Trpml1 agonists and uses thereof

Abstract

Described herein are bicyclic TRPML1 agonists and pharmaceutical compositions comprising said agonists. The subject compounds and compositions are useful for the treatment of TRPML1 -mediated disorders or diseases.

Description

WSGR Docket No. 57050-707.601TRPML1 AGONISTS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 755,071 filed February 6, 2025; which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] TRPML1, also named Mucolipin-1, is a ligand-gated cation channel expressed mostly in intracellular organelles like the late endosome and lysosome of many mammalian cells. This channel is member of the large family of Transient receptor potential (TRP) channels and has, with TRPML2 and TRPML3, two close analogues. Loss-of-function mutations in the gene encoding for TRPML1, the 12,000 base pair gene MCOLN-1 located in human chromosome 19p 13, are the direct cause of Type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease.

[0003] At the molecular level, TRPML1 is a Ca2+-permeable, non-selective cation channel formed of four six-transmembrane spanning proteins each of 580 amino acids. The channel opens upon binding of its endogenous ligand phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2)) to its pore region. Channel activity is modulated by pH and PtdIns(4,5)P2 levels. TRPML1 is an inwardly rectifying channel permeable to different mono- and divalent cations, including Na+, K+, Ca2+, and Fe2+. Its N-terminal API sequence targets the channel to the lysosome while a C-terminal AP2 sequence is responsible for intracellular trafficking and internalization. In addition, TRPML1 has four putative N-linked glycosylation sites in its luminal loop between TM1 and 2. It is reported that TRPML channels can be formed as homo -tetramers (e.g., TRPML1, TRPML2, and TRPML3) but also in some cases as heterotetramers where one channel is composed of different members of the TRPML family.

[0004] TRPML 1 is found in all mammalian tissues with highest expression levels in brain, spleen, liver, kidney, and heart. Expression is found in many cell types, including neurons, myeloid cells, macrophages, microglia, podocytes, and muscle cells. TRPML 1 is involved in function of late endosome / lysosomes (LELs), more specifically in protein trafficking, lysis, and autophagy.

[0005] Lysosomes are organelles filled with hydrolytic enzymes, characterized by a low luminal pH of about 5, a high luminal Ca2+concentration of about 0.5 mM, and a membrane polarization of about +60 mV.

[0006] TRPML 1 in LELs is reported to be responsible for the formation of transport vesicles, and it is required for the reformation of lysosomes from LEL hybrid organelles and autolysosomes, mostly due to its Ca2+permeability. TRPML 1 is likely also important for iron release from the lysosome after degradation of iron-binding proteins like cytochrome C. In addition, TRPML 1 is reported to regulate autophagy, probably in an mTOR-independent manner, by promoting TFEB translocation to the nucleus via calcineurin activation.WSGR Docket No. 57050-707.601SUMMARY OF THE INVENTION

[0007] In Type IV mucolipidosis (MLIV), the lack of functional TRPML1 leads to severe intellectual disability, motor deficits, retinal degeneration, and systemic symptoms leading to a strongly reduced life expectancy. Cells from MLIV patients show increased autophagosomes, accumulation of lysofuscin, and lipid accumulation in the lysosomes.

[0008] Failure of TRPML1 -dependent autophagosome-lysosome fusion is also thought to impair clearance of apoptotic neurons by macrophages and microglia cells. Experimental results suggest involvement of TRPML1 in neurodegenerative diseases like Alzheimer's and amyotrophic lateral sclerosis (ALS). For example, Alzheimer's disease related loss-of-function mutations in presenilin 1 lead to dysregulation of lysosomal Ca2+homeostasis via TRPML1 modulation. On the other side, overexpression of TRPML1 in rodent Alzheimer's models reduced neuronal apoptosis and rescued memory impairments. Pharmacological activation of TRPML1 showed similar effects, clearing accumulated sphingolipids and A peptides from lysosomes. In another study TRPML1 activation was sufficient to upregulate lysosomal exocytosis, rescue defective a-syn secretion and prevent a-syn accumulation in iPSC-derived dopaminergic neurons from patients expressing mutant PARK9. Similarly, TRPML1 activation rescued motor neurons from death and ER stress induced by the cycad neurotoxin beta-methylamino-L-alanine, L-BMAA as a model for ALS.

[0009] Therefore, it is desired to develop TRPML1 modulators to rescue impaired lysosomal function and cellular autophagy in neurodegenerative diseases.

[0010] Despite widespread interest for several years across the pharmaceutical industry, currently described small molecule TRPML1 agonists are not optimized for functional activity and drug like properties. Consequently, there is still an unmet need for compounds which can efficiently stimulate TRPML1 and that can be delivered to the different target organs which are sites of any TRPML1-mediated pathology.

[0011] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I) as disclosed herein.

[0012] Disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 57050-707.601Formula (II) as disclosed herein.

[0013] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III) as disclosed herein.

[0014] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0015] Also disclosed herein is a method of treating a TRPML1 -mediated disorder or disease in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0017] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense,WSGR Docket No. 57050-707.601that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

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

[0019] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0020] “Oxo” refers to =0.

[0021] “Amino” refers to -NH2.

[0022] “Hydroxy” refers to -OH.

[0023] “Carboxyl” refers to -COOH.

[0024] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2-methyl-l-butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3 -methyl -2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2 -ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range, such as “Ci-Ce alkyl,” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is independently optionally substituted with halogen.

[0025] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about theWSGR Docket No. 57050-707.601double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2O7UCH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkenyl,” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is independently optionally substituted with halogen.

[0026] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range, such as “C2-C6 alkynyl,” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is independently optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is independently optionally substituted with halogen.

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

[0028] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -WSGR Docket No. 57050-707.601COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is independently optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is independently optionally substituted with halogen.

[0029] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is independently optionally substituted with halogen.

[0030] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 folly saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 folly saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 folly saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered folly saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl.Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclofl. l.l]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl,WSGR Docket No. 57050-707.601cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is independently optionally substituted with halogen.

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

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

[0033] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0034] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0035] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0036] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0037] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -WSGR Docket No. 57050-707.601CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is independently optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is independently optionally substituted with halogen.

[0038] “Heterocycloalkyl” refers to a 3 - to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-Ci5 fully saturated heterocycloalkyl or C2-Ci5 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-Cio fully saturated heterocycloalkyl or C2-Cio heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-Cs fully saturated heterocycloalkyl or C2-Cs heterocycloalkenyl), from two to seven carbon atoms (e.g., C -C? fully saturated heterocycloalkyl or CS-C? heterocycloalkenyl), from two to six carbon atoms (e.g., C2-Ce fully saturated heterocycloalkyl or CS-C? heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C3fully saturated heterocycloalkyl or C2-C3heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-I,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-I,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The termWSGR Docket No. 57050-707.601heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 - to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is independently optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is independently optionally substituted with halogen.

[0039] “Heteroaryl” refers to a 5 - to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-memberedWSGR Docket No. 57050-707.601heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is independently optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is independently optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is independently optionally substituted with halogen.

[0040] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0041] The term “one or more” when referring to an optional substituent means that the subject group is independently optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is independently optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is independently optionally substituted with one, two, or three substituents. In some embodiments, the subject group is independently optionally substituted with one or two substituents. In some embodiments, the subject group is independently optionally substituted with one substituent. In some embodiments, the subject group is independently optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.WSGR Docket No. 57050-707.601

[0042] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0043] “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0044] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0045] As used herein, a “disease or disorder associated with TRPML1” or, alternatively, “a TRPML1 -mediated disease or disorder” means any disease or other deleterious condition in which TRPML1, or a mutant thereof, is known or suspected to play a role.Compounds

[0046] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, useful in the treatment of a TRPML1 -mediated disease or disorder. Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that are TRPML1 agonists.

[0047] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I);wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;WSGR Docket No. 57050-707.601and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;Z1is -CH2-, -CH(CH3)-, -CH2CH2-, or -C(=O)-;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R11on the same atom are taken together to form an oxo;q is 0, 1, 2, 3, 4, 5, or 6;R12is hydrogen, -CN, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;R13is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’;or R12and R13are taken together with the atoms to which they are attached to form a 4- to 7-membered heterocycloalkyl independently optionally substituted with one or more R14;WSGR Docket No. 57050-707.601each R14is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R14on the same atom are taken together to form an oxo;and / or two R14on separate atoms are taken together with the atom to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R”;and / or two R14on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R”;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Csalkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-Csalkyl, or Ci-Csheteroalkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R” on the same atom are taken together to form an oxo.

[0048] In some embodiments of a compound of Formula (I), X is CRX. In some embodiments of a compound of Formula (I), X is N.WSGR Docket No. 57050-707.601

[0049] In some embodiments of a compound of Formula (I), Rxis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), Rxis hydrogen.

[0050] In some embodiments of a compound of Formula (I), Y is CRY. In some embodiments of a compound of Formula (I), Y is N.

[0051] In some embodiments of a compound of Formula (I), RYis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), RYis hydrogen.

[0052] In some embodiments of a compound of Formula (I), W is absent. In some embodiments of a compound of Formula (I), W is -C(=O)-.

[0053] In some embodiments of a compound of Formula (I), R9is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R9is hydrogen.

[0054] In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R10is hydrogen.

[0055] In some embodiments of a compound of Formula (I), R12is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R12is -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R12is -S(=O)2NRcRd, -C(=O)Ra, or -C(=O)ORb. In some embodiments of a compound of Formula (I), R12is -S(=O)2NRcRd. In some embodiments of a compound of Formula (I), R12is -C(=O)Ra. In some embodiments of a compound of Formula (I), R12is -C(=O)ORb.

[0056] In some embodiments of a compound of Formula (I), R13is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R13is hydrogen.

[0057] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0058] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5 -membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0059] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0060] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.WSGR Docket No. 57050-707.601

[0061] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5 -membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0062] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0063] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom that is S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0064] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 5 -membered heterocycloalkyl optionally comprising one additional heteroatom that is S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0065] In some embodiments of a compound of Formula (I), R12and R13are taken together with the atoms to which they are attached to form a 6-membered heterocycloalkyl optionally comprising one additional heteroatom that is S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

[0066] In some embodiments, the compound of Formula (I) is of Formula (la):wherein:each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R11on the same atom are taken together to form an oxo;q is 0, 1, 2, 3, 4, 5, or 6;Ring B is a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S;WSGR Docket No. 57050-707.601each R14is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R14on the same atom are taken together to form an oxo;and / or two R14on separate atoms are taken together with the atom to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R”;and / or two R14on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R”; andt is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0067] In some embodiments of a compound of Formula (I) or (la), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I) or (la), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S.

[0068] In some embodiments of a compound of Formula (I) or (la), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S. In some embodiments of a compound of Formula (I) or (la), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S.

[0069] In some embodiments of a compound of Formula (I) or (la), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom that is S. In some embodiments of a compound of Formula (I) or (la), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom that is S.

[0070] In some embodiments of a compound of Formula (I) or (la), Ring B is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la), Ring B is a 6-membered heterocycloalkyl.

[0071] In some embodiments of a compound of Formula (I) or (la), each R14is independently Ci-Cealkyl; and / or two R14on the same atom are taken together to form an oxo; and / or two R14on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la), each R14is independently Ci-Cealkyl; and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I) or (la), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la), each R14is independently Ci-Cealkyl and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la), two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (I) or (la), two R14on theWSGR Docket No. 57050-707.601same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (I) or (la), two R14on the same carbon are taken together to form a cyclopropyl.

[0072] In some embodiments of a compound of Formula (I) or (la), t is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (I) or (la), t is 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (I) or (la), t is 2, 3, or 4. In some embodiments of a compound of Formula (I) or (la), t is 4. In some embodiments of a compound of Formula (I) or (la), t is 6.of Formula (some embodiments of a compound of Formula (I) or (la),

[0074] In some embodiments of a compound of Formula ("WSGR Docket No. 57050-707.601

[0075] In some embodiments of a compound of Formula (I) or (la), each R11is independently halogen, -CN, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl. In some embodiments of a compound of Formula (I) or (la), each R11is independently Ci-Cealkyl.

[0076] In some embodiments of a compound of Formula (I) or (la), q is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (la), q is 0 or 1. In some embodiments of a compound of Formula (I) or (la), q is 0. In some embodiments of a compound of Formula (I) or (la), q is 1. In some embodiments of a compound of Formula (I) or (la), q is 2.

[0077] In some embodiments of a compound of Formula (I) or (la), Z1is -CH2- or -C(=O)-. In some embodiments of a compound of Formula (I) or (la), Z1is -CH2-.

[0078] In some embodiments of a compound of Formula (I) or (la), R2is Ci-Cealkyl independently optionally substituted with one or more R3. In some embodiments of a compound of Formula (I) or (la), R2is Ci-C6alkyl.

[0079] In some embodiments of a compound of Formula (I) or (la), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (I) or (la), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la), R2is heterocycloalkyl or aryl. In some embodiments of a compound of Formula (I) or (la), R2is phenyl.

[0080] In some embodiments of a compound of Formula (someembodiments of a compound of Formula (I) or (la), R2is. In some embodiments of a compoundof Formula (

[0081] In some embodiments of a compound of Formula (I) or (la), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (I) or (la), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la), each R3is independently halogen, -ORa, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la), each R3is independently halogen or -ORa. In some embodiments of a compound of Formula (I) or (la), each R3is independently -ORa.

[0082] In some embodiments of a compound of Formula (I) or (la), Ring A is a cycloalkyl or heterocycloalkyl.WSGR Docket No. 57050-707.601

[0083] In some embodiments of a compound of Formula (I) or (la), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (I) or (la), Ring A is phenyl.

[0084] In some embodiments of a compound of Formula (I) or (la), Ring A is a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0085] In some embodiments of a compound of Formula (I) or (la), Ring A is a 6-membered heteroaryl comprising one or two heteroatoms selected that are N. In some embodiments of a compound of Formula (I) or (la), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (I) or (la), Ring A is pyridinyl.

[0086] In some embodiments of a compound of Formula (I) or (la), Ring A is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0087] In some embodiments of a compound of Formula (I) or (la), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some embodiments of a compound of Formula (I) or (la), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl. In some embodiments of a compound of Formula (I) or (la), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or pyrazolyl.

[0088] In some embodiments of a compound of Formula (I) or (la), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’ ; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (I) or (la), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (I) or (la), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound of Formula (I) or (la), each R1is independently halogen or -CN.

[0089] In some embodiments of a compound of Formula (I) or (la), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (la), n is 1 or 2. In some embodiments of a compound of Formula (I) or (la), n is 0. In some embodiments of a compound of Formula (I) or (la), n is 1. In some embodiments of a compound of Formula (I) or (la), n is 2.WSGR Docket No. 57050-707.601

[0092] In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog (equivalent to Z1is absent). In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog by at least 2 log unit. In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog by at least 1 log unit. In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog by at least 0.5 log unit. In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog by at least 0.4 log unit. In some embodiments, the compound of Formula (I) or (la) is generally more potent than its corresponding directly linked analog by at least 0.3 log unit.

[0093] In some embodiments, the compound of Formula (I) or (la), wherein Z1cannot be absent, is generally more soluble than its corresponding directly linked analog (equivalent to Z1is absent).

[0094] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 57050-707.601Formula (II);wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independentlyWSGR Docket No. 57050-707.601optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;Z2is absent, -O-, -S-, -NR4-, -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, *-OC(R5)2-, *-C(R5)2C(R5)2NR4-, *-NR4C(R5)2C(R5)2-, *- C(R5)2C(R5)2O-, or *-OC(R5)2C(R5)2-; wherein * is the attachment point to Ring C;R4is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R6is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R6on the same atom are taken together to form an oxo;p is 0, 1, 2, 3, or 4;and / or R4and one R6are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;R7is Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;R8is hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or - L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;WSGR Docket No. 57050-707.601each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -S(=O)Ci-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi- C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -S(=O)Ci-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi- C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, or Ci-C3heteroalkyl;and / or two R” on the same atom are taken together to form an oxo;provided that the compound is not:

[0095] In some embodiments of a compound of Formula (II), X is CRX. In some embodiments of a compound of Formula (II), X is N.

[0096] In some embodiments of a compound of Formula (II), Rxis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), Rxis hydrogen.

[0097] In some embodiments of a compound of Formula (II), Y is CRY. In some embodiments of a compound of Formula (II), Y is N.

[0098] In some embodiments of a compound of Formula (II), RYis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), RYis hydrogen.

[0099] In some embodiments of a compound of Formula (II), W is absent. In some embodiments of a compound of Formula (II), W is -C(=O)-.

[0100] In some embodiments of a compound of Formula (II), R9is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R9is hydrogen.WSGR Docket No. 57050-707.601

[0101] In some embodiments of a compound of Formula (II), R10is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (II), R10is hydrogen.

[0102] In some embodiments, the compound of Formula (II) is of Formula (Ila):Formula (Ila).

[0103] In some embodiments of a compound of Formula (II) or (Ila), Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring C.

[0104] In some embodiments of a compound of Formula (II) or (Ila), Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-S(=O)2NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring C.

[0105] In some embodiments of a compound of Formula (II) or (Ila), Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring C.

[0106] In some embodiments of a compound of Formula (II) or (Ila), Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-C(=O)NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring C.

[0107] In some embodiments of a compound of Formula (II) or (Ila), Z2is *-C(R5)2NR4- or *-C(R5)2O-; wherein * is the attachment point to Ring C.

[0108] In some embodiments of a compound of Formula (II) or (Ila), Z2is *-C(R5)2NR4- wherein * is the attachment point to Ring C.

[0109] In some embodiments of a compound of Formula (II) or (Ila), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R4is hydrogen.

[0110] In some embodiments of a compound of Formula (II) or (Ila), each R5is independently hydrogen.

[0111] In some embodiments of a compound of Formula (II) or (Ila), Ring C is aryl or heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring C is phenyl.

[0112] In some embodiments of a compound of Formula (II) or (Ila), each R6is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), each R6is independently halogen or Ci-Cealkyl.

[0113] In some embodiments of a compound of Formula (II) or (Ila), p is 0 or 1. In some embodiments of a compound of Formula (II) or (Ila), p is 0. In some embodiments of a compound of Formula (II) or (Ila), p is 1.WSGR Docket No. 57050-707.601

[0114] In some embodiments of a compound of Formula (II) or (Ila), R7is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R7is Ci-Cealkyl.

[0115] In some embodiments of a compound of Formula (II) or (Ila), R8is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), R8is Ci-Cealkyl.

[0116] In some embodiments of a compound of Formula (II) or (Ila), R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (II) or (Ila), R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl.

[0117] In some embodiments of a compound of Formula (II) or (Ila), R2is Ci-Cealkyl independently optionally substituted with one or more R3.

[0118] In some embodiments of a compound of Formula (II) or (Ila), R2is Ci-Cealkyl.

[0119] In some embodiments of a compound of Formula (II) or (Ila), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

[0120] In some embodiments of a compound of Formula (II) or (Ila), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0121] In some embodiments of a compound of Formula (II) or (Ila), R2is aryl, or heteroaryl.

[0122] In some embodiments of a compound of Formula (II) or (Ila), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (II) or (Ila), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), each R3is independently halogen, -ORa, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (II) or (Ila), each R3is independently halogen or -ORa. In some embodiments of a compound of Formula (II) or (Ila), each R3is independently -ORa.

[0123] In some embodiments of a compound of Formula (II) or (Ila), Ring A is a cycloalkyl or heterocycloalkyl.

[0124] In some embodiments of a compound of Formula (II) or (Ila), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is phenyl.

[0125] In some embodiments of a compound of Formula (II) or (Ila), Ring A is a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0126] In some embodiments of a compound of Formula (II) or (Ila), Ring A is a 6-membered heteroaryl comprising one or two heteroatoms selected that are N. In some embodiments of a compound of Formula (II) or (Ila), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is pyridinyl.WSGR Docket No. 57050-707.601

[0127] In some embodiments of a compound of Formula (II) or (Ila), Ring A is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0128] In some embodiments of a compound of Formula (II) or (Ila), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl. In some embodiments of a compound of Formula (II) or (Ila), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or pyrazolyl.

[0129] In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -C(=O)NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen or -CN. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently -CN.

[0130] In some embodiments of a compound of Formula (II) or (Ila), n is 0, 1, or 2. In some embodiments of a compound of Formula (II) or (Ila), n is 1 or 2. In some embodiments of a compound of Formula (II) or (Ila), n is 0. In some embodiments of a compound of Formula (II) or (Ila), n is 1. In some embodiments of a compound of Formula (II) or (Ila), n is 2.

[0131] Also disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III);wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;WSGR Docket No. 57050-707.601each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or *-OC(R5)2C(R5)2-; wherein * is the attachment point to Ring D;R4is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -WSGR Docket No. 57050-707.601NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R15on the same atom are taken together to form an oxo;m is 0, 1, 2, 3, or 4;L1is -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Csalkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3heteroalkyl, Ci-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;and / or two R” on the same atom are taken together to form an oxo.

[0132] In some embodiments of a compound of Formula (III), X is CRX. In some embodiments of a compound of Formula (III), X is N.

[0133] In some embodiments of a compound of Formula (III), Rxis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (III), Rxis hydrogen.WSGR Docket No. 57050-707.601

[0134] In some embodiments of a compound of Formula (III), Y is CRY. In some embodiments of a compound of Formula (III), Y is N.

[0135] In some embodiments of a compound of Formula (III), RYis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (III), RYis hydrogen.

[0136] In some embodiments of a compound of Formula (III), W is absent. In some embodiments of a compound of Formula (III), W is -C(=O)-.

[0137] In some embodiments of a compound of Formula (III), R9is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (III), R9is hydrogen.

[0138] In some embodiments of a compound of Formula (III), R10is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (III), R10is hydrogen.

[0139] In some embodiments, the compound of Formula (III) is of Formula (Illa):Formula (Illa).

[0140] In some embodiments of a compound of Formula (III) or (Illa), Z3is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring D.

[0141] In some embodiments of a compound of Formula (III) or (Illa), Z3is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-S(=O)2NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring D.

[0142] In some embodiments of a compound of Formula (III) or (Illa), Z3is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring D.

[0143] In some embodiments of a compound of Formula (III) or (Illa), Z3is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-C(=O)NR4-, or *-C(R5)2O-; wherein * is the attachment point to Ring D.

[0144] In some embodiments of a compound of Formula (III) or (Illa), Z3is *-C(R5)2NR4- or *-C(R5)2O-; wherein * is the attachment point to Ring D.

[0145] In some embodiments of a compound of Formula (III) or (Illa), Z3is *-C(R5)2NR4- wherein * is the attachment point to Ring D.

[0146] In some embodiments of a compound of Formula (III) or (Illa), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (III) or (Illa), R4is hydrogen.

[0147] In some embodiments of a compound of Formula (III) or (Illa), each R5is independently hydrogen.WSGR Docket No. 57050-707.601

[0148] In some embodiments of a compound of Formula (III) or (Illa), Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (III) or (Illa), Ring D is phenyl.

[0149] In some embodiments of a compound of Formula (III) or (Illa), each R15is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (III) or (Illa), each R15is independently halogen or Ci-Cealkyl.

[0150] In some embodiments of a compound of Formula (III) or (Illa), m is 0 or 1. In some embodiments of a compound of Formula (III) or (Illa), m is 0. In some embodiments of a compound of Formula (III) or (Illa), m is 1.

[0151] In some embodiments of a compound of Formula (III) or (Illa), L1is -CH2CH2-. In some embodiments of a compound of Formula (III) or (Illa), L1is -CH2CH2CH2-. In some embodiments of a compound of Formula (III) or (Illa), L1is -CH2CH2CH2CH2.

[0152] In some embodiments of a compound of Formula (III) or (Illa), R2is Ci-Cealkyl independently optionally substituted with one or more R3.

[0153] In some embodiments of a compound of Formula (III) or (Illa), R2is Ci-Cealkyl.

[0154] In some embodiments of a compound of Formula (III) or (Illa), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

[0155] In some embodiments of a compound of Formula (III) or (Illa), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

[0156] In some embodiments of a compound of Formula (III) or (Illa), R2is aryl, or heteroaryl.

[0157] In some embodiments of a compound of Formula (III) or (Illa), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (III) or (Illa), each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3is independently halogen, -ORa, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3is independently halogen or -ORa. In some embodiments of a compound of Formula (III) or (Illa), each R3is independently -ORa.

[0158] In some embodiments of a compound of Formula (III) or (Illa), Ring A is a cycloalkyl or heterocycloalkyl.

[0159] In some embodiments of a compound of Formula (III) or (Illa), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (III) or (Illa), Ring A is phenyl.

[0160] In some embodiments of a compound of Formula (III) or (Illa), Ring A is a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0161] In some embodiments of a compound of Formula (III) or (Illa), Ring A is a 6-membered heteroaryl comprising one or two heteroatoms selected that are N. In some embodiments of a compoundWSGR Docket No. 57050-707.601of Formula (III) or (Illa), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (III) or (Illa), Ring A is pyridinyl.

[0162] In some embodiments of a compound of Formula (III) or (Illa), Ring A is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0163] In some embodiments of a compound of Formula (III) or (Illa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some embodiments of a compound of Formula (III) or (Illa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl. In some embodiments of a compound of Formula (III) or (Illa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or pyrazolyl.

[0164] In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -C(=O)NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen or -CN. In some embodiments of a compound of Formula (III) or (Illa), each R1is independently -CN.

[0165] In some embodiments of a compound of Formula (III) or (Illa), n is 0, 1, or 2. In some embodiments of a compound of Formula (III) or (Illa), n is 1 or 2. In some embodiments of a compound of Formula (III) or (Illa), n is 0. In some embodiments of a compound of Formula (III) or (Illa), n is 1. In some embodiments of a compound of Formula (III) or (Illa), n is 2.

[0166] Disclosed herein is a compound of Formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 57050-707.601wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent, -C(=O)-, or Ci-Cealkylene;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3a;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3b;each R3ais independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3bis independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl is independently optionally substituted with one or more R’ ; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”; Z4is absent, -CH2-, -CH(CH3)-, -CH2CH2-, or -C(=O)-;WSGR Docket No. 57050-707.601each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R11on the same atom are taken together to form an oxo;q is 0, 1, 2, 3, 4, 5, or 6;Ring B is a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S;each R14is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R14on the same atom are taken together to form an oxo;and / or two R14on separate atoms are taken together with the atom to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R”;and / or two R14on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R”; andt is 0, 1, 2, 3, 4, 5, 6, 7, or 8.each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Csalkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R’ on the same atom are taken together to form an oxo;WSGR Docket No. 57050-707.601each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-Csalkyl, or Ci-Csheteroalkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R” on the same atom are taken together to form an oxo.

[0167] In some embodiments of a compound of Formula (IV), X is CRX. In some embodiments of a compound of Formula (IV), X is N.

[0168] In some embodiments of a compound of Formula (IV), Rxis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), Rxis hydrogen.

[0169] In some embodiments of a compound of Formula (IV), Y is CRY. In some embodiments of a compound of Formula (IV), Y is N.

[0170] In some embodiments of a compound of Formula (IV), RYis hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), RYis hydrogen.

[0171] In some embodiments of a compound of Formula (IV), W is absent. In some embodiments of a compound of Formula (IV), W is -C(=O)-. In some embodiments of a compound of Formula (IV), W is Ci-Cealkylene. In some embodiments of a compound of Formula (IV), W is CH2.

[0172] In some embodiments of a compound of Formula (IV), R9is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R9is hydrogen.

[0173] In some embodiments of a compound of Formula (IV), R10is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV), R10is hydrogen.

[0174] In some embodiments, the compound of Formula (IV) is of Formula (IVa):Formula (IVa).

[0175] In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S.

[0176] In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S. In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 6-memberedWSGR Docket No. 57050-707.601heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S.

[0177] In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom that is S. In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom that is S.

[0178] In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), Ring B is a 6-membered heterocycloalkyl.

[0179] In some embodiments of a compound of Formula (IV) or (IVa), each R14is independently Ci-Cealkyl; and / or two R14on the same atom are taken together to form an oxo; and / or two R14on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R14is independently Ci-Cealkyl; and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl; wherein each alkyl is independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (IV) or (IVa), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R14is independently Ci-Cealkyl and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa), two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (IV) or (IVa), two R14on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), two R14on the same carbon are taken together to form a cyclopropyl.

[0180] In some embodiments of a compound of Formula (IV) or (IVa), t is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (IV) or (IVa), t is 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (IV) or (IVa), t is 2, 3, or 4. In some embodiments of a compound of Formula (IV) or (IVa), t is 4. In some embodiments of a compound of Formula (IV) or (IVa), t is 6.of Formulasome embodiments of a compound of Formula (IV) orsome embodiments of a compound of Formula (IV) orWSGR Docket No. 57050-707.601

[0182] In some embodiments of a compound of Formulasome embodiments of a compound of Formulasome embodiments of a compound of Formula

[0183] In some embodiments of a compound of Formula (IV) or (IVa), each R11is independently halogen, -CN, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl. In some embodiments of a compound of Formula (IV) or (IVa), each R11is independently Ci-Cealkyl.

[0184] In some embodiments of a compound of Formula (IV) or (IVa), q is 0, 1, or 2. In some embodiments of a compound of Formula (IV) or (IVa), q is 0 or 1. In some embodiments of a compound of Formula (IV) or (IVa), q is 0. In some embodiments of a compound of Formula (IV) or (IVa), q is 1. In some embodiments of a compound of Formula (IV) or (IVa), q is 2.

[0185] In some embodiments of a compound of Formula (IV) or (IVa), R2is Ci-Cealkyl independently optionally substituted with one or more R3a. In some embodiments of a compound of Formula (IV) or (IVa), R2is Ci-Cealkyl.

[0186] In some embodiments of a compound of Formula (IV) or (IVa), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R3b. In some embodiments of a compound of Formula (IV) or (IVa), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa), R2is heterocycloalkyl or aryl. In some embodiments of a compound of Formula (IV) or (IVa), R2is phenyl. In some embodiments of a compound of Formula (IV) or (IVa), R2is cycloalkyl independently optionally substituted with one or more R3b. In some embodiments of a compound of Formula (IV) or (IVa), R2is cyclopropyl.WSGR Docket No. 57050-707.601

[0187] In some embodiments of a compound of Formula (IV) or (IVa), each R3ais independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (IV) or (IVa), each R3ais independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R3ais independently halogen, -ORa, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R3ais independently halogen or -ORa. In some embodiments of a compound of Formula (IV) or (IVa), each R3ais independently -ORa.

[0188] In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’, and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen, -ORa, Ci-Cealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen or -ORa. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently -ORa. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (IV) or (IVa), each R3bis independently halogen.

[0189] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is a cycloalkyl or heterocycloalkyl.

[0190] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is phenyl or heteroaryl. In some embodiments of a compound of Formula (IV) or (IVa), Ring A is phenyl.

[0191] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0192] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is a 6-membered heteroaryl comprising one or two heteroatoms selected that are N. In some embodiments of a compound of Formula (IV) or (IVa), Ring A is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (IV) or (IVa), Ring A is pyridinyl.

[0193] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0194] In some embodiments of a compound of Formula (IV) or (IVa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some embodiments of a compound of Formula (IV) or (IVa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, or pyrazolyl. In some embodiments of aWSGR Docket No. 57050-707.601compound of Formula (IV) or (IVa), Ring A is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or pyrazolyl.

[0195] In some embodiments of a compound of Formula (IV) or (IVa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (IV) or (IVa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci-Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”. In some embodiments of a compound of Formula (IV) or (IVa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci-C6alkyl, or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (IV) or (IVa), each R1is independently halogen or -CN.

[0196] In some embodiments of a compound of Formula (IV) or (IVa), n is 0, 1, or 2. In some embodiments of a compound of Formula (IV) or (IVa), n is 1 or 2. In some embodiments of a compound of Formula (IV) or (IVa), n is 0. In some embodiments of a compound of Formula (IV) or (IVa), n is 1. In some embodiments of a compound of Formula (IV) or (IVa), n is 2.

[0197] In some embodiments of a compound of Formula (IV) or (IVa), Z4is absent or -CH2-.

[0198] In some embodiments of a compound of Formula (IV) or (IVa), Z4is -CH2-. In some embodiments of a compound of Formula (IV) or (IVa), Z4is -CH2-.

[0199] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R”. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ . In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.WSGR Docket No. 57050-707.601

[0200] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ ; and wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R”. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen.

[0201] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R”. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’ .

[0202] In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl independently optionally substituted with one or more R’ . In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cealkyl.

[0203] In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen.

[0204] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”.

[0205] In some embodiments of a compound disclosed herein, L is absent or Ci-Csalkylene. In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is Ci-Csalkylene. In some embodiments of a compound disclosed herein, L is absent or -CH2-. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2.

[0206] In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)2Ci-C3alkyl, -NH2, -NHCi-Csalkyl, or -N(Ci-C3alkyl)2; wherein each alkyl isWSGR Docket No. 57050-707.601optionally substituted with one or more halogen; and / or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, -NHCi-C3alkyl, or -N(Ci-C3alkyl)2; wherein each alkyl is optionally substituted with one or more halogen; and / or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, or -NH2; wherein each alkyl is optionally substituted with one or more halogen; and / or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi-C3alkyl, or -NH2. In some embodiments of a compound disclosed herein, each R’ is independently halogen.

[0207] In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, or Ci-C3heteroalkyl; wherein each alkyl is optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, Ci-C3alkyl, or Ci-C3heteroalkyl; wherein each alkyl is optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, Ci-C3alkyl, or Ci-C3heteroalkyl; wherein each alkyl is optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, Ci-C3alkyl, or Ci-C3heteroalkyl. In some embodiments of a compound disclosed herein, each R” is independently halogen, -OH, -OCi-C3alkyl, or Ci-C3alkyl. In some embodiments of a compound disclosed herein, each R” is independently halogen or Ci-C3alkyl.

[0208] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0209] In some embodiments, the compound is selected from a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, found in Table 1.Table 1WSGR Docket No. 57050-707.601<WSGR Docket No. 57050-707.601>WSGR Docket No. 57050-707.601WSGR Docket No. 57050-707.601WSGR Docket No. 57050-707.601<<"WSGR Docket No. 57050-707.601WSGR Docket No. 57050-707.601WSGR Docket No. 57050-707.601WSGR Docket No. 57050-707.601* stereochemistry assigned arbitrarily.

[0210] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.

[0211] The OR label (or) denotes a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with pure structures isolated, multiple OR labels (OR indicates purity) with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0212] The AND label (and or &) denotes both isomers are present at the depicted stereochemical center. Assigning different numerical values to the AND labels denotes that they are independent of each other. The use of AND labels with the same values indicate that the two stereocenters are relative to each other and can only change in concert.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0213] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods providedWSGR Docket No. 57050-707.601herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0214] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents.

[0215] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0216] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treatingWSGR Docket No. 57050-707.601diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0217] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0218] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0219] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.WSGR Docket No. 57050-707.601

[0220] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(CI.C4 alkyl)4 hydroxide, and the like.

[0221] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0222] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0223] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Tautomers

[0224] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and one or more adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.Method of Treatment

[0225] Provided herein are methods for treating TRPML1 -mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound disclosed herein effective to reduce or prevent said disorder in the subject, in combination with at leastWSGR Docket No. 57050-707.601one additional agent for the treatment of said disorder that is known in the art. Certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more additional agents for the treatment of TRPML1 -mediated disorders.

[0226] Also, provided herein are compounds for use in the manufacture of a medicament for the treatment of a TRPML1 mediated disease. Further provided herein is a method of treatment of a disease mediated by TRPML1 activity, in a mammalian subject, which comprises administering a therapeutically effective amount of a compound disclosed herein.

[0227] TRPML1 -mediated diseases include proliferative disorders, such as cancers, inflammatory disorders, pain, neurodegenerative disorders, cognitive and psychiatric disorders, and other diseases as disclosed below.

[0228] TRPML1 -mediated disorder or disease is aging, bone diseases, cardiovascular diseases, congenital developmental disorders, eye diseases, hematological and solid malignancies, infectious diseases, inflammatory diseases, liver diseases, metabolic diseases, neurological or neurodegenerative diseases, pancreatitis, renal diseases, skeletal muscle disorders, obesity, lysosomal storage diseases, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget’s disease, or pulmonary diseases.

[0229] In some embodiments, the TRPML1 -mediated disorder or disease is Aicardi-Goutieres syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-telangiectasia, autism spectrum disorders, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant diseases, Chronic Wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jacob disease, Danon disease, Duchenne muscular dystrophy, exotic ungulate encephalopathy, Fabre disease, Fatal Familial insomnia, Friedreich ataxia, Feline spongiform encephalopathy, Fragile X, frontal temporal dementia, Gaucher disease, Gerstmann-Straussler-Scheinker disease, Giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington's disease, Infantile Refsum disease, JUNQ and IPOD, Krabbe’s disease, Kuru, Leukoencephalopathy, Lewy Body dementia, locomotor ataxia, Lyme disease, Machado Joseph disease, major depressive disorder, MPS-III, mucolipidosis, multiple sulfatase deficiency, multiple systems atrophy, myofibrillar myopathies, myotonic dystrophy, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Parkinson's disease, Parkinsonism, Pick's disease, polyglutamine diseases, Pompe disease, pontocerebellar hypoplasia, prion diseases, progressive nuclear palsy, progressive Supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie, Shy -Drager syndrome, spinal muscular atrophy, spinocerebellar ataxias, sporadic familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, transneuronal degeneration, tuberous Sclerosis, Spinocerebellar Ataxia’s, or vascular dementia.

[0230] In some embodiments, the TRPML1 -mediated disorder or disease is age-related macular degeneration, non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), retinal cell degeneration in glaucoma, retinitis pigmentosa, acute kidney injury, atherosclerosis, Crohn’s disease, diabeticWSGR Docket No. 57050-707.601nephropathy, female infertility, H. pylori infections, hypochlorhydria, pancreatitis, retinal detachment, type 2 diabetes mellitus, ulcerative colitis, or sarcopenia.

[0231] The compounds disclosed herein are useful for the treatment of neurodegenerative disorders of various origins such as Alzheimer’s disease and other dementia conditions such as Lewy body dementia, fronto -temporal dementia and other tauopathies; amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease and other parkinsonian syndromes; Huntington’s disease; HIV -induced neuroinflammation; essential tremors; other spinocerebellar degenerations, neuropathies such as Charcot-Marie-Tooth neuropathy and other TRPML1 -mediated diseases such as Type IV mucolipidosis (MLIV). The compounds disclosed herein are also useful for the treatment of neurological conditions such as epilepsy including simple partial seizure, complex partial seizure, secondary generalized seizure, further including absence seizure, myoclonic seizure, clonic seizure, tonic seizure, tonic clonic seizure, and atonic seizure, and for prevention and treatment of status epilepticus (SE).

[0232] The compounds disclosed herein are also useful for the treatment of cognitive disorders and of psychiatric disorders. Psychiatric disorders include, and are not limited to major depression, dysthymia, mania, bipolar disorder (such as bipolar disorder type I, bipolar disorder type II), cyclothymic disorder, rapid cycling, ultradian cycling, mania, hypomania, schizophrenia, schizophreniform disorders, schizoaffective disorders, personality disorders, attention disorders with or without hyperactive behavior, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorder due to a general medical condition, substance-induced psychotic disorders or a psychotic disorder not otherwise specified, anxiety disorders such as generalized anxiety disorder, panic disorders, post-traumatic stress disorder, impulse control disorders, phobic disorders, dissociative states. The compounds disclosed herein are also useful for the treatment of smoking addiction, drug addiction, or alcoholism. The compounds disclosed herein are particularly useful for the treatment of bipolar disorders, psychosis, anxiety, or addiction.

[0233] The compounds disclosed herein are useful in the prevention or treatment of neuroinflammation and CNS damage induced by HIV infection and of HIV-associated neurocognitive deficits. The compounds disclosed herein are useful in the prevention or treatment of neuropathic pain. Neuropathic pain syndromes include, and are not limited to: chemotherapy -induced peripheral neuropathy, diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV -related neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia, Morton’s neuralgia, causalgia; and pain resulting from physical trauma, amputation, phantom limb, cancer, toxins or chronic inflammatory conditions; central pain such as the one observed in thalamic syndromes, mixed central and peripheral forms of pain such as complex regional pain syndromes (CRPS) also called reflex sympathetic dystrophies.

[0234] The compounds disclosed herein are also useful for the treatment of pain, including chronic pain. Chronic pain includes, and is not limited to, chronic pain caused by inflammation or an inflammatory-related condition, osteoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (resulting from systematic, regional or primary spine disease such asWSGR Docket No. 57050-707.601radiculopathy), bone pain (due to osteoarthritis, osteoporosis, bone metastasis or unknown reasons), pelvic pain, spinal cord injury-associated pain, cardiac chest pain, non-cardiac chest pain, central poststroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry’s disease, AIDS pain, geriatric pain or pain caused by headache, temporomandibular joint syndrome, gout, fibrosis or thoracic outlet syndromes, in particular rheumatoid arthritis and osteoarthritis.

[0235] The compounds disclosed herein are also useful in the treatment of acute pain caused by acute injury, illness, sport-medicine injuries, carpal tunnel syndrome, bums, musculoskeletal sprains and strains, musculotendinous strain, cervicobrachial pain syndromes, dyspepsia, gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis, or surgery (such as open heart or bypass surgery), post-operative pain, kidney stone pain, gallbladder pain, gallstone pain, obstetric pain, or dental pain.

[0236] The compounds disclosed herein are also useful in the treatment of headaches such as migraine, tension type headache, transformed migraine or evolutive headache, cluster headache, as well as secondary headache disorders, such as the ones derived from infections, metabolic disorders or other systemic illnesses and other acute headaches, paroxysmal hemicrania and the like, resulting from a worsening of the above mentioned primary and secondary headaches.

[0237] The compounds disclosed herein are also useful in the treatment of diseases such as vertigo, tinnitus, muscle spasm, and other disorders including and not limited to cardiovascular diseases (such as cardiac arrhythmia, cardiac infarction or angina pectoris, hypertension, cardiac ischemia, cerebral ischemia) endocrine disorders (such as acromegaly or diabetes insipidus) diseases in which the pathophysiology of the disorder involves excessive or hypersecretory or otherwise inappropriate cellular secretion of an endogenous substance (such as catecholamine, a hormone or a growth factor).

[0238] The compounds disclosed herein are also useful in the selective treatment of liver disease, such as inflammatory liver diseases, for example chronic viral hepatitis B, chronic viral hepatitis C, alcoholic liver injury, primary biliary cirrhosis, autoimmune hepatitis, liver fibrosis, non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), and liver transplant rejection.

[0239] The compounds disclosed herein inhibit inflammatory processes affecting all body systems. Therefore, they are useful in the treatment of inflammatory processes of the musculoskeletal system of which the following is a list of examples but it is not comprehensive of all target disorders: arthritic conditions such as ankylosing spondylitis, cervical arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, rheumatic disease; disorders affecting skin and related tissues: eczema, psoriasis, dermatitis and inflammatory conditions such as sunbum; disorders of the respiratory system: asthma, allergic rhinitis and respiratory distress syndrome, lung disorders in which inflammation is involved such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and endocrinological systems: periarthritis nodosa, thyroiditis, aplastic anaemia, scleroderma, myasthenia gravis, multiple sclerosis and other demyelinating disorders, encephalomyelitis, sarcoidosis, nephritic syndrome, Bechet’s syndrome, polymyositis, gingivitis.WSGR Docket No. 57050-707.601

[0240] The compounds disclosed herein are also useful in the treatment of gastrointestinal (GI) tract disorders such as inflammatory bowel disorders (IBD) including but not limited to ulcerative colitis, Crohn’s disease, ileitis, proctitis, celiac disease, enteropathies, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis resulting after proctocolectomy and post ileonatal anastomosis, and irritable bowel syndrome including any disorders associated with abdominal pain and / or abdominal discomfort such as pylorospasm, nervous indigestion, spastic colon, spastic colitis, spastic bowel, intestinal neurosis, functional colitis, mucous colitis, laxative colitis and functional dyspepsia; but also for treatment of atrophic gastritis, gastritis varioliforme, ulcerative colitis, peptic ulceration, pyrosis, and other damage to the GI tract, for example, by Helicobacter pylori, gastroesophageal reflux disease, gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders, such as non-ulcerative dyspepsia (NUD); pancreatitis, emesis, diarrhea, visceral inflammation, and hypochlorhydria.

[0241] The compounds disclosed herein are also useful in the treatment of disorders of the genitourinary tract such as overactive bladder, prostatitis (chronic bacterial and chronic nonbacterial prostatitis), prostadynia, interstitial cystitis, urinary incontinence, and benign prostatic hyperplasia, annexities, pelvic inflammation, bartholinitis and vaginitis. In particular, overactive bladder and urinary incontinence.

[0242] The compounds disclosed herein are also useful in the treatment of renal disorders including diabetic nephropathy, renal allograft rejection, infectious renal diseases, IgA nephropathy, fibrotic kidney disease, lupus nephritis, glomerulonephritis, acute kidney injury, and renal carcinoma.

[0243] The compounds disclosed herein are also useful in the treatment of ophthalmic diseases such as retinitis, retinitis pigmentosa, retinopathies, uveitis, acute injury to the eye tissue, age-related macular degeneration, glaucoma, retinal cell degeneration in glaucoma, conjunctivitis, and retinal detachment.

[0244] The compounds disclosed herein are also useful in the treatment of eating disorders such as anorexia nervosa including the subtypes restricting type and binge -eating / purging type; bulimia nervosa including the subtypes purging type and non-purging type; obesity; compulsive eating disorders; binge eating disorder; and eating disorder not otherwise specified.

[0245] The compounds disclosed herein are also useful in the treatment of allergic dermatitis, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, Sjogren’s syndrome, glomerulonephritis, atherosclerosis, growth, and metastases of malignant cells, myoblastic leukemia, diabetes (type 2 diabetes mellitus), meningitis, osteoporosis, bum injury, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, glaucoma, and female infertility.

[0246] In some embodiments, the compounds and pharmaceutical compositions of the present disclosure are useful in the treatment or prevention of progression of cancer. In some embodiments, the cancer is a hematologic malignancy or solid tumor. Hematologic malignancies include leukemias, lymphomas, multiple myeloma, and subtypes thereof. Lymphomas can be classified various ways, often based on the underlying type of malignant cell, including Hodgkin’s lymphoma (often cancers of Reed-Sternberg cells, but also sometimes originating in B cells; all other lymphomas are non -Hodgkin’sWSGR Docket No. 57050-707.601lymphomas), B-cell lymphomas, T-cell lymphomas, mantle cell lymphomas, Burkitt’s lymphoma, follicular lymphoma, and others as defined herein and known in the art.

[0247] B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), and others as defined herein and known in the art.

[0248] T-cell lymphomas include T-cell acute lymphoblastic leukemia / lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), T-cell chronic lymphocytic leukemia (T-CLL) Sezary syndrome, and others as defined herein and known in the art.

[0249] Leukemias include acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL) hairy cell leukemia (sometimes classified as a lymphoma) and others as defined herein and known in the art.

[0250] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma.

[0251] Solid tumors include melanomas, neuroblastomas, gliomas or 5 carcinomas such as tumors of the brain, head and neck, breast, lung (e.g., non-small cell lung cancer, NSCLC), reproductive tract (e.g., ovary), upper digestive tract, pancreas, liver, renal system (e.g., kidneys), bladder, prostate and colorectum.

[0252] Besides being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.Dosing

[0253] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0254] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0255] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency ofWSGR Docket No. 57050-707.601administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0256] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Routes of Administration

[0257] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0258] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate-release formulation. In some embodiments, the compound described herein is administered topically.Pharmaceutical Compositions / Formulations

[0259] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0260] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent uponWSGR Docket No. 57050-707.601the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0261] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fdling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, and any combinations thereof.

[0262] The pharmaceutical compositions described herein are administered to a subject by appropriate administration routes, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0263] Pharmaceutical compositions including compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0264] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.WSGR Docket No. 57050-707.601

[0265] Pharmaceutical compositions that are administered orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

[0266] Pharmaceutical compositions for parental use are formulated as infusions or injections. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes sterile aqueous solutions, or dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and any combinations thereof. In some embodiments, the pharmaceutical compositions further comprise a preservative to prevent growth of microorganisms.Combination

[0267] Disclosed herein are methods of treating a TRPML1 -mediated disorder or disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0268] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.SYNTHETIC PROCEDURES

[0269] Abbreviations which are used in the description of the Schemes and the Examples that follows include:ACN: AcetonitrileCH3I: lodomethaneDCM: DichloromethaneDMF: DimethylformamideDMSO: DimethylsulfoxideWSGR Docket No. 57050-707.601ESI: Electrospray ionizationEtOAc: Ethyl acetateh: hourK2CO3: Potassium carbonateM: MolarMeOH: MethanolMin: Minute(s)MS: Molecular sievesNMR: Nuclear Magnetic ResonanceNaH : Sodium hydrideNaOH: Sodium hydroxideNa2SC>4: Sodium sulfateon: overnightrt: Room TemperatureSEM: 2-(chloromethoxy)ethyl-trimethyl-silaneTFA: Trifluoroacetic acidTHF: TetrahydrofuranTEA: TriethylamineUPLC-MS: Ultra Performance Liquid Chromatography-Mass Spectrometryy: yield or yields.

[0270] The following examples illustrate the present invention. Unless explicitly stated otherwise, all measurements (especially percentages and amounts) relate to weight.

[0271] For the synthesis of the examples of the invention, commercially available starting materials are used; the non-commercially available building blocks have been synthesized using the following procedures.Synthesis of Intermediate A: l-[(lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]butan-l-oneReag. A cas:113451 -59-5

[0272] Step 1: DIEA (396 pL, 2.27 mmol) and butyryl chloride (172 pL, 1.66 mmol) were added to a mixture of (lS,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (CAS: 113451-59-5, 300 mg, 1.51 mmol) in dry DCM (16.0 mb) at 23°C under nitrogen. The mixture was stirred at 23 °C for 2 h. The mixture was diluted with H2O (30.0 mb) and extracted with DCM (3 x 15.0 mb). The combined organic extracts were dried (MgSCE), fdtered, and concentrated. The residue was purified by silica gel column chromatographyWSGR Docket No. 57050-707.601(12 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (360 mg, 89%).

[0273] Step 2: TLA (517 pL, 6.71 mmol) was added to a mixture of tert-butyl (lS,4S)-5-butanoyl-2,5- diazabicyclo[2.2.1]heptane-2 -carboxylate (360 mg, 1.34 mmol) in DCM (8.00 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and concentrated. The residue was purified by preparative HPLC chromatography (LUNA, Silica) with water [0.1% TLA] and ACN (5-95%) to provide the title compound as a solid (150 mg, 67%). 'HNMR (400 MHz, DMSO-d6) 59.09 (s, 1H), 8.71 (s, 1H), 4.69 (d, J = 9.4 Hz, 1H), 4.39 (d, 1H), 3.54 (d, J = 1.8 Hz, 1H), 3.45 - 3.26 (m, 1H), 2.39 - 2.17 (m, 1H), 2.16 - 1.90 (m, 2H), 1.86 - 1.71 (m, 1H), 1.57 - 1.42 (m, 2H), 0.91 - 0.82 (m, 3H)Synthesis of Intermediate B: l-[(lS,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]butan-l-onecas:57260-71-6

[0274] Step 1: DIEA (422 pL, 2.42 mmol) and butyryl chloride (183 pL, 1.77 mmol) were added to a mixture of mono-BOC-Piperazine (CAS:57260-71-6, 300 mg, 1.61 mmol) in dry DCM (17.0 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 2 h. The mixture was diluted with H2O (30.0 mL) and extracted with DCM (3 x 15.0 mL). The combined organic extracts were dried (MgSCL), filtered and concentrated. The residue was purified by silica gel column chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (413 mg, 100%).

[0275] Step 2: TLA (863 pL, 11.2 mmol) was added to a mixture of tert-butyl 4-butanoylpiperazine- 1-carboxylate (410 mg, 1.60 mmol) in DCM (9.00 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and concentrated. The residue was purified by preparative HPLC chromatography (LUNA, Silica) with water [0.1% TLA] and ACN (5-95%) to provide the title compound as a solid (240 mg, 96%). 'HNMR (400 MHz, DMSO-d6) 58.85 (s, 1H), 3.63 (t, J = 4.9 Hz, 2H), 3.08 (d, J = 19.6 Hz, 2H), 2.31 (t, J = 7.4 Hz, 1H), 1.51 (h, J = 7.4 Hz, 1H), 0.89 (t, J = 7.4 Hz, 1H)Synthesis of Intermediate C: 7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride

[0276] Step 1: w-BuLi (2.50 M in hexanes, 15.0 mL, 37.5 mmol) was added to a mixture of DIPEA (5.55 mL, 39.6 mmol) in THE (15.0 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to a mixture of tert-butyl 6-oxo-l,3,4,7,8,8a-hexahydropyrrolo[l,2-a]pyrazine-2-carboxylate (CAS: 1429200-16-7, 1.32 g, 5.50 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78WSGR Docket No. 57050-707.601°C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixture was diluted with sat. aq. NH4C1 (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were, dried (MgSCL). fdtered, and concentrated. The residue was purified by reverse phase chromatography (C 18, 86 g cartridge) with [10 mM (NH4XHCO2)] and ACN (30- 100%) to provide a title compound as a solid (700 mg, 96%).

[0277] Step 2: Tert-butyl 7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazine-2- carboxylate (870 mg, 3.24 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 20.0 mL, 80.0 mmol) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and diluted with ACN (100 mL). The mixture was concentrated to provide a title compound as a solid (680 mg, 99%). ’H NMR (500 MHz, DMSO-de) 59.41 (s, 2H), 3.96 - 3.89 (m, 1H), 3.75 (dtd, J = 11.3, 7.6, 3.7 Hz, 1H), 3.43 (dd, J = 12.2, 3.7 Hz, 1H), 3.30 (dd, J = 12.5, 3.6 Hz, 1H), 3.05 (ddd, J = 14.0, 12.7, 3.7 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.65 (t, J = 11.9 Hz, 1H), 2.07 (dd, J = 12.7, 7.1 Hz, 1H), 1.49 (dd, J = 12.8, 8.0 Hz, 1H), 1.09 (s, 3H), 1.02 (s, 3H).Synthesis of Intermediate D: 7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido [l,2-a]pyrazin-6-one hydrochloride> "

[0278] Step 1: BOC2O (0.781 mL, 3.40 mmol) was added to a mixture of 1,2,3,4,7,8,9,9a- octahydropyrido[l,2-a]pyrazin-6-one hydrochloride (CAS: 930782-67-5, 0.540 g, 2.83 mmol), and TEA (0.789 mL, 5.66 mmol) in DCM (20.0 mL) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 16 h and diluted with H2O (5.00 mL). The aqueous phase was extracted with DCM (2 x 30.0 mL), and the combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-10%) to provide the title compound as a solid (720 mg, 96%).

[0279] Step 2: w-BuLi (2.50 M in hexanes, 5.00 mL, 12.5 mmol) was added to a mixture of DIPEA (1.90 ml, 13.6 mmol) in THF (8.60 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to a mixture of tert-butyl 6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine-2-carboxylate (0.720 g, 2.83 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78 °C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixture was diluted with sat. aq. NH4CI (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purified by reverse phase chromatography (C18, 86 g cartridge) with [10 mM (NH4)(HCC>2)] and ACN (30-100%) to provide a title compound as a solid (622 mg, 76%).WSGR Docket No. 57050-707.601

[0280] Step 3: Tert-butyl 6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine-2-carboxylate (0.720 g, 2.83 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 6.00 mb, 24.0 mmol) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 4 h and diluted with ACN (40.0 mL). The mixture was concentrated to provide a title compound as a solid (516 mg, 92%). ’H NMR (500 MHz, DMSO-de) 5 9.46 (s, 2H), 4.54 - 4.47 (m, 1H), 3.74 - 3.63 (m, 1H), 3.28 (d, J = 10.1 Hz, 1H), 3.25 - 3.20 (m, 1H), 2.86 - 2.74 (m, 3H), 1.94 - 1.85 (m, 1H), 1.67 - 1.52 (m, 3H), 1.12 (s, 3H), 1.09 (s, 3H).Synthesis of Intermediate E: (9aS)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-

[0281] Step l: w-BuLi (2.50 M in hexanes, 5.00 mL, 12.5 mmol) was added to a mixture of DIPEA (1.90 ml, 13.6 mmol) in THF (8.60 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to amixture of 1,1 -Dimethylethyl (9aS)-octahydro-6-oxo-2H-pyrido[ l,2-a]pyrazine-2 -carboxylate (CAS:2763584-39-8, 0.720 g, 2.83 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78 °C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixture was diluted with sat. aq. NFLCl (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCL), filtered, and concentrated. The residue was purified by reverse phase chromatography (C18, 86 g cartridge) with [10 mM (NH4XHCO2)] and ACN (30-100%) to provide the title compound as a solid (622 mg, 76%).

[0282] Step 2: (9aS)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (0.720 g, 2.83 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 6.00 mL, 24.0 mmol) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 4 h and diluted with ACN (40.0 mL). The mixture was concentrated to provide a title compound as a solid (516 mg, 92%). ’H NMR (500 MHz, DMSO-de) 59.46 (s, 2H), 4.54 - 4.47 (m, 1H), 3.74 - 3.63 (m, 1H), 3.28 (d, J = 10.1 Hz, 1H), 3.25 -3.20 (m, 1H), 2.86 - 2.74 (m, 3H), 1.94 - 1.85 (m, 1H), 1.67 - 1.52 (m, 3H), 1.12 (s, 3H), 1.09 (s, 3H).Synthesis of Intermediate F: (9aR)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-

[0283] Step l: w-BuLi (2.50 M in hexanes, 5.00 mL, 12.5 mmol) was added to a mixture of DIPEA (1.90 ml, 13.6 mmol) in THF (8.60 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to amixture of 1,1 -Dimethylethyl (9a / ?)-octahydro-6-oxo-2 / / -pyrido| l.2-«|pyrazinc-2 -carboxylate (CAS:2763584-74-l, 0.720 g, 2.83 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78 °C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixture wasWSGR Docket No. 57050-707.601diluted with sat. aq. NH4CI (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purified by reverse phase chromatography (C18, 86 g cartridge) with [10 mM (NH4XHCO2)] and ACN (30-100%) to provide a title compound as a solid (622 mg, 76%).

[0284] Step 2: (9aR)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (0.720 g, 2.83 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 6.00 mL, 24.0 mmol) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 4 h and diluted with ACN (40.0 mL). The mixture was concentrated to provide a title compound as a solid (516 mg, 92%). ’H NMR (500 MHz, DMSO-d6) 59.46 (s, 2H), 4.54 - 4.47 (m, 1H), 3.74 - 3.63 (m, 1H), 3.28 (d, J = 10.1 Hz, 1H), 3.25 -3.20 (m, 1H), 2.86 - 2.74 (m, 3H), 1.94 - 1.85 (m, 1H), 1.67 - 1.52 (m, 3H), 1.12 (s, 3H), 1.09 (s, 3H).Synthesis of Intermediate G: (3aS)-2,2-dimethyl-3,3a,4,5,6,7-hexahydroisothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride

[0285] Step 1: LiHMDS (1 M in THF, 41.9 mL, 41.9 mmol) was added to a solution of tert-butyl (3R)-4-methylsulfonyl-3-(methylsulfonyloxymethyl)piperazine-l-carboxylate (CAS: 2839555-18-7, 3.90 g, 10.5 mmol) in THF (25.0 mL) at - 78 °C. The mixture was stirred at 23 °C for 1 h and diluted with sat. aq. NaHCOs (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na2SC>4), filtered, and concentrated. The residue was purified by silica gel chromatography (50 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (1.85 g, 64%).

[0286] Step 2: Freshly prepared LiDA (1 M in THF, 26.8 mL, 26.8 mmol) was added to a mixture of tert-butyl (3aS)-l,l-dioxo-2,3,3a,4,6,7-hexahydroisothiazolo[2,3-a]pyrazine-5-carboxylate (1.85 g, 6.69 mmol) and iodomethane (2.38 mL, 38.2 mmol) in THF (25.0 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h and at 23 °C for 1 h and diluted with sat. aq. NH4C1 (25.0 mL) and water (25.0 mL). The aqueous phase was extracted with EtOAc (2 x 40.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na2SO4), filtered, and concentrated to provide the title compound as a solid (1.60 g, 79%).Step 3: HC1 (4 M in 1,4-dioxane, 6.00 mL, 24.0 mmol) was added to tert-butyl (3aS)-2,2-dimethyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-isothiazolo[2,3-a]pyrazine-5-carboxylate (1.60 g, 5.26 mmol) at 23 °C. The mixture was stirred at 23 °C for 3 h and diluted with Et2O (10.0 mL). The solid was filtered, washed with Et2O (2 x 10.0 mL) and dried to provide the title compound as a solid (1.12 g, 89%). ’H NMR (400 MHz, DMSO-d6) 59.42 (s, 2H), 3.52 - 3.48 (m, 1H), 3.45 - 3.40 (m, 1H), 3.40 - 3.32 (m, 2H), 3.02 (td, J = 12.4, 2.6 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.81 - 2.72 (m, 1H), 2.37 - 2.28 (m, 1H), 1.82 (dd, J = 13.2, 8.7 Hz, 1H), 1.38 (s, 3H), 1.33 (s, 3H).WSGR Docket No. 57050-707.601Synthesis of Intermediate H: (3aR)-2,2-dimethyl-3,3a,4,5,6,7-hexahydroisothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloride

[0287] Step 1: LiHMDS (1 M in THF, 41.9 mL, 41.9 mmol) was added to a solution of tert-butyl (3S)-4-methylsulfonyl-3-(methylsulfonyloxymethyl)piperazine-l-carboxylate (CAS: 1613193-77-3, 3.90 g, 10.5 mmol) in THF (25.0 mL) at - 78 °C. The mixture was stirred at 23 °C for 1 h and diluted with sat. aq. NaHCOs (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na2SC>4), filtered, and concentrated. The residue was purified by silica gel chromatography (50 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (1.85 g, 64%).

[0288] Step 2: Freshly prepared LiDA (1 M in THF, 26.8 mL, 26.8 mmol) was added to a mixture of tert-butyl (3aR)-l,l-dioxo-2,3,3a,4,6,7-hexahydroisothiazolo[2,3-a]pyrazine-5-carboxylate (1.85 g, 6.69 mmol) and iodomethane (2.38 mL, 38.2 mmol) in THF (25.0 mL) at -78 °C. The mixture was stirred at -78 °C for 1 h and at 23 °C for 1 h and diluted with sat. aq. NH4C1 (25.0 mL) and water (25.0 mL). The aqueous phase was extracted with EtOAc (2 x 40.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na2SO4), filtered, and concentrated to provide the title compound as a solid (1.60 g, 79%).

[0289] Step 3: HC1 (4 M in 1,4-dioxane, 6.00 mL, 24.0 mmol) was added to tert-butyl (3aR)-2,2-dimethyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-isothiazolo[2,3-a]pyrazine-5-carboxylate (1.60 g, 5.26 mmol) at 23 °C. The mixture was stirred at 23 °C for 3 h and diluted with Et2O (10.0 mL). The solid was filtered, washed with Et2O (2 x 10.0 mL) and dried to provide the title compound as a solid (1.12 g, 89%). 'HNMR (400 MHz, DMSO-d6) 59.42 (s, 2H), 3.52 - 3.48 (m, 1H), 3.45 - 3.40 (m, 1H), 3.40 -3.32 (m, 2H), 3.02 (td, J = 12.4, 2.6 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.81 - 2.72 (m, 1H), 2.37 - 2.28 (m, 1H), 1.82 (dd, J = 13.2, 8.7 Hz, 1H), 1.38 (s, 3H), 1.33 (s, 3H).Synthesis of Intermediate I: (8aR)-7,7-dimethyl-l,2,3,4,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one;hydrochloride

[0290] Step l: w-BuLi (2.50 M in hexanes, 15.0 mL, 37.5 mmol) was added to a mixture of DIPEA (5.55 mL, 39.6 mmol) in THF (15.0 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to a mixture of 1,1 -Dimethylethyl (8aR)-hexahydro-6-oxopyrrolo[l,2-a]pyrazine-2(lH)-carboxylate ( CAS: 2412857-06-6, 1.32 g, 5.50 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78 °C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixtureWSGR Docket No. 57050-707.601was diluted with sat. aq. NH4C1 (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCh). filtered, and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 86 g cartridge) with [10 mM (NH4XHCO2)] and ACN (30-100%) to provide a title compound as a solid (700 mg, 96%).

[0291] Step 2: Tert-butyl (8aR)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazine-2-carboxylate (870 mg, 3.24 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 20.0 mL, 80.0 mmol) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and diluted with ACN (100 mL). The mixture was concentrated to provide a title compound as a solid (680 mg, 99%). ’H NMR (500 MHz, DMSO-de) 59.41 (s, 2H), 3.96 - 3.89 (m, 1H), 3.75 (dtd, J = 11.3, 7.6, 3.7 Hz, 1H), 3.43 (dd, J = 12.2, 3.7 Hz, 1H), 3.30 (dd, J = 12.5, 3.6 Hz, 1H), 3.05 (ddd, J = 14.0, 12.7, 3.7 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.65 (t, J = 11.9 Hz, 1H), 2.07 (dd, J = 12.7, 7.1 Hz, 1H), 1.49 (dd, J = 12.8, 8.0 Hz, 1H), 1.09 (s, 3H), 1.02 (s, 3H).Synthesis of Intermediate J: (8aS)-7,7-dimethyl-l,2,3,4,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one;hydrochloride

[0292] Step 1: w-BuLi (2.50 M in hexanes, 15.0 mL, 37.5 mmol) was added to a mixture of DIPEA (5.55 mL, 39.6 mmol) in THF (15.0 mL) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to a mixture of 1,1 -Dimethylethyl (8aS)-hexahydro-6-oxopyrrolo[l,2-a]pyrazine-2(H7)-carboxylate (CAS: 2412856-87-0, 1.32 g, 5.50 mmol), iodomethane (2.02 mL, 32.5 mmol) in THF (20.0 mL) at -78 °C under nitrogen. The mixture was stirred at -72 °C for 1 h and at 23 °C for 1 h. The mixture was diluted with sat. aq. NH4CI (5.00 mL). The aqueous phase was extracted with DCM (2 x 20.0 mL), and the combined organic extracts were dried (MgSCfi). filtered, and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 86 g cartridge) with [10 mM (NH4XHCO2)] and ACN (30-100%) to provide a title compound as a solid (700 mg, 96%).

[0293] Step 2: Tert-butyl (8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazine-2-carboxylate (870 mg, 3.24 mmol) was diluted in HC1 (4 M in 1,4-dioxane, 20.0 mL, 80.0 mmol) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and diluted with ACN (100 mL). The mixture was concentrated to provide a title compound as a solid (680 mg, 99%). ’H NMR (500 MHz, DMSO-de) 59.41 (s, 2H), 3.96 - 3.89 (m, 1H), 3.75 (dtd, J = 11.3, 7.6, 3.7 Hz, 1H), 3.43 (dd, J = 12.2, 3.7 Hz, 1H), 3.30 (dd, J = 12.5, 3.6 Hz, 1H), 3.05 (ddd, J = 14.0, 12.7, 3.7 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.65 (t, J = 11.9 Hz, 1H), 2.07 (dd, J = 12.7, 7.1 Hz, 1H), 1.49 (dd, J = 12.8, 8.0 Hz, 1H), 1.09 (s, 3H), 1.02 (s, 3H).WSGR Docket No. 57050-707.601Example 1: 4-[({5,7-Diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]-N,N-dimethylbenzene-l-sulfonamideStep 1: 4-[({5,7-Diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]-JV,V-dimethylbenzene-l-sulfonamide

[0294] 4-(Aminomcthyl)-A.A-dimcthylbcnzcncsulfonamidc (CAS: 210918-25-5, 70.1 mg, 0.327 mmol) was added to a mixture of 4-chloro-5.7-diphcnyl-7 / / -pyrrolo|2.3-t / |pyrimidinc (CAS: 287177-10-0, 50.0 mg, 0.164 mmol) and DIEA (57.1 pL, 0.0980 mmol) in DMSO (1.20 mL) at 23 °C. The mixture was stirred at 120 °C for 16 h, cooled to 23 °C and diluted with water (2.00 mL). The aqueous phase was extracted with EtOAc (3 x 2.00 mL), and the combined organic extracts were washed with brine (5 x 2.00 mL), dried (MgSCL). filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in w-heptane (0-75%) to provide the title compound as a solid (63.0 mg, 80%).Example 2: Ethyl 4-({5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methyl)piperazine-l-carboxylateStep 1: 4-ethenyl-5,7-diphenyl-7H-pyrrolo [2, 3-d] pyrimidine

[0295] PdCl2(PPh3)2 (68.9 mg, 0.0980 mmol) was added to a mixture of 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-a pyrimidine (CAS:287177-10-0, 300 mg, 0.981 mmol), vinylboronic acid pinacol ester (226 mg, 1.47 mmol) and K2CO3 (407 mg, 3.38 mmol) in 1,4-dioxane (12.0 mL) and water (3.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 25.0 mL), and the combined organic extracts were washed with brine (2 x 50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in cyclohexane (0-25%) to provide the title compound as a solid (178 mg, 61%).Step 2: 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbaldehyde

[0296] NaIO4 (117 mg, 0.552 mmol) was added to a mixture of 4-ethenyl-5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (82.0 mg, 0.276 mmol) and OsO4 (21.0 mg, 0.0830 mmol) in 1,4-dioxane (2.75 mL) and water (1.35 mL) at 23 °C. The mixture was stirred at 23 °C for 16 h and diluted with water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 5.00 mL), and the combined organic extracts were washed with brine (2 x 10.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (23.0 mg, 28%).Step 3: Ethyl 4-({5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methyl)piperazine-l-carboxylate

[0297] 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbaldehyde (23.0 mg, 0.0770 mmol) was added to amixture of ethyl 1 -piperazinecarboxylate (CAS: 120-43-4, 18.2 mg, 0.115 mmol) in DCM (0.400 mL) at 23 °C. The mixture was stirred at 23 °C for 2 h and NaBH(OAc)3 (24.4 mg, 0.115 mmol) was added. The mixture was stirred at 23 °C for 16 h and diluted with water (1.00 mL). The aqueous phase was extracted with DCM (3 x 1.00 mL), and the combined organic extracts were washed with brine (2 x 1.00 mL) dried (MgSO4), filtered, and concentrated. The residue was purified by silica gelWSGR Docket No. 57050-707.601chromatography (4 g cartridge) using a gradient of EtOAc in n-heptane (0-50%) to provide the title compound (13.0 mg, 38%).Example 3: 4-[({l,3-Diphenyl-lH-pyrrolo[3,2-c]pyridin-4-yl}amino)methyl]-AyV-dimethylbenzene-1-sulfonamideStep 1: 4-chloro-3-iodo-l-phenyl-lH-pyrrolo[2,3-c]pyridine

[0298] Cui (74.9 mg, 0.393 mmol) and (lS,2S)-(+)-l,2-diaminocyclohexane (449 mg, 3.93 mmol) were added to a degassed mixture of 4-Chloro-3-iodo-lH-pyrrolo[3,2-c]pyridine (CAS: 1190313-39-3, 1.20 g, 7.87 mmol), iodobenzene (1.75 mL, 15.7 mmol) and K3PO4 (3.34 g, 15.7 mmol) in 1,4-dioxane (40.0 mL) at 23°C under nitrogen. The mixture was stirred at 100 °C for 16 h and diluted with DCM (100 mL). The mixture was fdtered through Celite, washed with DCM (100 mL), and the fdtrate was concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (1.56 g, 87%).Step 2: 4-[({l,3-Diphenyl-lH-pyrrolo[3,2-c]pyridin-4-yl}amino)methyl]-AyV-dimethylbenzene-l-sulfonamide

[0299] 4-(Aminomcthyl)-A.A-dimcthylbcnzcncsiilfonamidc (CAS:210918-25-5, 135 mg, 0.630 mmol) was added to a mixture of 4-chloro- 1 ,3-diphenyl- l / / -pyrrolo|3.2-c (pyridine (96.0 mg, 0.315 mmol) and DIEA (165 pL, 0.945 mmol) in NMP (0.950 mL). The mixture was stirred at 200 °C for 2 h and diluted with water (2.00 mL). The aqueous phase was extracted with EtOAc (3 x 2.00 mL), and the combined organic extracts were washed with brine (5 x 2.00 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NELXHCO3)] and MeCN (5-100%) to provide the title compound (63.0 mg, 41%).Example 4: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-Af^V-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0300] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, (5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0301] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and ISfeCCL (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filteredWSGR Docket No. 57050-707.601through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: AyV-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0302] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 202 mg, 0.945 mmol) and K2CO3 (131 mg, 0.945 mmol) were added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.472 mmol) in 1,4-dioxane (3.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, cooled to 23 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (149 mg, 58%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0303] TEA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NH4OH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0304] Cui (6.00 mg, 0.0320 mmol) was added to a mixture of K2CO3 (44.0 mg, 0.319 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (4.50 mg, 0.0320 mmol), 3 -bromobenzonitrile (CAS:6952-59-6, 58.0 mg, 0.319 mmol) and N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (65.0 mg, 0.160 mmol) in 1,4-dioxane (7.50 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 3.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (37.0 mg, 45%).Example 5: Ethyl 4-{5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl}piperazine-l-carboxylateStep 1: Methyl 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate

[0305] Pd(OAc)2 (22.0 mg, 0.0980 mmol) was added to a degassed mixture of 4-chloro-5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine (CAS:287177-10-0, 200 mg, 0.654 mmol), l,l'-bis(diphenyl-phosphino)ferrocene (54.4 mg, 0.0980 mmol) and NEb, (0.181 mL, 1.31 mmol) in a mixture of DMA (5.60 mL) and MeOH (1.60 mL) at 23°C under nitrogen. The mixture was stirred under carbon monoxideWSGR Docket No. 57050-707.601(10 bar) at 80 °C for 16 h, cooled to 23 °C and diluted with EtOAc (15.0 mL). The organic phase was washed with sat. aq. NH4CI (15.0 mL) solution, dried (MgSCh). fdtered and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (152 mg, 71%).Step 2: 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid

[0306] LiOH (1 M in H2O, 0.911 mL, 0.911 mmol) was added to a mixture of methyl 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate (150 mg, 0.455 mmol) in MeOH (2.3 mL) at 23 °C. The mixture was stirred at 23 °C for 16 h and diluted with 2 M aq. HC1 to pH 2. The solid was filtered and dried to provide the title compound as a solid (140 mg, 98%).Step 3: Ethyl 4-{5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl}piperazine-l-carboxylate

[0307] HATU (127 mg, 0.333 mmol) was added to a mixture of 5,7-diphenyl-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylic acid (70.0 mg, 0.222 mmol), DIEA (0.155 mL, 0.888 mmol) and ethyl 1-piperazinecarboxylate (CAS: 120-43-4, 0.0490 mL, 0.333 mmol) in DME (0.880 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and directly purified by preparative HPLC (BEH, C18) with water [10 mM (NH4)(HCOs)] and MeCN (5-100%) to provide the title compound (82.0 mg, 81%).Example 6: N,N-Dimethyl-4-({[5-phenyl-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0308] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DML (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0309] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS: 98-80-6, 2.88 g, 23.6 mmol) and Na2CO3 (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%).WSGR Docket No. 57050-707.601Step 3: AyV-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0310] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 202 mg, 0.945 mmol) and K2CO3 (131 mg, 0.945 mmol) were added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.472 mmol) in 1,4-dioxane (3.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, cooled to 23 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (149 mg, 58%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0311] TFA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NH4OH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: N,N-Dimethyl-4-({[5-phenyl-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0312] (lS,2S)-(+)-N,N'-Dimethyl-l,2-cyclohexanediamine (8.40 mg, 0.0600 mmol) was added to a mixture of 4-iodopyridine (CAS: 15854-87-2, 120 mg, 0.590 mmol), N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (120 mg, 0.29 mmol), Cui (11.2 mg, 0.06 mmol) and K2CO3 (82 mg, 0.59 mmol) in 1,4-dioxane (1.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 16 h, cooled to 23 °C and diluted with brine (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 15.0 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound (110 mg, 77%). 60 mg was further purified by reverse phase chromatography (Cl 8, 13 g cartridge) with water [10 mM (NH4)(HCO3)] and MeCN (0-95%).Example 7: Af^V-Dimethyl-4-({methyl[5-phenyl-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamideStep 1: N^V-Dimethyl-4-({methyl[5-phenyl-7-(pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0313] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4 A.A-dimcthy 1-4-( { [5 -phenyl-7 -(pyridin-4-yl)-7H-pyrrolo [2,3 -d]pyrimidin-4-yl]amino }methyl)benzene- 1 -sulfonamide Example 6 (50.0 mg, 0.100 mmol) in DMF (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 30 min. Mel (8.00 pL, 0.120 mmol) was added at 23 °C under nitrogen. The mixture was stirred at 23 °C for 16 h and diluted with water (10.0 mL). The aqueous phase was extracted with EtOAcWSGR Docket No. 57050-707.601(3 x 15.0 mL). The combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 13 g cartridge) with water and MeCN (0-95%) to provide the title compound (24.0 mg, 47%).Example 8: Ethyl 4-[[7-(3-cyanophenyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-1-carboxylateStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0314] NaH (60% in mineral oil, 4.14 g, 104 mmol) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 18.1 g, 64.8 mmol) in DMF (300 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 15 min. 2-(chloromethoxy)ethyl-trimethyl-silane (CAS:76513-69-4, 13.8 mL, 77.7 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NLLCl (300 mL) and EtOAc (500 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed with water (2 x 500 mL), brine (2 x 250 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography twice (330 g cartridge) using a gradient of EtOAc in hexanes (0-15%) to provide the title compound as a solid (19.4 g, 73%).Step 2: 2-[(4-chloro-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

[0315] Pd(dppf)C12.DCM (598 mg, 0.732 mmol) was added to a degassed mixture of 2-[(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane (6.00 g, 14.6 mmol), phenylboronic acid (CAS: 98-80-6, 2.14 g, 17.6 mmol) and K3PO4 (6.22 g, 29.3 mmol) in 1,4-dioxane (45.0 mL) and water (15.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (200 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a solid (3.82 g, 73%).Step 3: Trimethyl-[2-[(5-phenyl-4-vinyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane

[0316] Pd(PPh3) 2CI2 (0.244 g, 0.347 mmol) was added to a degassed mixture of 2-[(4-chloro-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane (2.50 g, 6.95 mmol), 4, 4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.28 g, 8.34 mmol) and K2CO3 (1.92 g, 13.9 mmol) in 1,4-dioxane (19.0 mL) and water (6.25 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (200 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of EtOAc in hexanes (0-40%) to provide the title compound as a liquid (2.08 g, 85%).Step 4: 5-Phenyl-7-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidine-4-carbaldehyde

[0317] OsO4(4 wt% in water, 5.85 mL, 0.939 mmol) was added to a mixture of trimethyl-[2-[(5-phenyl-4-vinyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane (1.10 g, 3.13 mmol) and NaIO4 (1.34 g, 6.26 mmol) in 1,4-dioxane (10.0 mL) and water (5.00 mL) at 23 °C. The mixture was stirred at 23 °C for 1 h and diluted with brine (15.0 mL). The aqueous phase was extracted with DCM (3 x 20.0 mL), and the combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purifiedWSGR Docket No. 57050-707.601by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a liquid (418 mg, 60% purity, 23%).Step 5: Ethyl 4-[[5-phenyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l-carboxylate

[0318] AcOH (0.0508 m , 0.887 mmol) was added to (5-phenyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-4-carbaldehyde (418 mg, 0.887 mmol) and ethyl piperazine- 1 -carboxylate (CAS: 120-43-4, 443 mg, 2.66 mmol) in DCM (8.00 m ) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min, and NaBH(OAc)3 (376 mg, 1.77 mmol) was added. The mixture was stirred at 23 °C for 1 h and poured into water (15.0 mb). The aqueous phase was extracted with DCM (3 x 15.0 mb). The combined organic extracts were washed with brine (10.0 mb), dried (ISfeSCE), fdtered and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a liquid (454 mg, 98%).Step 6: Ethyl 4-[(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l-carboxylate

[0319] Ethane- 1,2-diamine (0.0245 mb, 0.366 mmol) and TBAF (1 M in THF, 4.58 mb, 4.58 mmol) were added to a solution of ethyl 4-[[5-phenyl-7-(2 -trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l -carboxylate (454 mg, 0.916 mmol) in THF (10.0 mb) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and of MeOH in DCM (0 to 40%) to provide the title compound as an oil (309 mg, 92%)Step 7: Ethyl 4-[[7-(3-cyanophenyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l-carboxylate

[0320] Cui (4.17 mg, 0.0219 mmol) was added to a mixture of ethyl 4-[(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l -carboxylate (40.0 mg, 0.109 mmol), (S,S)-(+)-N,N’ -dimethyl- 1,2-cyclohexanediamine (2.34 mg, 0.0164 mmol) and K3PO4 (46.5 mg, 0.219 mmol) in DMF (1.00 mb) at 23 °C under nitrogen. The mixture was stirred at 50 °C for 1 h, at 75 °C for 1 h and cooled to 23 °C. The residue was purified by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (5-75%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO2)] and MeCN (38-48%) to provide the title compound (5.40 mg, 11%).Example 9: Ethyl 4-[[7-(3-cyanophenyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-1-carboxylateStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0321] NaH (60% in mineral oil, 4.14 g, 104 mmol) was added to a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 18.1 g, 64.8 mmol) in DMF (300 mb) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 15 min. 2-(chloromethoxy)ethyl-trimethyl-silane (CAS:76513-69-4, 13.8 mb, 77.7 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NH4CI (300 mb) and EtOAc (500 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL), and the combined organic extracts were washed withWSGR Docket No. 57050-707.601water (2 x 500 mL), brine (2 x 250 mL), dried (Na2SC>4), filtered, and concentrated. The residue was purified by silica gel chromatography twice (330 g cartridge) using a gradient of EtOAc in hexanes (0-15%) to provide the title compound as a solid (19.4 g, 73%).Step 2: 2-[(4-chloro-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane

[0322] Pd(dppf)C12.DCM (598 mg, 0.732 mmol) was added to a degassed mixture of 2-[(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane (6.00 g, 14.6 mmol), phenylboronic acid (CAS: 98-80-6, 2.14 g, 17.6 mmol) and K3PO4 (6.22 g, 29.3 mmol) in 1,4-dioxane (45.0 mL) and water (15.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (200 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a solid (3.82 g, 73%).Step 3: Trimethyl-[2-[(5-phenyl-4-vinyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane

[0323] Pd(PPh3) 2CI2 (0.244 g, 0.347 mmol) was added to a degassed mixture of 2-[(4-chloro-5-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane (2.50 g, 6.95 mmol), 4, 4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.28 g, 8.34 mmol) and K2CO3 (1.92 g, 13.9 mmol) in 1,4-dioxane (19.0 mL) and water (6.25 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (200 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of EtOAc in hexanes (0-40%) to provide the title compound as a liquid (2.08 g, 85%).Step 4: 5-Phenyl-7-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidine-4-carbaldehyde

[0324] OsO4(4 wt% in water, 5.85 mL, 0.939 mmol) was added to a mixture of trimethyl-[2-[(5-phenyl-4-vinyl-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl]silane (1.10 g, 3.13 mmol) and NaIO4 (1.34 g, 6.26 mmol) in 1,4-dioxane (10.0 mL) and water (5.00 mL) at 23 °C. The mixture was stirred at 23 °C for 1 h and diluted with brine (15.0 mL). The aqueous phase was extracted with DCM (3 x 20.0 mL), and the combined organic extracts were dried (MgSCL), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a liquid (418 mg, 60% purity, 23%).Step 5: Ethyl 4-[[5-phenyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l-carboxylate

[0325] AcOH (0.0508 mL, 0.887 mmol) was added to (5-phenyl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidine-4-carbaldehyde (418 mg, 0.887 mmol) and ethyl piperazine- 1 -carboxylate (CAS: 120-43-4, 443 mg, 2.66 mmol) in DCM (8.00 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min, and NaBH(OAc)3 (376 mg, 1.77 mmol) was added. The mixture was stirred at 23 °C for 1 h and poured into water (15.0 mL). The aqueous phase was extracted with DCM (3 x 15.0 mL). The combined organic extracts were washed with brine (10.0 mL), dried (ISfeSCL), filtered and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a liquid (454 mg, 98%).WSGR Docket No. 57050-707.601Step 6: Ethyl 4-[(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l-carboxylate

[0326] Ethane- 1,2-diamine (0.0245 mL, 0.366 mmol) and TBAF (1 M in THF, 4.58 mL, 4.58 mmol) were added to a solution of ethyl 4-[[5-phenyl-7-(2 -trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l -carboxylate (454 mg, 0.916 mmol) in THF (10.0 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and of MeOH in DCM (0 to 40%) to provide the title compound as an oil (309 mg, 92%)Step 7: Ethyl 4-[[7-(3-cyanophenyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]methyl]piperazine-l-carboxylate

[0327] Cui (5.00 mg, 0.0263 mmol) was added to a mixture of ethyl 4-[(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l -carboxylate (26.0 mg, 0.0711 mmol), 3 -iodobenzonitrile (CAS:69113-59-3, 17.5 mg, 0.0764 mmol), (S,S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (5.00 mg, 0.0438 mmol) and K3PO4 (30.0 mg, 0.141 mmol) in DMF (1.00 mL) at 23 °C under nitrogen. The mixture was stirred at 50 °C for 1 h, at 75 °C for 1 h and cooled to 23 °C. The residue was purified by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (5-75%) to provide the title compound (11.0 mg, 33%).Example 10: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl](methyl)amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0328] NaH (60% in mineral oil, 9.2 mg, 0.23 mmol) was added to a mixture of 4-({ [7-(3-cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide Example 4 (90.0 mg, 0.177 mmol) in DMF (0.800 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 30 min and Mel (13 pL, 0.210 mmol) was added. The mixture was stirred at 23 °C for 1 h and poured into water (20.0 mL). The mixture was filtered, and the solid was washed with water (20.0 mL) and dried. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in n-heptane (0-40%) to provide the title compound (50.0 mg, 54%).Example 11 : 4-({ [7-(4-Cyanophenyl)-5-phenyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl] amino}methyl)-AyV-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0329] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidineWSGR Docket No. 57050-707.601

[0330] PdCl2(PPh3)2(691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and Na2CO3(4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, fdtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: AyV-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0331] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 202 mg, 0.945 mmol) and K2CO3(131 mg, 0.945 mmol) were added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.472 mmol) in 1,4-dioxane (3.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, cooled to 23 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (149 mg, 58%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0332] TFA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NELOH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: 4-({[7-(4-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0333] Cui (5.00 mg, 0.0250 mmol) was added to a mixture of N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (50.0 mg, 0.123 mmol) K2CO3(34.0 mg, 0.245 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (3.5 mg, 0.025 mmol) and 4-bromobenzonitrile (CAS: 623 -00-7, 45.0 mg, 0.245 mmol) in 1,4 dioxane (0.600 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 times), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NELXHCOs)] and MeCN (5-100%) to provide the title compound (15.0 mg, 24%).Example 12: 3-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidineWSGR Docket No. 57050-707.601

[0334] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NILCl (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), fdtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0335] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and ISfeCOs (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: AyV-dimethyl-3-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0336] 3-(aminomethyl)-N,N-dimethylbenzene-l-sulfonamide hydrochloride (CAS: 855249-83-1, 279 mg, 1.11 mmol) and K2CO3 (230 mg, 1.67 mmol) were added to the mixture of 4-chloro-5-phenyl-7-{ [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.556 mmol) in 1,4-dioxane (4.00 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h and diluted with water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 25.0 mL), and the combined organic extracts were washed with brine (2 x 25.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in n-heptane (0-40%) to provide the title compound as a solid (80 mg, 27%).Step 4: AyV-dimethyl-3-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0337] TFA (0.172 mL, 2.24 mmol) was added to a mixture of N,N-dimethyl-3-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (80.1 mg, 0.149 mmol) in DCM (0.600 mL) at 5 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. 1,4-Dioxane (0.750 mL) and NH4OH (25% in water, 0.600 mL) were added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (48 mg, 79%).WSGR Docket No. 57050-707.601Step 5: 3-( ![7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d|pyrimidin-4-yl|amino)methyl)- / V, / V-dimethylbenzene-l-sulfonamide

[0338] Cui (6.5 mg, 0.031 mmol) was added to a mixture ofN,N-dimethyl-3-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (48.0 mg, 0.118 mmol), K2CO3 (43.0 mg, 0.307 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (4.40 mg, 0.0310 mmol) and 3 -bromobenzonitrile (CAS: 6952-59-6, 27.0 mg, 0.153 mmol) in 1,4-dioxane (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 10.0 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5 100%) to provide the title compound (25.0 mg, 42%).Example 13: 4-({[7-(3-Cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0339] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4- {[(5-iodo-7- { [2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo [2, 3-d] pyrimidin-4-yl)amino]methyl}-AyV-dimethylbenzene-l-sulfonamide

[0340] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 314 mg, 1.46 mmol) and K2CO3 (202 mg, 1.46 mmol) were added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.732 mmol) in 1.4-dioxane (5.21 mL) at 23 °C. The mixture was stirred at 110 °C for 18 h and poured into cold water (50.0 mL). The mixture was filtered, washed with water (30.0 mL), and the solid was dried to provide the title compound as a solid (430 mg, quantitative).Step 3: A^A-dimethyl-4-({[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0341] Pd2(dba)3 (87.1 mg, 0.0950 mmol) was added to a mixture of 4-{[(5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}-N,N dimethylbenzene-l-sulfonamide (430 mg, 0.732 mmol), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (0.160 mL, 1.10 mmol), NEts (0.203 mL, 1.46 mmol) and X-Phos (45.4 mg, 0.0950 mmol) in degassed 1,4-dioxane (3.13 ml) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 3 h, cooled to 23 °C, filtered through Celite,WSGR Docket No. 57050-707.601washed with EtOAc (10.0 mL), and the filtrate was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc. (3 x 30.0 mL), and the combined organic extracts were washed with brine (2 x 30.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (150 mg, 35%).Step 4: AyV-dimethyl-4-({[5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl] amino}methyl)benzene-l-sulfonamide

[0342] Pd(dppf)C12-DCM (18.7 mg, 0.0260 mmol) was added to a mixture of N,N-dimethyl-4-({[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (150 mg, 0.255 mmol), 2-iodopyridine (CAS: 5029-67-4, 57.6 mg, 0.281 mmol) and K2CO3 (141 mg, 1.02 mmol) in DMF (3.60 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 3 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in cyclohexane (0-60%) to provide the title compound as a solid (90 mg, 66%).Step 5: AyV-dimethyl-4-({ [5-(pyridin-2-yl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0343] TFA (0.193 mL, 2.51 mmol) was added to amixture ofN,N-dimethyl-4-({[5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (90.0 mg, 0.167 mmol) in DCM (0.800 mL) at 0 °C. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (0.778 mL) and NH4OH (25% in water, 0.788 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0- 10%) to provide the title compound as a solid (60 mg, 88%).Step 6: 4-({[7-(3-Cyanophenyl)-5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0344] Cui (5.60 mg, 0.0290 mmol) was added to a mixture of K2CO3 (40.6 mg, 0.294 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (4.20 mg, 0.0290 mmol), 3 -bromobenzonitrile (CAS: 6952-59-6, 53.5 mg, 0.294 mmol) and N,N-dimethyl-4-({[5-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (60.0 mg, 0.147 mmol) in 1,4-dioxane (0.700 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 1.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide the title compound (31 mg, 41%).Example 14: 4-({[l-(3-Cyanophenyl)-3-phenyl-lH-pyrrolo[2,3-b]pyridin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1: 3-{4-chloro-lH-pyrrolo[2,3-b]pyridin-l-yl}benzonitrile

[0345] (lS,2S)-(+)-l,2-diaminocyclohexane (374 mg, 3.23 mmol) and 3 -iodobenzonitrile (CAS:69113-59-3, 3.00 g, 13.1 mmol) were added to a mixture of 4-chloro-7-azaindole (CAS:55052-28-WSGR Docket No. 57050-707.6013, 1.00 g, 6.55 mmol), Cui (62.4 mg, 0.328 mmol) and K3PO4 (2.78 g, 13.1 mmol) in 1,4-dioxane (12.0 mL) at 23 °C under nitrogen. The mixture was stirred at 120 °C for 3 h, cooled to 23 °C, diluted with water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried (MgSCL). fdtered and concentrated to provide the title compound as a solid (1.64 g, 99%).Step 2: 3- {4-chloro-3-iodo-lH-pyrrolo [2,3-b] pyridin-l-yl}benzonitrile

[0346] NIS (2.18 g, 9.70 mmol) was added to amixture of 3-{4-chloro-lH-pyrrolo[2,3-b]pyridin-l-yl} benzonitrile (1.64 g, 6.47 mmol) in DMF (32.0 mL) at 23 °C. The reaction mixture was stirred at 50 °C for 8 h, cooled to 23 °C and diluted with water (150 mL). The aq. phase was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with sat. aq. NaHCOs (2 x 50.0 mL), 5% aq. Na2S3O3(2 x 50.0 mL), brine (2 x 50.0 mL), dried (MgSO4), filtered, and concentrated to provide the title compound as a solid (2.29 g, 93%).Step 3: 3- {4-chloro-3-phenyl-lH-pyrrolo [2,3-b] pyridin-l-yl}benzonitrile

[0347] PdCl2(PPh3)2(46.2 mg, 0.0660 mmol) was added to a mixture of 3-{4-chloro-3-iodo-lH-pyrrolo[2,3-b]pyridin-l-yl}benzonitrile (500 mg, 1.32 mmol), phenylboronic acid (CAS:98-80-6, 193 mg, 1.58 mmol) and Na2CO3(279 mg, 2.63 mmol) in 1,4-dioxane (20.0 mL) and water (5.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (30.0 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in cyclohexane (0-60%) to provide the title compound as a solid (295 mg, 68%).Step 4: AyV-dimethyl-4-({[5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl] amino}methyl)benzene-l-sulfonamide

[0348] Pd2(dba)3(14.0 mg, 0.0150 mmol) was added to amixture of KOtBu (42.5 mg, 0.379 mmol), Xantphos (13.0 mg, 0.0230 mmol), 4-(aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 65.0 mg, 0.303 mmol) and 3-{4-chloro-3-phenyl-lH-pyrrolo[2,3-b]pyridin-l-yl}benzonitrile (50.0 mg, 0.152 mmol) in 1,4-dioxane (1.40 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 3 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 1.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, C18) with water [10 mM (NH4)(HCO3)] and MeCN (5-100%) to provide the title compound (11 mg, 17%).Example 15: 4-({[l-(3-Cyanophenyl)-3-phenyl-lH-pyrrolo[3,2-c]pyridin-4-yl]amino}methyl)-Af^V-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0349] NaH (60% in mineral oil, 734 mg, 18.4 mmol) was added portion wise to a mixture of 4-chloro-lH-pyrrolo [3 ,2 -c] pyridine (CAS:60290-21-3, 2.00 g, 13.1 mmol) in DMF (59.2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 3.23 mL, 16.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NH4CI (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (MgSO4),WSGR Docket No. 57050-707.601filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in n-heptane (0-5%) to provide the title compound as an oil (2.08 g, 56%).Step 2: 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0350] NIS (597 mg, 2.65 mmol) was added to a mixture of 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (500 mg, 1.77 mmol) in DMF (8.50 mL) at 23 °C. The mixture was stirred at 50 °C for 2 h, cooled to 23 °C and diluted with water (80 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with sat. aq. NaHCOs (2 x 50.0 mL), 5% aq. Na2S20s solution (2 x 50.0 mL), brine (2 x 50.0 mL), dried (MgSO4), filtered, and concentrated to provide the title compound as a solid (637 mg, 88%).Step 3: 4-chloro-3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0351] Na2COs (311 mg, 2.94 mmol) and PdC12(PPh3)2 (51.5 mg, 0.0700 mmol) were added to a mixture of 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (600 mg, 1.47 mmol) and phenylboronic acid (CAS:98-80-6, 218 mg, 1.76 mmol) in 1,4-dioxane (22.0 mL) and water (5.40 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h, cooled to 23 °C, filtered through Celite. The filtrate was concentrated, and the residue was diluted with water (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic extracts were washed with brine (30.0 mL), water (30.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in cyclohexane and (0-20%) to provide the title compound as a solid (475 mg, 90%).Step 4: AyV-dimethyl-4-{[(3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridin-4-yl)amino]methyl}benzene-l-sulfonamide

[0352] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 298 mg, 1.39 mmol) was added to a mixture ofPd2(dba)s (64.0 mg, 0.0700 mmol), Xantphos (60.0 mg, 0.100 mmol), KOtBu (195 mg, 1.74 mmol) and 4-chloro-3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (250 mg, 0.700 mmol) in 1,4-dioxane (7.00 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 3 h, cooled to 23 °C, and diluted with EtOAc (20.0 mL). The mixture was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in DCM (20.0 mL) and the organic phase was washed with water (2 x 10.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in n-heptane (0-50%) to provide the title compound as a solid (251 mg, 67%).Step 5: AyV-dimethyl-4-[({3-phenyl-lH-pyrrolo[3,2-c]pyridin-4-yl}amino)methyl]benzene-l-sulfonamide

[0353] TFA (534 pL, 6.93 mmol) was added to a mixture of N,N-dimethyl-4-{[(3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl } - IH-pyrrolo [3 ,2-c | pyridi n-4-y I )am i no | meth l [ benzene- 1 -sulfonamide (248 mg, 0.46 mmol) in DCM (1.80 mL) at 23 °C. The mixture was stirred at 23 °C for 16 h and concentrated. The residue was dissolved in 1,4-dioxane (2.30 mL) and NFLOH (25% in water, 1.85 mL) was added at 23 °C. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, and concentrated. TheWSGR Docket No. 57050-707.601residue was purified by silica gel chromatography (8 g cartridge) using a gradient of MeOH (10% NH4OH) in DCM (0-5%) to provide the title compound as a solid (106 mg, 56%).Step 6: 4-({[l-(3-Cyanophenyl)-3-phenyl-lH-pyrrolo[3,2-c]pyridin-4-yl]amino}methyl)-Af^V-dimethylbenzene-l-sulfonamide

[0354] Cui (9.30 mg, 0.0500 mmol.) was added to a mixture of N,N-dimethyl-4-[({3-phenyl-lH-pyrrolo[3,2-c]pyridin-4-yl}amino)methyl]benzene-l-sulfonamide (76.0 mg, 0.190 mmol), K2CO3 (67.0 mg, 0.490 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (6.90 mg, 0.0500 mmol) and 3-bromobenzonitrile (CAS:6952-59-6, 44.0 mg, 0.240 mmol) in 1,4-dioxane (0.750 mb) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 10.0 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (02%) to provide the title compound (81 mg, 61%).Example 16: 4-({[7-(3-Cyanophenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamideStep 1 : 4-chloro-5-methyl-7-{ [2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo [2, 3-d] pyrimidine

[0355] NaH 60% oil dispersion (167 mg, 4.18 mmol) was added portion wise to a mixture of 4-chloro-5-methyl-7h-pyrrolo[2,3-d]pyrimidine (CAS: 1618-36-6, 500 mg, 2.98 mmol) in DMF (13.5 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min and 2-(trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 735 pL, 3.73 mmol) was added at 0 °C. The mixture was stirred at 23 °C for 18 h and diluted with sat. aq. NH4CI (130 mL). The aqueous phase was extracted with EtOAc (3 x 200 mL), and the combined organic extracts were washed with water (200 mL), brine (200 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of EtOAc in n-heptane (0-20%) to provide the title compound as an oil (565 mg, 64%).Step 2: AyV-dimethyl-4-{[(5-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0356] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 360 mg, 1.68 mmol) was added to a mixture ofK^COs (232 mg, 1.68 mmol) and 4-chloro-5-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 0.840 mmol) in 1,4-dioxane (6.00 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h and poured into cold water (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were washed with brine (30.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in n-hetpane (040%) to provide the title compound as a solid (82 mg, 21%).Step 3: AyV-dimethyl-4-[({5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0357] TFA (194 pL, 2.52 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (80.0 mg, 0.168 mmol) in DCM (0.780 mL) at 23 °C. The mixture was stirred at 23 °C for 16 h andWSGR Docket No. 57050-707.601concentrated. The residue was dissolved in 1,4-dioxane (0.780 mL) and NH4OH (25% in water, 0.800 mL) was added at 23 °C. The mixture was stirred at 90 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (4 g cartridge) using a gradient of MeOH in DCM (0-10%) to provide the title compound as a solid (50 mg, 86%).Step 4: 4-({[7-(3-Cyanophenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-JV,A-dimethylbenzene-l-sulfonamide

[0358] Cui (5.50 mg, 0.0300 mmol) was added to a mixture of K2CO3 (40.0 mg, 0.29 mmol), (1S,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (4.20 mg, 0.0300 mmol), 3 -bromobenzonitrile (CAS:6952-59-6, 53.0 mg, 0.290 mmol) and N,N-dimethyl-4-[({5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino) methyl]benzene-l -sulfonamide (50.0 mg, 0.145 mmol) in 1,4-dioxane (0.700 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 10.0 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NELXHCO3)] and MeCN (5-100%) to provide the title compound (11 mg, 17%).Example 17: A- [7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl]-4-(dimethylsulfamoyl)benzamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0359] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0360] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and Na2CO3 (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: 5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0361] NH3 (gas) was bubbled to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.833 mmol) in MeOH (4.30 mL)WSGR Docket No. 57050-707.601at 23°C under nitrogen. The mixture was stirred at 130 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-60%) to provide the title compound as a solid (200 mg, 71%).Step 4: 4-(dimethylsulfamoyl)-JV-(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide

[0362] DIEA (307 pL, 1.76 mmol) and HATU (335 mg, 0.88 mmol) were added to a mixture of 4-(dimethylsulfamoyl)benzoic acid (CAS: 1206-37-7, 162 mg, 0.710 mmol) and 5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (200 mg, 0.590 mmol) in DMF (3.00 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in n-heptane (0-50%) to provide the title compound as a solid (175 mg, 54%).Step 5: 4-(dimethylsulfamoyl)-A-{5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide

[0363] TBAF (1 M in THF, 1.90 mL, 1.90 mmol) and ethylenediamine (11.0 pL, 0.159 mmol) were added to a mixture of 4-(dimethylsulfamoyl)-N-(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzamide (175 mg, 0.317 mmol) in THF (3.20 mL) at 23 °C. The mixture was stirred at 75 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (70 mg, 52%).Step 6: A-[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-4-(dimethylsulfamoyl)benzamide

[0364] Cui (1.50 mg, 0.0100 mmol) was added to a mixture of K3PO4 (71.0 mg, 0.330 mmol), (lS,2S)-(+)-l,2-diaminocyclohexane (9.50 mg, 0.0900 mmol), 3 -iodobenzonitrile (CAS:69113-59-3,76.0 mg, 0.330 mmol) and 4-(dimethylsulfamoyl)-N-{5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide (70.0 mg, 0.166 mmol) in 1,4-dioxane (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 130 °C for 8 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 10.0 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NFLXHCOs)] and MeCN (5-95%) to provide the title compound (14 mg, 16%).Example 18: 4-[[[7-(4-Cyanophenyl)-5-(2-pyridyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]-AyV-dimethyl-benzenesulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0365] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4,4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 gWSGR Docket No. 57050-707.601cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 2- [ [4-Chloro-5-(2-pyridyl)pyrrolo [2, 3-d] pyrimidin-7-yl]methoxy] ethyl-trimethyl-silane

[0366] 2-Pyridylzinc bromide (CAS:218777-23-2, 9.86 mL, 4.93 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (2.00 g, 4.88 mmol) and Pd(PPhs)4 (0.282 g, 0.244 mmol) in THF (24.0 mL) at 23 °C under nitrogen. The mixture was stirred at 70 °C for 6 h, cooled to 23 °C and diluted with water (20 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (10.0 mL), dried (MgSO4), fdtered, and concentrated. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (2.35 g, 75% purity, quant).Step 3: / V, / V-dimethyl-4-[[[5-(2-pyridyl)-7-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]benzenesulfonamide

[0367] 4-(Aminomethyl)-N,N-dimethyl-benzenesulfonamide (CAS:210918-25-5, 136 mg, 0.623 mmol) was added to a mixture of 2-[[4-chloro-5-(2-pyridyl)pyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl-trimethyl -silane (250 mg, 75% purity, 0.520 mmol) and K2CO3 (215 mg, 1.56 mmol) in 1,4-dioxane (10.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h, cooled to 23 °C, and diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (10.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by reverse phase chromatography (Cl 8, 60 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (5-70%) to provide the title compound as a solid (109 mg, 37%).Step 4: / V, / V-dimethyl-4-[[[5-(2-pyridyl)-7H-pyrrolo[2,3-d|pyrimidin-4-yl]amino]methyl] benzenesulfonamide

[0368] Ethane- 1,2-diamine (0.00540 mL, 0.0809 mmol) and TBAF (1 M in THE, 1.01 mL, 1.01 mmol) were added to a solution of N,N-dimethyl-4-[[[5-(2-pyridyl)-7-(2-trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]benzenesulfonamide (109 mg, 0.202 mmol) in THF (5.00 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (25 g cartridge) using a gradient of MeOH in DCM (0-40%) and by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (0-80%) to provide the title compound as a solid (67.4 mg, 78%).Step 5: 4- [ [ [7-(4-Cyanophenyl)-5-(2-pyridyl)pyrr olo [2, 3-d] pyrimidin-4-yl] amino] methyl] -N,N-dimethyl-benzenesulfonamide

[0369] Cui (1.57 mg, 0.00826 mmol) was added to a mixture of N,N-dimethyl-4-[[[5-(2-pyridyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]benzenesulfonamide (67.5 mg, 0.165 mmol), 4-bromobenzonitrile (CAS:623-00-7, 45.1 mg, 0.248 mmol), K3PO4 (70.2 mg, 0.330 mmol) and transdiaminocyclohexane (1.89 mg, 0.0165 mmol) in 1,4-dioxane (4.50 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 48 h and diluted with water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (10.0WSGR Docket No. 57050-707.601mL), dried (MgSCh). filtered, and concentrated. The residue was purified by reverse phase chromatography (C 18, 12 g cartridge) with water [10 mM (NH4XHCO2)] and MeCN (5 100%) and by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound (13.0 mg, 15%).Example 19: 4-({[l-(3-Cyanophenyl)-3-phenyl-lH-indol-4-yl]amino}methyl)-Af^V-dimethylbenzene-1-sulfonamideStep 1: 4-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole

[0370] NaH (60% dispersion in mineral oil, 571 mg, 14.3 mmol) was added portion wise to a solution of 4-bromoindole (CAS:52488-36-5, 2.00 g, 10.2 mmol) in DMF (45.0 ml) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(chloromethoxy)ethyl-trimethyl-silane (CAS:76513-69-4, 2.51 ml, 12.8 mmol) was added at 0 °C. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C, and diluted with sat. aq. NH4CI (500 ml). The aqueous phase was extracted with EtOAc (2 x 300 mL), and the combined organic extracts were washed with water (200 ml), brine (200 ml), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (80 g cartridge) using a gradient of EtOAc in cyclohexane (0-5%) to provide the title compound as an oil (2.73 g, 82%).Step 2: 4-bromo-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole

[0371] NIS (1.03 g, 4.60 mmol) was added to amixture of 4-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole (1.00 g, 3.07 mmol) in DMF (15.0 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (3 x 100.0 mL), and the combined organic phases were washed with sat. aq. NaHCOs (100 mL), 5% aq. Na2S3O3(100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.24 g, 89%).Step 3: 4-bromo-3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole

[0372] Phenylboronic acid (CAS:98-80-6, 399 mg, 3.28 mmol) was added to a mixture of PdCl2(PPh3)2(95.8 mg, 0.14 mmol), Na3CO3(579 mg, 5.46 mmol) and 4-bromo-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole (1.23 g, 2.73 mmol) in amixture of 1,4-dioxane (27.0 mL) and water (6.80 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 3 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (2 x 50.0 mL), and the filtrate was concentrated. The residue was diluted with water (40.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (418 mg, 38%).Step 4: AyV-dimethyl-4-{[(3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indol-4-yl)amino]methyl}benzene-l-sulfonamide

[0373] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 221 mg, 1.03 mmol) was added to amixture ofPd3(dba)3(94.4 mg, 0.100 mmol), Xantphos (89.5 mg, 0.160 mmol), KOtBu (289 mg, 2.58 mmol) and 4-bromo-3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indole (415 mg,WSGR Docket No. 57050-707.6011.03 mmol) in 1,4-dioxane (10.4 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 3 h, cooled to 23 °C, diluted with EtOAc (30.0 mL), fdtered through Celite, washed with EtOAc (2 x 30.0 mL), and the filtrate was concentrated. The residue was diluted with water (40.0 mL). The aqueous phase was extracted with DCM (3 x 10.0 mL), and the combined organic extracts were dried (MgSCL). filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-25%) to provide the title compound as a solid (382 mg, 69%).Step 5: AyV-dimethyl-4-{[(3-phenyl-lH-indol-4-yl)amino]methyl}benzene-l-sulfonamide

[0374] TBAE (1 M in THE, 2.60 mL, 2.60 mmol) and ethylenediamine (14.5 pL, 0.220 mmol) were added to a mixture of N,N-dimethyl-4-{[(3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-indol-4-yl)amino]methyl}benzene-l-sulfonamide (232 mg, 0.430 mmol) in THF (4.30 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 4 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-30%) to provide the title compound as a solid (152 mg, 87%).Step 6: 4-({[l-(3-Cyanophenyl)-3-phenyl-lH-indol-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0375] Cui (9.80 mg, 0.0500 mmol) was added to a mixture of N,N-dimethyl-4-{[(3-phenyl-lH-indol-4-yl)amino]methyl}benzene-l-sulfonamide (80.0 mg, 0.19 mmol), K2CO3 (70.9 mg, 0.510 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (7.30 mg, 0.0500 mmol) and 3 -bromobenzonitrile (CAS:6952-59-6, 46.7 mg, 0.26 mmol) in 1,4-dioxane (0.800 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 10.0 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC chromatography (BEH, C18) with water (0,1% TFA) and MeCN (50-100%) to provide the title compound (66.0 mg, 66%).Example 20: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}methyl)-Af^V-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0376] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0377] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acidWSGR Docket No. 57050-707.601(CAS:98-80-6, 2.88 g, 23.6 mmol) and ISfeCOs (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, fdtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: AyV-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]methyl}benzene-l-sulfonamide

[0378] NaH (60% in oil, 23.4 mg, 0.590 mmol) was added to a mixture of 4-(hydroxymethyl)-N,N-dimethylbenzene-1 -sulfonamide (CAS:58804-18-5, 126 mg, 0.590 mmol) in THF (3.50 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 10 min. The solution of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.39 mmol) in THF (1.70 mL) was added to the mixture at 0 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and concentrated. The residue was diluted with water (20.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) with EtOAc and n-heptane (0-40%) to provide the title compound as a solid (189 mg, 90%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]benzene-l-sulfonamide

[0379] TBAF (1 M in THF, 2.07 mL, 2.07 mmol) and ethylenediamine (10.4 mg, 0.173 mmol) were added to N,N-dimethyl-4- { [(5 -phenyl-7 - { [2-(trimethylsilyl)ethoxy]methyl } -7H-pyrrolo [2,3 -d]pyrimidin-4-yl)oxy]methyl}benzene-l-sulfonamide (186 mg, 0.345 mmol) in THF (3.50 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 3 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-2%) to provide the title compound as a solid (80.0 mg, 57%).Step 5: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}methyl)-Af^V-dimethylbenzene-l-sulfonamide

[0380] 3 -Bromobenzonitrile (CAS:6952-59-6, 68.6 mg, 0.377 mmol) was added to a mixture of N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)methyl]benzene-l-sulfonamide (77.0 mg, 0.189 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (5.40 mg, 0.0380 mmol), Cui (7.20 mg, 0.0380 mmol) and K2CO3 (52.1 mg, 0.377 mmol) in 1,4-dioxane (0.750 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 1.50 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, C18) with water (10 mM NH4HCO3) and MeCN (5 95%) to provide the title compound (68.3 mg, 71%).Example 21 : 4-({ [7-(3-Cyanophenyl)-5-(propan-2-yl)-7H-pyrrolo [2, 3-d] pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidineWSGR Docket No. 57050-707.601

[0381] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NlLCl (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), fdtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-(prop-l-en-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidine

[0382] 2-Isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (CAS: 126726-62-3, 345 pL, 1.83 mmol) was added to a mixture of PdCh(PPh3)2 (85.6 mg, 0.120 mmol), K2CO3 (506 mg, 3.66 mmol) and 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.22 mmol) in 1,4-dioxane (12.0 mL) and water (4.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, filtered through Celite, and the filtrate was diluted with water (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were washed with brine (30.0 mL) dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-20%) to provide the title compound as a solid (349 mg, 88%).Step 3: AyV-dimethyl-4-({[5-(prop-l-en-2-yl)-7-{[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl] amino}methyl)benzene-l-sulfonamide

[0383] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 304 mg, 1.43 mmol) was added to a mixture ofK^COs (280 mg, 2.03 mmol) and 4-chloro-5-(prop-l-en-2-yl)-7-{[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidine (219 mg, 0.680 mmol) in 1,4-dioxane (4.00 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 16 h and diluted with water (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic extracts were washed with brine (30.0 mL) dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (220 mg, 65%).Step 4: AyV-dimethyl-4-({[5-(propan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl] amino}methyl)benzene-l-sulfonamide

[0384] Pd / C (10% on charcoal, 151.7 mg, 0.140 mmol) was added to a mixture ofN,N-dimethyl-4-( { [5 -(prop- 1 -en-2-yl)-7 - { [2-(trimethylsilyl)ethoxy]methyl } -7H-pyrrolo [2,3 -d]pyrimidin-4-yl] amino }methyl)benzene-l -sulfonamide (286 mg, 0.570 mmol) in MeOH (5.70 mL) at 23 °C under nitrogen. The mixture was purged with hydrogen and stirred at 23°C under 3 bar of pression for 1 h, filtered through Celite, washed with MeOH (2 x 15.0 mL), and the filtrate was concentrated to provide the title compound as a solid (307 mg).WSGR Docket No. 57050-707.601Step 5: / V, / V-dimethyl-4-(![5-(propan-2-yl)-7H-pyrrolo[2,3-d|pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0385] TBAF (1 M in THF, 4.22 mL, 4.22 mmol) and ethylenediamine (20.0 pL, 0.300 mmol) were added to a mixture of N,N -dimethyl -4-({ [5 -(propan-2 -yl)-7-{ [2-(trimethylsilyl)ethoxy]methyl }-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (304 mg, 0.600 mmol) in THF (6.00 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 3 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (82.0 mg, 36%).Step 6: 4-({[7-(3-Cyanophenyl)-5-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-JV,2V-dimethylbenzene-l-sulfonamide

[0386] 3 -Bromobenzonitrile (CAS:6952-59-6, 48.7 mg, 0.268 mmol) was added to a mixture of N,N-dimethyl-4-({[5-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (50.0 mg, 0.134 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (3.80 mg, 0.0270 mmol), Cui (5.10 mg, 0.0270 mmol) and K2CO3 (37.0 mg, 0.268 mmol) in 1,4-dioxane (0.530 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 2 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 1.50 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NFLXHCO3)] and MeCN (5 100%) to provide the title compound (27.0 mg, 43%).Example 22: Af^V-Dimethyl-4-({[7-(2-methylpyridin-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0387] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0388] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and Na2CO3 (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4),WSGR Docket No. 57050-707.601filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: JV,2V-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0389] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 202 mg, 0.945 mmol) and K2CO3 (131 mg, 0.945 mmol) were added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.472 mmol) in 1,4-dioxane (3.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, cooled to 23 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (149 mg, 58%).Step 4: Af^V-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0390] TFA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NH4OH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: AyV-Dimethyl-4-({[7-(2-methylpyridin-4-yl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0391] Cui (5.00 mg, 0.0250 mmol) was added to a mixture of N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (50.0 mg, 0.123 mmol), K2CO3 (34.0 mg, 0.245 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (3.50 mg, 0.0250 mmol) and 4-iodo-2 -methylpyridine (CAS:2282-65-l, 54 mg, 0.245 mmol) in 1,4-dioxane (0.600 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 3 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 5.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide the title compound (31.0 mg, 50%).Example 23: Ethyl 4-{[7-(4-cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methyl}piperazine-l-carboxylateStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0392] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), driedWSGR Docket No. 57050-707.601(MgS04), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0393] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and ISfeCOs (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mb) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: Methyl 5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate

[0394] Pd(dppf)C12-DCM (378 mg, 0.517 mmol) was added to a degassed mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (930 mg, 2.58 mmol), and NEt3 (1.44 mL, 10.3 mmol) in MeOH (85.0 mL) at 23 °C under nitrogen. The mixture was stirred under 10 bar carbon monoxide at 80 °C for 18 h and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in n-heptane (030%) to provide the title compound as a solid (755 mg, 76%).Step 4: (5-Phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanol

[0395] NaBEL (1.12 g, 29.5 mmol) was added portionwise to amixture of methyl 5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-4-carboxylate (755 mg, 1.97 mmol) in MeOH (7.70 mL) at 0 °C. The mixture was stirred at 23 °C for 18 h and diluted with sat. aq. NH4CI solution (30.0 mL). The aqueous phase was extracted with DCM (3 x 50.0 mL), and the combined organic extracts were washed with brine (30.0 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (301 mg, 43%).Step 5: 4-(Chloromethyl)-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidineMeSO2Cl (78 pL, 1.01 mmol) was added to amixture of (5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanol (300 mg, 0.84 mmol) in dry DCM (20.0 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and concentrated to provide the title compound as a solid (322 mg).Step 6: Ethyl 4-[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l-carboxylate

[0396] Ethyl 1 -piperazinecarboxylate (CAS: 120-43-4, 252 pL, 1.72 mmol) was added to a mixture of NEts (477 pL, 3.44 mmol) and 4-(chloromethyl)-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-WSGR Docket No. 57050-707.601pyrrolo[2,3-d]pyrimidine (322 mg, 0.86 mmol) in dry DCM (4.30 mL) at 23 °C under nitrogen. The mixture was stirred at 40 °C for 16 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (257 mg, 60%).Step 7: Ethyl 4-({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methyl)piperazine-l-carboxylate

[0397] TBAF (IM in THF, 3.63 mL, 3.63 mmol) and ethylenediamine (17.3 pL, 0.26 mmol) were added to a mixture of ethyl 4-[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methyl]piperazine-l -carboxylate (257 mg, 0.52 mmol) in THF (5.20 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 16 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (162 mg, 86%).Step 8: Ethyl 4-{[7-(4-cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methyl}piperazine-1-carboxylate

[0398] Ethyl 4-({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}methyl)piperazine-l-carboxylate (50.0 mg, 0.14 mmol) was dissolved in dry 1,4-dioxane (0.550 mL). Cui (5.2 mg, 0.03 mmol), K3PO4 (58.1 mg, 0.27 mmol), (lS,2S)-(+)-l,2-Diaminocyclohexane (3.9 mg, 0.03 mmol) and 4-Iodobenzonitrile (CAS:3058-39-7, 62.7 mg, 0.27 mmol) were added at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h and cooled to 23 °C. The mixture was filtered through Celite, washed with EtOAc (3 x 5.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC chromatography (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (23 mg, 36%).Example 24: 4-[4-({[4-(dimethylsulfamoyl)phenyl]methyl}amino)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl]benzamideStep 1: 4-[4-({[4-(dimethylsulfamoyl)phenyl]methyl}amino)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl] benzamide

[0399] Acetaldoxime (71.0 pL, 1.18 mmol) was added to a mixture of triphenylphosphine (18.0 mg, 0.069 mmol), Pd(OAc)2 (13.5 mg, 0.059 mmol) and 4-({[7-(4-cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide Example 11 (100 mg, 0.197 mmol) in EtOH (3.50 mL) and water (0.600 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 3 h and cooled to 23 °C. The mixture was filtered through Celite, washed with EtOAc, and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (90 mg, 87%).Example 25: N4-[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-Nl,Nl-dimethylbenzene-l,4-disulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0400] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chlorideWSGR Docket No. 57050-707.601(CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), fdtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0401] PdCl2(PPh3)2(691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and Na3CO3(4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: Nl,Nl-dimethyl-N4-(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidin-4-yl)benzene- 1 ,4-disulfonamide

[0402] NaH (19.5 mg, 0.813 mmol) was added to a mixture of 5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine (180 mg, 0.529 mmol) in DMF (2.00 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 10 min. 4-(dimethylsulfamoyl)benzene-l -sulfonyl chloride (CAS:677782-39-7, 158 mg, 0.529 mmol) was added at 0 °C. The mixture was stirred at 23 °C for 2 h and poured into cold water and ice. The aqueous phase was extracted with DCM (3 x 10.0 mL), and the combined organic extracts were washed with brine (8.00 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (92 mg, 38%).Step 4: Nl,Nl-dimethyl-N4-{5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzene-l,4-disulfonamide

[0403] TFA (0.172 mL, 2.233 mmol) was added to amixture of N1,N1 -dimethyl -N4-(5-phenyl-7-{ [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzene-l,4-disulfonamide (87.5 mg, 0.149 mmol) in DCM (0.600 mL) at 0 °C. The mixture was stirred at 23 °C for 16 h and concentrated. The residue was dissolved in 1,4-dioxane (0.750 mL) and aq. NH4OH (25%, 0.600 mL) was added at 23 °C. The mixture was stirred at 90 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-3%) to provide the title compound as a solid (52 mg, 76%).Step 5: N4-[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-Nl,Nl-dimethylbenzene-l,4-disulfonamide

[0404] Cui (2.5 mg, 0.013 mmol) and (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (2 mg, 0.013 mmol) were added to a degassed mixture of Nl,Nl-dimethyl-N4-{5-phenyl-7H-pyrrolo[2,3-WSGR Docket No. 57050-707.601d]pyrimidin-4-yl}benzene-l,4-disulfonamide (30.0 mg, 0.066 mmol), 3 -iodobenzonitrile (CAS:69113-59-3, 30.0 mg, 0.131 mmol) and K3PO4 (28.0 mg, 0.131 mmol) in DMF (0.300 mb) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 6 h, cooled to 23°C, and concentrated. The residue was purified by preparative HPLC (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide the title compound (13 mg, 35%).Example 26: 4-({[7-(3-Cyanophenyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1 : 4-chloro-2-methyl-7-{ [2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo [2, 3-d] pyrimidine

[0405] NaH (60% in mineral oil, 3.34 g, 83.5 mmol) was added to a mixture of 4-chloro-2-methyl-7h-pyrrolo[2,3-d]pyrimidine (CAS:71149-52-5, 10.0 g, 59.7 mmol) in DMF (300 m ) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 13.8 g, 74.6 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and diluted with sat. aq. NH4CI (1.00 L). The aqueous phase was extracted with EtOAc (2 x 500 m ), and the combined organic extracts were washed with water (300 mb), brine (300 mb), dried (MgSCh), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (9.72 g, 55%).Step 2: 4-chloro-5-iodo-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0406] NIS (5665.1 mg, 25.18 mmol) was added to a mixture of 4-chloro-2-methyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (5.00 g, 16.8 mmol) in DMF (85.0 mb) at 23 °C under nitrogen. The mixture was stirred at 60 °C for 6 h and diluted with water (1.20 E). The aqueous phase was extracted with EtOAc (3 x 500 mb), and the combined organic phases were washed with sat. aq. NaHCOs (300 mb), 5% aq. Na2S20s (300 mb), brine (300 mb), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) with heptane and EtOAc (0-10%) to provide the title compound as a solid (5.83 g, 82%).Step 3: 4-chloro-2-methyl-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d] pyrimidine

[0407] Na2COs (1250.6 mg, 11.8 mmol) and PdC^PPhsX (207.1 mg, 0.30 mmol) was added to a mixture of 4-cyanophenylboronic acid (CAS: 126747-14-6, 863 mg, 7.08 mmol) and 4-[({7-iodo-5-phenyl-5H-pyrrolo [3 ,2-d]pyrimidin-4-yl } amino)methyl] -N,N-dimethylbenzene- 1 -sulfonamide (2.50 g, 5.90 mmol) in 1,4-dioxane (60.0 mb) and water (15.0 mb) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 5 h and cooled to 23 °C. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was diluted with EtOAc (400 mb), washed with water (80.0 mb), brine (80.0 mb), dried (MgSO4), filtered, and concentrated. The residue was purified by reverse phase chromatography (C18, 120 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound as a solid (1.60 g, 73%).Step 4: N,N-dimethyl-4-{[(2-methyl-5-phenyl-7-{[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamideWSGR Docket No. 57050-707.601

[0408] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 636 mg, 2.96 mmol) was added to a mixture ofK^COs (499 mg, 3.60 mmol) and 4-chloro-2-methyl-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 0.80 mmol) in 1,4-dioxane (4.80 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 48 h, cooled to 23 °C, and diluted with water (100 mL). The aqueous phase was extracted with EtOAc (3 x 40.0 mL), and the combined organic extracts were dried (MgSCL). fdtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAC in heptane (025%) to provide the title compound as a solid (226.0 mg, 51%).Step 5: N,N-dimethyl-4-[({2-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0409] TBAF (IM in THF, 2.83 mL, 2.83 mmol) and ethylenediamine (12.1 mg, 0.20 mmol) were added to a mixture of N,N -dimethyl -4- {[(2 -methyl-5 -phenyl-7-{ [2-(trimethylsilyl)ethoxy]methyl }-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (223 mg, 0.40 mmol) in THF (4.00 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 4 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-2%) to provide the title compound as a solid (143 mg, 87%).Step 6: 4-({[7-(3-Cyanophenyl)-2-methyl-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0410] 3-Iodobenzonitrile (CAS:69113-59-3, 56.5 mg, 0.25 mmol) was added to a mixture ofN,N-dimethyl-4-[( { 2-methyl-5 -phenyl-7H-pyrrolo [2,3 -d]pyrimidin-4-yl } amino)methyl]benzene- 1 -sulfonamide (52.0 mg, 0.12 mmol), (lS,2S)-(+)-N,N'-Dimethyl-l,2-cyclohexanediamine (3.5 mg, 0.03 mmol), Cui (4.7 mg, 0.03 mmol) and K2CO3 (52.4 mg, 0.25 mmol) in dry 1,4-dioxane (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 18 h and cooled to 23 °C. The mixture was filtered through celite, washed with EtOAc (3 x 1.50 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NFLXHCO3)] and MeCN (20-100%) to provide the title compound (39.7 mg, 62%).Example 27: 4-({[7-(3-Cyanophenyl)-2-(2-methylpropyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1: 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0411] NaH (60% in mineral oil, 2.98 g, 74.5 mmol) was added portion wise to a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (CAS:90213-66-4, 10.0 g 53.2 mmol) in dry DMF (260 ml) at 0 °C. The mixture was stirred at 0 °C for 30 min. 2-(trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 13.1 mL, 66.5 mmol) was added at 0 °C. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NH4CI (500 ml). The aqueous phase was extracted with EtOAc (2 x 500 mL), and the combined organic extracts were washed with brine (300 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as an oil (12.1 g, 71%).Step 2: 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidineWSGR Docket No. 57050-707.601

[0412] NIS (530 mg, 2.36 mmol) was added to a mixture of 2,4-dichloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.57 mmol) in dry DMF (8.00 mL) at 23 °C under nitrogen. The mixture was stirred at 50 °C for 16 h and diluted with water (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic phases were washed with sat. aq. NaHCOs (50.0 mL), 5% aq. Na2S20s (50.0 mL), brine (50.0 mL), dried (MgSO4), fdtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (614 mg, 88%).Step 3: 2,4-dichloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0413] Phenylboronic acid (CAS:98-80-6, 191 mg, 1.56 mmol) was added to amixture oflS^COs (276 mg, 2.61 mmol), PdC12(PPh3)2 (45.7 mg, 0.07 mmol) and 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidine (579 mg, 1.30 mmol) in amixture of 1,4-dioxane (20.0 mL) and water (5.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and cooled to 23 °C. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was diluted with EtOAc (20.0 mL) and washed with water (10.0 mL), brine (10.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (502 mg, 97%).Step 4: 4- {[(2-chloro-5-phenyl-7- { [2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2, 3-d] pyrimidin-4-yl)amino]methyl}-N,N-dimethylbenzene-l-sulfonamide

[0414] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 270 mg, 1.26 mmol) was added to amixture ofK^COs (317 mg, 2.29 mmol) and 2,4-dichloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (452 mg, 1.15 mmol) in dry 1,4-dioxane (7.00 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 16 h and diluted with water (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 10.0 mL), and the combined organic phases were washed with brine (30 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-40%) to provide the title compound as a solid (401 mg, 61%).Step 5: N,N-dimethyl-4-({[2-(2-methylpropyl)-5-phenyl-7-{[2-(trim ethylsilyl) ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0415] 2-Methylpropylzinc bromide (CAS: 126403-67-6, 0.5 M in THF, 1.05 pL, 0.52 mmol) was added to amixture of Pd(dppf)C12 (38.4 mg, 0.052 mmol) and 4-{[(2-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy] methyl} -7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}-N,N-dimethylbenzene-1-sulfonamide (150 mg, 0.26 mmol) in 1,4-dioxane (0.800 mL) at 23 °C under nitrogen. The mixture was stirred at 60 °C for 16 h, cooled to 23 °C, and diluted with brine (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 10.0 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in cyclohexane (0-40%) to provide the title compound as a solid (127 mg, 81%).WSGR Docket No. 57050-707.601Step 6: N,N-dimethyl-4-({ [2-(2-methylpropyl)-5-phenyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide

[0416] TBAF (IM in THF, 1.50 mL, 1.50 mmol) and ethylenediamine (7.1 pL, 0.110 mmol) were added to a mixture of N,N -dimethyl -4-({[2-(2-methylpropyl)-5-phenyl-7-{[2-(trimethylsilyl)ethoxy] methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)benzene-l-sulfonamide (127 mg, 0.210 mmol) in THF (2.10 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 4 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (60 mg, 60%).Step 7: 4-( { [7-(3-Cyanophenyl)-2-(2-methylpr opyl)-5-phenyl-7H-pyr rolo [2,3-d] pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0417] N,N-dimethyl-4-( { [2-(2-methylpropyl)-5 -phenyl-7H-pyrrolo [2,3 -d]pyrimidin-4-yl] amino } methyl)benzene-l -sulfonamide (60.0 mg, 0.130 mmol) was dissolved in dry 1,4-dioxane (0.520 mL). Cui (4.9 mg, 0.03 mmol), K3PO4 (54.9 mg, 0.26 mmol), (lS,2S)-(+)-l,2-diaminocyclohexane (3.7 mg, 0.03 mmol) and 3-Iodobenzonitrile (CAS: 69113-59-3, 59.3 mg, 0.26 mmol) were added at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h and cooled to 23 °C. The mixture was filtered through Celite, washed with EtOAc (3 x 5.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC chromatography (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (50-100%) to provide the title compound (14.4 mg, 20%).Example 28: 4-(4-{[(3,4-Dihydro-2H-l,5-benzodioxepin-7-yl)methyl]amino}-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)benzonitrileStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0418] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0419] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and Na2CO3 (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mL) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4),WSGR Docket No. 57050-707.601filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: N-[(3,4-dihydro-2H-l,5-benzodioxepin-7-yl)methyl]-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[0420] 3,4-dihydro-2H-l,5-benzodioxepin-7-yhnethanamine (CAS:23475-00-5, 90.0 mg, 0.500 mmol) was added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (150 mg, 0.417 mmol) andNEts (0.173 mL, 1.25 mmol) in n-butanol (1.80 mL) at 23 °C. The mixture was stirred at 100 °C for 2 h and cooled to 23 °C. Additional 3,4-dihydro-2H-l,5-benzodioxepin-7-ylmethanamine (80.0 mg, 0.44 mmol) andNEts (0.153 mL, 1.11 mmol) were added, and the mixture was stirred for 3 h at 100 °C, cooled to 23 °C and concentrated. The residue was diluted with water (3.00 mL). The aqueous phase was extracted with EtOAc (3 x 5.00 mL). The combined organic extracts were washed with brine (3.00 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in cyclohexane (0-50%) to provide the title compound as a solid (132 mg, 63%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0421] TFA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NH4OH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: 4-({[7-(3-Cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-AyV-dimethylbenzene-l-sulfonamide

[0422] Cui (6.00 mg, 0.0320 mmol) was added to a mixture of K2CO3 (44.0 mg, 0.319 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (4.50 mg, 0.0320 mmol), 3 -bromobenzonitrile (CAS:6952-59-6, 58.0 mg, 0.319 mmol) and N,N-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide (65.0 mg, 0.160 mmol) in 1,4-dioxane (7.50 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 3.00 mL), and the filtrate was concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (37.0 mg, 45%).Example 29: 4-({[7-(3-Cyanophenyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1: 3-{4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile

[0423] 3-Iodobenzonitrile (CAS:69113-59-3, 1.09 g, 4.773 mmol) was added to a mixture of 4-Chloro-5-methyl-7h-pyrrolo[2,3-d]pyrimidine (CAS: 1618-36-6, 500 mg, 2.98 mmol), (lS,2S)-(+)-N,N'-WSGR Docket No. 57050-707.601Dimethyl- 1,2-cyclohexanediamine (212 mg, 1.492 mmol), Cui (284 mg, 1.492 mmol) and K3PO4 (1.26 g, 5.97 mmol) in dry 1,4-dioxane (5.50 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h and cooled to 23 °C. The mixture was fdtered through Celite, washed with EtOAc (3 x 10.0 mL), and the fdtrate was concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in n-heptane (0-30%) to provide the title compound as solid (205 mg, 25%).Step 2: 4-({ [7-(3-Cyanophenyl)-5-methyl-7H-pyrrolo [2, 3-d] pyrimidin-4-yl] oxy}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0424] NaH (60% in mineral oil, 11.0 mg, 0.279 mmol) was added to a mixture of 4-(hydroxymethyl)-N,N-dimethylbenzene-l -sulfonamide (CAS:58804-18-5, 63.5 mg, 0.279 mmol) in THF (1.70 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 10 min. A solution of 3-{4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (50.0 mg, 0.186 mmol) in THF (0.800 mL) was added at 0°C under nitrogen. The mixture was stirred at 90 °C for 2 h and concentrated. The residue was diluted with water (3.00 mL). The aqueous phase was extracted with EtOAc (3 x 3.00 mL), and the combined organic phases were dried (MgSO4), filtered, and concentrated. The residue was purified by preparative HPLC chromatography (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (20-100%) to provide the title compound (29 mg, 35%).Example 30: 4-({[7-(3-Cyanophenyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1 : 3- {4-chloro-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-7-yl}benzonitrile

[0425] Pyridine (0.662 mL, 3.60 mmol) was added to a mixture of 3-cyanophenylboronic acid (CAS: 150255-96-2, 5.26 g, 35.0 mmol) and 4A molecular sieves (3 g) in DMF (130 mL) at 23 °C. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol), Cu(OAc)2 (650 mg, 3.58 mmol) and TEMPO (3.07 g, 19.7 mmol) were added, and the mixture was stirred at 65 °C for 3 h and at 25°C for 72 h. NH3 in MeOH was added, and the mixture was filtered, washed with DCM (2 x 50.0 mL). The filtrate was washed with brine (2 x 150 mL). The aq. phase was extracted with DCM (2 x 50 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in heptane (0-100%), then using a gradient of MeOH in EtOAc (0-20%) to provide the title compound as a solid (5.07 g, 76%).Step 2: 4-({ [7-(3-cyanophenyl)-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-4-yl] amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0426] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 186 mg, 0.867 mmol) was added to a mixture of 3-{4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (165 mg, 0.434 mmol) and K2CO3 (120 mg, 0.867 mmol) in 1,4-dioxane (3.00 mL). The mixture was stirred at 110 °C for 18 h and diluted with water (10.0 mL). The mixture was filtered, washed with water (5.00 mL), and the solid was dried to provide the title compound (302 mg).Step 3: 4-({[7-(3-Cyanophenyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideWSGR Docket No. 57050-707.601

[0427] 4-Tolylboronic acid (CAS:5720-05-8, 17.5 mg, 0.129 mmol), Na2CO3 (23.0 mg, 0.215 mmol) and PdCl2(PPh3)2 (7.5 mg, 0.011 mmol) were added to a suspension of 4-({[7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide (60.0 mg, 0.107 mmol) in a mixture of 1,4-dioxane (0.800 mb) and water (0.300 mb) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and cooled to 23 °C. The mixture was fdtered through Celite, washed with MeOH (2 x 3.00 mb), and the fdtrate was concentrated. The residue was purified by preparative HPLC chromatography (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (35 mg, 62%).Example 31: 4-({[5-(2-Chlorophenyl)-7-(3-cyanophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1 : 3- {4-chloro-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-7-yl}benzonitrile

[0428] Pyridine (0.662 mb, 3.60 mmol) was added to a mixture of 3-cyanophenylboronic acid (CAS: 150255-96-2, 5.26 g, 35.0 mmol) and 4A molecular sieves (3 g) in DMF (130 mb) at 23 °C. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol), Cu(OAc)2(650 mg, 3.58 mmol) and TEMPO (3.07 g, 19.7 mmol) were added, and the mixture was stirred at 65 °C for 3 h and at 25°C for 72 h. NH3 in MeOH was added, and the mixture was filtered, washed with DCM (2 x 50.0 mb). The filtrate was washed with brine (2 x 150 mb). The aq. phase was extracted with DCM (2 x 50 mb), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in heptane (0-100%), then using a gradient of MeOH in EtOAc (0-20%) to provide the title compound as a solid (5.07 g, 76%).Step 2: 4-({ [7-(3-cyanophenyl)-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-4-yl] amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0429] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 186 mg, 0.867 mmol) was added to a mixture of 3-{4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (165 mg, 0.434 mmol) and K2CO3 (120 mg, 0.867 mmol) in 1,4-dioxane (3.00 mb). The mixture was stirred at 110 °C for 18 h and diluted with water (10.0 mb). The mixture was filtered, washed with water (5.00 mb), and the solid was dried to provide the title compound (302 mg).Step 3: 4-({[5-(2-Chlorophenyl)-7-(3-cyanophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0430] 2-Chlorophenylboronic acid (CAS:3900-89-8, 20.0 mg, 0.129 mmol), Na2CO3 (23.0 mg, 0.215 mmol) and PdC^PPhsX (7.5 mg, 0.011 mmol) were added to a mixture of 4-({[7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide (60.0 mg, 0.107 mmol) in a mixture of 1,4-dioxane (0.800 mb) and water (0.300 mb) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and cooled to 23 °C. The mixture was filtered through Celite, washed with MeOH (2 x 3.00 mb), and the filtrate was concentrated. The residue was purified by preparative HPLC chromatography (BEH, C18) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to provide the title compound (36.0 mg, 62%).WSGR Docket No. 57050-707.601Example 32: 4-({[l-(3-Cyanophenyl)-3-methyl-lH-pyrrolo[3,2-c]pyridin-4-yl] amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0431] NaH (60% in mineral oil, 734 mg, 18.4 mmol) was added portion wise to a mixture of 4-chloro-lH-pyrrolo [3 ,2 -c] pyridine (CAS:60290-21-3, 2.00 g, 13.1 mmol) in DMF (59.2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 3.23 mL, 16.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NH4CI (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (MgSCL). filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in n-heptane (0-5%) to provide the title compound as an oil (2.08 g, 56%).Step 2: 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0432] NIS (597 mg, 2.65 mmol) was added to a mixture of 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (500 mg, 1.77 mmol) in DMF (8.50 mL) at 23 °C. The mixture was stirred at 50 °C for 2 h, cooled to 23 °C and diluted with water (80 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with sat. aq. NaHCOs (2 x 50.0 mL), 5% aq. Na2S20s solution (2 x 50.0 mL), brine (2 x 50.0 mL), dried (MgSO4), filtered, and concentrated to provide the title compound as a solid (637 mg, 88%).Step 3: 4-chloro-3-methyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0433] Dimethylzinc (CAS:544-97-8, 10 w / w% in toluene, 5.08 mL, 4.89 mmol) and PdCh(PPh3)2 (171 mg, 0.25 mmol) were added to a mixture of 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (500 mg, 1.22 mmol) in THF (4.40 mL) at 23 °C under nitrogen. The mixture was stirred at 70 °C for 2 h and diluted with ice-water (30.0 mL). The aqueous phase was extracted with EtOAc (3 x 30.0 mL), and the combined organic phases were washed with brine (30.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24g cartridge) using a gradient of EtOAc in cyclohexane (0-30%) to provide the title compound as a solid (161 mg, 44%).Step 4: N,N-dimethyl-4-{[(3-methyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridin-4-yl)amino]methyl}benzene-l-sulfonamide

[0434] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 72.2 mg, 0.34 mmol) was added to a mixture ofKOtBu (42.3 mg, 0.42 mmol), Pd2(dba)s (15.4 mg, 0.02 mmol), Xantphos (14.6 mg, 0.03 mmol) and 4-chloro-3-methyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (50.0 mg, 0.17 mmol) in dry 1,4-dioxane (1.50 mL) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 3 h, cooled to 23 °C and diluted with EtOAc (10.0 mL). The mixture was filtered through Celite, washed with DCM, and the filtrate was concentrated. The residue was dissolved in DCM (15.0 mL), washed with water (2 x 15.0 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (54 mg, 68%).WSGR Docket No. 57050-707.601Step 5: 4-({[l-(3-Cyanophenyl)-3-methyl-lH-pyrrolo[3,2-c]pyridin-4-yl] amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0435] 3-Iodobenzonitrile (CAS: 69113-59-3, 30.6 mg, 0.13 mmol) was added to a mixture ofN,N-dimethyl-4-[({3-methyl-lH-pyrrolo[3,2-c]pyridin-4-yl}amino)methyl]benzene-l-sulfonamide (23.0 mg, 0.07 mmol), (lS,2S)-(+)-N,N'-dimethyl-l,2-cyclohexanediamine (1.9 mg, 0.013 mmol), Cui (2.5 mg, 0.013 mmol) and K3PO4 (28.4 mg, 0.13 mmol) in dry 1,4-dioxane (0.300 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h and cooled to 23 °C. The mixture was filtered through Celite, washed with EtOAc (3 x 1.50 mL) and the filtrate was concentrated. The residue was purified by purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (20-100%) to provide the title compound (9.3 mg, 31%).Example 33: 2-(7-(3-cyanophenyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethyl-2,3,4,5-tetrahydro-lH-benzo[c]azepine-7-sulfonamideStep 1 : - {4-chloro-5-iodo-7H-pyrrolo [2,3-d]pyrimidin-7-yl}benzonitrile

[0436] Pyridine (0.662 mL, 3.60 mmol) was added to a mixture of 3-cyanophenylboronic acid (CAS: 150255-96-2, 5.26 g, 35.0 mmol) and 4A molecular sieves (3 g) in DMF (130 mL) at 23 °C. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol), Cu(OAc)2 (650 mg, 3.58 mmol) and TEMPO (3.07 g, 19.7 mmol) were added, and the mixture was stirred at 65 °C for 3 h and at 25°C for 72 h. NH3 in MeOH was added, and the mixture was filtered, washed with DCM (2 x 50.0 mL). The filtrate was washed with brine (2 x 150 mL). The aq. phase was extracted with DCM (2 x 50 mL), and the combined organic extracts were dried (MgSO^, filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in heptane (0-100%), then using a gradient of MeOH in EtOAc (0-20%) to provide the title compound as a solid (5.07 g, 76%).Step 2: 3- {4-chloro-5-phenyl-7H-pyrrolo [2, 3-d] pyrimidin-7-yl}benzonitrile

[0437] PdCl2(PPh3)2 (46.0 mg, 0.066 mmol) was added to a degassed mixture of 3-{4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (500 mg, 1.31 mmol), phenylboronic acid (CAS:98-80-6, 196 mg, 1.58 mmol) and Na2CO3 (278 mg, 2.63 mmol) in 1,4-dioxane (13.0 mL) and water (3.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 3 h, cooled to 23 °C, and diluted with water (10.0 mL). The mixture was filtered, washed with water (3 x 15.0 mL), and the solid was dried to provide the title compound as a solid (310 mg, 71%).Step 3: 2-(7-(3-cyanophenyl)-5-phenyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N,N-dimethyl-2, 3,4,5-tetrahydro-lH-benzo [c] azepine-7-sulfonamide

[0438] K2CO3 (66 mg, 0.476 mmol) was added to a mixture of N,N-dimethyl-2,3,4,5-tetrahydro-lH-2-benzazepine-7-sulfonamide (CAS:427891-88-l, 63.0 mg, 0.218 mmol) and 3-{4-chloro-5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (45.0 mg, 0.136 mmol) in dry 1,4-dioxane (1.00 mL) at 23 °C under nitrogen. The resulting mixture was stirred at 110 °C for 16 h and cooled to 23 °C. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (5-95%) to afford the title compound (20 mg, 27%).WSGR Docket No. 57050-707.601Example 34: 4-({[7-(3-Cyanophenyl)-5-(piperidin-l-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamideStep 1 : 3- {4-chloro-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-7-yl}benzonitrile

[0439] Pyridine (0.662 mL, 3.60 mmol) was added to a mixture of 3-cyanophenylboronic acid (CAS: 150255-96-2, 5.26 g, 35.0 mmol) and 4A molecular sieves (3 g) in DMF (130 mL) at 23 °C. 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol), Cu(OAc)2 (650 mg, 3.58 mmol) and TEMPO (3.07 g, 19.7 mmol) were added, and the mixture was stirred at 65 °C for 3 h and at 25°C for 72 h. NIL in MeOH was added, and the mixture was filtered, washed with DCM (2 x 50.0 mL). The filtrate was washed with brine (2 x 150 mL). The aq. phase was extracted with DCM (2 x 50 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in heptane (0-100%), then using a gradient of MeOH in EtOAc (0-20%) to provide the title compound as a solid (5.07 g, 76%).Step 2: 4-({ [7-(3-cyanophenyl)-5-iodo-7H-pyrrolo [2, 3-d] pyrimidin-4-yl] amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0440] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 186 mg, 0.867 mmol) was added to a mixture of 3-{4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl}benzonitrile (165 mg, 0.434 mmol) and K2CO3 (120 mg, 0.867 mmol) in 1,4-dioxane (3.00 mL). The mixture was stirred at 110 °C for 18 h and diluted with water (10.0 mL). The mixture was filtered, washed with water (5.00 mL), and the solid was dried to provide the title compound (302 mg).Step 3: 4-({[7-(3-Cyanophenyl)-5-(4-methylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide

[0441] Piperidine (CAS: 110-89-4, 16.0 pL, 0.161 mmol), CsF (25.0 mg, 0.161 mmol), Cui (2.0 mg, 0.011 mmol,) and L-proline (2.0 mg, 0.016 mmol) were added to a solution of 4-({[7-(3-cyanophenyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino}methyl)-N,N-dimethylbenzene-l-sulfonamide (30.0 mg, 0.054 mmol) in dry DMSO (0.500 mL) at 23 °C under nitrogen atmosphere. The mixture was stirred at 50°C for 3 h and at 23°C for 12 h. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (BEH, Cl 8) with water [10 mM (NH4XHCO3)] and MeCN (0-20%) to afford the title compound as a solid (5 mg, 19%).Example 35: 4-[[[7-(4,4-difluoropiperidine-l-carbonyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]-N,N-dimethyl-benzenesulfonamideStep 1: 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0442] NaH (60% in mineral oil, 1.00 g, 25.1 mmol) was added to a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (CAS: 123148-78-7, 5.00 g, 17.9 mmol) in DMF (80.7 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 4.84 mL, 22.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and diluted with sat. aq. NH4CI (100 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were washed with water (40.0 mL), brine (40.0 mL), driedWSGR Docket No. 57050-707.601(MgS04), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in heptane (0-10%) to provide the title compound as a solid (5.54 g, 76%).Step 2: 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

[0443] PdCl2(PPh3)2 (691 mg, 1.00 mmol) was added to a mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (8.06 g, 19.7 mmol), phenylboronic acid (CAS:98-80-6, 2.88 g, 23.6 mmol) and ISfeCOs (4.17 g, 39.4 mmol) in 1,4-dioxane (290 mb) and water (73.0 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h, cooled to 23 °C, filtered through Celite, washed with EtOAc (3 x 70.0 mL), and the filtrate was concentrated. The residue was diluted with EtOAc (200 mL) and washed with water (50.0 mL), brine (50.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (330 g cartridge) using a gradient of EtOAc in cyclohexane (0-10%) to provide the title compound as a solid (1.99 g, 28%). Step 3: AyV-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide

[0444] 4-(Aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS:210918-25-5, 202 mg, 0.945 mmol) and K2CO3 (131 mg, 0.945 mmol) were added to a mixture of 4-chloro-5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (170 mg, 0.472 mmol) in 1,4-dioxane (3.40 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, cooled to 23 °C, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in heptane (0-40%) to provide the title compound as a solid (149 mg, 58%).Step 4: AyV-dimethyl-4-[({5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)methyl]benzene-l-sulfonamide

[0445] TLA (311 pL, 4.05 mmol) was added to a mixture of N,N-dimethyl-4-{[(5-phenyl-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl}benzene-l-sulfonamide (145 mg, 0.270 mmol) in DCM (1.25 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (1.25 mL) and 25% aq. NH4OH (1.25 mL) was added. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (65.0 mg, 59%).Step 5: 4-[[[7-(4,4-difluoropiperidine-l-carbonyl)-5-phenyl-pyrrolo[2,3-d]pyrimidin-4-yl]amino]methyl]-N,N-dimethyl-benzenesulfonamide

[0446] N,N-dimethyl-4-[[(5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]methyl]benzene sulfonamide (45.0 mg, 0.110 mmol) andNEts (46.2 pL, 0.331 mmol) in DCM (1.00 mL) were added to a mixture of triphosgene (32.8 mg, 0.110 mmol) in DCM (1.00 mL) at 0 °C under nitrogen. The mixture was stirred for 15 min and 4,4-difluoropiperidine (CAS:21987-29-l, 40.1 mg, 0.331 mmol) andNEts (46.2 pL, 0.331 mmol) in DCM (1.00 mL) were added at 0 °C. The mixture was stirred at 23 °C for 1 h. The mixture was diluted with sat. aq. NaHCOs (2.00 mL). The aqueous phase was extracted with DCM (2 x 10.0 mL). The combined organic extracts were washed with brine (10.0 mL), dried (ISfeSCL),WSGR Docket No. 57050-707.601filtered and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexane (0-100%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NEfiXEICOs)] and MeCN (59-69%) to provide the title compound (5.45 mg, 9%).Example 36: 4-[({l-Cyclohexyl-3-phenyl-lH-pyrrolo[3,2-c]pyridin-4-yl} amino)methyl]-N,N-dimethylbenzene-l-sulfonamideStep 1: 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0447] NaH (60% in mineral oil, 734 mg, 18.4 mmol) was added portion wise to a mixture of 4-chloro-lH-pyrrolo [3 ,2 -c] pyridine (CAS:60290-21-3, 2.00 g, 13.1 mmol) in DMF (59.2 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (CAS:76513-69-4, 3.23 mL, 16.4 mmol) was added at 0 °C under nitrogen. The mixture was stirred at 23 °C for 2 h, cooled to 0 °C and diluted with sat. aq. NH4CI (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) using a gradient of EtOAc in n-heptane (0-5%) to provide the title compound as an oil (2.08 g, 56%).Step 2: 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0448] NIS (597 mg, 2.65 mmol) was added to a mixture of 4-chloro-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (500 mg, 1.77 mmol) in DMF (8.50 mL) at 23 °C. The mixture was stirred at 50 °C for 2 h, cooled to 23 °C and diluted with water (80 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts were washed with sat. aq. NaHCOs (2 x 50.0 mL), 5% aq. Na2S20s solution (2 x 50.0 mL), brine (2 x 50.0 mL), dried (MgSO4), filtered, and concentrated to provide the title compound as a solid (637 mg, 88%).Step 3: 4-chloro-3-phenyl-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine

[0449] Na2COs (311 mg, 2.94 mmol) and PdC^PPhsX (51.5 mg, 0.0700 mmol) were added to a mixture of 4-chloro-3-iodo-l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrrolo[3,2-c]pyridine (600 mg, 1.47 mmol) and phenylboronic acid (CAS:98-80-6, 218 mg, 1.76 mmol) in 1,4-dioxane (22.0 mL) and water (5.40 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h, cooled to 23 °C, filtered through Celite. The filtrate was concentrated, and the residue was diluted with water (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 50.0 mL), and the combined organic extracts were washed with brine (30.0 mL), water (30.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in cyclohexane and (0-20%) to provide the title compound a...

Claims

WSGR Docket No. 57050-707.601CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;WSGR Docket No. 57050-707.601each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;Z1is -CH2-, -CH(CH3)-, -CH2CH2-, or -C(=O)-;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R11on the same atom are taken together to form an oxo;q is 0, 1, 2, 3, 4, 5, or 6;R12is hydrogen, -CN, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein the alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;R13is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’;or R12and R13are taken together with the atoms to which they are attached to form a 4- to 7-membered heterocycloalkyl independently optionally substituted with one or more R14;each R14is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R14on the same atom are taken together to form an oxo;and / or two R14on separate atoms are taken together with the atom to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R”;and / or two R14on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R”;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independentlyWSGR Docket No. 57050-707.601optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Csalkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-Csalkyl, or Ci-Csheteroalkyl; wherein each alkyl is optionally substituted with one or more halogen;and / or two R” on the same atom are taken together to form an oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is CRX.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen, halogen, or Ci-Cealkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CRY.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-707.601RYis hydrogen, halogen, or Ci-Cealkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is absent.

11. The compound of any one of claims 1 -9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -C(=O)-.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen, halogen, or Ci-Cealkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen, halogen, or Ci-Cealkyl.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12is hydrogen, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-C6alkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12is -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or Ci-C6alkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12is -S(=O)2NRcRd, -C(=O)Ra, or -C(=O)ORb.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R13is hydrogen or Ci-Cealkyl.WSGR Docket No. 57050-707.60120. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R13is hydrogen.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12and R13are taken together with the atoms to which they are attached to form a 5 - or 6- membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

22. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12and R13are taken together with the atoms to which they are attached to form a 5 -membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

23. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12and R13are taken together with the atoms to which they are attached to form a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S; and wherein the heterocycloalkyl is independently optionally substituted with one or more R14.

24. The compound of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is of Formula (la):Formula (la);wherein:each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R11on the same atom are taken together to form an oxo;q is 0, 1, 2, 3, 4, 5, or 6;WSGR Docket No. 57050-707.601Ring B is a 5- or 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S;each R14is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ ;and / or two R14on the same atom are taken together to form an oxo;and / or two R14on separate atoms are taken together with the atom to which they are attached to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each independently optionally substituted with one or more R”;and / or two R14on the same carbon are taken together to form a cycloalkyl or heterocycloalkyl; each independently optionally substituted with one or more R”; andt is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

25. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 5 -membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S.

26. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S.

27. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 5 -membered heterocycloalkyl.

28. The compound of claim 24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is a 6-membered heterocycloalkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R14is independently Ci-Cealkyl; and / or two R14on the same atom are taken together to form an oxo; and / or two R14on the same carbon are taken together to form a cycloalkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R14is independently Ci-Cealkyl and / or two R14on the same atom are taken together to form an oxo.

31. The compound of any one of claims 1 -29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:two R14on the same atom are taken together to form an oxo.

32. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-707.601stereoisomer thereof, wherein:two R14on the same carbon are taken together to form a cycloalkyl.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:t is 0, 1, 2, 3, 4, 5, or 6.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:t is 2, 3, 4, 5, or 6.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:t is 2, 3, or 4.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R11is independently halogen, -CN, Ci-Cealkyl, C2-Cealkenyl, or C2-Cealkynyl.

41. The compound of any one of claims 1 -40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-707.601each R11is independently Ci-Cealkyl.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:q is 0, 1, or 2.

43. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:q is 0 or 1.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z1is -CH2- or -C(=O)-.

45. The compound of any one of claims 1 -44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z1is -CH2-.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-Cealkyl independently optionally substituted with one or more R3.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-C6alkyl.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R3is independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl.

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R3is independently halogen, -ORa, cycloalkyl, or heterocycloalkyl.

51. The compound of any one of claims 1 -45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

52. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.WSGR Docket No. 57050-707.60153. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is heterocycloalkyl or aryl.

54. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

55. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

56. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl or heteroaryl.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

60. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 6-membered heteroaryl comprising one or two heteroatoms selected that are N.

61. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is a 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, -L-cycloalkyl, -L-WSGR Docket No. 57050-707.601heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

63. The compound of any one of claims 1 -62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci- Cealkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’ ; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, Ci- Cealkyl, or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ .

65. The compound of any one of claims 1 -64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen or -CN.

66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0, 1, or 2.

67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1 or 2.

68. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

69. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-707.60170. The compound of any one of claims 1-57 or 69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

71. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (II);wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;WSGR Docket No. 57050-707.601Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;Z2is absent, -O-, -S-, -NR4-, -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, *-OC(R5)2-, *-C(R5)2C(R5)2NR4-, *-NR4C(R5)2C(R5)2-, *- C(R5)2C(R5)2O-, or *-OC(R5)2C(R5)2-; wherein * is the attachment point to Ring C;R4is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R6is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R6on the same atom are taken together to form an oxo;p is 0, 1, 2, 3, or 4;and / or R4and one R6are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;R7is Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;WSGR Docket No. 57050-707.601R8is hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or - L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -S(=O)Ci-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi- C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -OCi-C3haloalkyl, -S(=O)Ci-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(Ci-C3alkyl)2, -NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi- C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, or Ci-C3heteroalkyl;and / or two R” on the same atom are taken together to form an oxo;provided that the compound is not:WSGR Docket No. 57050-707.60172. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is CRX.

73. The compound of claim 71 or 72, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen, halogen, or Ci-Cealkyl.

74. The compound of any one of claims 71-73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen.

75. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is N.

76. The compound of any one of claims 71-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CRY.

77. The compound of any one of claims 71-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen, halogen, or Ci-Cealkyl.

78. The compound of any one of claims 71-77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen.

79. The compound of any one of claims 71-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

80. The compound of any one of claims 71-79, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is absent.

81. The compound of any one of claims 71 -79, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -C(=O)-.

82. The compound of any one of claims 71-81, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-707.601stereoisomer thereof, wherein:R9is hydrogen, halogen, or Ci-Cealkyl.

83. The compound of any one of claims 71 -82, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.

84. The compound of any one of claims 71-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen, halogen, or Ci-Cealkyl.

85. The compound of any one of claims 71 -84, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen.

86. The compound of claim 71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (II) is of Formula (Ila):Formula (Ila).

87. The compound of any one of claims 71-86, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring C.

88. The compound of any one of claims 71-87, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-S(=O)2NR4-, or *-C(R5)2O-;wherein * is the attachment point to Ring C.

89. The compound of any one of claims 71-88, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z2is *-C(R5)2NR4- or *-C(R5)2O-; wherein * is the attachment point to Ring C.

90. The compound of any one of claims 71-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z2is *-C(R5)2NR4- wherein * is the attachment point to Ring C.

91. The compound of any one of claims 71 -90, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen or Ci-Cealkyl.WSGR Docket No. 57050-707.60192. The compound of any one of claims 71-91, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen.

93. The compound of any one of claims 71 -92, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R5is independently hydrogen.

94. The compound of any one of claims 71-93, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring C is aryl or heteroaryl.

95. The compound of any one of claims 71 -94, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring C is phenyl.

96. The compound of any one of claims 71-95, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R6is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl.

97. The compound of any one of claims 71-96, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R6is independently halogen or Ci-Cealkyl.

98. The compound of any one of claims 71-97, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:p is 0 or 1.

99. The compound of any one of claims 71-98, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:p is 0.

100. The compound of any one of claims 71-99, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7is hydrogen or Ci-Cealkyl.

101. The compound of any one of claims 71-100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7is Ci-Cealkyl.

102. The compound of any one of claims 71-101, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R8is hydrogen or Ci-Cealkyl.

103. The compound of any one of claims 71-102, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R8is Ci-C6alkyl.

104. The compound of any one of claims 71-99, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-707.601R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”.

105. The compound of any one of claims 71-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-Cealkyl independently optionally substituted with one or more R3.

106. The compound of any one of claims 71-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-C6alkyl.

107. The compound of any one of claims 71-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

108. The compound of any one of claims 71-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

109. The compound of any one of claims 71-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is aryl, or heteroaryl.

110. The compound of any one of claims 71-109, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl or heteroaryl.

111. The compound of any one of claims 71-110, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.

112. The compound of any one of claims 71-111, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

113. The compound of any one of claims 71-112, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen or -CN.

114. The compound of any one of claims 71-113, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently -CN.

115. The compound of any one of claims 71-114, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-707.601stereoisomer thereof, wherein:n is 0, 1, or 2.

116. The compound of any one of claims 71-115, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1 or 2.

117. The compound of any one of claims 71-115, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

118. A compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (III);wherein:Ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;W is absent or -C(=O)-;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;WSGR Docket No. 57050-707.601R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl independently optionally substituted with one or more R’ ;R2is Ci-Cealkyl independently optionally substituted with one or more R3;or R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each R3is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkenyl and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or *-OC(R5)2C(R5)2-; wherein * is the attachment point to Ring D;R4is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;Ring D is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R15is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SF5, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, C2-C6alkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R15on the same atom are taken together to form an oxo;m is 0, 1, 2, 3, or 4;L1is -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-;each Rais independently Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rbis independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rcand Rdare independently hydrogen, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independentlyWSGR Docket No. 57050-707.601optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Csalkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl;and / or two R’ on the same atom are taken together to form an oxo;each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3heteroalkyl, Ci-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl;and / or two R” on the same atom are taken together to form an oxo.

119. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is CRX.

120. The compound of claim 118 or 119, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen, halogen, or Ci-Cealkyl.

121. The compound of any one of claims 118-120, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen.

122. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is N.

123. The compound of any one of claims 118-122, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CRY.

124. The compound of any one of claims 118-123, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen, halogen, or Ci-Cealkyl.

125. The compound of any one of claims 71-77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen.

126. The compound of any one of claims 118-122, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-707.601stereoisomer thereof, wherein:Y is N.

127. The compound of any one of claims 118-126, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is absent.

128. The compound of any one of claims 118-126, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -C(=O)-.

129. The compound of any one of claims 118-128, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen, halogen, or Ci-Cealkyl.

130. The compound of any one of claims 118-129, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.

131. The compound of any one of claims 118-130, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen, halogen, or Ci-Cealkyl.

132. The compound of any one of claims 118-131, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen.

133. The compound of claim 118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (III) is of Formula (Illa):Formula (Illa).

134. The compound of any one of claims 118-133, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z3is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(=O)NR4-, *-NR4C(=O)-, *-S(=O)2NR4-, *-NR4S(=O)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring D.

135. The compound of any one of claims 118-134, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z3is *-C(R5)2NR4- wherein * is the attachment point to Ring D.

136. The compound of any one of claims 118-135, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-707.601stereoisomer thereof, wherein:R4is hydrogen or Ci-Cealkyl.

137. The compound of any one of claims 118-136, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen.

138. The compound of any one of claims 118-137, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R5is independently hydrogen.

139. The compound of any one of claims 118-138, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring D is aryl or heteroaryl.

140. The compound of any one of claims 118-139, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring D is phenyl.

141. The compound of any one of claims 118-140, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R15is independently halogen, -CN, -OH, -ORa, -NRcRd, or Ci-Cealkyl.

142. The compound of any one of claims 118-141, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R15is independently halogen or Ci-Cealkyl.

143. The compound of any one of claims 118-142, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 0 or 1.

144. The compound of any one of claims 118-143, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 0.

145. The compound of any one of claims 118-144, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L1is -CH2CH2-.

146. The compound of any one of claims 118-144, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L1is -CH2CH2CH2-.

147. The compound of any one of claims 118-144, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L1is -CH2CH2CH2CH2.

148. The compound of any one of claims 118-147, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-Cealkyl independently optionally substituted with one or more R3.WSGR Docket No. 57050-707.601149. The compound of any one of claims 118-148, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is Ci-C6alkyl.

150. The compound of any one of claims 118-148, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

151. The compound of any one of claims 118-148, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is aryl or heteroaryl.

152. The compound of any one of claims 118-151, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl or heteroaryl.

153. The compound of any one of claims 118-152, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.

154. The compound of any one of claims 118-153, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen, -CN, -OH, -ORa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’; and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”.

155. The compound of any one of claims 118-154, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen or -CN.

156. The compound of any one of claims 118-155, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently -CN.

157. The compound of any one of claims 118-156, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0, 1, or 2.

158. The compound of any one of claims 118-157, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1 or 2.

159. The compound of any one of claims 118-158, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.WSGR Docket No. 57050-707.601160. A compound, selected from a compound found in the specification and in Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

161. A pharmaceutical composition comprising a compound of any one of claims 1-160, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

162. A method of treating a TRPML1 -mediated disorder or disease; the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-160, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

163. The method of claim 162, wherein the TRPML1 -mediated disorder or disease is aging, bone diseases, cardiovascular diseases, congenital developmental disorders, eye diseases, hematological and solid malignancies, infectious diseases, inflammatory diseases, liver diseases, metabolic diseases, neurological or neurodegenerative diseases, pancreatitis, renal diseases, skeletal muscle disorders, obesity, lysosomal storage diseases, hypertrophic cardiomyopathy, dilated cardiomyopathy, inclusion body myositis, Paget’s disease, or pulmonary diseases.

164. The method of claim 162, wherein the TRPML1 -mediated disorder or disease is Aicardi- Goutieres syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxiatelangiectasia, autism spectrum disorders, Batten disease, bipolar disorder, cerebral ataxia, Charcot-Marie-Tooth variant diseases, chronic wasting disease, corticobasal degeneration, corticobasal syndrome, bovine spongiform encephalopathy, Creutzfeldt-Jacob disease, Danon disease, Duchenne muscular dystrophy, exotic ungulate encephalopathy, Fabre disease, Fatal Familial insomnia, Friedreich ataxia, Feline spongiform encephalopathy, Fragile X, frontal temporal dementia, Gaucher disease, Gerstmann-Straussler-Scheinker disease, Giant axonal neuropathy, GM1 and GM2 gangliosidosis, Huntington's disease, Infantile Refsum disease, JUNQ and IPOD, Krabbe’s disease, Kuru, Leukoencephalopathy, Lewy Body dementia, locomotor ataxia, Lyme disease, Machado Joseph disease, major depressive disorder, MPS-III, mucolipidosis, multiple sulfatase deficiency, multiple systems atrophy, myofibrillar myopathies, myotonic dystrophy, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Parkinson's disease, Parkinsonism, Pick's disease, polyglutamine diseases, Pompe disease, pontocerebellar hypoplasia, prion diseases, progressive nuclear palsy, progressive Supranuclear palsy, pyruvate dehydrogenase deficiency, Sandhoff disease, schizophrenia, scrapie, Shy-Drager syndrome, spinal muscular atrophy, spinocerebellar ataxias, sporadic familial insomnia, subacute degeneration of the spinal cord, subacute sclerosing panencephalitis, Tay-Sachs disease, transneuronal degeneration, tuberous Sclerosis, Spinocerebellar Ataxia’s, or vascular dementia.

165. The method of claim 162, wherein the TRPML1 -mediated disorder or disease is age-related macular degeneration, non-alcoholic steatohepatitis (NASH), metabolic dysfunction- associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), retinal cell degeneration in glaucoma, retinitis pigmentosa, acute kidney injury, atherosclerosis, Crohn’s disease, diabetic nephropathy, female infertility, H. pylori infections, hypochlorhydria,WSGR Docket No. 57050-707.601pancreatitis, retinal detachment, type 2 diabetes mellitus, ulcerative colitis, or sarcopenia.

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