 [M+H] + .

[1015] Step 3: methyl 6-((lH-pyrazol-l-yl)methyl)-5-methoxynicotinate

[1016] To a degassed solution of 2-((lH-pyrazol-l-yl)methyl)-5-bromo-3-methoxy pyridine (1.5 g, 5.59 mmol) in methanol (60 mL) was added Et3N (2.32 mL, 16.78 mmol), Pd(dppf)Cl2.DCM (0.32 g, 0.39 mmol). The reaction mixture was heated to 80 °C in a pressure vessel with 80 PSI carbon monoxide pressure for 16 h. The reaction mixture was allowed to cool to RT, filtered through a pad of celite and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as eluent to get the title compound (1.1 g, 79.5%). LC-MS: 248.1 [M+H] + .

[1017] Step 4: 6-((lH-pyrazol-l-yl)methyl)-5-methoxy nicotinic acid

[1018] To a stirred solution of methyl 6-((lH-pyrazol-l-yl)methyl)-5-methoxy nicotinate (0.8 g, 3.23 mmol) in THF (8 mL), MeOH (4 mL) and water (4 mL) was added LiOH.H2O (0.387 g, 16.18 mmol) and stirred at RT for 12 h. The reaction mixture was evaporated and diluted with ice cold water, pH was adjusted to 5 using 1 N HCI to get the solid mass. The solid mass was filtered, washed with ice cold water and dried under vacuum to get the title compound (0.45 g, 60%). LC-MS: 234.1 [M+H] + .

[1019] Step 5: 6-((lH-pyrazol-l-yl)methyl)-5-methoxy nicotinic acid perfluorophenyl ester

[1020] To a solution of 6-((lH-pyrazol-l-yl)methyl)-5-methoxy nicotinic acid (0.2 g, 0.85 mmol), 2,3,4,5,6-pentafluorophenol (0.19 g, 1.03 mmol) and DMAP (0.021 g, 0.17 mmol) in DCM (4 mL) was added EDC.HCI (0.247 g, 1.28 mmol) at 0 °C followed by stirring at RT for 12 h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2S04, filtered and concentrated to get the crude compound which was further purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as eluent to get the title compound (0.12 g, 35%). LC-MS: 400.0 [M+H] + .

[1021] Intermediate 30: Perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypicolinate

[1022]

[1023] Step 1: (6-chloro-2-methoxypyridin-3-yl)methanol

[1024] To a solution of 6-chloro-2-methoxynicotinaldehyde (2.0 g, 11.65 mmol) in MeOH (60 mL) was added NaBH4(1.76 g, 11.65 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (2 g, 99%). LC-MS: 174.1 [M+H] + .

[1025] Step 2: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-methoxypyridine

[1026] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications (2 g, 80%). LC-MS: 224 [M+H] + .

[1027] Step 3: methyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylate

[1028] The title compound compound was prepared using a similar procedure described in Step 3 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 248.1 [M+H] + .

[1029] Step 4: 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid

[1030] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 234.1 [M+H] + .

[1031] Step 5: perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylate

[1032] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 400.0 [M+H] + .

[1033] Intermediate 40: Perfluorophenyl 5-((lH-pyrazol-l-yl)methyl)-6-methylpicolinic acid

[1034]

[1035] Step 1: 6-Chloro-2-methylnicotinaldehyde

[1036] To a stirred solution of 3-bromo-6-chloro-2-methylpyridine (2.0 g, 9.68 mmol) in THF at -78 °C was added n-BuLi (7.26 mL, 11.62 mmol, 1.6 M in THF) and stirred at same temperature for 30 min. To the reaction mixture was then added DMF (1.41 g, 19.37 mmol) drop wise at -78 °C and slowly warmed to RT and stirred for 2 h. The reaction mixture was cooled to -78 °C, quenched with brine and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent to get the title compound (0.61 g, 40%). LC-MS: 154.2 [M-H] - .

[1037] Step 2: (6-Chloro-2-methylpyridin-3-yl)methanol

[1038] To a stirred solution of 6-chloro-2-methylnicotinaldehyde (0.6 g, 3.85 mmol) in THF (20 mL) at 0 °C was added NaBH4(0.438 g, 37.83 mmol) and stirred at RT for 1 h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated to get the title compound (0.51 g, 85%). LC-MS: 158.1 [M+H] + .

[1039] Step 3: 3-((lH-Pyrazol-l-yl)methyl)-6-chloro-2-methylpyridine

[1040] The title compound was prepared using similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 208.0 [M+H] + .

[1041] Step 4: Methyl 5-((lH-pyrazol-l-yl)methyl)-6-methylpicolinic acid

[1042] The title compound compound was prepared using similar procedure described in Step 3 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 232.2 [M+H] + .

[1043] Step 5: 5-((lH-Pyrazol-l-yl)methyl)-6-methylpicolinic acid

[1044] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 218.1 [M+H] + .

[1045] Step 6: 5-((lH-Pyrazol-l-yl)methyl)-6-methylpicolinic acid perfluorophenyl ester

[1046] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 384.2 [M+H] + .

[1047] Intermediate 41: 5-((lH-Pyrazol-l-yl)methyl)-4-methoxypicolinic acid

[1048]

[1049] Step 1: 6-Chloro-4-methoxynicotinic acid methyl ester

[1050] To a solution of methyl 4,6-dichloronicotinate (5.0 g, 24.26 mmol) in methanol (50 mL) was added NaOMe (5.4 g, 100.13 mmol) at 0 °C and the reaction mixture was allowed to warm up to RT slowly and stirred for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound which was carried to the next step without further purification (2.0 g, 41%): LC-MS: 202.0 [M+H] + .

[1051] Step 2: (6-Chloro-4-methoxypyridin-3-yl)methanol

[1052] To a stirred solution of methyl 6-chloro-4-methoxynicotinate (2.5 g, 12.4 mmol) in THF (40 mL) was added LiBH4(12.4 mL, 24.8 mmol) at 0 °C and stirred at 70 °C for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to afford the title compound (2.12 g, 99%). LC-MS: 173.4 [M+H] + .

[1053] Step 3: 5-((lH-Pyrazol-l-yl)methyl)-2-chloro-4-methoxypyridine

[1054] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 223.7 [M+H] + .

[1055] Step 4: Methyl 5-((lH-pyrazol-l-yl)methyl)-4-methoxypyridinecarboxylate

[1056] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 248.9 [M+H] + .

[1057] Step 5: 5-((lH-pyrazol-l-yl)methyl)-4-methoxypyridinecarboxylic acid

[1058] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 234.1 [M+H] + .

[1059] Intermediate 45: 5-((1H-Pyrazol-1-yl)methyl)-6-(difluoromethoxy)picolinic acid

[1060] Step 1: (6-Chloro-2-(difluoromethoxy)pyridin-3-yl)methanol

[1061] To a solution of 6-chloro-2-(difluoromethoxy)nicotinic acid (0.5 g, 2.23 mmol) in THF was added 1,1'-carbonyldiimidazole (0.72 g, 4.47 mmol) at 0 °C. The reaction mixture was then allowed to warm up to RT slowly and was maintained for 5 h. Sodium borohydride (0.42 g, 11.18 mmol) was then added to the reaction mixture at 0 °C. The reaction mixture was then allowed to warm up to RT slowly and was maintained for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 10% ethyl acetate in hexane as eluent to get the title compound (0.45 g, 96%). LC-MS: 207.6 [M-H] - .

[1062] Step 2: 3-((lH-pyrazol-l-yl)methyl)-6-chloro-2-(difluoromethoxy)pyridine

[1063] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 259.8 [M+H] + .

[1064] Step 3: Methyl 5-((lH-pyrazol-l-yl)methyl)-6-(difluoromethoxy)picolinic acid

[1065] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 268.0 [M-H] + .

[1066] Step 4: 5-((lH-pyrazol-l-yl)methyl)-6-(difluoromethoxy)picolinic acid

[1067] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 268.0 [M-H] - .

[1068] Intermediate 76: 5-((lH-pyrazol-l-yl)methyl)-6-(trifluoromethoxy)picolinic acid

[1069] Step 1: 6-chloro-2-(trifluoromethoxy)nicotinic acid

[1070] To a solution of 2-chloro-6-(trifluoromethoxy)pyridine (1.0 g, 5.06 mmol) in anhydrous THF (30 mL) was added LDA (freshly prepared from n-BuLi (2.0 mL, 5.0 mmol, 2.5 M in hexane) and diisopropyl amine (0.65 g, 5.06 mmol) in THF (10 mL)) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h. Using a cannula, the reaction mixture was transferred in a crushed dry ice RB flask at 0 °C and stirred at rt for 30 min. The reaction mixture was quenched with ice water and pH was adjusted to -3 using 2N HCI to get a precipitate. The precipitate was filtered and dried under vacuum to get the title compound (0.5 g, 40.9 %) LC-MS: 240.0 [M-H] - .

[1071] Step 2: (6-chloro-2-(trifluoromethoxy)pyridin-3-yl)methanol

[1072] To a solution of 6-chloro-2-(trifluoromethoxy)nicotinic acid (0.40 g, 1.655 mmol) in THF (10 ml) was added CDI (0.806 g, 4.96 mmol) at 0 °C and the reaction mixture was stirred at rt for 2 h. A solution of NaBH4(0.43 g, 11.59 mmol) in water (2 ml) was added to the reaction mixture at 0 °C and the whole reaction mixture was stirred at rt for 1 h. The reaction mixture was acidified with HCI and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 5% methanol in DCM as eluent to get the title compound (0.2 g, 53.07%). 1 HNMR (DMSO-D6, 400 MHz): δ 8.12 (d, 1H), 7.58 (d, 1H), 5.58 (s, 1H), 4.52 (s, 2H).

[1073] Step 3: 3-((1H-Pyrazol-1-yl)methyl)-6-chloro-2-(trifluoromethoxy)pyridine

[1074] The title compound was prepared using similar procedure described in step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 278.0 [M+H] +

[1075] Step 4: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-(trifluoromethoxy)pyridinecarboxylate

[1076] The title compound was prepared using similar procedure described in step 3 of Intermediate 28 using appropriate reagents with suitable modifications. LC-MS: 302.1 [M+H] + .

[1077] Step 5: 5-((1H-Pyrazol-1-yl)methyl)-6-(trifluoromethoxy)pyridinecarboxylic acid

[1078] The title compound was prepared using similar procedure described in step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 288.0 [M+H] +

[1079] Intermediate 77: Perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-(difluoromethyl)picolinic acid

[1080]

[1081] Step 1: 6-Chloro-2-(difluoromethyl)-3-methylpyridine

[1082] To a solution of 6-chloro-3-methylpyridinecarboxaldehyde (0.9 g, 5.78 mmol) in DCM (20 ml) was added DAST (2.79 g, 17.35 mmol) at 0 °C over 10 min. The reaction mixture was then allowed to warm to RT and stirred for 3 h. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude material. The crude material was purified by silica gel flash column chromatography using 5% methanol in DCM as eluent to get the title compound (0.91 g, 88.58%). LC-MS: 178.0 [M+H] +

[1083] Step 2: 3-(Bromomethyl)-6-chloro-2-(difluoromethyl)pyridine

[1084] The title compound was prepared using similar procedure described in Step 2 of Intermediate 1 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-D6, 400 MHz): δ

[1085] 7.92 (d, 1H), 7.48 (d, 1H), 6.70 (t, 1H), 4.69 (s, 2H).

[1086] Step 3: 3-((1H-Pyrazol-1-yl)methyl)-6-chloro-2-(difluoromethyl)pyridine

[1087] The title compound was prepared using similar procedure described in Step 3 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 244.1 [M+H] + .

[1088] Step 4: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-(difluoromethyl)pyridinecarboxylate

[1089] The title compound was prepared using similar procedure described in Step 3 of Intermediate 28 using appropriate reagents with suitable modifications. LC-MS: 268.1 [M+H] + .

[1090] Step 5: 5-((1H-Pyrazol-1-yl)methyl)-6-(difluoromethyl)pyridinecarboxylic acid

[1091] The title compound was prepared using similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 254.1 [M+H] + .

[1092] Step 6: 5-((lH-Pyrazol-l-yl)methyl)-6-(difluoromethyl)picolinic acid perfluorophenyl ester

[1093] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using the appropriate reagents with suitable modifications. LC-MS: 420.1 [M+H] + .

[1094] Intermediate 80: Perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)picolinic acid

[1095]

[1096] Step 1: 6-Hydroxy-2-(trifluoromethyl)nicotinic acid

[1097] To a stirred solution of (Z)-3-amino-4,4,4-trifluorobut-2-enoic acid ethyl ester (5.0 g 27.30 mmol) in 25% sodium methoxide in methanol (29.5 mL) was added 2,3-dichloromethyl propionate (4.71 g, 30.03 mmol) drop wise at 0 °C and stirred for 30 min at 0 °C. Then the reaction mixture was heated to 60 °C. Subsequently, 20% sodium hydroxide aqueous solution (73.5 mL) was added slowly to the reaction mixture at 60 °C over 2 h. The reaction mixture was allowed to cool to 0 °C and pH was adjusted to -3 using concentrated HC1, which resulted in a precipitate. The precipitate was filtered and washed with water to get the title compound (4.3 g, 90.6%). LC-MS: 208.0 [M+H] + .

[1098] Step 2: 6-Chloro-2-(trifluoromethyl)nicotinic acid

[1099] To a stirred solution of 6-hydroxy-2-(trifluoromethyl)nicotinic acid (2.5 g, 12.05 mmol) and Et3N (2.4 g 24.14 mmol) in xylene (2.5 mL) was added POCl3(2.5 mL 27.03 mmol) at 0 °C followed by stirring at 140 °C for 5 h. The reaction mixture was allowed to cool to RT and adjusted to pH-3 using aqueous sulfuric acid. The aqueous layer was extracted with xylene. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to get the crude compound (2.2 g). LC-MS: 226.0 [M+H] +

[1100] Step 3: 6-Chloro-2-(trifluoromethyl)nicotinic acid (isobutyl carbonate) anhydride

[1101] To a stirred solution of 6-chloro-2-(trifluoromethyl)nicotinic acid (2.2 g, 9.75 mmol) and isobutyl chloroformate (1.66 g, 12.19 mmol) in THF (25 mL) was added Et3N (1.48 g 14.63 mmol) at 0 °C followed by stirring at RT for 2 h. The reaction was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to get crude material. The crude was purified by silica gel flash column chromatography using 5% ethyl acetate in hexane as eluent to get the title compound (1.51 g, 47.5%). 1 H NMR, CDC13, 400 MHz): δ 7.21 (d, 1H), 7.69 (d, 1H), 4.18 (d, 2H), 2.14-2.06 (m, 1H), 0.96 (d, 6H).

[1102] Step 4: (6-chloro-2-(trifluoromethyl)pyridin-3-yl)methanol

[1103] The title compound was prepared using similar procedure described in step 2 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 212.0 [M+H] +

[1104] Step 5: 3-((1H-pyrazol-1-yl)methyl)-6-chloro-2-(trifluoromethyl)pyridine

[1105] The title compound was prepared using similar procedure described in step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 262.0 [M+H] + .

[1106] Step 6: methyl 5-((1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)pyridinecarboxylate

[1107] The title compound was prepared using similar procedure described in step 3 of Intermediate 28 using appropriate reagents with suitable modifications. LC-MS: 286.1 [M+H] + .

[1108] Step 7: 5-((1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)pyridinecarboxylic acid

[1109] The title compound was prepared using similar procedure described in step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 272.0 [M+H] + .

[1110] Step 8: perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)pyridinecarboxylate

[1111] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using the appropriate reagents with suitable modifications. LC-MS: 438.0 [M+H] + .

[1112] Intermediate 81 : Perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpicolinic acid

[1113]

[1114] Step 1: (Z)-3-amino-3-cyclopropylacrylic acid ethyl ester

[1115] To a stirred solution of ethyl 3-cyclopropyl-3-oxopropanoate (5.0 g, 35.17 mmol) in MeOH (100 mL) was added ammonium acetate (13.55 g 175.87 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated, then diluted with DCM (50 mL) and stirred for 30 min to get solid mass. The solid mass was filtered and washed with DCM. The combined filtrate was concentrated to get crude compound (6.55 g). LC-MS: 142.2 [M+H] + .

[1116] Step 2: (2E,4Z)-4-(amino(cyclopropyl)methylidene)pent-2-enedioic acid 5-ethyl 1-methyl ester

[1117] To a stirred solution of (Z)-3-amino-3-cyclopropylacrylic acid ethyl ester (6.5 g, 46.04 mmol) in toluene (75 mL) was added methyl propiolate (5.42 g, 55.25 mmol) and stirred at 90 °C for 48 h. The reaction mixture was allowed to cool to RT and concentrated to get crude compound which was used for the next step without any further purification (5.11 g, 46.38 %). LC-MS: 238.1 [M-H] - .

[1118] Step 3: 2-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester

[1119] To a stirred solution of (2E,4Z)-4-(amino(cyclopropyl)methylene)pent-2- enedioic acid 5-ethyl 1-methyl ester (5.1 g, 21.31 mmol) in DMF (50 mL) was added NaOtBu (0.30 g, 3.19 mmol) at 0 °C followed by stirring at 90 °C for 12 h. The reaction mixture was allowed to cool to RT and quenched with ice water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 60-70% ethyl acetate in hexane as eluent to get the title compound (1.2 g, 29.14%). LC-MS: 194.1 [M+H] + .

[1120] Step 4: 6-Chloro-2-cyclopropyl nicotinic acid methyl ester

[1121] To a stirred solution of methyl 2-cyclopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1.1 g, 5.69 mmol) in phenyl dichlorophosphate (10 mL) was stirred at 180 °C for 10 min. The reaction mixture was added to ice water and extracted with EtOAc. The organic layer was washed with aqueous NaHC03solution, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 05-10% ethyl acetate in hexane as eluent to get the title compound (1.2 g, 29.1%). LC-MS: 212.0 [M+H] + .

[1122] Step 5: (6-Chloro-2-cyclopropylpyridin-3-yl)methanol

[1123] The title compound was prepared using similar procedure described in step 2 of Intermediate 31 using appropriate reagents with suitable modifications. LC-MS: 184.1 [M+H] + .

[1124] Step 6: 3-((1H-Pyrazol-1-yl)methyl)-6-chloro-2-cyclopropylpyridine

[1125] The title compound was prepared using similar procedure described in step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 234.1 [M+H] + .

[1126] Step 7: Methyl 5-((1H-pyrazol-1-yl)methyl)-6-cyclopropylpyridinecarboxylate

[1127] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 28 using appropriate reagents with suitable modifications. LC-MS: 258.1 [M+H] + .

[1128] Step 8: 5-((lH-Pyrazol-l-yl)methyl)-6-cyclopropylpyridinecarboxylic acid

[1129] The title compound was prepared using a similar procedure described in Step 4 of Intermediate 1 using appropriate reagents with suitable modifications. LC-MS: 244.1 [M+H] + .

[1130] Step 9: 5-((lH-Pyrazol-l-yl)methyl)-6-cyclopropylpyridinecarboxylic acid perfluorophenyl ester

[1131] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 410.1 [M+H] + .

[1132] Intermediate 99: 5-((1H-Pyrazol-1-yl)methyl)-1-methyl-6-oxo-1,6-dihydropyridine-2- carboxylic acid

[1133]

[1134] Step 1: 5-((lH-Pyrazol-l-yl)methyl)-6-oxo-l,6-dihydropyridine-2-carboxylic acid

[1135] Methyl 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylate (0.5 g, 2.02 mmol) was dissolved in 6N HCI in water (12 mL) and refluxed at 100 °C for 12 h. The reaction mixture was concentrated and washed with diethyl ether to get the crude title compound (0.5 g). LC-MS: 220.1 [M+H] + .

[1136] Step 2: Methyl 5-((lH-pyrazol-l-yl)methyl)-l-methyl-6-oxo-l,6-dihydropyridine-2- carboxylate

[1137] To a solution of 5-((lH-pyrazol-l-yl)methyl)-6-oxo-l,6-dihydropyridine-2- carboxylic acid (0.3 g, 1.37 mmol) in DMF (10 mL) was added Cs2C03(0.892 g, 2.73 mmol) and Mel (0.389 g, 2.73 mmol) successively at 0 °C. The reaction mixture was allowed to warm up to RT slowly and stirred for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 0-5% methanol in dichloromethane as eluent to get the title compound. (0.26 g, 76.9%). LC-MS: 248.1 [M+H] + .

[1138] Step 3: 5-((lH-pyrazol-l-yl)methyl)-l-methyl-6-oxo-l,6-dihydropyridine-2- carboxylic acid

[1139] Methyl 5-((lH-pyrazol-l-yl)methyl)-l-methyl-6-oxo-l,6-dihydropyridine-2- carboxylate (0.26 g, 1.05 mmol) was dissolved in 6N HCI in water (12 mL) and refluxed at 100 °C for 12 h. The reaction mixture was concentrated and washed with diethyl ether to get the crude title compound (0.24 g). LC-MS: 234.1 [M+H] + .

[1140] Intermediate 100: Perfluorophenyl 5-((1H-pyrazol-1-yl)methyl)-6-ethoxypicolinate

[1141]

[1142] Step 1: 6-chloro-2-ethoxynicotinaldehyde

[1143] To a solution of 2-chloro-6-ethoxypyridine (1.5 g, 9.51 mmol) in THF (40 mL) was added n-BuLi (8.93 mL, 14.29 mmol, 1.6 M in THF) at -78 °C and stirred at same temperature for 30 min. To the reaction mixture was then added DMF (0.69 g, 9.54 mmol) drop wise at -78 °C and allowed to warm up to RT slowly and stirred for 16 h. The reaction mixture was cooled to -78 °C, quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 15% ethyl acetate in hexane as eluent to get the title compound (0.50 g, 28.30%). LC-MS: 186.0 [M+H] + .

[1144] Step 2: (6-chloro-2-ethoxypyridin-3-yl)methanol

[1145] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 30 using appropriate reagents with suitable modifications (0.40 g, 98.98%).

[1146] 1 H NMR (CDC13, 400 MHz): δ 7.70 (d, 1H), 7.57 (d, 1H), 6.92 (d, 1H), 6.90 (s, 1H), 6.69 (d, 1H), 6.64 (d, 1H), 4.71 (d, 2H), 4.67 (d, 2H), 4.64 (d, 2H), 4.45 (q, 2H), 4.38 (q, 4H), 1.43 - 1.26 (m, 9H).

[1147] Step 3: 3-((lH-pyrazol-l-yl)methyl)-6-chloro-2-ethoxypyridine

[1148] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications (0.48 g, 95.71%). 1 H NMR (DMSO-D6, 400 MHz): δ 7.88 (d, 1H), 7.79 (d, 1H), 7.78 (d, 1H), 7.53 (dd, 1H), -7.48 - 7.46 (m, 2H), 7.42 (d, 1H), 7.27 (d, 1H), 7.04 (d, 1H), 6.82 (d, 1H), 6.79 (s, 1H), 6.42 (d, 1H), 6.33 (d, 1H), 6.28 - 6.27 (m, 2H), 5.38 (s, 2H), 5.35 (s, 2H), 5.26 (s, 2H), 4.30 (q, 2H), 4.26 (q, 4H), 1.33 - 1.28 (m, 9H).

[1149] Step 4: methyl 5-((lH-pyrazol-l-yl)methyl)-6-ethoxypyridinecarboxylate

[1150] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 29 using appropriate reagents with suitable modifications (0.40 g, 80.87%). 1H NMR (CDC13, 400 MHz): δ 7.61 (d, 1H), 7.58-7.57 (m, 3H), 7.5d-7.52 (m, 3H), 7.48 (d, 1H), 7.24-7.21 (m, 2H), 6.84-6.82 (m, 1H), 6.57 (dd, 1H), 6.37 (dd, 1H), 6.33 (dd, 1H), 6.31 (dd, 1H), 5.66 (s, 2H), 5.36 (s, 2H), 5.35 (s, 2H), 4.55 (q, 2H), 4.46-4.38 (m, 4H), 3.99 (s, 3H), 3.96 (s, 6H), 1.46-1.26 (m, 9H).

[1151] Step 5: 5-((lH-Pyrazol-l-yl)methyl)-6-ethoxypicolinic acid

[1152] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications (0.22 g, 54.82%). LC-MS: 414.1 [M+H] + .

[1153] Step 6: Perfluorophenyl 5-((lH-pyrazol-l-yl)methyl)-6-ethoxypicolinate

[1154] The title compound was prepared using a similar procedure described in Step 5 of Intermediate 29 using appropriate reagents with suitable modifications (0.22 g, 54.82%). LC-MS: 414.1 [M+H] + .

[1155] d) Sulfinyl intermediate

[1156] Intermediate 82: 5-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6- methoxypicolinamide Intermediate 83 to 87

[1157]

[1158] Step 1: 2,6-Dimethoxybenzenesulfinamide

[1159] To a solution of 2-bromo-1,3-dimethoxybenzene (2 g, 9.21 mmol) in THF (15 mL) was added n-BuLi (17.3 mL, 27.64 mmol, 1.6 M in hexanes) at -78 °C and stirred at same temperature for 1 h. Then SO2 gas was bubbled into the reaction mixture at -78 °C for 30 min. The whole reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated to get a solid mass. The solid mass was dissolved in toluene and oxalyl chloride (0.93 mL, 10.8 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was again dissolved in DCM (10 mL) and 7 N methanolic ammonia (30 mL) was added to the reaction mixture and stirred at RT for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 60% ethyl acetate in hexanes as eluent to get the title compound (0.5 g, 34.5%). LC-MS: 202.1 [M+H] + .

[1160] Step 2: 5-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6- methoxypyridinecarboxamide

[1161] To a solution of 5-((1H-pyrazol-1-yl)methyl)-6-methoxypyridinecarboxylic acid perfluorophenyl ester (0.15 g, 0.37 mmol) and 2,6-dimethoxybenzenesulfonamide (0.091 g, 0.45 mmol) in THF (5 mL) was added LiHMDS (1.12 mL, 1.13 mmol, 1.0 M in THF) and stirred at RT for 10 min. The reaction mixture was quenched with saturated NH4Cl solution and extracted with 10% MeOH in DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 2-5% MeOH in DCM as eluent to get the title compound (0.12 g, 76.6%). LC-MS: 415.0 [M-H] - .

[1162] Example 1. Compound 1: 4-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 2-methoxybenzamide

[1163] The following intermediates listed in Table 10 were prepared following similar procedures as described hereinabove for Intermediate 82 using appropriate reagents known to those skilled in the art with suitable modifications.

[1164] Table 10. Intermediates

[1165]

[1166]

[1167] Intermediate 119: 5-((lH-Pyrazol-l-yl)methyl)-N-((3-chloro-2,6- dimethoxyphenyl)sulfinyl)-6-methoxypyridinecarboxamide

[1168]

[1169] Step 1: 5-((lH-Pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6- methoxypyridinecarboxamide

[1170] The title compound was prepared using a similar procedure as described in Step 2 of Intermediate 82 using appropriate reagents with suitable modifications. (0.2 g, 17.71%). LC-MS: 449.0 [M-H] - .

[1171] Intermediates 120 to 131

[1172] The following intermediates listed in Table 11 were prepared following a similar procedure as described above for Intermediate 119 and Step 2 of Intermediate 82 using appropriate reagents known to those skilled in the art with suitable modifications.

[1173] Table 11

[1174]

[1175]

[1176] General Synthetic Scheme:

[1177] Certain compounds of the present application can be prepared by following the procedures as given in General Scheme-I.

[1178] General Scheme: I

[1179]

[1180] General Scheme - I for the synthesis of compounds represented by Formula (I') is depicted in the scheme above. Compound of formula (K1) undergoes a reduction reaction in a suitable solvent and a suitable reducing reagent to give compound of formula (K2) which upon further reaction of compound of formula (B1) in the presence of a suitable substituent reagent and solvent can provide compound of formula (K3). Compound of formula (K3) undergoes an oxidation reaction followed by a substitution reaction to give compound of formula (K4) which upon further hydrolysis in a suitable base and solvent gives compound of formula (K5). Reaction of compound of formula (K5) with pentafluorophenol in a suitable solvent gives ester compound of (K6). Compound of formula (K6) can react with formula (B2) in a suitable reagent and solvent to give compound of formula (I').

[1181] General Scheme: II

[1182]

[1183] General Scheme - II for the synthesis of compounds represented by Formula (I") is depicted in the scheme above. Reaction of compound of formula (D1) in a suitable solvent and with an alkylating reagent gives compound of formula (D2) which upon further substitution reaction in the presence of a suitable substituent reagent and solvent can provide compound of formula (D3). Reaction of compound of formula (D3) with formula (B3) gives compound of formula (D4) which upon further hydrolysis in a suitable base and solvent gives compound of formula (D5). Reaction of compound of formula (D5) with an alcohol in a suitable solvent gives ester compound of (D6). Compound of formula (D6) can react with formula (B4) in a suitable reagent and solvent to give compound of formula (I").

[1184] e) Compound Examples

[1185] Example 2. Compound 26: N-(2-Methoxyphenyl)sulfonyl-3-methoxy-4-(pyrazol-1- ylmethyl)benzamide Example 3. Compound 45: N-(5-Bromo-2,4-dimethoxy-phenyl)sulfonyl-3-methoxy-4- (pyrazol-1-ylmethyl)benzamide

[1186]

[1187] To a solution of 4-((lH-pyrazol-l-yl)methyl)-2-methoxybenzoic acid (0.2 g, 0.86 mmol) in THF (10 mL) was added CDI (0.16 g, 1.03 mmol) and stirred at RT for 1 h. The reaction mixture was cooled to 0 °C, added 2,6-dimethoxybenzenesulfonamide (0.2 g, 0.94 mmol), DBU (0.18 g, 1.2 mmol) and stirred at the same temperature for 15 min, then gradually warmed to RT and stirred overnight. The reaction mixture was concentrated to get crude compound. The crude compound was purified by preparative HPLC to get the title compound (0.015 g, 4%).

[1188] Preparative HPLC method: mobile phase A - 0.05% TFA in water; B - Acetonitrile; column used - Luna OmegaPS, C-18 (250 x 21.2 mm), 5μ. Gradient program: 0% B for 10 min, 20% B for 2 min, 40% B for 10 min. LC-MS: 432.2 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 11.27 (s, 1H), 7.87 (d, 1H), 7.55-7.45 (m, 3H), 7.07, (s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 6.75 (d, 1H), 6.30 (t, 1H), 5.39 (s, 2H), 3.88 (s, 3H), 3.79 (s, 6H).

[1189] Example 4. Compound 70: N-(2,3-Dihydrobenzofuran-7-yl)sulfonyl-3-methoxy-4- (pyrazol-1-ylmethyl)benzamide Example 5. Compound 14: 4-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 3-methoxybenzamide

[1190]

[1191] To a solution of 4-((1H-pyrazol-1-yl)methyl)-3-methoxybenzoic acid perfluorophenyl ester (0.100 g, 0.251 mmol), 2-methoxybenzenesulfonamide (0.056 g, 0.301 mmol) in THF (3 mL) was added LiHMDS (1.0 M in THF) (1.0 mL, 1.0 mmol) and the whole reaction mixture was stirred at RT for 10 min. The reaction mixture was quenched with ice, followed by dilution with saturated NH4CI solution and extraction with ethyl acetate. The organic layer was dried over Na2S04and concentrated to get crude compound which was further purified by prep TLC eluting in 80% ethyl acetate in hexane (0.03 g, 30%): LC-MS: 402.3 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 12.50 (s, 1H), 7.91 (dd, 1H), 7.78 (d, 1H), 7.63 (dd, 1H), 7.55 (d, 1H), 7.47 (dd, 1H), 7.41 (dd, 1H), 7.21 (d, 1H), 7.16 (t, 1H), 6.78 (d, 1H), 6.31 (t, 1H), 5.33 (s, 2H), 3.91 (d, 3H), 3.85 (d, 3H).

[1192] Example 6. Compounds 2 to 65 Example 7. Compound 201: 5-((1H-Pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2- methoxyphenyl)sulfonyl)picolinamide

[1193]

[1194] A vial equipped with a stir bar was charged with 5-bromo-2,4-dimethoxy- benzenesulfonamide (1.00 eq, 40 mg, 0.135 mmol) and 3-methoxy-4-(pyrazol-l- ylmethyl)benzoic acid (1.24 eq, 39 mg, 0.167 mmol) and 4-dimethylaminopyridine (4.00 eq, 66 mg, 0.540 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.50 eq, 39 mg, 0.203 mmol) was added to the reaction vial and stirred at room temperature under nitrogen for 1.5 h. The reaction mixture was diluted with DCM (5 mL), quenched with water (15 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified via HPLC (Column: Luna 5 uM, C18, LC Column 100 x 30 mm. Flow: 42 mL / min. Gradient: 13-70%; Isocratic at 70%; Acetonitrile - Water. Run Time: 14 min. Modifier: 0.1% Formic Acid) to give the title compound (48 mg, 0.092 mmol, 68%): LC-MS: 512 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ

[1195] 12.54 (s, 1H), 7.94 (s, 1H), 7.78 (dd, J = 2.3, 0.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.47 (dd, J = 1.9, 0.7 Hz, 1H), 7.41 (dd, J = 7.9, 1.6 Hz, 1H), 6.86 (s, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.28 (t, J = 2.1 Hz, 1H), 5.33 (s, 2H), 3.97 (s, 3H), 3.91 (d, J = 6.1 Hz, 6H).

[1196] Example 8. Compound 202: 6-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 5-methoxynicotinamide Example 9. Compound 203: 5-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 6-methoxypicolinamide

[1197]

[1198] Dissolve 3-methoxy-4-(pyrazol-l-ylmethyl)benzamide (1.00 eq, 40 mg, 0.173 mmol) in DMF (1.5 mL) and cool to 0 °C. Add sodium hydride 60% in mineral oil (1.30 eq, 5.4 mg, 0.225 mmol) and stir for 30 min. Add 2,3-dihydro-l-benzofuran-7-sulfonyl chloride (1.10 eq, 42 mg, 0.190 mmol) and stir for 2 h while allowing to warm to room temperature. Purify the reaction mixture directly by HPLC on Kinetex 5um C18 column (size: 100 x 30.0 mm; gradient: 5-55% 0.1% formic acid in ACN over 0.1% formic acid in water) followed by lyophilization to give the title compound (3.4 mg, 5% yield): LC-MS: m / z = 414.1 [M+H] + 1H NMR (400 MHz, DMSO) δ 7.75 (s, 1H), 7.54 (d, J = 1.5 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 7.8, 1.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.27 (t, J = 2.1 Hz, 1H), 5.31 (s, 2H), 4.56 (s, 2H), 3.87 (s, 3H), 3.18 (s, 2H).

[1199] Example 10. Compound 224: 5-((1H-Pyrazol-1-yl)methyl)-6-methoxy-N-((2,4,6- trimethoxyphenyl)sulfonyl)picolinamide Example 11. Compound 264: 5-((1H-Pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2- methoxyphenyl)sulfonyl)picolinamide

[1200]

[1201] Step 1: 3-methoxy-4-methylbenzoic acid methyl ester

[1202] To a stirred solution of 3-hydroxy-4-methylbenzoic acid (20 g, 32.8 mmol) in DMF (250 mL) cooled to 0 °C was added NaH (7.9 g, 328.62 mmol) and iodomethane (24.6 mL, 394.3 mmol) sequentially at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was poured into ice water to get a precipitate which was filtered and washed with water and dried under vacuum to get the title compound (20 g, 97.4%). LC-MS: 181.3 [M+H] + .

[1203] Step 2: 4-(bromomethyl)-3-methoxybenzoic acid methyl ester

[1204] ​To a solution of methyl 3-methoxy-4-methylbenzoate (23 g, 127.63 mmol) in CC14(300 mL) was added NBS (31.8 g, 178.69 mmol) and benzoyl peroxide (BPO, 4.63 g, 19.14 mmol) and stirred at 75 °C overnight. The reaction mixture was then cooled to RT and diluted with DCM and washed with water. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound (33 g) which was used for the next step without further purification. LC-MS: 260.9 [M+H] + .

[1205] Step 3: Methyl 4-((lH-pyrazol-l-yl)methyl)-3-methoxybenzoate

[1206] To a stirred solution of methyl 4-(bromomethyl)-3-methoxybenzoate (33 g, 127.36 mmol) and 1H-pyrazole (13 g, 191.04 mmol) in DMF (300 mL) was added K2C03(44 g, 318.41 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 10-40% ethyl acetate in hexane as eluent to get the title compound (11 g, 35%). LC-MS: 247.2 [M+H] + .

[1207] Step 4: 4-((lH-pyrazol-l-yl)methyl)-3-methoxybenzoic acid

[1208] To a stirred solution of methyl 4-((lH-pyrazol-l-yl)methyl)-3-methoxybenzoate (10 g, 40.6 mmol) in THF (150 mL), MeOH (40 mL) and water (60 mL) was added LiOH.H20 (4.87 g, 203.03 mmol) and stirred at RT for 12 h. The reaction mixture was diluted with ice cold water, pH was adjusted to 3 using 1 N HCI solution to get the precipitate. The precipitate was filtered, washed with water and dried under vacuum to get the title compound (9 g, 95%). LC-MS: 233.2 [M+H] + .

[1209] Step 5: Perfluorophenyl 4-((lH-pyrazol-l-yl)methyl)-3-methoxybenzoate

[1210] To a solution of 4-((lH-pyrazol-l-yl)methyl)-2-methoxybenzoic acid (1.2 g, 5.17 mmol) and 2,3,4,5,6-pentafluorophenol (1.14 g, 6.20 mmol) in DCM (25 mL) were added DMAP (0.127 g, 1.03 mmol) and EDC.HC1 (1.49 g, 7.75 mmol) successively and stirred at RT for 12 h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound which was purified by silica gel flash column chromatography using 10-15% ethyl acetate in hexane as eluent to get the title compound (1.8 g, 87%). LC-MS: 399.1 [M+H] + .

[1211] Step 6: 4-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3- methoxybenzamide

[1212] To a solution of 4-((lH-pyrazol-l-yl)methyl)-3-methoxybenzoic acid perfluorophenyl ester (1 g, 2.551 mmol) and 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.545 g, 2.511 mmol) in THF (30 mL) was added LiHMDS (7.51 mL, 7.53 mmol, 1.0 M in THF) and stirred at RT for 10 min. The reaction mixture was quenched with saturated NH4C1 solution and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 60-80% EtOAc in hexane as eluent to get the title compound which was again triturated in ethyl acetate to get the title compound (0.3 g, 28%). LC-MS: 432.2 [M+H] + ; 1 HNMR (DMSO-D6, 400 MHz): δ 12.20 (s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.48 (d, 1H), 7.45 (dd, 2H), 6.85-6.75 (m, 3H), 6.28 (t, 1H), 5.34 (s, 2H), 3.92 (s, 3H), 3.78 (s, 6H).

[1213] ​

[1214] The following compounds listed in Table 12 were prepared following similar procedures as described above using appropriate reagents known to those skilled in the art with suitable modifications. The intermediates and example procedures for coupling are shown in the table below. Intermediates if not indicated as synthesized were commercially available.

[1215] Table 12. Compound synthesis and characterization

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226] ​ ​

[1227]

[1228] To a solution of 5-((lH-pyrazol-l-yl)methyl)picolinic acid (0.25 g, 1.229 mmol) in THF (5 mL) was added CDI (0.4 g, 2.46 mmol) and stirred at RT for 1 h. The reaction mixture was cooled to 0 °C, added 5-(tert-butyl)-2-methoxybenzenesulfonamide (Intermediate 17, 0.45 g, 1.84 mmol), DBU (0.75 g, 4.92 mmol) and stirred at same temperature for 15 min, then gradually warmed to RT and stirred for 12 h. The reaction mixture was concentrated to get crude compound. The crude compound was purified by preparative HPLC to get the title compound (0.03 g, 4%). LC-MS: 429.1 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz): δ 11.71 (s, 1H), 8.57 (s, 1H), 7.95-7.91 (m, 2H), 7.87 (d, 1H), 7.74 (dd, 1H), 7.68 (d, 1H), 7.51 (dd, 1H), 7.12 (d, 1H), 6.31 (t, 1H), 5.51 (s, 2H), 3.78 (s, 3H), 1.29 (s, 9H).

[1229] ​ ​

[1230]

[1231] To a solution of 6-((lH-pyrazol-l-yl)methyl)-5-methoxynicotinic acid perfluorophenyl ester (0.12 g, 0.301 mmol), 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.078 g, 0.361 mmol) in THF (4 mL) was added LiHMDS (1.0 M in THF) (1 mL, 1.2 mmol) and the whole reaction mixture was stirred at RT for 30 min. The reaction mixture was quenched with ice water and saturated NH4CI solution successively and extracted with ethyl acetate. The organic layer was dried over Na2S04and concentrated to get the crude compound which was further purified by preparative TLC eluting in 80% ethyl acetate in hexane (0.01 g, 8%): LC-MS: 433.1 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 12.60 (s, 1H), 8.52 (s, 1H), 7.82 (br s, 1H), 7.72 (s, 1H), 7.38 (d, 1H), 7.33 (br s, 1H), 6.70 (br m, 2H), 6.23 (t, 1H), 5.42 (s, 2H), 3.89 (s, 3H), 3.70 (s, 6H).

[1232] ​ ​

[1233]

[1234] Step 1: (6-chloro-2-methoxypyridin-3-yl)methanol

[1235] To a solution of 6-chloro-2-methoxynicotinaldehyde (10 g, 87.42 mmol) in MeOH (200 mL) was added NaBH4(13.3 g, 349.7 mmol) at 0 °C and stirred at RT for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (9.5 g, 94%). LC-MS: 174.0 [M+H] + .

[1236] Step 2: 3-((lH-Pyrazol-l-yl)methyl)-6-chloro-2-methoxypyridine

[1237] To a solution of 6-chloro-2-methoxypyridin-3-yl)methanol (16 g, 92.16 mmol) and l-(methylsulfonyl)-lH-pyrazole (16.16, 110.6 mmol) in acetonitrile (150 mL) was added Cs2CO3(60 g, 325.82 mmol) and stirred at 70 °C for 2 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to get the crude compound which was further purified by silica gel column chromatography using 20-30% ethyl acetate in hexane as eluent to afford the title compound (20 g, 95.8%). LC-MS: 224.1 [M+H] + .

[1238] Step 3: Methyl 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylate

[1239] To a degassed solution of 3-((lH-pyrazol-l-yl)methyl)-6-chloro-2-methoxypyridine (20 g, 89.42 mmol) and Et3N (37.8 mL, 268.26 mmol) in methanol (400 mL) was added Pd(dppf)Cl2-DCM (7.32 g, 8.94 mmol). The reaction mixture was heated to 80 °C in a pressure vessel with 80 PSI carbon monoxide pressure for 16 h. The reaction mixture was allowed to cool to RT, filtered through a pad of celite and concentrated to get the crude compound. The crude compound was further purified by silica gel column chromatography using 30-50% ethyl acetate in hexane as eluent to afford the title compound (16 g, 72.37%). LC-MS: 248.0 [M+H] + .

[1240] Step 4: 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylic acid

[1241] To a stirred solution of methyl 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridine- carboxylate (5 g, 20.22 mmol) in THF (40 mL), methanol (20 mL) and water (20 mL) was added LiOH.H2O (3.4 g, 41.96 mmol) and stirred at room temperature for 12 h. The reaction mixture was diluted with ice cold water, pH was adjusted to 4 using aqueous citric acid solution to get a precipitate. The precipitate was filtered, washed with water and dried under vacuum to get the title compound (4.5 g, 95.5 %): LC-MS: 234.1 [M+H] + .

[1242] Step 5: Perfluorophenyl 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylate

[1243] To a stirred solution of 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylic acid (1.0 g, 4.28 mmol), 2,3,4,5,6-pentafluorophenol (0.947 g, 5.144 mmol) in DCM (20 mL) was added DMAP (0.106 g, 0.85 mmol) and EDC-HCl (1.65 g, 8.57 mmol) successively at 0 °C and stirred at RT for 12 h. The reaction mixture was quenched with ice cold water and extracted with DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 15-30% ethyl acetate in hexane as eluent to get the title compound (1.5 g, 87.6 %). LC-MS: 400.0 [M+H] + .

[1244] Step 6: 5-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6- methoxypyridineamide

[1245] To a solution of 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridine carboxylic acid perfluorophenyl ester (0.6 g, 1.50 mmol) and 2,6-dimethoxybenzenesulfonamide (intermediate 22, 0.327 g, 1.50 mmol) in THF (20 mL) was added LiHMDS (1.5 mL, 1.50 mmol, 1.0 M in THF) and stirred at RT for 10 min. The reaction mixture was quenched with ice water and saturated NH4C1 solution successively and extracted with 10% MeOH in DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was further purified by silica gel flash column chromatography using 2-5% MeOH in DCM as eluent to get the crude compound. The crude compound was triturated in ethyl acetate to get the pure title compound (0.2 g, 30.8%): LC-MS: 433.2 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): d 11.56 (s, 1H), 7.85 (dd, 1H), 7.55-7.48 (m, 3H), 7.20 (d, 1H), 6.78 (d, 2H), 6.32 (dd, 1H), 5.36 (s, 2H), 4.11 (s, 3H), 3.77 (s, 6H).

[1246] ​ ​

[1247]

[1248] Step 1: 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)pyridine amide

[1249] To a solution of 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridine carboxylic acid perfluorophenyl ester (1.25 g, 3.15 mmol) and 2,4,6-trimethoxybenzenesulfonamide (commercially available, 0.6 g, 2.43 mmol) in THF (40 mL) was added LiHMDS (2.5 mL, 2.43 mmol, 1.0 M in THF) and stirred at RT for 10 min. The reaction mixture was quenched with ice water and saturated NH4C1 solution successively and extracted with 10% MeOH in DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was further purified by silica gel flash column chromatography using 2-5% MeOH in DCM as eluent and triturated in ethyl acetate to get the title compound (0.38 g, 34%): LC-MS: 461.1 [M-H] - ;1 HNMR (DMSO-d6, 400 MHz): δ 11.51 (s, 1H), 7.83 (dd, 1H), 7.54-7.50 (m, 2H), 7.19 (d, 1H), 6.31 (dd, 1H), 6.27 (s, 2H), 5.35 (s, 2H), 4.07 (s, 3H), 3.82 (s, 3H), 3.76 (s, 6H).

[1250] ​ Sulfonyl)-4-methoxy-pyrimidine-2-carboxamide

[1251]

[1252] Step 1: 5-bromo-2-chloro-4-methoxy pyrimidine

[1253] To a solution of 5-bromo-2,4-dichloropyrimidine (10 g, 43.88 mmol) in MeOH (100 mL) was added NaOMe (7.7 mL, 43.88 mmol, 25% in MeOH) at 0 °C and stirred at same temperature for 2 h. The reaction was quenched with ice water and evaporated completely to get a precipitate. The precipitate was filtered and washed with water to get the title compound (10 g). LC-MS: 224.9 [M+H] + .

[1254] Step 2: (2-chloro-4-methoxy pyrimidin-5-yl)methanol

[1255] To a solution of 5-bromo-2-chloro-4-methoxy pyrimidine (10 g, 44.75 mmol) in toluene (150 mL) was added n-BuLi (29.3 mL, 46.99 mmol, 1.6 M in hexane) at -78 °C and stirred at same temperature for 30 min. Ethyl formate (3.98 g, 53.7 mmol) was added to the reaction mixture at -78 °C and stirred for 30 min. The reaction mixture was diluted with MeOH (20 mL) and NaBH4 (2.03 g, 37.84 mmol) was added to it at -78 °C and stirred at same temperature for 15 min. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to get the crude material. The crude compound was purified by silica gel flash column chromatography using 40% ethyl acetate in hexane as eluent to get the title compound (4 g, 51.2%). LC-MS: 175.1 [M+H] + .

[1256] Step 3: methyl 5-(hydroxymethyl)-4-methoxy pyrimidine-2-carboxylate

[1257] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 28 using appropriate reagents with suitable modifications. LC-MS: 199.1 [M+H] + .

[1258] Step 4: 5-((lH-Pyrazol-l-yl)methyl)-4-methoxy-pyrimidine-2-carboxylic acid methyl ester

[1259] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications. LC-MS: 249.1 [M+H] + .

[1260] Step 5: 5-((lH-Pyrazol-l-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-4- methoxy-pyrimidine-2-carboxamide

[1261] To a solution of 5-((lH-pyrazol-l-yl)methyl)-4-methoxy-pyrimidine-2-carboxylic acid methyl ester (0.2 g, 0.806 mmol) and 5-(tert-butyl)-2-methoxybenzenesulfonamide (Intermediate 17, 0.098 g, 0.403 mmol) in DCE (5 mL) was added titanium(IV) chloride (0.07 mL, 0.6 mmol) at 50 °C, followed by stirring at 115 °C for 16 h. The reaction was allowed to cool to RT and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound: LC-MS: 460.1 [M+H] + ; 1 H NMR (CD3OD, 400 MHz): δ 8.19 (s, 1H), 8.08 (d, 1H), 7.80 (d, 1H), 7.73 (dd, 1H), 7.57 (d, 1H), 7.13 (d, 1H), 6.38 (dd, 1H), 5.41 (s, 2H), 4.14 (s, 3H), 3.89 (s, 3H), 1.38 (s, 9H).

[1262] Example 12. Compounds 204 to 231, 235, 236, 239 to 241, 245 and 253

[1263] The following compounds listed in Table 13 were prepared following similar procedures as described above using appropriate reagents with suitable modifications known to those skilled in the art. The intermediates and example procedures used for coupling are shown in the table below. The intermediates, if not indicated to be synthesized, are commercially available.

[1264] Table 13. Compound synthesis and characterization

[1265]

[1266]

[1267]

[1268]

[1269]

[1270]

[1271] Example 13. Compound 243: 5-((lH-pyrazol-l-yl)methyl)-N-(2,6-dimethoxyphenylsulfonyl)- 6-methoxypyridinecarboxamide Example 14. Compounds 71, 232 and 261 to 263

[1272]

[1273] To a solution of 5-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)- 6-methoxypyridinecarboxamide (0.1 g, 0.24 mmol) in ACN (5 mL) was added KOtBu (0.05 g, 0.48) and HMDS (0.116 g, 0.72 mmol) and NCS (0.096 g, 0.72 mmol) successively at 0 °C and stirred for 15 min. Then additional HMDS (0.116 g, 0.72 mmol) and NCS (0.096 g, 0.72 mmol) were added to the reaction mixture at 0 °C, then stirred at rt for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound (0.03 g). LC-MS: 432.2 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ 7.82 (d, 1H), 7.63 (d, 1H), 7.50-7.48 (m, 2H), 7.46-7.43 (m, 2H), 7.18 (d, 1H), 6.78 (d, 2H), 6.31 (dd, 1H), 3.93 (s, 3H), 3.77 (s, 6H).

[1274] Compound 243 was separated into its individual isomers by chiral HPLC with any assigned stereochemistry.

[1275]

[1276] Compound 243a: Peak 1: LC-MS: 432.1 [M+H] + ; 1H NMR (CD3OD, 400 MHz): δ 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.51 (t, 1H), 7.24 (d, 1H), 6.81 (d, 2H), 6.37 (dd, 1H), 5.38 (s, 2H), 4.06 (s, 3H), 3.86 (s, 6H).

[1277]

[1278] Compound 243b: Peak 2: LC-MS: 432.1 [M+H] + ; 1 H NMR (CD3OD, 400 MHz): δ 7.78 (d, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.51 (t, 1H), 7.24 (d, 1H), 6.81 (d, 2H), 6.37 (dd, 1H), 5.38 (s, 2H), 4.06 (s, 3H), 3.86 (s, 6H).

[1279] Example 15: (Compound 265) 5-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)- 6-ethylpyridinecarboxamide

[1280] The following compounds listed in Table 14 were prepared following similar procedures as described above for Compound 243 using appropriate reagents known to those skilled in the art with suitable modifications.

[1281] Table 14. Compound synthesis and characterization

[1282]

[1283]

[1284] Example 16: (Compound -266) 5-((lH-pyrazol-l-yl)methyl)-N-((5-(l-hydroxy-2-methylpropan-2- yl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridinecarboxamide Example 17: (Compound 267) 6-((lH-pyrazol-l-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)- 1-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide

[1285]

[1286] Step 1: 6-chloro-2-ethylnicotinic acid methyl ester

[1287] To a solution of methyl 2-ethyl-6-oxo-l,6-dihydropyridine-3-carboxylate (1.0 g, 5.51 mmol) in dichloro-hydroxy-(phenoxy) phosphonium (11.64 g, 55.18 mmol) and stirred at 180 °C for 10 min. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered, and concentrated to get crude compound which was further purified by silica gel flash column chromatography using 20-30% ethyl acetate in hexane as eluent to get the title compound as white solid (0.8 g, 72.61%). LC-MS: 200.1 [M+H] + .

[1288] Step 2: (6-chloro-2-ethylpyridin-3-yl)methanol

[1289] The title compound was prepared using similar procedure as described in step 1 of Intermediate 30 using appropriate reagents with suitable modifications (0.7 g). LC-MS: 172.1 [M+H] + .

[1290] Step 3: 3-((lH-pyrazol-l-yl)methyl)-6-chloro-2-ethylpyridine

[1291] The title compound was prepared using similar procedure as described in step 2 of Intermediate 29 using appropriate reagents with suitable modifications (0.9 g, 99.55%). LC-MS: 222.1 [M+H] + .

[1292] Step 4: methyl 5-((lH-pyrazol-l-yl)methyl)-6-ethylpyridinecarboxylate

[1293] The title compound was prepared using similar procedure as described in step 3 of Intermediate 29 using appropriate reagents with suitable modifications. (0.65 g, 83.91%). LC-MS: 246.2 [M+H] + .

[1294] Step 5: 5-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6- ethylpyridinecarboxamide

[1295] To a stirred solution of methyl 5-((lH-pyrazol-l-yl)methyl)-6-ethylpyridine carboxylate (0.20 g, 0.815 mmol), 2,6-dimethoxybenzenesulfonamide (0.17 g, 0.0.815 mmol) in THF (40 mL) was added DIPEA (0.35 mL, 2.03 mmol) and TMA (0.14 g, 2.03 mmol) at 0 °C and stirred at 70 °C for 12 h. The reaction mixture was quenched with ice cold water and extracted with 10% methanol and DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the title crude compound. The crude compound was purified by preparative HPLC to get the title compound (0.13 g, 37.05%). LC-MS: 431.1 [M+H] + ; 1 HNMR (DMSO-D6, 400 MHz): δ 11.15 (brs, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.55-7.51 (m, 2H), 7.34 (d, 1H), 6.80 (d, 2H), 6.34 (dd, 1H), 5.55 (s, 2H), 3.77 (s, 6H), 2.96 (q, 2H), 1.27 (t, 3H).

[1296] Example 18: (Compound 268) 5-((lH-pyrazol-l-yl)methyl)-N-((3-ethyl-2,4,6-trimethoxyphenyl)sulfonyl)- 6-methoxypyridinecarboxamide Example 19: (Compound 269) 5-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6- methoxypyridinecarboxamide

[1297]

[1298] Step 1: Methyl 2-(4-methoxyphenyl)acetate

[1299] To a solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.08 mmol) in methanol (70 mL) was added sulfuric acid (2.95 g, 30.08 mmol) and stirred at 70 °C for 12 h. The reaction mixture was evaporated, quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over Na2S04, filtered, and concentrated to get the crude compound which was carried to the next step without purification (5.0 g). 1 H NMR (CDC13, 400 MHz): δ 7.23 (d, 2H), 6.90 (d, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 3.62 (s, 2H).

[1300] Step 2: Methyl 2-(3-bromo-4-methoxyphenyl)acetate

[1301] To a stirred solution of AlCl3(1.11 g, 8.23 mmol) in DCM (10 mL) was added methyl 2-(4- methoxyphenyl)acetate (3.0 mL, 16.64 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was quenched with ice water and extracted with DCM. The organic layer was washed with sodium thiosulfate, dried over Na2S04, filtered, and concentrated to get the crude compound which was used for the next step without purification. (3.0 g). 1 H NMR (DMSO-D6, 400 MHz): δ 7.49 (d, 2H), 7.24 (dd, 1H), 7.06 (d, 1H), 3.83 (s, 3H), 3.64 (s, 3H).

[1302] Step 3: Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate

[1303] To a stirred solution of methyl 2-(3-bromo-4-methoxyphenyl)acetate (3.0 g, 11.57 mmol) and iodomethane (4.93 g, 34.73 mmol) in THF (30 mL) was added KOt-Bu (3.89 g, 34.73 mmol) at -78 °C and stirred for 60 min at same temperature. The reaction mixture was then allowed to warm to rt and stirred for 12 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2S04, and concentrated to get the crude compound. The crude compound was purified by silica gel flash chromatography using 0-30% ethyl acetate in hexane as eluent to get the pure title compound (3.2 g, 96.24%). LC-MS: 289.0 [M+2+H] + .

[1304] Step 4: 2-(3-Bromo-4-methoxyphenyl)-2-methylpropan-1-ol

[1305] To a stirred solution of methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate (2.5 g, 8.70 mmol) in THF (15 mL) was added LAH (0.26 g, 0.80 mmol) at 0 °C and stirred for 1 h at same temperature. The reaction mixture was quenched with saturated sodium sulfate and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated to get the crude compound which was used for the next step without purification (2.3 g). 1 H NMR (DMSO-d6, 400 MHz): δ 7.50 (s, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 4.68 (t, 1H), 3.81 (s, 3H), 3.38 (d, 2H), 1.18 (s, 6H).

[1306] Step 5: (2-(3-bromo-4-methoxyphenyl)-2-methylpropoxy)(tert-butyldimethylsilanyl)dimethylsilane

[1307] To a solution of 2-(3-bromo-4-methoxyphenyl)-2-methylpropan-1-ol (1.0 g, 3.85 mmol) in DCM (25 mL) was added imidazole (0.52 g, 7.71 mmol) and TBDMSCl (0.68 g, 4.63 mmol) sequentially at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction mixture was added to ice water and extracted with DCM. The organic layer was washed with brine, dried over Na2S04and concentrated to get crude compound. The crude compound was purified by silica gel flash chromatography using 0-10% ethyl acetate in hexane as eluent to get pure title compound (1 g, 69.40%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.52 (s, 1H), 7.33 (d, 1H), 7.02 (d, 1H), 3.81 (s, 3H), 3.48 (s, 2H), 1.21 (s, 6H), 0.82 (s, 9H), 0.014 (s, 6H).

[1308] Step 6: 5-(1-((tert-butyldimethylsilanyl)oxy)-2-methylpropan-2-yl)-2-methoxybenzenesulfonamide

[1309] To a solution of (2-(3-bromo-4-methoxyphenyl)-2-methylpropoxy)(tert- butyldimethylsilanyl)dimethylsilane (1.0 g, 2.67 mmol) in THF (20 mL) was added n-BuLi (5.0 mL, 8.03 mmol, 1.6 M in hexane) at -78 °C and stirred for 1 h at same temperature. Then S02gas was bubbled into the reaction mixture for 30 min at -78 °C. The whole reaction mixture was stirred for 1 h at 0 °C. The reaction mixture was concentrated to get solid mass. The solid mass was dissolved in DCM and NCS (1.07 g, 8.03 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with ice water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude compound. The crude compound was again dissolved in DCM (5 mL) and 7 N methanolic ammonia (10 mL) was added to the reaction mixture and stirred for 30 min at RT. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get crude which was carried to the next step without purification. (0.3 g). LC-MS: 374.2 [M+H] + .

[1310] Step 7: 5-((lH-Pyrazol-l-yl)methyl)-N-((5-(l-((tert-butyldimethylsilyl)oxy)-2- methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridine amide

[1311] To a solution of 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridine carboxylic acid perfluorophenyl ester (0.40 g, 1.002 mmol) and 5-(l-((tert-butyldimethylsilyl)oxy)-2- methylpropan-2-yl)-2-methoxybenzenesulfonamide (0.29 g, 0.80 mmol) in THF (10 mL) was added LiHMDS (2.0 mL, 2.0 mmol, 1.0 M in THF) and stirred at RT for 10 min. The reaction mixture was quenched with saturated NH4CI solution and extracted with 10% MeOH in DCM. The organic layer was dried over Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 2-5% MeOH in DCM as eluent to get the title compound (0.3 g, 50.85%). LC-MS: 589.2 [M+H] + .

[1312] Step 8: 5-((lH-Pyrazol-l-yl)methyl)-N-((5-(l-hydroxy-2-methylpropan-2-yl)-2- methoxyphenyl)sulfonyl)-6-methoxypyridine amide

[1313] To a solution of 5-((lH-pyrazol-l-yl)methyl)-N-((5-(l-((tert-butyldimethylsilyl)oxy)-2- methylpropan-2-yl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridine amide (0.30 g, 0.51 mmol) in THF 15 mL was added TBAF (0.28 g, 1.73 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred at RT for 12 h. The reaction mixture was concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound (0.140 g, 57.85%). LC-MS: 475.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): d 11.65 (s, 1H), 7.87 (d, 1H), 7.84 (d, 1H), 7.67 (dd, 1H), 7.53-7.50 (m, 2H), 7.21 (d, 1H), 7.16 (d, 1H), 6.31 (dd, 1H), 5.36 (s, 2H), 4.13 (s, 3H), 3.83 (s, 3H), 3.41 (s, 2H), 1.24 (s, 6H).

[1314] Example 20: (Compound 270) 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6-tris(methoxy-d3)phenyl)sulfonyl)pyridinecarboxamide Example 21: (Compound 271) 5-((lH-pyrazol-l-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-4- methoxy-pyrimidine-2-carboxamide

[1315]

[1316] Step 1: 6-chloro-2-methoxynicotinic acid methyl ester

[1317] To a solution of methyl 2,6-dichloronicotinate (2.0 g, 9.70 mmol) in DCM (10 mL) was added NaOMe (2.28 mL, 43.88 mmol, 25% in MeOH) at 0 °C and stirred at RT for 12 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to get the crude which was used for the next step without purification. (2.0 g) LC-MS: 202.0 [M+H] + .

[1318] Step 2: Methyl 2-methoxy-6-vinyl nicotinate

[1319] The title compound was prepared using similar procedure described in step 1 of Intermediate 88 using appropriate reagents with suitable modifications. (0.8 g, 41.74%) LC-MS: 194.1 [M+H] + .

[1320] Step 3: Methyl 6-formyl-2-methoxynicotinate

[1321] To a solution of methyl 2-methoxy-6-vinyl nicotinate (0.5 g, 2.58 mmol) in water-THF (5 mL and 5 mL) was added 4% aqueous solution of osmium tetraoxide (0.007 g, 0.020 mmol) and sodium periodate (1.10 g, 5.17 mmol) successively at 0 °C. The reaction mixture was allowed to warm to RT and stirred at RT for 12 h. The reaction was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 20-60% ethyl acetate in hexane as eluent to get the title compound (0.3 g, 59.39%). LC-MS: 196.1 [M+H] + .

[1322] Step 4: Methyl 6-(hydroxymethyl)-2-methoxynicotinate

[1323] The title compound was prepared using similar procedure described in step 1 of Intermediate 30 using appropriate reagents with suitable modifications (0.25 g). LC-MS: 198.1 [M+H] + .

[1324] Step 5: 6-((lH-Pyrazol-l-yl)methyl)-2-methoxynicotinic acid methyl ester

[1325] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 29 using appropriate reagents with suitable modifications (0.23 g, 73.36%). LC-MS: 248.1 [M+H] + .

[1326] Step 6: 6-((lH-Pyrazol-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid

[1327] The title compound was prepared using a similar procedure described in Step 1 of Intermediate 99 using appropriate reagents with suitable modifications (0.2 g). LC-MS: 220.1 [M+H] + .

[1328] Step 7: 6-((lH-Pyrazol-l-yl)methyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid

[1329] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 99 using appropriate reagents with suitable modifications (0.2 g). LC-MS: 248.1 [M+H] + .

[1330] Step 8: 6-((lH-Pyrazol-l-yl)methyl)-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid

[1331] The title compound was prepared using a similar procedure described in Step 3 of Intermediate 99 using appropriate reagents with suitable modifications (0.07 g). LC-MS: 234.1 [M+H] + .

[1332] Step 9: 6-((lH-Pyrazol-l-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-l- methyl-2-oxo-l,2-dihydropyridine-3-carboxamide

[1333] To a solution of 6-((1H-pyrazol-1-yl)methyl)-1-methyl-2-oxo-1,2-dihydropyridine-3- carboxylic acid (0.07 g, 0.3 mmol) in THF (5 mL) was added CDI (0.15 g, 0.900 mmol) and stirred at RT for 1 h. The reaction mixture was cooled to 0 °C and to this was added 5-(tert-butyl)-2-methoxybenzenesulfonamide (0.08 g, 0.36 mmol), DBU (0.14 g, 0.900 mmol) and stirred at same temperature for 15 min. The reaction mixture was then allowed to warm to RT and stirred overnight. The reaction mixture was quenched with ice cold water and extracted with 10% methanol and DCM. The organic layer was dried over Na2S04, filtered and concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound (30 mg, 21.81%). LC-MS: 459.2 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 13.06 (s, 1H), 8.18 (d, 1H), 7.86-7.84 (m, 2H), 7.71 (dd, 1H), 7.61 (dd, 1H), 7.16 (d, 1H), 6.41 (dd, 1H), 5.71 (d, 1H), 5.68 (s, 2H), 3.81 (s, 3H), 3.65 (s, 3H), 1.28 (s, 9H).

[1334] Example 22: 5-((lH-pyrazol-l-yl)methyl)-N-(5-(l-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonyl)- 6-methoxypyridinecarboxamide (Compounds 290a and 290b) Example 23: 4-((lH-pyrazol-l-yl)methyl)-N-(5-(l-hydroxy-2-methylpropan-2-yl)-2-methoxyphenylsulfonyl)- 3-methoxybenzamide (Compounds 291a and 291b)

[1335]

[1336] Step 1: 2,4,6-Trimethoxy-3-vinylbenzenesulfonamide

[1337] The title compound was prepared using a similar procedure as described in Step 1 of Intermediate 88 using appropriate reagents with suitable modifications. 1 H NMR (DMSO-D6, 400 MHz): δ 6.68-6.61 (m, 1H), 6.54 (s, 1H), 5.91 (d, 1H), 5.27 (d, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.71 (s, 1H).

[1338] Step 2: 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxy-3-vinylphenyl)sulfonyl)picolinamide

[1339] The title compound was prepared using a similar procedure described in Example 10 using appropriate reagents with suitable modifications (0.16 g). LC-MS: 489.1 [M+H] + .

[1340] Step 3: 5-((lH-Pyrazol-l-yl)methyl)-N-((3-ethyl-2,4,6-trimethoxyphenyl)sulfonyl)-6- methoxypyridine amide

[1341] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 88 using appropriate reagents with suitable modifications (4 mg, 2.66%). LC-MS: 491.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 10.24 (br s, 1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.52 (d, 1H), 7.22 (d, 1H), 6.35 (dd, 1H), 6.28 (s, 1H), 5.37 (s, 2H), 4.13 (s, 3H), 4.03 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 2.62 (q, 2H), 1.13 (t, 3H).

[1342] Example 24: 4-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)(methylamino)(oxy)-l6-sulfenyl)-3- methoxybenzamide (Compound 292) Step 2: 5-((lH-Pyrazol-l-yl)methyl)-N-((2,6-dimethoxy-4-(pyridin-3-ylethynyl)phenyl)sulfonyl)- 6-methoxypyridine amide

[1343]

[1344] Step 1: 5-((lH-Pyrazol-l-yl)methyl)-N-((4-iodo-2,6-dimethoxyphenyl)sulfonyl)-6- methoxypyridine amide

[1345] The title compound was prepared using a similar procedure described in Example 10 using appropriate reagents with suitable modifications. LC-MS: 559.0 [M+H] + .

[1346] Step 2: 5-((lH-Pyrazol-l-yl)methyl)-N-((2,6-dimethoxy-4-(pyridin-3-ylethynyl)phenyl)sulfonyl)- 6-methoxypyridine amide

[1347] To a degassed solution of 5-((lH-pyrazol-l-yl)methyl)-N-((4-iodo-2,6- dimethoxyphenyl)sulfonyl)-6-methoxypyridine amide (0.09 g, 0.16 mmol), 3- ethynylpyridine (0.019 g, 0.19 mmol) and DIPEA (0.3 mL, 1.6 mmol) in DMF (5 mL) was added cuprous iodide (0.003 g, 0.1 mmol) and Pd(PPh3)2Cl2(0.019 g, 0.1 mmol). The reaction mixture was heated at 70 °C for 12 h. The reaction mixture was allowed to cool to RT, diluted with water and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound (7 mg, 8.15%). LC-MS: 534.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 8.82 (dd, 1H), 8.62 (d, 1H), 8.03-8.00 (m, 1H), 7.83 (d, 1H), 7.65-7.62 (m, 2H), 7.60-7.48 (m, 3H), 7.19 (d, 1H), 6.96 (br s, 1H), 6.31 (dd, 1H), 5.34 (s, 2H), 4.06 (s, 3H), 3.79 (s, 6H).

[1348] Example 25: 5-((lH-pyrazol-l-yl)methyl)-N-(3-chloro-2,6-dimethoxyphenylsulfonyl)-6-methoxypyridinecarboxamide (Compounds 293a and 293b) Example 26. Compounds 294, 294a, 294b, 295a, 295b, 296a, 296b, 297, 298a, 298b, 299,

[1349]

[1350] Step 1: 2,4,6-trifluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[1351] To a solution of 2,4,6-trifluorobenzenesulfonyl chloride (3.0 g, 13.00 mmol) in DCM (30 mL) was added Et3N (5.44 mL, 39.03 mmol) and bis(4- methoxybenzyl)amine (4 g, 15.61 mmol) successively at 0 °C. The reaction mixture was allowed to warm to rt, stirred for 12 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with brine and dried over anhydrous Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 20-30% ethyl acetate in hexane as eluent to get the title compound as off-white solid. (4.9 g, 83.5%). 1H NMR (CDC13, 400 MHz): δ 7.05 (d, 4H), 6.79 (d, 4H), 6.80 - 6.70 (m, 2H), 4.42 (s, 4H), 3.80 (s, 6H).

[1352] Step 2: 2,4,6-tris(methoxy-d3)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[1353] To a solution of 2,4,6-trifluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (0.1 g, 0.22 mmol) in THF (1 mL) was added freshly prepared 20% NaOCD3 solution (0.25 mL, 0.88 mmol) to the reaction mixture at rt. The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 30-40% ethyl acetate in hexane as eluent to get the title compound (0.105 g, 95.25%). LC-MS: 497.2 [M+H] + .

[1354] Step 3: 2,4,6-tris(methoxy-d3)benzenesulfonamide

[1355] To a solution of 2,4,6-tris(methoxy-d3)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (2.5 g, 5.03 mmol) in DCM (10 mL) was added TFA (20 mL) at rt. The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was concentrated followed by neutralization with saturated NaHC03and extraction with 10% MeOH in DCM. The organic layer was washed with brine solution and dried over anhydrous Na2S04, filtered, and concentrated to get the crude. The crude compound was purified by silica gel flash column chromatography using 80-100% ethyl acetate in hexane as eluent and recrystallized using DCM to get the title compound (0.55 g, 42.6%). LC-MS: 257.1 [M+H] + . 1 H NMR (DMSO-D6, 400 MHz): δ 6.81 (br s, 2H), 6.28 (s, 2H).

[1356] Step 4: 5-((lH-pyrazol-l-yl)methyl)-6-methoxy-N-((2,4,6-tris(methoxy-d3)phenyl)sulfonyl)picolinamide

[1357] To a suspension of 5-((lH-pyrazol-l-yl)methyl)-6-methoxypyridinecarboxylic acid (1.6 g, 6.86 mmol) in ACN (30 mL) was added citric acid (0.395 g, 2.05 mmol and CDI (1.98 g, 10.29 mmol) sequentially at rt and stirred for 2 h. To the reaction mixture was added 2,4,6-tris(methoxy-d3)benzenesulfonamide (1.58 g, 6.17 mmol) and DBU (2.11 g, 10.97 mmol) sequentially at rt and stirred for 3 h at rt. The reaction mixture was quenched with saturated citric acid solution and extracted with 10% MeOH in DCM. The organic layer was washed with brine and dried over anhydrous Na2S04, filtered, and concentrated to get the crude compound. The crude compound was purified by silica gel flash column chromatography using 0-1% MeOH in DCM as eluent and re-crystallized using ethyl acetate to get the title compound (1.6 g, 49.46%). LC-MS: 472.2 [M+H] + . 1 H NMR (DMSO-D6, 400 MHz): δ 11.16 (br s, 1H), 7.85 (dd, 1H), 7.55-7.51 (m, 2H), 7.21 (d, 1H), 6.32 (dd, 1H), 6.30 (s, 2H), 5.37 (s, 2H), 4.12 (s, 3H).

[1358] ​ ​

[1359]

[1360] Step 1: 5-((lH-pyrazol-l-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)- 4-methoxy pyrimidine-2-carboxamide

[1361] To a solution of methyl 5-((lH-pyrazol-l-yl)methyl)-4-methoxypyrimidine-2- carboxylate (Intermediate 11a) (0.2 g, 0.806 mmol) and 5-ethyl-2-methoxybenzenesulfonamide (Intermediate 20) (0.174 g, 0.806 mmol) in THF (10 mL) was added DIPEA (0.35 mL, 2.5 mmol), trimethylaluminum (0.119 mg, 2.5 mmol) at 0 °C, then the reaction mixture was stirred at 70 °C for 16 h. The reaction was allowed to cool to RT and diluted with 10% MeOH in DCM. The reaction mixture was filtered through celite, dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound was purified by preparative HPLC to get the title compound as off-white solid. LC-MS: 432.1 [M+H]+ ; 1 H NMR (DMSO-D6, 400 MHz): δ 12.28 (br s, 1H), 8.24 (s, 1H), 7.85 (d, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 7.49 (d, 1H), 7.17 (d, 1H), 6.30 (dd, 1H), 5.36 (s, 2H), 4.05 (s, 3H), 3.83 (s, 3H), 2.65 (q, 2H), 1.19 (t, 3H).

[1362] The following compounds listed in Table 15 were prepared following similar procedures as described above (Example 21) using appropriate reagents known to those skilled in the art with appropriate modifications.

[1363] Table 15

[1364]

[1365]

[1366] The following compounds listed in Table 16 were prepared following similar procedures as described above (Example 10) using appropriate reagents known to those skilled in the art with appropriate modifications.

[1367] Table 16:

[1368]

[1369]

[1370]

[1371]

[1372] ​ ​

[1373]

[1374] Step 1: 4-(1-(benzyloxy)-2-methylprop-2-yl)-2-bromo-1-methoxybenzene

[1375] NaH (0.226 g, 9.84 mmol) was added to a stirred solution of 2-(3-bromo-4-methoxyphenyl)-2-methylprop-1-ol (1.7 g, 6.56 mmol) in THF (30 mL) at 0 °C. After 20 min, (bromomethyl)benzene (2.2 g, 13.12 mmol) was added to the reaction mixture at 0 °C. The reaction mixture was heated to 60 °C and maintained for 16 h. The reaction mixture was cooled to rt, quenched with ice water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to give the crude compound. The crude compound was purified by silica gel rapid column chromatography using 20% ​​ethyl acetate in hexane as eluent to give the title compound (1.4 g, 61.1%). 1 H NMR (DMSO-D6, 400MHz): δ7.52(d,1H),7.36–7.31(m,3H),7.29–7.23(m,3H),7.04(d,1H),4.45(s,2H),3.82(s,3H),3.42(s,2H),1.25(s,6H).

[1376] Step 2: 5-(1-(benzoxy)-2-methylpropyl-2-yl)-2-methoxybenzenesulfonyl chloride

[1377] The title compound was prepared using a similar procedure to that described in step 3 of intermediate 89, with appropriate reagents with suitable modifications. (1.4 g, 61.1%). 1 H NMR (DMSO-D6, 400MHz): δ7.73(d,1H),7.34–7.31(m,3H),7.30–7.26(m,3H),6.90(d,1H),4.45(s,2H),3.73(s,3H),3.41(s,2H),1.26(s,6H).

[1378] Step 3: 5-(1-(benzoxy)-2-methylpropyl-2-yl)-2-methoxybenzenesulfinamide

[1379] The title compound was prepared using a similar procedure to that described in step 1 of intermediate 108 with appropriate reagents with suitable modifications. (0.29 g, 16.87%) 1 H NMR(DMSO-D6,400MHz): δ7.78(d,1H),7.45(dd,1H),7.35–7.26(m,5H),7.02( d,1H),5.92(s,2H),4.47(s,2H),3.81(s,3H),3.47–3.42(m,2H),1.30(s,6H).

[1380] Step 4: 5-((lH-Pyrazol-l-yl)methyl)-N-((5-(l-(phenylmethoxy)-2- methylprop-2-yl)-2-methoxyphenyl)sulfinyl)-6-methoxypyridinecarboxamide

[1381] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 82 using appropriate reagents with suitable modifications (0.21 g, 30.57%). LC-MS: 547.1 [M-H]-.

[1382] Step 5: 5-((lH-Pyrazol-l-yl)methyl)-N-(5-(l-(phenylmethoxy)-2-methylprop-2- yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypyridinecarboxamide

[1383] The title compound was prepared using a similar procedure described in Example 13 using appropriate reagents with suitable modifications (0.370 g); LC-MS: 564.2 [M+H] + .

[1384] Step 6: 5-((lH-Pyrazol-l-yl)methyl)-N-(5-(l-hydroxy-2-methylprop-2-yl)-2- methoxyphenylsulfonimidoyl)-6-methoxypyridinecarboxamide

[1385] To a solution of 5-((lH-Pyrazol-l-yl)methyl)-N-(5-(l-(phenylmethoxy)-2- methylprop-2-yl)-2-methoxyphenylsulfonimidoyl)-6-methoxypyridinecarboxamide (0.31 g, 0.0.55 mmol) in ethanol (15 mL) was carefully added 10% Pd-C (0.11 g, ~10% W / W) and stirred under hydrogen positive pressure using a balloon for 12 h. The reaction mixture was filtered through celite and the filtrate was concentrated to get the crude compound as a white solid. The crude compound was purified by preparative HPLC to get the racemic title compound (60 mg).

[1386] Step 7: Intermediate 131f was separated into its individual enantiomers by chiral HPLC. (6.2 mg (peak 1) + 8.2 mg (peak 2) = (15 mg, 7.68%), with any assigned stereochemistry.

[1387]

[1388] Compound 290a: Peak 1; LCMS: 474.2 [M+H] + ; 1H NMR (DMSO-D6, 400 MHz): δ 7.87 (d, 1H), 7.81 (dd, 1H), 7.61-7.59 (d, 2H), 7.49 (dd, 1H), 7.44 (br s, 2H), 7.18 (d, 1H), 7.11 (d, 1H), 6.30 (dd, 1H), 5.31 (s, 2H), 4.76 (t, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.40 (d, 2H), 1.23 (s, 6H).

[1389]

[1390] Compound 290b: Peak 2; LCMS: 474.1 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 7.87 (d, 1H), 7.81 (dd, 1H), 7.61-7.59 (d, 2H), 7.49 (dd, 1H), 7.44 (br s, 2H), 7.18 (d, 1H), 7.11 (d, 1H), 6.30 (dd, 1H), 5.31 (s, 2H), 4.76 (t, 1H), 3.93 (s, 3H), 3.79 (s, 3H), 3.40 (d, 2H), 1.23 (s, 6H).

[1391] ​ ​

[1392] Step 1: 5-((1H-Pyrazol-1-yl)methyl)-N-((5-(1-(phenylmethoxy)-2-methylpropan-2-yl)-2- methoxyphenyl)sulfinyl)-6-methoxypyridinecarboxamide

[1393] The title compound was prepared using a similar procedure described in Step 2 of Intermediate 82 using appropriate reagents with suitable modifications. LCMS: 548.2 [M+H] +

[1394] Step 2: 4-((1H-Pyrazol-1-yl)methyl)-N-(5-(1-(phenylmethoxy)-2-methylpropan-2-yl)-2- methoxyphenylsulfonimidoyl)-3-methoxybenzamide

[1395] The title compound was prepared using a similar procedure described in Example 13 using appropriate reagents with suitable modifications. LCMS: 563.1 [M+H] +

[1396] Step 3: 4-((lH-Pyrazol-l-yl)methyl)-N-(5-(l-hydroxy-2-methylpropan-2-yl)-2- methoxyphenylsulfonyl)benzamide

[1397] The title compound was prepared using a similar procedure described in Step 2 of Example 88 using the appropriate reagents with suitable modifications. The crude compound was purified by preparative HPLC to obtain the racemic title compound (100 mg).

[1398] Step 4: Intermediate 132c was separated into its individual enantiomers by chiral HPLC (15 mg (peak 1) + 20 mg (peak 2) = (35 mg, 10.7%), with any assigned stereochemistry.

[1399]

[1400] Compound-291a; LCMS: 473.2 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 7.87 (d, 1H), 7.75 (d, 1H), 7.59 (dd, 1H), -7.53-7.46 (m, 5H), 7.11 (d, 1H), 6.80 (d, 1H), 6.28 (dd, 1H), 5.32 (s, 2H), 4.77 (t, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.40 (dd, 2H), 1.23 (d, 6H).

[1401]

[1402] Compound-291b; LCMS: 473.2 [M+H] + ; 1 H NMR (DMSO-D6, 400 MHz): δ 7.85 (d, 1H), 7.76 (dd, 1H), 7.58 (dd, 1H), -7.53-7.46 (m, 5H), 7.11 (d, 1H), 6.80 (d, 1H), 6.28 (dd, 1H), 5.32 (s, 2H), 4.76 (t, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 3.40 (d, 2H), 1.23 (d, 6H).

[1403] ​ ​

[1404]

[1405] Step 1 : 4-((1 H-Pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)(methylamino)(oxo)- 16-sulfenyl)-3-methoxybenzamide

[1406] To a solution of 5-((1 H-pyrazol-1 -yl)methyl)-N-((2,6-dimethoxyphenyl)sulfinyl)-6- methoxypyridinecarboxamide (0.02 g, 0.048 mmol) in ACN (2.0 ml) was added potassium tert-butoxide (0.011 g, 0.09 mmol) followed by NCS (0.038 g, 0.28 mmol) and methylamine in THF (2.0 M) (0.15 mL, 0.28 mmol) at 0 °C. The reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched with water and extracted in 10% methanol in DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to get the crude compound. The crude compound (0.01 g, 46.87%) was purified by preparative TLC using 100% EtOAc as eluent. LC-MS: 445.1 [M+H] + ; 1 H NMR (CDCI3, 400 MHz): d 7.71 (d, 1 H), 7.69 (d, 1 H), 7.54 (d, 1 H), 7.47-7.42 (m, 2H), 7.14-7.11 (m, 1 H), 6.96 (d, 1 H), 6.66 (d, 2H), 6.26 (dd, 1 H), 5.37 (s, 2H), 3.93 (s, 6H), 3.90 (s, 3H), 2.83 (d, 3H).

[1407] ​ ​

[1408]

[1409] Step 1 : Compound 293 was prepared using a similar procedure described in Example 13 using appropriate reagents with suitable modifications. The crude compound was purified by preparative HPLC to get racemic title compound (70 mg).

[1410] Step 2: Compound 293 was separated into its individual enantiomers by chiral HPLC with any assigned stereochemistry.

[1411]

[1412] Compound 293a; LC-MS: 466.1 [M+H] + ; 1H NMR (CDC13, 400 MHz): δ 7.93 (d, 1H), 7.60 (d, 1H), 7.53-7.50 (m, 2H), 7.21 (d, 1H), 6.77 (d, 1H), 6.73 (br s, 2H), 6.35 (dd, 1H), 5.38 (s, 2H), 4.12 (s, 3H), 4.05 (s, 3H), 3.80 (s, 3H).

[1413]

[1414] Compound 293b; LC-MS: 466.1 [M+H] + ; 1 H NMR (CDC13, 400 MHz): δ 7.93 (d, 1H), 7.60 (d, 1H), 7.53-7.50 (m, 2H), 7.21 (d, 1H), 6.77 (d, 1H), 6.73 (br s, 2H), 6.35 (dd, 1H), 5.38 (s, 2H), 4.12 (s, 3H), 4.05 (s, 3H), 3.80 (s, 3H).

[1415] ​ 299a, 299b, 300a, 300b, ...

Claims

1. A compound of Formula (J): (J) or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or heteroaryl; X is O or NR 4 ; Ring B is phenyl or heteroaryl; L is -Ci-C4alkylene-, -(Ci-C4alkylene)-O-, or -O-; each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e ; Each R 1a and R 1b Independently hydrogen or C1-C6 alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c1 R 1c2 , OH, or -CN; Each R 1c1 and R 1c2 Independently hydrogen or C1-C6 alkyl; each R is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 1d independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10 aryl or heteroaryl; Each R 1e Independently, it is a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R groups on adjacent carbons 1 groups combine with the atoms to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN; the subscript n is 0, 1, 2, 3, or 4; and R 2 is heteroaryl, which is substituted by 0, 1, 2, 3, or 4 R 2a substituents; Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2; Each R 2b and R 2c Independently hydrogen or C1-C6 alkyl; each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or, two R on the same carbon atom 3 together represent oxo; Each R 3a and R 3b Independently hydrogen or C1-C6 alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c1 R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c2 , OH, or -CN; Each R 3c1 and R 3c2 Independently hydrogen or C1-C6 alkyl; Each R 3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group; Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; R 4 is hydrogen or CrC6alkyl; the subscript q is 0, 1, 2, 3, or 4; wherein each heterocycloalkyl is a 3- to 8-membered ring comprising 1-4 heteroatoms each independently N, O, or S; and each heteroaryl is a 5- to 6-membered ring comprising 1-4 heteroatoms each independently N, O, or S.

2. The compound of claim 1, having Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein L is -Ci-C4alkylene-, -(Ci-C4alkylene)-O-, or -O-; the subscript n is 0, 1, 2, 3, or 4; and Each R 1 Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a -C(O)OR 1a -OC(O)R 1a -C(O)N(R) 1a (R) 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a (R) 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R) 1a (R) 1b -S(O)(NH)R 1a -S(O)(NH)N(R) 1a (R) 1b ), -N(R 1a (R) 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C) 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R... 1c Substitution, with each alkoxy and alkynyl group via 0, 1, 2, or 3 R groups. 1d Substitution, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is determined by 0, 1, 2, or 3 R groups. 1e replace; Each R 1a and R 1b Independently hydrogen or C1-C6 alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c1 R 1c2 , OH, or -CN; each R 1c1 and R 1c2 is independently hydrogen or C1-C6alkyl; each R is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 1d is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10 is independently deuterium, C3-C8cyc Each R 1e Independently, it is a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R groups on adjacent carbons 1 groups combine with the atoms to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN; the subscript q is 0, 1, 2, 3, or 4; R 2 is heteroaryl, which is substituted by 0, 1, 2, 3, or 4 R 2a substituents; Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2; Each R 2b and R 2c Independently hydrogen or C1-C6 alkyl; each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or, two R on the same carbon atom 3 together represent oxo; Each R 3a and R 3b Independently hydrogen or C1-C6 alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c1 R 3c2 , OH, or -CN; Each R 3c1 and R 3c2 Independently hydrogen or C1-C6 alkyl; Each R 3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group; Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; wherein each heterocycloalkyl is a 3- to 8-membered ring comprising 1-4 heteroatoms each independently N, O, or S; and each heteroaryl is a 5- to 6-membered ring comprising 1-4 heteroatoms each independently N, O, or S.

3. The compound of claim 2, having Formula (la): (la) or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 or 3, or a pharmaceutically acceptable salt thereof, having Formula (lb): (lb) 5. The compound of any one of claims 2-4, or a pharmaceutically acceptable salt thereof, wherein 6. The compound of any one of claims 2-5, or a pharmaceutically acceptable salt thereof, wherein 7. The compound of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, wherein 8. The compound of any one of claims 2-7, or a pharmaceutically acceptable salt thereof, wherein Group having the structure:

9. The compound of any one of claims 2-8, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl or heteroaryl, wherein each alkyl group is derived from 0, 1, 2 or 3 R groups. 1c Substitution, and each alkoxy and alkynyl group is substituted with 0, 1, 2 or 3 R groups. 1d Replace; or Alternatively, two R on adjacent carbons 1 C5-C8 cycloalkyl or heterocycloalkyl, taken together with the atom to which they are attached.

10. The compound of any one of claims 2-9, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 aryl or heteroaryl, wherein each alkyl group is derived from 0 or 1 R 1c Substitution, and each alkoxy and alkynyl group is via 0 or 1 R 1d Replace; or Alternatively, two R on adjacent carbons 1 C5-C8 cycloalkyl or heterocycloalkyl, taken together with the atom to which they are attached.

11. The compound of any one of claims 2-10, or a pharmaceutically acceptable salt thereof, wherein each R 1a and R 1b is independently hydrogen or C1-C4alkyl.

12. The compound of any one of claims 2-11, or a pharmaceutically acceptable salt thereof, wherein each R is independently halogen, -NR 1c independently halogen, -NR 1c1 R 1c2 , OH, or -CN.

13. The compound of any one of claims 2-12, or a pharmaceutically acceptable salt thereof, wherein Each R 1d It is a heteroaryl group on its own. L is -CH2-, -CH2O-, or -O-. Each R 1e It is independently C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl or –CN.

14. The compound of any one of claims 2-13, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it is CH3, CH2CH3, -C(CH3)3, OCH3, CH2CH3, -OCH(CH3)2, OCH2-pyridyl, C(CH3)2OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, OH, cyclopropyl, cyclopropyloxy, cyclobutyloxy, phenyl, or pyrazolyl; or alternatively, two R on adjacent carbons 1 combined with the atom to which they are attached form a cyclopentyl, cyclohexyl, dihydrofuran, tetrahydrofuran, methyltetrahydrofuran, 1,3-dioxol, dihydro-1,3-oxazine, or methyldihydrofuran. L is -CH2-.

15. The compound of any one of claims 2-14, or a pharmaceutically acceptable salt thereof, wherein 16. The compound of any one of claims 2-15, or a pharmaceutically acceptable salt thereof, wherein 17. The compound of any one of claims 2-16, or a pharmaceutically acceptable salt thereof, wherein 18. The compound of any one of claims 2-17, or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with 0, 1, or 2 R 2a substituents.

19. The compound of any one of claims 2-18, or a pharmaceutically acceptable salt thereof, wherein Each R 2a It is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH or –CN. ​ each R 2b and R 2c independently hydrogen or C1-C4alkyl. ​ R 2 To ​ R 2 To 20. The compound of any one of claims 2 to 19, or a pharmaceutically acceptable salt thereof, wherein Each R 3 Independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a -C(O)OR 3a -OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b -S(O)2R 3a -S(O)2N(R) 3a (R) 3b ), OH, -CN, C3-C8 cycloalkyl or heterocyclic alkyl.

21. The compound of any one of claims 2 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b independently hydrogen or C1-C4alkyl.

22. The compound of any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, wherein each R 3c halogen, -NR 3c1 R 3c2 , OH or -CN.

23. The compound of any one of claims 2 to 22, or a pharmaceutically acceptable salt thereof, wherein Each R 3d It is a heteroaryl group on its own.

24. The compound of any one of claims 2 to 23, or a pharmaceutically acceptable salt thereof, wherein Each R 3e It is independently a C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

25. The compound of any one of claims 2 to 24, or a pharmaceutically acceptable salt thereof, wherein Each R 3 It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN or C3-C8 cycloalkyl.

26. The compound of any one of claims 2 to 25, or a pharmaceutically acceptable salt thereof, wherein Each R 3 It is independently a C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

27. The compound of any one of claims 2 to 26, or a pharmaceutically acceptable salt thereof, wherein Each R 3 Independently, it is Me, oMe, OEt, CHF2, CF3, OCHF2, OCF3, F, Br, CN, or cyclopropyl.

28. The compound of any one of claims 2 to 27, or a pharmaceutically acceptable salt thereof, wherein subscript q is 1, 2, or 3.

29. The compound of any one of claims 2 to 28, or a pharmaceutically acceptable salt thereof, wherein subscript n is 1 or 2.

30. The compound of any one of claims 2 to 29, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in Table 1.

31. The compound of any one of claims 2 to 29, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

32. The compound of any one of claims 2 to 29, having the structure:

33. The compound of any one of claims 2 to 29, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

34. The compound of any one of claims 2 to 29, having the structure:

35. The compound of claim 1, having Formula (II): or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e ; each R 1a and R 1b is independently hydrogen or C1-C6alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c1 R 1c2 , OH, or -CN; each R 1c1 and R 1c2 independently hydrogen or Ci-C6alkyl; each R is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 1d independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10 aryl or heteroaryl; Each R 1e Independently, it is a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R groups on adjacent carbons 1 groups combine with the atoms to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN; L is -Ci-C4alkylene-, -(Ci-C4alkylene)-O-, or -O-; R 2 is heteroaryl, which is substituted by 0, 1, 2, 3, or 4 R 2a substituents; Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2; each R 2b and R 2c is independently hydrogen or C1-C6alkyl; Y is CH, CR 3 or N; each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or, two R on the same carbon atom 3 together represent oxo; Each R 3a and R 3b Independently hydrogen or C1-C6 alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c1 R 3c2 , OH, or -CN; each R 3c1 and R 3c2 independently hydrogen or Ci-C6alkyl; Each R 3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group; Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; subscript n is 0, 1, 2, 3, or 4; and subscript q is 0, 1, 2, 3, or 4; wherein each heterocycloalkyl is a 3- to 8-membered ring including 1-4 heteroatoms each independently N, O, or S; and each heteroaryl is a 5- to 6-membered ring including 1-4 heteroatoms each independently N, O, or S.

36. The compound of claim 35, having Formula (IIa): or a pharmaceutically acceptable salt thereof.

37. The compound of claim 35 or 36, or a pharmaceutically acceptable salt thereof, having Formula (IIb):

38. The compound of claim 35 or 36, or a pharmaceutically acceptable salt thereof, having Formula (IIc):

39. The compound of any one of claims 35 to 38, or a pharmaceutically acceptable salt thereof, wherein group having the structure:

40. The compound of any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, -CN, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl or heteroaryl, wherein each alkyl group is derived from 0, 1, 2 or 3 R groups. 1c Substitution, and each alkoxy and alkynyl group is substituted with 0, 1, 2 or 3 R groups. 1d Replace; or Alternatively, two R on adjacent carbons 1 C5-C8 cycloalkyl or heterocycloalkyl, taken together with the atom to which they are attached.

41. The compound of any one of claims 35 to 40, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it is C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), C6-C 10 aryl or heteroaryl, wherein each alkyl group is derived from 0 or 1 R 1c Substitution, and each alkoxy and alkynyl group is via 0 or 1 R 1d Replace; or Alternatively, two R on adjacent carbons 1 C5-C8 cycloalkyl or heterocycloalkyl, taken together with the atom to which they are attached.

42. The compound of any one of claims 35-41, or a pharmaceutically acceptable salt thereof, wherein each R 1a and R 1b is independently hydrogen or C1-C3alkyl.

43. The compound of any one of claims 35-42, or a pharmaceutically acceptable salt thereof, wherein each R is independently H, -OH, -NR 1c halogen, -NR 1c1 R 1c2 , OH or -CN.

44. The compound of any one of claims 35-43, or a pharmaceutically acceptable salt thereof, wherein Each R 1d It is a heteroaryl group on its own.

45. The compound of any one of claims 35-44, or a pharmaceutically acceptable salt thereof, wherein Each R 1e It is independently a C1-C4 alkyl, C1-C4 alkoxy, halogen, C1-C4 haloalkyl or -CN.

46. The compound of any one of claims 35-45, or a pharmaceutically acceptable salt thereof, wherein Each R 1 Independently, it can be CH3, CH2CH3, -C(CH3)3, OCH3, CH2CH3, -OCH(CH3)2, -C(CH3)2OH, -C(CH3)(CH2CH3)OH, F, Cl, Br, CF3, OCHF2, OCF3, OCH2CF3, cyclopropyl, cyclopropyloxy, cyclobutyloxy, or or two R on adjacent carbons 1 R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, 47. The compound of any one of claims 35-46, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CH2O-, or -0-.

48. The compound of any one of claims 35-47, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.

49. The compound of any one of claims 35-48, or a pharmaceutically acceptable salt thereof, wherein R 2 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with 0, 1, or 2 R 2a substituents.

50. The compound of any one of claims 35-49, or a pharmaceutically acceptable salt thereof, wherein Each R 2a It is independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH or –CN.

51. The compound of any one of claims 35-50, or a pharmaceutically acceptable salt thereof, wherein each R 2b and R 2c independently hydrogen or C1-C4alkyl.

52. The compound of any one of claims 35-51, or a pharmaceutically acceptable salt thereof, wherein R 2 To 53. The compound of any one of claims 35-52, or a pharmaceutically acceptable salt thereof, wherein Each R 3 Independently C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a -C(O)OR 3a -OC(O)R 3a -C(O)N(R) 3a (R) 3b ), -N(R 3a )C(O)(R 3b -S(O)2R 3a -S(O)2N(R) 3a (R) 3b ), OH, -CN, C3-C8 cycloalkyl or heterocyclic alkyl.

54. The compound of any one of claims 35-53, or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b independently hydrogen or C1-C4alkyl.

55. The compound of any one of claims 35-57, or a pharmaceutically acceptable salt thereof, wherein each R is independently H, -OH, -NR 3c halogen, -NR 3c1 R 3c2 , OH, or -CN.

56. The compound of any one of claims 35-54, or a pharmaceutically acceptable salt thereof, wherein Each R 3d It is a heteroaryl group on its own.

57. The compound of any one of claims 35-56, or a pharmaceutically acceptable salt thereof, wherein Each R 3e It is independently a C1-C4 alkyl, C1-C4 alkoxy, halogen, or C1-C4 haloalkyl.

58. The compound of any one of claims 35-55, or a pharmaceutically acceptable salt thereof, wherein Each R 3 It is independently a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, or C3-C8 cycloalkyl.

59. The compound of any one of claims 35-58, or a pharmaceutically acceptable salt thereof, wherein Each R 3 It is independently a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, -CN, or C3-C6 cycloalkyl.

60. The compound of any one of claims 35-59, or a pharmaceutically acceptable salt thereof, wherein Each R 3 It can be independently Me, OMe, CHF2, CF3, OCHF2, OCF3 or cyclopropyl.

61. The compound of any one of claims 35-60, or a pharmaceutically acceptable salt thereof, wherein subscript q is 1, 2, or 3.

62. The compound of any one of claims 35-61, or a pharmaceutically acceptable salt thereof, wherein subscript n is 0 or 1.

63. The compound of any one of claims 35-62, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in Table 2.

64. The compound of any one of claims 35-62, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

65. The compound of any one of claims 35-62, having the structure:

66. The compound of any one of claims 35-62, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

67. The compound of any one of claims 35 to 62, having the structure:

68. The compound of any one of claims 35 to 62, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure:

69. The compound of any one of claims 35 to 62, having the structure:

70. The compound of claim 1, having Formula (III): (III) or a pharmaceutically acceptable salt thereof, wherein L is -Ci-C4alkylene-, -(Ci-C4alkylene)-O-, or -O-; each R 1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a , -C(O)OR 1a , -OC(O)R 1a , -C(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a )(R 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a , -S(O)2R 1a , -S(O)2N(R 1a )(R 1b ), -S(O)(NH)R 1a , -S(O)(NH)N(R 1a )(R 1b ), -N(R 1a )(R 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 1c , each alkoxy and alkynyl is substituted with 0, 1, 2, or 3 R 1d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 1e ; Each R 1a and R 1b Independently hydrogen or C1-C6 alkyl; Each R 1c Independently C1-C6 alkoxy, halogen, C1-C6 haloalkoxy, -NR 1c1 R 1c2 OH or -CN; Each R 1c1 and R 1c2 Independently hydrogen or C1-C6 alkyl; each R is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 1d independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10 independently deuterium, C3-C8 Each R 1e Independently, it is a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R groups on adjacent carbons 1 groups combine with the atoms to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN; the subscript n is 0, 1, 2, 3, or 4; and R 2 is heteroaryl, which is substituted by 0, 1, 2, 3, or 4 R 2a substituents; Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2; each R 2b and R 2c independently hydrogen or Ci-C6alkyl; each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or, two R on the same carbon atom 3 together represent oxo; each R 3a and R 3b independently hydrogen or Ci-C6alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c1 R 3c2 , OH, or -CN; each R 3c1 and R 3c2 is independently hydrogen or C1-C6alkyl; Each R 3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group; Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; R 4 is hydrogen or CrC6alkyl; the subscript q is 0, 1, 2, 3, or 4; wherein each heterocycloalkyl is a 3- to 8-membered ring including 1-4 heteroatoms each independently N, O, or S; and each heteroaryl is a 5- to 6-membered ring including 1-4 heteroatoms each independently N, O, or S.

71. The compound of claim 70, having Formula (Ilia): (Ilia) or a pharmaceutically acceptable salt thereof.

72. The compound of claim 70 or 71, or a pharmaceutically acceptable salt thereof, having Formula (IIIb): (IIIb) 73. The compound of any one of claims 70 to 72, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in Table 3.

74. The compound of claim 1, having Formula (IV): (IV) or a pharmaceutically acceptable salt thereof, wherein L is -Ci-C4alkylene-, -(Ci-C4alkylene)-O-, or -O-; the subscript n is 0, 1, 2, 3, or 4; and the subscript q is 0, 1, 2, 3, or 4; Each R 1 Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 1a -C(O)OR 1a -OC(O)R 1a -C(O)N(R) 1a (R) 1b ), -N(R 1a )C(O)(R 1b ), -OC(O)N(R 1a (R) 1b ), -N(R 1a )C(O)(OR 1b ), -S(O)R 1a -S(O)2R 1a -S(O)2N(R) 1a (R) 1b -S(O)(NH)R 1a -S(O)(NH)N(R) 1a (R) 1b ), -N(R 1a (R) 1b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 Aryl, (C1-C3 alkyl) (C6-C) 10 aryl), -O-(C6-C) 10 Aryl), heteroaryl, (C1-C3 alkyl) (heteroaryl) or –O- (heteroaryl), wherein each alkyl group is derived from 0, 1, 2, 3, 4, 5 or 6 R... 1c Substitution, with each alkoxy and alkynyl group via 0, 1, 2, or 3 R groups. 1d Substitution, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is determined by 0, 1, 2, or 3 R groups. 1e replace; each R 1a and R 1b is independently hydrogen or C1-C6alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 1c1 R 1c2 , OH, or -CN; each R 1c1 and R 1c2 is independently hydrogen or C1-C6alkyl; each R is independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 1d independently deuterium, C3-C8cycloalkyl, heterocycloalkyl, C6-C10aryl, or heteroaryl; 10 aryl or heteroaryl; Each R 1e Independently, it is a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, or -CN; Alternatively, two R groups on adjacent carbons 1 groups combine with the atoms to which they are attached to form a C5-C8 cycloalkyl or heterocycloalkyl, substituted with 0, 1, 2, 3, 4, 5, or 6 halogen, C1-C4 alkyl, OH, or -CN; wherein R 2 is heteroaryl, which is substituted by 0, 1, 2, 3, or 4 R 2a substituents; Each R 2a Independently, it is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 2b -C(O)OR 2b -OC(O)R 2b -C(O)N(R) 2b (R) 2c ), -N(R 2b )C(O)(R 2c -S(O)2R 2b -S(O)2N(R) 2b (R) 2c ), -N(R 2b (R) 2c ), OH, -CN or –NO2; each R 2b and R 2c is independently hydrogen or C1-C6alkyl; Y is CH, CR 3 or N; each R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 3a , -C(O)OR 3a , -OC(O)R 3a , -C(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(R 3b ), -OC(O)N(R 3a )(R 3b ), -N(R 3a )C(O)(OR 3b ), -S(O)R 3a , -S(O)2R 3a , -S(O)2N(R 3a )(R 3b ), -S(O)(NH)R 3a , -S(O)(NH)N(R 3a )(R 3b ), -N(R 3a )(R 3b ), OH, -CN, -NO2, C3-C8 cycloalkyl, (C1-C3 alkyl)(C3-C8 cycloalkyl), -O-(C3-C8 cycloalkyl), heterocycloalkyl, (C1-C3 alkyl)(heterocycloalkyl), -O-(heterocycloalkyl), C6-C 10 aryl, (C1-C3 alkyl)(C6-C 10 aryl), -O-(C6-C 10 aryl), heteroaryl, (C1-C3 alkyl)(heteroaryl), or -O-(heteroaryl), wherein each alkyl is substituted with 0, 1, 2, 3, 4, 5, or 6 R 3c , each alkoxy is substituted with 0, 1, 2, or 3 R 3d , and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is substituted with 0, 1, 2, or 3 R 3e ; or, two R on the same carbon atom 3 together represent oxo; each R 3a and R 3b is independently hydrogen or Ci-C6alkyl; each R is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c is independently C1-C6alkyl, halogen, C1-C6haloalkyl, -NR 3c1 R 3c2 , OH, or -CN; each R 3c1 and R 3c2 is independently hydrogen or C1-C6alkyl; Each R 3d It is independently a C3-C8 cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group; Each R 3e It is independently a C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 haloalkyl or C1-C6 haloalkoxy; R 4 is hydrogen or CrC6alkyl; each heterocycloalkyl is a 3- to 8-membered ring including 1-4 heteroatoms each independently N, O, or S; and each heteroaryl is a 5- to 6-membered ring including 1-4 heteroatoms each independently N, O, or S.

75. The compound of claim 74, having Formula (IVa): (IVa) or a pharmaceutically acceptable salt thereof.

76. The compound of claim 74 or 75, or a pharmaceutically acceptable salt thereof, having Formula (IVb): (IVb) 77. The compound of claim 74 or 75, or a pharmaceutically acceptable salt thereof, having Formula (IVc): (IVc) 78. The compound of any one of claims 74 to 77, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in Table 4.

79. The compound of claim 1, wherein the compound is selected from the group consisting of: 4-((lH-pyrazol-l-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-3- methoxybenzamide (14) e 4-((lH-pyrazol-l-yl)methyl)-3-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)benzamide 4-((lH-pyrazol-l-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3- methoxybenzamide (67), ​ ​ ​ ​ 5-((1H-Pyrazol-1-yl)methyl)-N-((2,6-dimethoxyphenyl)sulfonyl)-6-methoxypyridine amide (203), 5-((1H-Pyrazol-1-yl)methyl)-N-((5-ethyl-2-methoxyphenyl)sulfonyl)-6-methoxypyridine amide (204), 5-((1H-Pyrazol-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)pyridine amide (224), 5-((1H-Pyrazol-1-yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)pyridine amide (229), 5-((1H-Pyrazol-1-yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypyridine amide (241), 5-((1H-Pyrazol-1-yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypyridine amide (285), 4-((1H-Pyrazol-1-yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide (314), and pharmaceutically acceptable salts thereof.

80. The compound of claim 79, wherein the compound is 4-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-3-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

81. The compound of claim 79, wherein the compound is 4-((1H-pyrazol-1-yl)methyl)-N-((5-hydroxy-2-methoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

82. The compound of claim 79, wherein the compound is 4-((1H-pyrazol-1-yl)methyl)-N-((2-ethoxy-6-methoxyphenyl)sulfonyl)-3-methoxybenzamide, or a pharmaceutically acceptable salt thereof.

83. The compound of claim 79, wherein the compound is 4-((1H-pyrazol-1-yl)methyl)-3-methoxy-N-(2-methoxy-6-(2,2,2-trifluoroethoxy)phenylsulfonylimidamide), or a pharmaceutically acceptable salt thereof.

84. The compound of claim 79, wherein the compound is 5-((1H-pyrazol-1-yl)methyl)-N-((5-(tert-butyl)-2-methoxyphenyl)sulfonyl)-6-methoxypyridine amide, or a pharmaceutically acceptable salt thereof.

85. The compound of claim 79, wherein the compound is 5-((1H-pyrazol-1-yl)methyl)-6-methoxy-N-((2,4,6-trimethoxyphenyl)sulfonyl)pyridine amide, or a pharmaceutically acceptable salt thereof.

86. The compound of claim 79, wherein the compound is 5-((lH-pyrazol-l- yl)methyl)-6-cyclopropyl-N-((2,6-dimethoxyphenyl)sulfonyl)picolinamide or a pharmaceutically acceptable salt thereof.

87. The compound of claim 79, wherein the compound is 5-((lH-pyrazol-l- yl)methyl)-N-((3-chloro-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide or a pharmaceutically acceptable salt thereof.

88. The compound of claim 79, wherein the compound is 5-((lH-pyrazol-l- yl)methyl)-N-((4-bromo-2,6-dimethoxyphenyl)sulfonyl)-6-methoxypicolinamide or a pharmaceutically acceptable salt thereof.

89. The compound of claim 79, wherein the compound is 4-((lH-pyrazol-l- yl)methyl)-3-methoxy-N-((2-methyl-2,3-dihydrobenzofuran-7-yl)sulfonyl)benzamide or a pharmaceutically acceptable salt thereof.

90. A pharmaceutical composition comprising a compound of any one of claims 1-89 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

91. A compound of any one of claims 1-89 or a pharmaceutically acceptable salt thereof for use as a medicament.

92. A method of modulating KAT6A in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-89 or a pharmaceutically acceptable salt thereof.

93. A method of treating a disease or disorder mediated by KAT6A in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-89 or a pharmaceutically acceptable salt thereof.

94. The method of claim 93, wherein the disease or disorder is cancer.

95. The method of claim 94, wherein the cancer is selected from brain glioma, glioblastoma, astrocytoma, pleomorphic cell tumor, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colorectal cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, and thyroid cancer, lymphoblastic T-cell leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, megakaryoblastic leukemia, multiple myeloma, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, uterine cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, oral cancer, gastrointestinal stromal tumor, neuroendocrine cancer, testicular cancer, and virus-associated cancer.

96. Use of a compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder mediated by KAT6A.

97. A compound of any one of claims 1-89, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder mediated by KAT6A.

98. The method of any one of claims 93-95, further comprising administering an additional anti-cancer agent.

99. The method of claim 98, wherein the additional anti-cancer agent is selected from a HER2 inhibitor, an mTOR inhibitor, a CDK4 / 6 inhibitor, a CDK2 selective inhibitor, a CDK4 selective inhibitor, a PI3 kinase inhibitor, a PIK3CA inhibitor, an aromatase inhibitor, an antibody or inhibitor of PD-1, PD-L1, or CTLA-4, an antibody or inhibitor of EGFR, PGFR, or IGFR, a USP inhibitor, or an AKT inhibitor.

100. The method of claim 99, wherein the additional anti-cancer agent is a HER2 inhibitor.

101. The method of claim 100, wherein the HER2 inhibitor is selected from the group consisting of tucatinib, trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab emtansine, ado-trastuzumab emtansine, trastuzumab deruxtecan, pertuzumab, lapatinib, and neratinib.

102. The method of claim 99, wherein the anti-cancer agent is an mTOR inhibitor.

103. The method of claim 102, wherein the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus, and LY30234.

104. The method of claim 99, wherein the anti-cancer agent is a CDK4 / 6 inhibitor.

105. The method of claim 104, wherein the CDK4 / 6 inhibitor is selected from the group consisting of ribociclib, abemaciclib, golvodicitib, lasofoxifib, trilaciclib, and SHR6390.

106. The method of claim 99, wherein the additional anti-cancer agent is a CDK2 selective inhibitor.

107. The method of claim 112, wherein the CDK2 selective inhibitor is PF-07104091 (talacotib).

108. The method of claim 99, wherein the additional anti-cancer agent is a CDK4 selective inhibitor.

109. The method of claim 114, wherein the CDK-4 selective inhibitor is PF-07220060 (atetociclib).

110. The method of claim 99, wherein the anti-cancer agent is a PI3 kinase inhibitor.

111. The method of claim 102, wherein the PI3 kinase inhibitor is selected from the group consisting of perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.

112. The method of claim 99, wherein the additional anti-cancer agent is a PIK3CA inhibitor.

113. The method of claim 104, wherein the PIK3CA inhibitor is selected from the group consisting of alpelisib, taselisib, LY3023414, iniparib, STX-478, RLY-2608, LOXO-783, OKI-219, and TOS-358.

114. The method of claim 99, wherein the additional anti-cancer agent is an aromatase inhibitor.

115. The method of claim 106, wherein the aromatase inhibitor is selected from the group consisting of aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, formestane, fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatriene-3,17-dione, and 4-androstene-3,6,17-trione.

116. The method of claim 106, wherein the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, and exemestane.

117. The method of claim 199, wherein the additional anti-cancer agent is a USP1 inhibitor.

118. The method of claim 99, wherein the additional anti-cancer agent is an AKT inhibitor.

119. The method of claim 123, wherein the AKT inhibitor is selected from the group consisting of capivasatin, patidegib, afuresertib, and ulixertinib.

120. The method of claim 124, wherein the AKT inhibitor is capivasatin.

121. The method of any one of claims 93-95, further comprising administering an estrogen receptor antagonist or an estrogen receptor partial antagonist.

122. The method of claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a selective estrogen receptor modulator.

123. The method of claim 127, wherein the selective estrogen receptor modulator is selected from the group consisting of tamoxifen, endoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, elacestrant, and bazedoxifene.

124. The method of claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a selective estrogen receptor degrader.

125. The method of claim 129, wherein the selective estrogen receptor degrader is selected from the group consisting of fulvestrant, camizestrant, patupilone, imnistrant, elacestrant, and giredestrant.

126. The method of claim 130, wherein the selective estrogen receptor degrader is patupilone.

127. The method of claim 126, wherein the estrogen receptor antagonist or estrogen receptor partial antagonist is a full estrogen receptor antagonist.

128. The method of claim 132, wherein the full estrogen receptor antagonist is selected from the group consisting of fulvestrant and patupilone.

129. The method of claim 133, wherein the full estrogen receptor antagonist is patupilone.

Images