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. 57050-708.601TRPML1 AGONISTS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 755,143 filed February 6, 2025 and U. S. Provisional Application Serial No. 63 / 956,523 filed January 8, 2026; which are hereby incorporated by reference in their 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. 57050-708.601SUMMARY 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] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 57050-708.601nFormula (II) as disclosed herein.

[0013] 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.

[0014] 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

[0015] 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

[0016] 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, that 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.

[0017] 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 dictatesWSGR Docket No. 57050-708.601otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0018] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0019] “Oxo” refers to =0.

[0020] “Amino” refers to -NH2.

[0021] “Hydroxy” refers to -OH.

[0022] “Carboxyl” refers to -COOH.

[0023] “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.

[0024] “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 the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever 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 withWSGR Docket No. 57050-708.601one 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.

[0025] “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.

[0026] “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.

[0027] “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, -COOH, -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.

[0028] “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,WSGR Docket No. 57050-708.601fluoranthenyl, 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.

[0029] “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 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 - to 6-membered fully saturated cycloalkyl or a 5 - to 6-membered cycloalkenyl.Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, 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, bicyclo[l.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, cycloheptenyl, 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.WSGR Docket No. 57050-708.601

[0030] “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.

[0031] “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.

[0032] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0033] “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.

[0034] “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.

[0035] “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, CDs, CH2D, CHD2, CH2CD3, CD2CD3, CHDCDs, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CDs.

[0036] “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, -CH(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.WSGR Docket No. 57050-708.601

[0037] “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, heterocycloalkyl means a partially saturated or fully saturated 3- to 8-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyl means a fully saturated 3- to 8-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyl means a partially saturated or fully saturated 4- to 6-membered ring comprising one or two heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heterocycloalkyl means a fully saturated 4- to 6-membered ring comprising one or two 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, 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-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), 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-1, 3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The termWSGR Docket No. 57050-708.601heterocycloalkyl 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, -CF3, -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.

[0038] “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, heteroaryl means a fully aromatic 5- to 6-membered ring comprising one, two, three, or four 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, 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 heteroarylWSGR Docket No. 57050-708.601is 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-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 -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[I,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- 1H-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, -CF3, -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.

[0039] 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 ).

[0040] 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 independentlyWSGR Docket No. 57050-708.601optionally substituted with two substituents. In some embodiments, the subject group is independently optionally substituted with three substituents.

[0041] 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.

[0042] “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.

[0043] “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.

[0044] 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

[0045] 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.

[0046] Disclosed herein is 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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 eachWSGR Docket No. 57050-708.601cycloalkyl, 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 C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R2is C1-C6alkyl 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, C1-C6alkyl, 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’;WSGR Docket No. 57050-708.601or 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, C1-C6alkyl, 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 C1-C6alkyl, 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, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHC1-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, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, or C1-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.WSGR Docket No. 57050-708.601

[0047] Also disclosed herein is 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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 C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R2is C1-C6alkyl 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,WSGR Docket No. 57050-708.601cycloalkyl, 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)-, or -CH2CH2-;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C6alkyl, 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, C1-C6alkyl, 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, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independentlyWSGR Docket No. 57050-708.601optionally 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 C1-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHC1-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, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, or C1-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;

[0048] In some embodiments of a compound of Formula (I), the compound is not:Cl

[0049] In some embodiments of a compound of Formula (I), X is CRX. In some embodiments of a compound of Formula (I), X is N.

[0050] In some embodiments of a compound of Formula (I), Rxis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), Rxis hydrogen.

[0051] In some embodiments of a compound of Formula (I), Y is CRY. In some embodiments of a compound of Formula (I), Y is N.

[0052] In some embodiments of a compound of Formula (I), RYis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), RYis hydrogen.

[0053] 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)-.

[0054] In some embodiments of a compound of Formula (I), R9is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), R9is hydrogen.WSGR Docket No. 57050-708.601

[0055] In some embodiments of a compound of Formula (I), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (I), R10is hydrogen.

[0056] 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 C1-C6alkyl. In some embodiments of a compound of Formula (I), R12is -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or C1-C6alkyl. 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.

[0057] In some embodiments of a compound of Formula (I), R13is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (I), R13is hydrogen.

[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- 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.

[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 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.

[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 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.

[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- 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.

[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 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.

[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 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.

[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- or 6-membered heterocycloalkyl optionally comprising oneWSGR Docket No. 57050-708.601additional 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 5 -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 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.

[0067] 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, C1-C6alkyl, 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, C1-C6alkyl, 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.WSGR Docket No. 57050-708.601

[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 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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 C1-C6alkyl; 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 C1-C6alkyl; 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 C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la), each R14is independently C1-C6alkyl 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 the same 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.

[0073] 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.WSGR Docket No. 57050-708.601O' o(R14)t

[0076] In some embodiments of a compound of Formula (I) or (la),(R14)t. In some embodiments of a compound of Formula (I) or (la), is oz'"b

[0077] In some embodiments of a compound of Formula (I) or (la), each R11is independently halogen, -CN, C1-C6alkyl, C2-Cealkenyl, or C2-Cealkynyl. In some embodiments of a compound of Formula (I) or (la), each R11is independently C1-C6alkyl.

[0078] 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 ofWSGR Docket No. 57050-708.601Formula (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.

[0079] In some embodiments of a compound of Formula (I) or (la), Z1is -CH2-, -CH(CH3)-, or -CH2CH2-. In some embodiments of a compound of Formula (I) or (la), Z1is -CH2- or -CH(CH3)-. In some embodiments of a compound of Formula (I) or (la), Z1is -CH2-.

[0080] In some embodiments of a compound of Formula (I) or (la), R2is C1-C6alkyl independently optionally substituted with one or more R3. In some embodiments of a compound of Formula (I) or (la), R2is C1-C6alkyl.

[0081] 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”.

[0082] 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.

[0083] 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.

[0084] In some embodiments of a compound of Formula (I) or (la), R2is,WSGR Docket No. 57050-708.601', / , ', ', or N. In some embodiments of a compound of Formula (I) or(la), R2is.

[0085] In some embodiments of a compound of Formula (I) or (la), Ring A is a cycloalkyl or heterocycloalkyl.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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, C1-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”. 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, C1-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”. 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, C1-C6alkyl, 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.

[0092] 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 ofWSGR Docket No. 57050-708.601Formula (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.G(Rl)nO Q

[0093] In some embodiments of a compound of Formula (I) or (la), is / CN F ci F P ft. ft" P A ft' P ft ft" P ° PF3VFVoF OV CN pV OH pV p^ O" pA OH2 / p^ ^p "-FT F prCNFCNNCCl X° Pftv-CN Pft PF^CN ft \x^CN ftP^CN r XP r r rFTFTp-O'0^F-OP r-O"F-O0^ p-o^o- c5 Q <, F, Pr, PT, Pr. PpP.xP, P Q. Hi P p P dr P CPCF- p^p 0X.P. P. P rr P p^0P p^p pft">'y ftF ft cp^p, or ' pft-WSGR Docket No. 57050-708.601

[0094] In some embodiments of a compound of Formula (I) or (la),

[0096] In some embodiments of a compound of Formula (I) or (la), CNor

[0097] In some embodiments of a compound of Formula (I) or (la),

[0099] 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 logWSGR Docket No. 57050-708.601unit. 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.

[0100] 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).

[0101] Also disclosed herein is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R6)PFormula (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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;WSGR Docket No. 57050-708.601R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;W is absent or -C(=O)-;R2is C1-C6alkyl 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 C1-C6alkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or C1-C6alkyl 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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 hydrogen, C1-C6alkyl, 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, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or - L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted withWSGR Docket No. 57050-708.601one 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 C1-C6alkyl, 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, C1-C6alkyl, 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, C1-C6alkyl, 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)C1-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-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)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-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.

[0102] In some embodiments of a compound of Formula (II), X is CRX. In some embodiments of a compound of Formula (II), X is N.

[0103] In some embodiments of a compound of Formula (II), Rxis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II), Rxis hydrogen.

[0104] In some embodiments of a compound of Formula (II), Y is CRY. In some embodiments of a compound of Formula (II), Y is N.

[0105] In some embodiments of a compound of Formula (II), RYis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II), RYis hydrogen.WSGR Docket No. 57050-708.601

[0106] 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)-.

[0107] In some embodiments of a compound of Formula (II), R9is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II), R9is hydrogen.

[0108] In some embodiments of a compound of Formula (II), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (II), R10is hydrogen.

[0109] In some embodiments, the compound of Formula (II) is of Formula (Ila):Formula (Ila).

[0110] 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. In some embodiments of a compound of Formula (II) or (Ila), Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring C. 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. In some embodiments of a compound of Formula (II) or (Ila), Z2is *-C(R5)2NR4-; wherein * is the attachment point to Ring C. In some embodiments of a compound of Formula (II) or (Ila), Z2is *-C(R5)2O-; wherein * is the attachment point to Ring C.

[0111] In some embodiments of a compound of Formula (II) or (Ila), R4is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila), R4is hydrogen.

[0112] In some embodiments of a compound of Formula (II) or (Ila), each R5is independently hydrogen.

[0113] 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.

[0114] In some embodiments of a compound of Formula (II) or (Ila), each R6is independently halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila), each R6is independently halogen or C1-C6alkyl.

[0115] 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. 57050-708.601

[0116] In some embodiments of a compound of Formula (II) or (Ila), R7is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila), R7is C1-C6alkyl.

[0117] In some embodiments of a compound of Formula (II) or (Ila), R8is hydrogen or C1-C6alkyl. In some embodiments of a compound of Formula (II) or (Ila), R8is C1-C6alkyl.

[0118] 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.

[0119] In some embodiments of a compound of Formula (II) or (Ila), R2is C1-C6alkyl independently optionally substituted with one or more R3. In some embodiments of a compound of Formula (II), R2is C1-C6alkyl.

[0120] 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”.

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

[0122] 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”.

[0123] In some embodiments of a compound of Formula (II) or (Ila), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (II) or (Ila), In some embodiments of a compound of Formula (II), R2is aryl, or heteroaryl.

[0124] 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.

[0125] In some embodiments of a compound of Formula (II) or (Ila), Ring A is a cycloalkyl or heterocycloalkyl.

[0126] 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.

[0127] 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.WSGR Docket No. 57050-708.601

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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, C1-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”. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, C1-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”. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, C1-C6alkyl, or -L-cycloalkyl; 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 or -CN. In some embodiments of a compound of Formula (II) or (Ila), each R1is independently -CN.

[0132] 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.

[0133] Disclosed herein is a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 57050-708.601Formula (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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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, -O-, -S-, -NH-, -N(CH₃)-, -C(=O)-, or C1-C6alkylene;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R2is C1-C6alkyl 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”;WSGR Docket No. 57050-708.601each 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 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”; Z3is absent, -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, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C6alkyl, 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, C1-C6alkyl, 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, C1-C6alkyl, 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”;WSGR Docket No. 57050-708.601L is absent or C1-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHC1-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, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, or C1-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.

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

[0135] In some embodiments of a compound of Formula (III), Rxis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (III), Rxis hydrogen.

[0136] In some embodiments of a compound of Formula (III), Y is CRY. In some embodiments of a compound of Formula (III), Y is N.

[0137] In some embodiments of a compound of Formula (III), RYis hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (III), RYis hydrogen.

[0138] 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)-. In some embodiments of a compound of Formula (III), W is -O-, -S-, or -NH-. In some embodiments of a compound of Formula (III), W is C1-C6alkylene. In some embodiments of a compound of Formula (III), W is CH2.

[0139] In some embodiments of a compound of Formula (III), R9is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (III), R9is hydrogen.

[0140] In some embodiments of a compound of Formula (III), R10is hydrogen, halogen, or C1-C6alkyl. In some embodiments of a compound of Formula (III), R10is hydrogen.

[0141] In some embodiments, the compound of Formula (III) is of Formula (Illa):WSGR Docket No. 57050-708.601Formula (Illa).

[0142] In some embodiments of a compound of Formula (III) or (Illa), 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 (III) or (Illa), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of N, O, and S.

[0143] In some embodiments of a compound of Formula (III) or (Illa), 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 (III) or (Illa), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom selected from the group consisting of O and S.

[0144] In some embodiments of a compound of Formula (III) or (Illa), Ring B is a 5-membered heterocycloalkyl optionally comprising one additional heteroatom that is S. In some embodiments of a compound of Formula (III) or (Illa), Ring B is a 6-membered heterocycloalkyl optionally comprising one additional heteroatom that is S.

[0145] In some embodiments of a compound of Formula (III) or (Illa), Ring B is a 5-membered heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), Ring B is a 6-membered heterocycloalkyl.

[0146] In some embodiments of a compound of Formula (III) or (Illa), each R14is independently C1-C6alkyl; 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 (III) or (Illa), each R14is independently C1-C6alkyl; and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (Illa), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl; wherein each alkyl is independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (III) or (Illa), each R14is independently halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl. In some embodiments of a compound of Formula (III) or (Illa), each R14is independently C1-C6alkyl and / or two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (Illa), two R14on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (III) or (Illa), two R14on the same carbon are taken together to form a cycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), two R14on the same carbon are taken together to form a cyclopropyl.

[0147] In some embodiments of a compound of Formula (III) or (Illa), t is 0, 1, 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (III) or (Illa), t is 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (III) or (Illa), t is 2, 3, or 4. In some embodiments of a compound of Formula (III) or (Illa), t is 4. In some embodiments of a compound of Formula (III) or (Illa), t is 6.WSGR Docket No. 57050-708.601

[0150] In some embodiments of a compound of Formula (III) or (Illa),is In some embodiments of a compound of Formula (III) or (Illa),WSGR Docket No. 57050-708.601

[0151] In some embodiments of a compound of Formula (III) or (Illa), each R11is independently halogen, -CN, C1-C6alkyl, C2-Cealkenyl, or C2-Cealkynyl. In some embodiments of a compound of Formula (III) or (Illa), each R11is independently C1-C6alkyl.

[0152] In some embodiments of a compound of Formula (III) or (Illa), q is 0, 1, or 2. In some embodiments of a compound of Formula (III) or (Illa), q is 0 or 1. In some embodiments of a compound of Formula (III) or (Illa), q is 0. In some embodiments of a compound of Formula (III) or (Illa), q is 1. In some embodiments of a compound of Formula (III) or (Illa), q is 2.

[0153] In some embodiments of a compound of Formula (III) or (Illa), R2is C1-C6alkyl independently optionally substituted with one or more R3a. In some embodiments of a compound of Formula (III) or (Illa), R2is C1-C6alkyl.

[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 R3b. In some embodiments of a compound of Formula (III) or (Illa), R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (III) or (Illa), R2is heterocycloalkyl or aryl. In some embodiments of a compound of Formula (III) or (Illa), R2is phenyl. In some embodiments of a compound of Formula (III) or (Illa), R2is cycloalkyl independently optionally substituted with one or more R3b. In some embodiments of a compound of Formula (III) or (Illa), R2is cyclopropyl.

[0155] In some embodiments of a compound of Formula (III) or (Illa), 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 (III) or (Illa), each R3ais independently halogen, -CN, -OH, -ORa, -NRcRd, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3ais independently halogen, -ORa, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3ais independently halogen or -ORa. In some embodiments of a compound of Formula (III) or (Illa), each R3ais independently -ORa.

[0156] In some embodiments of a compound of Formula (III) or (Illa), each R3bis independently halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-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 (III) or (Illa), each R3bis independently halogen, -CN, -OH, -ORa, -NRcRd, C1-C6alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3bis independently halogen, -ORa, C1-C6alkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3bis independently halogen or -ORa. In some embodiments of a compound of Formula (III) or (Illa), each R3bis independently -ORa. In some embodiments of a compound of Formula (III) or (Illa),WSGR Docket No. 57050-708.601each R3bis independently halogen or C1-C6alkyl. In some embodiments of a compound of Formula (III) or (Illa), each R3bis independently halogen.

[0157] In some embodiments of a compound of Formula (III) or (Illa), Ring A is a cycloalkyl or heterocycloalkyl.

[0158] 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.

[0159] 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.

[0160] 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 compound of 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.

[0161] 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.

[0162] 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.

[0163] 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, C1-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”. In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, C1-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”. In some embodiments of a compound of Formula (III) or (Illa), each R1is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -NRcRd, -C(=O)NRcRd, C1-C6alkyl, or -L-cycloalkyl; 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 or -CN.

[0164] 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.WSGR Docket No. 57050-708.601

[0165] In some embodiments of a compound of Formula (III) or (Illa), Z3is absent. In some embodiments of a compound of Formula (III) or (Illa), Z3is absent, -CH2-, -CH(CH3)-, or -CH2CH2-. In some embodiments of a compound of Formula (III) or (Illa), Z3is absent or -CH2-.

[0166] In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, -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 C1-C6alkyl, -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 C1-C6alkyl 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 C1-C6alkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl or cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently C1-C6alkyl.

[0167] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, -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 C1-C6alkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, C1-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen.

[0168] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, -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 C1-C6alkyl independently optionally substituted with one or more R’.WSGR Docket No. 57050-708.601

[0169] In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl independently optionally substituted with one or more R’. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, C1-C6alkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceaminoalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl independently optionally substituted with one or more halogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or C1-C6alkyl.

[0170] In some embodiments of a compound disclosed herein, each Rcand Rdare independently C1-C6alkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen.

[0171] 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”.

[0172] In some embodiments of a compound disclosed herein, L is absent or C1-C3alkylene. In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C3alkylene. 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.

[0173] In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)2C1-C3alkyl, -NH2, -NHCi-Csalkyl, 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, -OC 1 -Chalky I. -NH2, -NHC’i -Chalky I. 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, -OC₁-C₃alkyl, 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, -OC₁-C₃alkyl, or -NH₂. In some embodiments of a compound disclosed herein, each R’ is independently halogen.

[0174] In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, -C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, or C₁-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, -OC1-C3alkyl, -NH2, -NHCi-Csalkyl, -N(Ci-C3alkyl)2, C1-C6alkyl. or C₁-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, -OC1-C3alkyl, -NH2, Ci-Csalkyl, or C₁-C₃heteroalkyl; wherein each alkyl is optionally substituted with one or more halogen;WSGR Docket No. 57050-708.601and / 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, -OC1-C3alkyl, -NH2, C1-C3alkyl, or C1-C3heteroalkyl. In some embodiments of a compound disclosed herein, each R” is independently halogen, -OH, -OC1-C3alkyl, or Ci-Csalkyl. In some embodiments of a compound disclosed herein, each R” is independently halogen or Ci-Csalkyl.

[0175] 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.

[0176] In some embodiments, the compound is selected from a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, found in Table 1.Table 1Ex. Structure Name1 m-[7-({[p- (dimethylaminosulfonyl)p. N. 1if TA henyl] methyl } amino) - 1 - methyl- 1,4,6-triaza- 1H- _N 1H \ inden-3 -yl] benzonitrileo=s=o2 m-[7-({[p- (dimethylaminosulfonyl)pJ henyl] methyl } amino) - 1 - rf TAN-^-N (2-pyridyl)- 1,4,6-triaza- lH-inden-3- fNH^3 yl] benzonitrile9 'o=s 1=o3 m-[7-({[p- (dimethylaminosulfonyl)prn T A henyl] methyl } amino) - 1 - phenyl- 1,4,6-triaza- 1H- inden-3 -yl] benzonitrilefNHo=s=oWSGR Docket No. 57050-708.601Ex. Structure Name4 p-[7-({[p- J (dimethylaminosulfonyl)p henyl] methyl } amino) - 1 - phenyl- 1,4,6-triaza- 1H-. N. _ (if VY inden-3 -yl] benzonitrile. NH / =\6 °o° — \ z=s=o° \ 1Z— V5 m-[7-({[p-Z=\ O / \ ^N(dimethylaminosulfonyl)p rn YA henyl] methyl } -N- methylamino)- 1 -phenyl- 1,4,6-triaza- lH-inden-3 - \\ \ z yl] benzonitrile o=s 1=o / N\6 r^\_ ^N m-(7-{[p- (dimethylaminosulfonyl)p henyl] methoxy } - 1 - N^XN isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile ro=s 1=o7 r?=\ _=lN m-(7-{[p- (xj / "(dimethylaminosulfonyl)p N^ 7 henyl] methoxy } - 1 - NOO methyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile Yo=s 1=o8 ethyl 4-{[3-(m- cyanophenyl)- 1 -phenyl- 1,4,6-triaza- lH-inden-7 - yl]methyl}-l- piperazinecarboxylateWSGR Docket No. 57050-708.601Ex. Structure Name9 m-(7-{[(8aS)-6,6- NJ' dimethyl-5 -oxo-2, 4a- if TN diazaoctahydro-2H- NXJA-N naphth-2-yl]methyl} - 1 - isopropyl- 1,4,6-triaza- 1H- Q^N< S'J inden-3 -yl)benzonitrile 10 kJ - m-(7-{[(8aR)-6,6- dimethyl-5 -oxo-2, 4a- <(. N T. J J diazaoctahydro-2H- naphth-2-yl]methyl} - 1 - isopropyl- 1,4,6-triaza- 1H- [^KTinden-3 -yl)benzonitrile 11 / -s=\ jsN tert-butyl 4- { [3 -(m- NJ / z\\\~ cyanophenyl)-l- isopropyl- 1,4,6-triaza- 1H- if VNNXA inden-7 -yl] methyl } - 1 - CooNZpiperazinecarboxylate l^rro \A°Q- "12 m-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile 13 r^N^N m-(7-{[(3aS)-2,2- NJ' dimethyl- 1, 1 -dioxo- 1 X6- thia-5, 7 a-diazaoctahydro-Nn^xnN 5 -indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- [^hTOxJ inden-3 -yl)benzonitrile 14 Q^Nm-(l-isopropyl-7- j^ {[(5R,7aS)-2,2,5- trimethyl-3-oxo-3a,6- Ov diazaoctahydro-6- indenyl]methyl } - 1,4,6- > JJ. triaza- 1 H-inden-3 - 0 yl)benzonitrile15 JJ--=Nm-{7-[(4-isobutyryl-l- >1. 7 piperazinyl)methyl] - 1 - 05 isopropyl- 1,4,6-triaza- 1H- •Y^N inden-3 -yl } benzonitrile f^'N'^WSGR Docket No. 57050-708.601Ex. Structure Name16 m-[7-({(3a'S,7a'S)-3'-oxo- 1', 4’, 5', 6', T, 7a’- hexahydro-3a',6'- diazaspiro [cyclopropane - l,2'-inden]-6'-yl}methyl)- 1 -isopropyl- 1H- 1,4,6- triazainden-3- yl] benzonitrile17 3-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3-yl)-2- fluorobenzonitrile m-(7-{[(7aS)-2,2- 18 O^ A\Nz\\ dimethyl-3-oxo-3a,6- X, r-°u- V' diazaoctahydro-6- N1X\N z V / J^ vX / JxX indenyl]methyl } - 1 -(2- < Y \ methoxyethyl)- 1,4,6- triaza- 1 H-inden-3 - °^y yl)benzonitrile, O “ucXvo o o 19 m-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 -(2- isopropoxyethyl)- 1,4,6- triaza- 1 H-inden-3 - yl)benzonitrile20 m-(7-{[(3aS)-2,2- Qr^ dimethyl- 1, 1 -dioxo- 1 X6- thia-5, 7 a-diazaoctahydro- 5 -indenyl]methyl } - 1 -(2- OO methoxyethyl)- 1,4,6- triaza- 1 H-inden-3 - 0. N. Jyl)benzonitrile o^J21 m-(l-isopropyl-7- Qr^ {[(5S,7aS)-2,2,5- trimethyl-3-oxo-3a,6- diazaoctahydro-6- NO-Nindenyl]methyl } - 1,4,6- triaza- 1 H-inden-3 - >$3< yl)benzonitrile 0WSGR Docket No. 57050-708.601Ex. Structure Name22 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- indenyl]methyl } - 1 -(2- methoxyethyl)- 1H- 1,4,6- triazainden-3 -yl) -4- fluorobenzonitrile 23 o o m-(7-{[(3aS,5S,7aS)- O^N2,2,5-trimethyl-3-oxo- blOsbz1,4, 5,6,7, 7a-hexahydro-z■=\ N / \OO 3a,6-diaza-6- \Z XX—._ indenyl]methyl } - 1 -(2- methoxyethyl)- 1H- 1,4,6- / 0 triazainden-3- \\ \ z yl)benzonitrile24 p-(7-{[(7aS)-2,2- u. dimethyl-3-oxo-3a,6- Jj^ lZ V 1 J X JX / Yxszszk'^" diazaoctahydro-6-. N. indenyl]methyl } - 1 -7isopropyl- 1,4,6-triaza- 1H- NOO inden-3 -yl)benzonitrile o o „ N. _ J o^z25 5-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3-yl)-2- fluorobenzonitrile 26 3-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3-yl)-4- fluorobenzonitrile 27 (3aS,7aS)-6-{[l- isopropyl-3-(p-tolyl)- 1,4,6-triaza- lH-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenoneWSGR Docket No. 57050-708.601Ex. Structure Name28 (3aS,7aS)-6-{[l- isopropyl-3-(o-tolyl)- 1,4,6-triaza- lH-inden-7 - NOO yl]methyl}-2,2-dimethyl- l^hr 3a,6-diazahexahydro- 3(lH)-indenone o=^29 5-(7-{[(7aS)-2,2- o dimethyl-3-oxo-3a,6- diazaoctahydro-6-Z~^ / \ indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3-yl)-3- \Z, J_ / \\ fluorobenzonitrile30* zny- S zNm-{l-[(S)-2- methoxypropyl] -7-NOw / x 1 { [(3aS,7aS)-2,2-dimethyl- ^ rC 3-oxo-l,4,5,6,7,7a-.. Xr. hexahydro-3a,6-diaza-6- indenyl]methyl } - 1 H- o / rl,4,6-triazainden-3- uocyl} benzonitrile31* O^Nm-{l-[(R)-2- methoxypropyl] -7- { [(3aS,7aS)-2,2-dimethyl-NO0 3-oxo-l,4,5,6,7,7a- hexahydro-3a,6-diaza-6- „ z*k J indenyl]methyl } - 1 H- l,4,6-triazainden-3- yl} benzonitrile32 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,6-diaza- 1H- inden-3-yl)-4- fluorobenzonitrile33 C^Nm-[(3'aS)-3- (cyclopropylmethyl)-2',2'- dimethyl-l'-oxo- N«P1N 3,5,5',7,7'a-pentaaza- l',2',3',3'a,4',5',6',7'- Z^isr octahydro-3H-4,5'- biindenyl-1-yl] benzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name34* m-{7-[(S)-l-[(7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl] ethyl]- 1- isopropyl- 1,4,6-triaza- 1H- inden-3 -yl } benzonitrile35* m-(7-{(R)-l-[(7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- CO 3a,6-diaza-6- indenyl]ethyl}-l-n. N _ J isopropyl- 1H- 1,4,6- triazainden-3- yl)benzonitrile36* z z m-{7-[(S)-l-[(7aS)-2,2- \ \ \\\\ dimethyl-3-oxo-3a,6-<\ _,o \O\\ \ V i f\\ diazaoctahydro-6- indenyl] ethyl] - 1 -(2- fyyC o O- isopropoxyethyl)- 1,4,6- triaza- 1 H-inden-3 - y.yl} benzonitrile37* o o o o m-(7-{(R)-l-[(7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- indenyl] ethyl } - 1 -(2- isopropoxyethyl)- 1H- l,4,6-triazainden-3- yl)benzonitrile38* m-(7-{(S)-l-[(3aS,7aS)- 2,2-dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- NQ 3a,6-diaza-6-r;O> — \ indenyl] ethyl } - 1 -(2- o-— methoxyethyl)- 1H- 1,4,6- o^y triazainden-3- yl)benzonitrile39* m-(7-{(R)-l-[(3aS,7aS)- 2,2-dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- indenyl] ethyl } - 1 -(2- methoxyethyl)- 1H- 1,4,6- triazainden-3- yl)benzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name40 m-(7-{2-[(7aR)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]ethyl}-l- isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile' \ x>o41 m-(7-{[(2R,5S)-4- isobutyryl-2,5 -dimethyl- 1 -piperazinyl]methyl } - 1 - ^ ~zz\= / \NOO isopropyl- 1,4,6-triaza- 1H- / / 5^ \ / AZ Z^, inden-3 -yl)benzonitrile Q^N^^.,Z / / ZV> Z- 42 m-(7-{[(2S,5R)-4- isobutyryl-2,5 -dimethyl- >k J, 1 -piperazinyl]methyl } - 1 -NOv isopropyl- 1,4,6-triaza- 1H- _ J > —f N / inden-3 -yl)benzonitrile43 m-(7-{[(3R,5S)-4- v^ " isobutyryl-3,5 -dimethyl- 1 -piperazinyl]methyl } - 1 - Ov isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile44 pv-sNm-(7-{[(7aS)-2,2- dimethyl-3-oxo-3a,6- ^N. j'fl T V) diazaoctahydro-6-N^N indenyl](²H₂)methyl}-1-D~rDz^~ isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile45 (7aS)-6-{[l-isopropyl-3- (2-methyl-4-pyridyl)- 1,4,6-triaza- lH-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenoneWSGR Docket No. 57050-708.601Ex. Structure Name46 (7aS)-6-{[l-isopropyl-3- (3-pyridyl)- 1,4,6-triaza- 1 H-inden-7 -yl]methyl } - 2,2-dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone47o o 4-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- A z=\Z- 3a,6-diaza-6- ^ v / / zindenyl]methyl } - 1 -ZMWw \ VZkZ^<^ >^ isopropyl- 1H- 1,4,6- > 1 / / <z triazainden-3 -yl) -3 - fluorobenzonitrile w z48 (3aS,7aS)-6-{[l- \Z— isopropyl-3-(m- methoxyphenyl)- 1H- z., z < \ •= —HN Z- l,4,6-triazainden-7- yl]methyl}-2,2-dimethyl- 1,4, 5,6,7, 7a-hexahydro- o 3a,6-diaza-3(2H)- indenone49 (3aS,7aS)-6-({l- r-N\3r-Fp > isopropyl-3-[2- (trifluoromethyl)-4- fl 'T y pyridyl]-lH-l,4,6- N^-N triazainden-7 -yl } methyl)- (^hr 2,2-dimethyl-l,4,5,6,7,7a- hexahydro-3a,6-diaza- 0= / 3(2H)-indenone50 Cl 5-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6-N^N indenyl]methyl } - 1 - f^lsr isopropyl- 1H- 1,4,6- triazainden-3 -yl) -2- chlorobenzonitrile 51 5-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3- yl)isophthalonitrileWSGR Docket No. 57050-708.601Ex. Structure Name52 (3aS,7aS)-6-[(l- isopropyl-3 -phenyl- 1,4,6- triaza- 1 H-inden-7 - Ow yl)methyl]-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone53 (3aS,7aS)-6-{[l- isopropyl-3-(4-methyl-2- pyridyl)- 1,4,6-triaza- 1H- NOO inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - °= / indenone54 (3aS,7aS)-6-({3-[m- Civf(difluoromethyl)phenyl] - 1 -isopropyl- 1,4,6-triaza- if YN^-xNzJ' 1 H-inden-7 -yl } methyl) - 2,2-dimethyl-3a,6- l^hTV\ ^- diazahexahydro-3 ( 1 H) - o=z N _ J indenoneVro55 (3aS,7aS)-6-({3-[2- O^F(difluoromethyl)-4- N _ Z pyridyl] - 1 -isopropyl- < Yv 1,4,6-triaza- lH-inden-7 - N^x-N yl}methyl)-2,2-dimethyl- l^hT 3a,6-diazahexahydro- 3(lH)-indenone o=z56 (3aS,7aS)-6-{[3-(p- fluorophenyl)-l- isopropyl- 1,4,6-triaza- 1H- inden-7 -yl] methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone57 F (7aS)-6-({ l-isopropyl-3- YprVsV FF[m- > L J (trifluoromethyl)phenyl] - fl 1,4,6-triaza- lH-inden-7 - yl}methyl)-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone o^Y1WSGR Docket No. 57050-708.601Ex. Structure Name58 o (3aS,7aS)-6-{[l- b isopropyl-3-(m-. N. J mesylphenyl)- 1H- 1,4,6- if triazainden-7 -yl]methyl } - 2,2-dimethyl-l,4,5,6,7,7a- hexahydro-3a,6-diaza- „. N. _ ) 3(2H)-indenone59 o 5-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- 7=\ v_ indenyl]methyl } - 1 -z4 z- isopropyl- 1H- 1,4,6- / triazainden-3 -yl) -2-11o / ^ anisonitrile60 / TV" (3aS,7aS)-6-{[l- JTX / JX / Oisopropyl-3-(m-tolyl)-lH- v / ^ \-x —z"l,4,6-triazainden-7- 1*VN< / L~N yl]methyl}-2,2-dimethyl- QZ--AZ” 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-3(2H)- o V=ro o o z indenone61 (3aS,7aS)-6-{[l- isopropyl-3-(m- trifluoromethoxyphenyl) - 1H- 1,4,6-triazainden-7 - yl]methyl}-2,2-dimethyl- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-3(2H)- indenone62 (3aS,7aS)-6-{[l- isopropyl-3-(4-pyridyl)- 1H- 1,4,6-triazainden-7 - yl]methyl}-2,2-dimethyl- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-3(2H)- indenone63 (3aS,7aS)-6-{[3-(2,4- difluorophenyl)- 1 - isopropyl- 1,4,6-triaza- 1H- inden-7 -yl] methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenoneWSGR Docket No. 57050-708.601Ex. Structure Name64 HO (3aS,7aS)-6-{[3-(2- fluoro-5 -hydroxyphenyl)- 1 -isopropyl- 1,4,6-triaza- h 1 H-inden-7 -yl]methyl } - 2,2-dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone65 o (3aS,7aS)-6-({3-[4- (difluoromethyl)-2- fluorophenyl]-l- isopropyl- 1,4,6-triaza- 1H- 'w- inden-7-yl}methyl)-2,2- \z,_ dimethyl-3a,6- / / diazahexahydro-3 ( 1 H) - indenone66 O,— N'0 / (3aS,7aS)-6-{[l- ol z Jx- isopropyl-3-(2-methoxy- A T 4-pyridyl)- 1,4,6-triaza- v, CKN-Ov 1 H-inden-7 -yl]methyl } - T" 2,2-dimethyl-3a,6- °^y diazahexahydro-3 ( 1 H) - o indenone67 (3aS,7aS)-6-({3-[5- (difluoromethyl)-2- fluorophenyl]-l- isopropyl- 1,4,6-triaza- 1H- inden-7-yl}methyl)-2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone68 f^X^-cx (3aS,7aS)-6-{[3-(m- (x jT chlorophenyl)-l- 7 isopropyl- 1,4,6-triaza- 1H- T v inden-7 -yl]methyl } -2,2- I^Yr dimethyl-3a,6-.NT diazahexahydro-3 ( 1 H) -0\2= indenone69 (3aS,7aS)-6-{[3-(m- cyclopropylphenyl) - 1 - isopropyl- 1,4,6-triaza- 1H- inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenoneWSGR Docket No. 57050-708.601Ex. Structure Name70 (3aS,7aS)-6-{[3-(m- / xxFyoFdifluoromethoxyphenyl) - 1 -isopropyl- 1,4,6-triaza- N _ / 1 H-inden-7 -yl]methyl } - if T \N^X-N 2,2-dimethyl-3a,6- diazahexahydro-3 ( 1 H) - ( hr indenone N. _ >0= / X71 (3aS,7aS)-6-({l- isopropyl-3-[m- (mesylmethyl)phenyl] - 1,4,6-triaza- lH-inden-7 - yl}methyl)-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone o72 ° 2-[m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- Tx o- diazaoctahydro-6- V>zz—\= indenyl]methyl } - 1 -vTv T? isopropyl- 1,4,6-triaza- 1H- V VvVrr ^ inden-3 -yl)phenyl] -2- o o omethylpropiononitrile73 (3aS,7aS)-6-{[3-(o- fluorophenyl)-l- isopropyl- 1,4,6-triaza- 1H- inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone74 (3aS,7aS)-6-{[3-(m- CkFfluorophenyl)-l-. N.n TO isopropyl- 1,4,6-triaza- 1H- N^V inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone75 N=\ _^N 5-(7-{[(3aS,7aS)-2,2- Y / O dimethyl-3-oxo-ZNO 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- l^br X~ indenyl]methyl } - 1 - isopropyl- 1H- 1,4,6- °^O>triazainden-3-yl)nicotinonitrileWSGR Docket No. 57050-708.601Ex. Structure Name76 (3aS,7aS)-6-{[l- isopropyl-3 -( 1 -methyl -4- pyrazolyl)- 1H- 1,4,6- triazainden-7 -yl]methyl } - 2,2-dimethyl-l,4,5,6,7,7a- hexahydro-3a,6-diaza- 3(2H)-indenone77 5-(7-{[(3aS,7aS)-2,2- o dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- o s Ozn 3a,6-diaza-6- indenyl]methyl } - 1 - isopropyl- 1H- 1,4,6- O p triazainden-3 -yl) -3 - thenonitrilev-o78 \ O T(3aS,7aS)-6-({3-[5- (difluoromethyl)-3 - pyridyl] - 1 -isopropyl -3V\\ zz-" A.^ J vV / J\\\Y, S / \^iz Z zZ^"'' / \ A.z1,4,6-triaza- lH-inden-7 - yl}methyl)-2,2-dimethyl- A / Vs'z \= vR 3a,6-diazahexahydro- SV¥V ° 3(lH)-indenone Avo o o o o79 (3aS,7aS)-6-({l- isopropyl-3-[2- (methoxymethyl)-4- pyridyl] - 1,4,6-triaza- 1H- inden-7-yl}methyl)-2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone80 (3aS,7aS)-6-({3-[m-(l- hydroxy-1- methylethyl)phenyl] - 1 - isopropyl- 1,4,6-triaza- 1H- inden-7-yl}methyl)-2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone81 (3aS,7aS)-6-{[3-(2- cyclopropyl-4-pyridyl)- 1 - isopropyl- 1,4,6-triaza- 1H- inden-7 -yl] methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenoneWSGR Docket No. 57050-708.601Ex. Structure Name82 (3aS,7aS)-6-{[3-(2- fluoro-5 -methoxyphenyl) - 1 -isopropyl- 1,4,6-triaza- 1 H-inden-7 -yl]methyl } - 2,2-dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone83 o o (3aS,7aS)-6-{[3-(2- fluoro-5-tolyl)-l-Fisopropyl- 1,4,6-triaza- 1H- % if n>N- inden-7 -yl]methyl } -2,2-2Az-Nf y / - \ / . dimethyl-3a,6- / diazahexahydro-3 ( 1 H) - 5TC-O* / indenone\ z> \\\84 ° (3aS,7aS)-6-({l- vL / .x / isopropyl-3-[m- ^\ 6 Z°- Ol J(methoxymethyl)phenyl] - 1,4,6-triaza- lH-inden-7 - ^.... v.v w- yl}methyl)-2,2-dimethyl- 3a,6-diazahexahydro- A 9 %v 9- 3(lH)-indenone o o o85 m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- indenyl]methyl } - 1 -[(3 - oxetanyl)methyl] - 1 H- l,4,6-triazainden-3- yl)benzonitrile86 m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - [(R) - perhydro-3 -furyl] -1,4,6- triaza- 1 H-inden-3 - yl)benzonitrile87 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl} - 1 -[(R)-2- methoxypropyl] - 1,4,6- triaza- 1 H-inden-3 -yl)-4- fluorobenzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name88 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl }-l-[(S)-2- methoxypropyl] -1,4,6- triaza- lH-inden-3 -yl)-4- fluorobenzonitrile89 o (3aS,7aS)-6-({3-[m- (difluoromethyl)phenyl] - / h 1 -[(R)-2 -methoxypropyl] - ^zpMz1,4,6-triaza- lH-inden-7 - yl}methyl)-2,2-dimethyl- Z- ^3a,6-diazahexahydro- A 3(lH)-indenone90 X 4. / 1 u. / 'U~' (3aS,7aS)-6-{[l- V° (cy / J 7 v / s clopropylmethyl) -3 -(2- j _ \ / GM VVA fluoro-5 -tolyl)- 1,4,6- IlS' J-zv'*z / / Ntriaza- 1 H-inden-7 -. zzz—- ^- ^^' Nyl]methyl}-2,2-dimethyl- / >r M? 3a,6-diazahexahydro- V V Vco o o 3(lH)-indenone o91 (3aS,7aS)-6-{[l- (cyclopropylmethyl) -3 -(2- fluoro-5 -methoxyphenyl) - 1,4,6-triaza- lH-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone92 (3aS,7aS)-6-{[l- (cyclopropylmethyl) -3 - (m-methoxyphenyl)- 1,4,6-triaza- lH-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone93 (3aS,7aS)-6-{[l- isopropyl-3-(4-methyl- 1,3 -thiazol-2-yl)- 1,4,6- triaza- 1 H-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenoneWSGR Docket No. 57050-708.601Ex. Structure Name94 m-[l- (cyclopropylmethyl) -7- {[(7aS)-2,2-dimethyl-3- oxo-3a,6-diazaoctahydro- 6-indenyl]methyl } - 1,4,6- triaza- 1 H-inden-3 - yl] benzonitrile95 m-(7-{[(7aS)-2,2- o o o dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - Q v^zmethyl- 1,4,6-triaza- 1H- inden-3 -yl)benzonitrile ZZ ^ ^AJ \ O~96 \ i\\ m-(7-{[(3aS,7aS)-2,2- z zT\\ dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- f >\\ 3a,6-diaza-6- vz— indenyl]methyl } - 1 -(2- zHx- trifluoromethoxy ethyl) - 1H- 1,4,6-triazainden-3 - yl)benzonitrile97 o Vr m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo- 1,4, 5,6,7, 7a-hexahydro- 3a,6-diaza-6- indenyl]methyl } - 1 -[(3 - methyl-3- oxetanyl)methyl] - 1 H- l,4,6-triazainden-3- yl)benzonitrile98 O^Nm- { 1 - [ ( S ) -2 -methoxy- 1 - methylethyl] -7- { [(3aS,7aS)-2,2-dimethyl- NOO 3-oxo-l,4,5,6,7,7a-.xA _<•-' hexahydro-3a,6-diaza-6- indenyl]methyl } - 1 H- O^S^i l,4,6-triazainden-3- yl} benzonitrile99 O^Nm-{ l-[(R)-2-methoxy-l- methylethyl]-7- { [(3aS,7aS)-2,2-dimethyl-NO0 3-oxo-l,4,5,6,7,7a- hexahydro-3a,6-diaza-6- indenyl]methyl } - 1 H- O:sZ l,4,6-triazainden-3-yl} benzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name100 m-( 1 - { [(S)-tetrahydro-2- furyl]methyl}-7- { [(3aS,7aS)-2,2-dimethyl- 3-oxo-l,4,5,6,7,7a- hexahydro-3a,6-diaza-6- indenyl]methyl } - 1 H- l,4,6-triazainden-3- yl)benzonitrile101 m-(7-{[(3aS,7aS)-2,2- o o dimethyl-3-oxo- oo 1,4, 5,6,7, 7a-hexahydro- b bboO ' Nzz=\< / Z-N 3a,6-diaza-6- indenyl]methyl } - 1 - { (2- b / zz> oxabicyclo [2.1.1 ]hex- 1 - N _ > H1AJOOOka N 'V- ziZrt / .- □= / T J y. yl)methyl}-lH-l,4,6- < KJ Jz / C" T / -r triazainden-3- / / yl)benzonitrile102 m-( 1 - { [(R)-tetrahydro-2- furyl]methyl}-7- { [(3aS,7aS)-2,2-dimethyl- NOO 3-oxo-l,4,5,6,7,7a- J hexahydro-3a,6-diaza-6- 'indenyl]methyl } - 1 H- l,4,6-triazainden-3- o 9A- yl)benzonitrile 103 m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl }-l-[(S)- perhydro-3 -furyl] -1,4,6- triaza- 1 H-inden-3 - yl)benzonitrile104 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl }-l-[(S)-2- methoxy- 1 -methylethyl] - 1,4,6-triaza- lH-inden-3 - yl)-4-fluorobenzonitrile105 3-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl} - 1 -[(R)-2- methoxy- 1 -methylethyl] - 1,4,6-triaza- lH-inden-3 - yl)-4-fluorobenzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name106 3 - [ 1 -(cyclopropylmethyl)- 7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1,4,6- triaza- 1 H-inden-3 -yl] -4- fluorobenzonitrile 107 o O o 3-(7-{[(3aS,7aS)-2,2-XzI~ I\ dimethyl-3-oxo-3a,6- bb diazaoctahydro-6-Z=\z=\ V / v / indenyl]methyl } - 1 -zzzisobutyl- 1,4,6-triaza- 1H- K Viz^zZ, Y ^ x^1 inden-3-yl)-4- A fluorobenzonitrile \\ zz108 3-(7-{[(3aS,7aS)-2,2- V! X. / i\ z-^ dimethyl-3-oxo-3a,6- diazaoctahydro-6- Crv indenyl]methyl } - 1 - [( R) - 1 - methylpropyl] - 1,4,6- J _ z triaza- 1 H-inden-3 -yl)-4- O o fluorobenzonitrile 109 m-{7-[(7S,8aS)-2,2- dimethyl-3 -oxooctahydro- 7 -indolizinyloxy] - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3 -yl } benzonitrile 110 m-{7-[(4R,7S,8aR)-2,2- dimethyl-3 -oxooctahydro- 7 -indolizinyloxy] - 1 - isopropyl- 1H- 1,4,6- triazainden-3- yl} benzonitrile111* m-{7-[(4R,7S,8aR)-2,2-, N _ O / ^Ndimethyl-3 -oxooctahydro- 7 -indolizinyloxy] - 1 - isopropyl- 1,4,6-triaza- 1H- XSYN^O XN ~ inden-3 -yl } benzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name112 (3aS,7aS)-6-{[l- isopropyl-3 -(tetrahydro- 4H-pyran-4-yl)- 1,4,6- triaza- 1 H-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone113 (3aS,7aS)-6-[(3- o cyclohexyl- 1 -isopropyl - JSL _ ( 1,4,6-triaza- lH-inden-7 - Y A (' VvN< Y~N yl)methyl]-2,2-dimethyl- 3a,6-diazahexahydro- (^ISTN _ J 3(lH)-indenoneOs / JX. / 114 (3aS,7aS)-6-[(3- cyclopentyl- 1 -isopropyl - _ _ LL1,4,6-triaza- lH-inden-7 - x fZ^^- yl)methyl]-2,2-dimethyl-ZH,- 3a,6-diazahexahydro- 3(lH)-indenone115 %o o oA9- " (3aS,7aS)-6-{[3-(4,4- difluorocyclohexyl) - 1 - isopropyl- 1,4,6-triaza- 1H- inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone116 (3aS,7aS)-6-{[3-(4,4- difluoro- 1 -cyclohexen- 1 - yl)- 1 -isopropyl- 1,4,6- triaza- 1 H-inden-7 - yl]methyl}-2,2-dimethyl- 3a,6-diazahexahydro- 3(lH)-indenone117 \ / (3aS,7aS)-6-({l- isopropyl-3 -[m-( 1 - O '-N. 7 methoxy- 1- NOO methylethyl)phenyl] - 1,4,6-triaza- lH-inden-7 - l^tr yl}methyl)-2,2-dimethyl-0=:3a,6-diazahexahydro- Y_J 3(lH)-indenoneWSGR Docket No. 57050-708.601Ex. Structure Name118 (3aS,7aS)-6-{[3-(5- ethoxy-2 -fluorophenyl)- 1 - isopropyl- 1,4,6-triaza- 1H- inden-7 -yl]methyl } -2,2- dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenoneo z119 III (3aS,7aS)-6-({3-[5- S j \ (cyclopropylmethoxy)-2- " Z / fluorophenyl]-l-ZA \? L- isopropyl- 1,4,6-triaza- 1H- \ / _ \Z-^ inden-7-yl}methyl)-2,2- 1 dimethyl-3a,6- diazahexahydro-3 ( 1 H) - 4 ■ CM indenoneJ. Ol / x J1 _ / ^ o \ / . vxxzZ— J,20 ^""(3aS,7aS)-6-({3-[2- HAV\ "z-.Z / °^,z. V^. ZV k= fluoro-5- (methoxymethyl)phenyl] - VPrr ° 1 -isopropyl- 1,4,6-triaza- o o o 1 H-inden-7 -yl } methyl) - 2,2-dimethyl-3a,6- diazahexahydro-3 ( 1 H) - indenone121 m-(7-{[(3aS,7aS)-2,2- dimethyl-3-oxo-3a,6- diazaoctahydro-6- indenyl]methyl } - 1 - isopropyl- 1,4,6-triaza- 1H- inden-3 -yl)benzamide122 \ / N-^ (8aS)-2- [ [5 -isopropy 1-7- [2-FV \ 9 (2,2,2-trifluoro-l,l-F Fdimethyl-ethyl)-4- py ridy l]py rrolo [3,2- I^ d]py rimidin-4-y 1] methyl] - 7,7-dimethyl-3,4,8,8a-AOQ< tetrahydro- IH-py rrolo [1,2- o a]pyrazin-6-one1233-[7-[[(8aS)-7,7-dimethyl-6- oxo-3,4,8, 8a-tetrahy dro-lH- pyrrolo [ 1,2-a]pyrazin-2- yl] methyl] -1-isopropyl- pyrrolo [3,2-b]pyridin-3 -yl] - 4-fluoro-benzonitrileWSGR Docket No. 57050-708.601Ex. Structure Name124(8aS)-2-[[3-[2-fluoro-5- (methoxy methy l)pheny 1] - 1 - isopropy 1-py rrolo [3,2- b]pyridin-7-yl]methyl]-7,7- dimethyl-3,4,8,8a- tetrahydro- IH-py rrolo [1,2- a]pyrazin-6-one125r / (8aS)-2-[[7-(lH-indol-7-yl)-No^O\ KI 5 -isopropy 1-py rrolo [3,2-Hd]py rimidin-4-y 1] methyl] - 7,7-dimethyl-3,4,8,8a- / 'z- / tetrahydro- IH-py rrolo [1,2-ACQ< a]pyrazin-6-oneo126 / Zi' (8aS)-2-[[3-[2-fluoro-5- o (methoxy methy l)pheny 1] - 1 - isopropy 1-pyrrolo [2,3 - c]py ridin-7 -y 1] methyl] -7,7- o dimethyl-3,4,8,8a- / ^ Z tetrahydro- IH-py rrolo [1,2- a]pyrazin-6-one127 o / 4-[4-[[(3aS)-2,2-dimethyl- Q-E 1, l-dioxo-3a, 4,6,7- A tetrahydro-3H- isothiazolo [2,3 -a]py razin-5 - vO yl] methyl] -5 -isopropy 1- pyrrolo [3,2-d]pyrimidin-7- yl] -3 -fluoro-benzonitrileo' °128(3aS)-5-[[7-(4- fluorophenyl)-5-isopropyl- pyrrolo [3,2-d]pyrimidin-4- yl]methyl]-2,2-dimethyl- 3a,4,6,7-tetrahydro-3H- isothiazolo[2,3-a]pyrazine1,1 -dioxide* stereochemistry assigned arbitrarily.

[0177] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.

[0178] 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).WSGR Docket No. 57050-708.601

[0179] 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

[0180] 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 provided herein, 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

[0181] 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,18O,17O,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 areWSGR Docket No. 57050-708.601within 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.

[0182] 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

[0183] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases 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.

[0184] 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.

[0185] 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.WSGR Docket No. 57050-708.601

[0186] 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.

[0187] 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+(C1.C4alkyl)4hydroxide, and the like.

[0188] 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

[0189] 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.

[0190] 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 canWSGR Docket No. 57050-708.601exist 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

[0191] 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

[0192] 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 least one 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.

[0193] 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.

[0194] TRPML1 -mediated diseases include proliferative disorders, such as cancers, inflammatory disorders, pain, neurodegenerative disorders, cognitive and psychiatric disorders, and other diseases as disclosed below.

[0195] 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.

[0196] 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-ScheinkerWSGR Docket No. 57050-708.601disease, 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.

[0197] 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, diabetic nephropathy, female infertility, H. pylori infections, hypochlorhydria, pancreatitis, retinal detachment, type 2 diabetes mellitus, ulcerative colitis, or sarcopenia.

[0198] 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).

[0199] 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. TheWSGR Docket No. 57050-708.601compounds disclosed herein are particularly useful for the treatment of bipolar disorders, psychosis, anxiety, or addiction.

[0200] 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.

[0201] 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 as radiculopathy), 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.

[0202] 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.

[0203] 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.

[0204] 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).WSGR Docket No. 57050-708.601

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.WSGR Docket No. 57050-708.601

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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’s lymphomas), B-cell lymphomas, T-cell lymphomas, mantle cell lymphomas, Burkitt’s lymphoma, follicular lymphoma, and others as defined herein and known in the art.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma.

[0218] 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.

[0219] 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 farmWSGR Docket No. 57050-708.601animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.Dosing

[0220] 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.

[0221] 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.

[0222] 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 of administration, 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.

[0223] 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

[0224] 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.

[0225] 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,WSGR Docket No. 57050-708.601for 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

[0226] 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.

[0227] 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 upon the 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.

[0228] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, filling 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.

[0229] 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,WSGR Docket No. 57050-708.601pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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

[0234] 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.WSGR Docket No. 57050-708.601

[0235] 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 PROCEDURESScheme 1Synthesis of Intermediates III a-gAlkyl halideoraryl halideCuI, K2CO3, 1,4-dioxaneStep laAlkyl halideormethansulfonateCs2CO3DMFStep lb

[0236] Step la: The suitable alkyl or aryl halide (2 eq.) was added to a mixture of Cui (0.4 eq.), (lS,2S)-(+)-N, N'-dimethyl-l,2-cyclohexanesdiamine (0.4 eq.), K₂CO₃ (2 eq.) and 7-Chloro-1,4,6-triaza-1H-indene or 7-Chloro-1,6-diaza-1H-indene (1 eq.) in 1,4-dioxane (26 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred for the suitable time at the suitable temperature and filtered through Celite. The filtrate was diluted with EtOAc, and the organic phase was washed with brine, dried (MgSO₄), filtered, and concentrated.

[0237] Step lb: The suitable alkyl halide or methanesulfonate (1.5 eq.) was added to a mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) or 7-Chloro-l,6-diaza-lH-indene (1 eq.) and Cs₂CO₃ (2 eq.) in DMF (17 mL / g starting material) at 23 °C. The mixture was stirred for the suitable time at the suitable temperature and diluted with water. The aq. phase was extracted with EtOAc. The combined organic phases were washed with water, brine, dried (Na₂SO₄), filtered, and concentrated.WSGR Docket No. 57050-708.601ReactionSynthetic Reaction Intermediate Structure Temperature Yield procedure Time(° C)Scheme 1Ill a NOQ* 120 3h 22%Cl Step laScheme 1m b 85 18h 43%Step lbCl Z '1V-oScheme 1III c 23 3d 46%a Step lbo—Scheme 1III d 23 Ih 76%Step lbCl 'AL _ Scheme 1III e 23 18h 57%Step lb_N _ _Scheme 1III f 80 2h 75%ci Step lb0—AL Scheme 1Ill g 80 2h 74%Step lbci0—Synthesis of intermediate III a

[0238] Step la: The title compound was prepared as described in the Scheme above using 2-lodopyridine (CAS: 5029-67-4, 692 pL, 6.51 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6, 500 mg, 3.26 mmol) to afford 2-{4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}pyridine (166 mg, 22%). Purification by silica gel chromatography using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (166 mg, 22%).Synthesis of intermediate III b

[0239] Step lb: The title compound was prepared as described in the Scheme above using a solution of [(3S)-tetrahydrofuran-3-yl] methane sulfonate (0.974 g, 5.86 mmol) in DMF (2.00 mL) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-[(3R)-tetrahydrofuran-3-yl]pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (0.372 g, 43%).WSGR Docket No. 57050-708.601Synthesis of intermediate III c

[0240] Step lb: The title compound was prepared as described in the Scheme above using l-iodo-2-methoxy-propane (0.460 mL, 3.91 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-[2-methoxypropyl]pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of MeCN in DCM (0-100%) to provide the title compound as a solid (339 mg, 46%).Synthesis of intermediate III d

[0241] Step lb: The title compound was prepared as described in the Scheme above using bromomethylcyclopropane (CAS: 7051-34-5, 6.32 mL, 65.1 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-(cyclopropylmethyl)pyrrolo[3,2-d]pyrimidine as solid (5.15 g, 76 %).Synthesis of intermediate III e

[0242] Step lb: The title compound was prepared as described in the Scheme above using 3-(bromomethyl)oxetane (0.408 mL, 4.23 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-(oxetan-3-ylmethyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (50-100%) to provide the title compound as a solid (416 mg, 57%).Synthesis of intermediate III f

[0243] Step lb: The title compound was prepared as described in the Scheme above using [(2R)-2-methoxypropyl] 4-methylbenzenesulfonate (2040 mM in DMF, 5.00 mL, 10.2 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-[(2R)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidine (1.73 g, 75 %).Synthesis of intermediate III g

[0244] Step lb: The title compound was prepared as described in the Scheme above using [(2S)-2-methoxypropyl] 4-methylbenzenesulfonate (2090 mM in DMF, 4.99 mL, 10.4 mmol) and 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6) to afford 4-chloro-5-[(2S)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (80 g cartridge) using the MeCN in DCM (15 %) to provide the title compound as a solid (1.75 g, 74 %).Scheme 2Synthesis of Intermediates IVWSGR Docket No. 57050-708.601NIS, DMF or MeCNStep laIV4-chloro-7-iodo- Cs2CO3DMF5H-pyrrolo[3,2- djpyrimidine Step lb

[0245] Step la: NIS (1.5) was added to a mixture of intermediate III or the suitable commercial starting material (1 eq.) in DMF (22 mL / g starting material) or MeCN (37 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred for the suitable time at the suitable temperature and diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with sat. aq. NaHCO₃, 5% aq. Na₂S₂O₃, brine, dried (MgSO₄), filtered, and concentrated.

[0246] Step lb: The suitable alkyl halide (2 eq.) was added to a mixture of 4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1 eq.), Cs₂CO₃ (1.5 eq.) in DMF (19 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred for the suitable time at the suitable temperature and diluted with water, DCM and 1 M HC1. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (Na2SO4), filtered and concentrated to provide the title compound as a solid.ReactionReactionIntermediate Structure Synthetic procedure Temperature Solvent Yield Time(° C)Scheme 2IV a 23 48h MeCN 74%Step laClScheme 2IV b 80 2h DMF 37%Cl Step laWScheme 2IV c 23 18h DMF 91%Step lbC|WSGR Docket No. 57050-708.601ReactionReactionIntermediate Structure Synthetic procedure Temperature Solvent Yield Time(° C)M _ / Scheme 2IV d 23 48h DMF 71%ClStep lbScheme 2IV e 23 4h DMF 80%Step lbCI ' \0—J Scheme 2IV f 23 24h DMF 75%Cl Step lao-_Synthesis of intermediate IV a

[0247] Step la: The title compound was prepared as described in the Scheme above using 4-chloro-5- isopropyl-pyrrolo[3,2-d]pyrimidine (CAS: 919278-25-4, 1.08 g, 5.52 mmol) to afford 4-chloro-7-iodo-5- isopropyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a solid (1.31 g, 74%).Synthesis of intermediate IV b

[0248] Step la: The title compound was prepared as described in the Scheme above using III a (257 mg, 1.11 mmol) to afford 2-{4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-5-yl}pyridine. Purification by silica gel chromatography using a gradient of EtOAc in cyclohexanes (0-50%) to provide the title compound as a solid (146 mg, 37%).Synthesis of intermediate IV c

[0249] Step lb: The title compound was prepared as described in the Scheme above using Bromomethylcyclopropane (CAS: 7051-34-5, 0.357 mL, 3.67 mmol) to afford 4-chloro-5-(cyclopropylmethyl)-7-iodo-pyrrolo[3,2-d]pyrimidine as a solid (583 mg, 91%);Synthesis of intermediate IV d

[0250] Step lb: The title compound was prepared as described in the Scheme above using 2-(2-bromoethoxy)propane (0.504 mL, 4.29 mmol) to afford 4-chloro-7-iodo-5-(2- isopropoxyethyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (20-60%) to provide the title compound as a solid (977 mg, 71%).Synthesis of intermediate IV e

[0251] Step lb: The title compound was prepared as described in the Scheme above using l-chloro-2-methoxy-ethane (0.573 mL, 6.26 mmol) and Nal (53.6 mg, 0.358 mmol) to afford 4-chloro-7-iodo-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (20-60%) to provide the title compound as a solid (534 mg, 80%).WSGR Docket No. 57050-708.601Synthesis of intermediate IV f

[0252] Step la: The title compound was prepared as described in the Scheme above using III c (339 mg, 1.50 mmol) to afford 4-chloro-7-iodo-5-(2-methoxypropyl)pyrrolo[3,2-d] pyrimidine. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-80%) to provide the title compound as a solid (396 mg, 75%).Scheme 3Synthesis of Intermediates Vboronic acidPdCl₂{PPh₃}₂, Na₂CO₃1,4-dioxane, H2OStep laboronic acidPd{dppf}Cl2·DCM, K₃PO₄t 1,4-dioxane, H,0, Step lbH JI boronic acidCl ” _IvPd(dppf)Cl2·DCM, K2CO31,4-dioxaneStep 1cboronic acidXPhos Pd G3, CsF1,4-dioxane, H2OStep Id

[0253] Step la: the suitable boronic acid (1.2 eq.) was added to a mixture of PdCl₂(PPh₃)₂ (0.05 eq.), Na₂CO₃ (1.7 eq.) and the suitable intermediate IV or commercial starting material (1 eq.) in 1,4-dioxane (28 mL / g starting material) and water (7 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h and diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated.

[0254] Step lb: 1,4 -Dioxane (25 mL / g starting material) and water (6.3 mL / g starting material) were added to a mixture of the suitable boronic acid (1.2 eq.), the suitable intermediate IV (1 eq.) and K₃PO₄ (2 eq.) at 23 °C. The mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.1 eq.) was added, and degassing was continued for 5 min. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and diluted with brine. The aq. phase was extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated.

[0255] Step 1c: Pd(dppf)Cl₂·DCM (0.1 eq.) was added to a mixture of the suitable intermediate IV (1 eq.), the suitable boronic acid (1.1 eq.) and K₂CO₃ (2 eq.) in 1,4-dioxane (10 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 40 h, cooled to 23 °C, filtered through Celite, washed with EtOAc and DCM and the filtrate was concentrated.WSGR Docket No. 57050-708.601

[0256] Step Id: XPhos Pd G3 (0.05 eq.) was added to a mixture of the suitable intermediate IV (1 eq.), the suitable boronic acid (1.1 eq.) and CsF (3 eq.) in 1,4-dioxane (5 mL / g starting material) and water (0.5 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 60 h, cooled to 23 °C and diluted with 2 M aq. K2CO3. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated.Intermediate Structure Synthetic procedure YieldScheme 3V a 41%Cl Step laz\\\J' \ LL Scheme 3V b 73%Step laci / =•»T Y5v / Scheme 3V c _ / 59%Step lbClScheme 3V d _ / 71%N^XN Step lbCl —Scheme 3V e 37%Step lbScheme 3V f 53%N?Step lb<^NCl } -WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure Yield FScheme 3V g 55%Step lbN<^AN?CIScheme 3V h _N. _ r 16%Step lbClScheme 3V i -N. _ r 47%Step 1cCl } — -YA Scheme 3_ rVj 18%Step IdCl — ■z^\ ^SNV# Scheme 3V k M _ r 60%Step lbCl' — <7, N. j' Scheme 3V I 49%Step lbClo^ZN.Scheme 3V m 26%Step lbCl — \O—.r==\_^-n<x j / "Scheme 3V n _ [ 41%NY^N Step lbCl' — \WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldEScheme 3V o 53%Step lbClC==\___i=N. N _ / Scheme 3V p 49%Step laCl 'Synthesis of intermediate V a

[0257] Step la: The title compound was prepared as described in the Scheme above using IV b (116 mg, 0.330 mmol) and 3-Cyanophenylboronic acid (CAS: 150255-96-2, 57.4 mg, 0.390 mmol) to afford 3-[4-chloro-5-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography using a gradient of EtOAc in cyclohexanes (0-50%) to provide the title compound as a solid (44 mg, 41%).Synthesis of intermediate V b

[0258] Step la: The title compound was prepared as described in the Scheme above using 4-chloro-7-iodo-5-phenyl-5H-pyrrolo[3,2-d]pyrimidine (CAS: 2306182-28-3, 281 mg, 0.790 mmol) and 3-cyanophenylboronic acid (CAS: 150255-96-2, 139 mg, 0.950 mmol) to afford 3-{4-chloro-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}benzonitrile. Purification by silica gel chromatography (12 g cartridge) with heptane and EtOAc (0-20%) to provide the title compound as a solid (190 mg, 73%).Synthesis of intermediate V c

[0259] Step lb: The title compound was prepared as described in the Scheme above using IV f (396 mg, 1.13 mmol) and (3-cyanophenyl)boronic acid (CAS: 150255-96-2, 199 mg, 1.35 mmol) to afford 3-[4-chloro-5-(2-methoxypropyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-80%) to provide the title compound as a solid (218 mg, 59%).Synthesis of intermediate V d

[0260] Step lb: The title compound was prepared as described in the Scheme above using (3-cyanophenyl)boronic acid (CAS: 150255-96-2, 411 mg, 2.80 mmol) and IV a (1.08 g, 5.52 mmol) to afford 3-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a solid (520 mg, 71%).Synthesis of intermediate V eWSGR Docket No. 57050-708.601

[0261] Step lb: The title compound was prepared as described in the Scheme above using IV a (320 mg, 0.995 mmol) and (3-cyano-2-fluoro-phenyl)boronic acid (181 mg, 1.09 mmol) to afford 3-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)-2 -fluoro-benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (114 mg, 37%).Synthesis of intermediate V f

[0262] Step lb: The title compound was prepared as described in the Scheme above using IV a (400 mg, 1.24 mmol) and (4 cyanophenyl)boronic acid (201 mg, 1.37 mmol) to afford 4-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (207 mg, 53%).Synthesis of intermediate V g

[0263] Step lb: The title compound was prepared as described in the Scheme above using IV a (500 mg, 1.55 mmol) and (3-cyano-4-fluoro-phenyl)boronic acid (282 mg, 1.71 mmol) to afford 5-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)-2 -fluoro-benzonitrile. Purification by silica gel chromatography (24g cartridge) using a gradient of EtOAc in hexanes (20-100%) to provide the title compound as a solid (319 mg, 85% purity, 55%).Synthesis of intermediate V h

[0264] Step lb: The title compound was prepared as described in the Scheme above using IV a (300 mg, 0.933 mmol) and (5-cyano-2-fluoro-phenyl)boronic acid (169 mg, 1.03 mmol), to afford 3-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)-4-fluoro-benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (50.0 mg, 16%).Synthesis of intermediate V i

[0265] Step 1c: The title compound was prepared as described in the Scheme above using IV a (300 mg, 0.933 mmol) and p-tolylboronic acid (140 mg, 1.03 mmol) to afford 4-chloro-5-isopropyl-7-(p-tolyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (131 mg, 47%).Synthesis of intermediate V j

[0266] Step Id: The title compound was prepared as described in the Scheme above using IV a (200 mg, 0.622 mmol) and o-tolylboronic acid (93.0 mg, 0.684 mmol) to afford 4-chloro-5-isopropyl-7-(o-tolyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-50%) to provide the title compound as an oil (33.3 mg, 18%).Synthesis of intermediate V k

[0267] Step lb: The title compound was prepared as described in the Scheme above using (3-cyanophenyl) boronic acid (256 mg, 1.74 mmol) and IV c (583 mg, 1.66 mmol), to afford 3-[4-chloro-5-(cyclopropylmethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatographyWSGR Docket No. 57050-708.601(40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (325 mg, 60%).Synthesis of intermediate V 1

[0268] Step lb: The title compound was prepared as described in the Scheme above using IV d (977 mg, 2.41 mmol) and (3-cyanophenyl)boronic acid (CAS: 150255-96-2, 389 mg, 2.65 mmol) to afford 3-[4-chloro-5-(2-isopropoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (480 mg, 49%).Synthesis of intermediate V m

[0269] Step lb: The title compound was prepared as described in the Scheme above using IV e (450 mg, 1.33 mmol) and (5-cyano-2-fluoro-phenyl)boronic acid (264 mg, 1.60 mmol) to afford 3-[4-chloro-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]-4-fluoro-benzonitrile. Purification by silica gel chromatography (80 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (122 mg, 26%).Synthesis of intermediate V n

[0270] Step lb: The title compound was prepared as described in the Scheme above using IV e (534 mg, 1.42 mmol) and (3-cyanophenyl)boronic acid (CAS: 150255-96-2, 230 mg, 1.57 mmol) to afford 3-[4-chloro-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (181 mg, 41%).Synthesis of intermediate V o

[0271] Step lb: The title compound was prepared as described in the Scheme above using IV a (500 mg, 1.55 mmol) and (3-cyano-5-fluoro-phenyl)boronic acid (282 mg, 1.71 mmol) to afford 3-(4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)-5-fluoro-benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (20-100%) to provide the title compound as a solid (289 mg, 90% purity, 53%).Synthesis of intermediate V p

[0272] Step la: The title compound was prepared as described in the Scheme above using 4-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (CAS: 1936622-34-2, 80.0 mg, 0.150 mmol) and 3-cyanophenylboronic acid (CAS: 150255-96-2, 120 mg, 0.810 mmol) to afford 3-{4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (90.0 mg, 49%). Scheme 4Synthesis of intermediate VIIIWSGR Docket No. 57050-708.6014-(aminomethyl)-N,N-dimethylbenzenesulfonamide- ►PyBOP, DBUDMFStep 1 O=S-O7-lodo-5-phenyl-5H-pyrrolo[3,2- VHidJpyrimidin-4-oiVii

[0273] Step 1: PyBOP (1.61 g, 3.09 mmol) and DBU (1.08 g, 7.12 mmol) were added to a mixture of 4-(aminomethyl)-N,N-dimethylbenzenesulfonamide (CAS: 210918-25-5, 763 mg, 3.56 mmol) and 7-iodo-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-ol (CAS: 2306182-56-7, 800 mg, 2.37 mmol) in DMF (13.0 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and diluted with water (300 mL). The aqueous phase was extracted with EtOAc (3 x 80.0 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (120 g cartridge) with heptane and EtOAc (0-25%) to provide the title compound as a solid (913 mg, 72%). Scheme 5Synthesis of intermediate XII.i r.ophsftyi boroi-iic add dimethylbenxsme’l-suifofsamideNaH, WStep X Step 24-chiftro7-i8do-S- {pqtrifnethyisit i) Xpyrrafc»|3,2-ctjpyrimidine5XX! XSWSGR Docket No. 57050-708.601

[0274] Step 1: Na2CO3 (259 mg, 2.40 mmol) and PdCl2(PPh3)2 (42.8 mg, 0.0610 mmol) were added to a mixture of 4-chloro-7-iodo-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine (500 mg, 1.22 mmol) and 3-cyanophenylboronic acid (215 mg, 1.46 mmol) in 1,4-dioxane (12.5 mL) and water (3.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h and filtered through celite. The filtrate was concentrated and diluted with water (50.0 mL). The aqueous phase was extracted with EtOAc (3 x 15.0 mL), and the combined organic extracts were washed with brine (5.00 mL), water (5.00 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) with heptane and EtOAc (0-20%) to provide the title compound as a solid (X, 320 mg, 68%).

[0275] Step 2: NaH (60% dispersion in mineral oil, 45.2 mg, 0.113 mmol) was added to a mixture of 4-(hydroxymethyl)-N,N-dimethylbenzene-1-sulfonamide (243 mg, 1.13 mmol) in THF (6.80 mL) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 10 min. A mixture of 3-(4-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile (290 mg, 0.750 mmol) in THF (3.30 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 5.00 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) with heptane and EtOAc (0-50%) to provide the title compound as a solid (XI, 190 mg, 45%).

[0276] Step 3: TBAF (1.04 g, 3.97 mmol) and ethylenediamine (17.1 mg, 0.280 mmol) were added to a mixture of 4-( { [7 -(3 -cyanophenyl) -5 - { [2-(trimethylsilyl)ethoxy]methyl } -5H-pyrrolo [3,2-d]pyrimidin-4-yl]oxy}methyl)-N,N-dimethylbenzene-1-sulfonamide (320 mg, 0.570 mmol) in THF (5.70 mL) at 23 °C under nitrogen. The mixture was stirred at 75 °C for 2 h and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) with heptane and EtOAc (0-50%) to provide the title compound as a solid (XII, 187 mg, 76%).Scheme 6Synthesis of Intermediates XIVMeMgBr, RuPhos, Pd(OAc)22-Me-THF Step la NIS 2,4,6-tnmethyi-l,3,5,2,4,6- DMF or MeCN trioxatriborinane Step 2a Br / 1 XRVX- A f JT K2CO3, Pd(dppf)Cl2-DCM V' 'I 1,4-dioxane ci NBS I Step lb Xfll MeCN XfVll!MeB(OH)2Step 2b KJCOJ, Pd(dppf)Ci2-DCM1,4-dioxane Step 1cWSGR Docket No. 57050-708.601

[0277] Step la: MeMgBr (3.4 M in 2-Me-THF, 1.5 eq.) was added to a mixture of intermediate III or the suitable starting material (1 eq.), RuPhos (0.08 eq.) and Pd(OAc)2 (0.05 eq.) in 2-Me-THF (13 mL / g of XXII) at 23 °C. The mixture was stirred at 23 °C for 16 h and diluted with sat. aq. NH4CI. H2O was added, and the organic phase was separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (Na2SO4), filtered, and concentrated.

[0278] Step lb: 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (3 eq.) was added to a mixture of intermediate III (1 eq.) and K2CO3 (2 eq.) in 1,4-dioxane (24 mL / g of III) at 23 °C. The mixture was degassed with nitrogen for 15 min. Pd(dppf)Cl₂·DCM (0.1 eq.) was added, and degassing was continued for 5 min. The mixture was stirred at 100 °C for 3 h. After cooling to 23 °C, the mixture was filtered through Celite, washed with EtOAc. The filtrate was washed with sat. aq. NaHCOs and brine. The aq. phase was extracted with 10% MeOH in DCM and EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated.

[0279] Step 1c: 1,4-Dioxane (7 mL / g starting material) was added to a mixture of intermediate III (1 eq.), MeB(OH)2 (1.5 eq.), K2CO3 (2.5 eq.) and Pd(dppf)C12'DCM (0.04 eq.) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h and diluted with sat. aq. K2CO3 and DCM. The aqueous phase was extracted with DCM, and the combined organic extracts were washed with water, dried (MgSO4), filtered, and concentrated.

[0280] Step 2a: NIS (1.2 eq.) was added to a mixture of XIII (1 eq.) in DMF (14 mL / g of starting material) or MeCN (9 mL / g starting material) at 23 °C. The mixture was stirred at the suitable temperature for the suitable time, covered with aluminum foil. The mixture was diluted with EtOAc. The organic phase was washed with sat. aq. Na2S2O3, sat. aq. NaHCO3 and brine. The combined aq. phases were extracted with EtOAc. The combined organic extracts were dried (Na₂SO₄), filtered, and concentrated.

[0281] Step 2b: NBS (1.05 eq.) was added to a mixture of XIII (1 eq.) in MeCN (4.7 mL / g of starting material) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 15 min and diluted with DCM and brine. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO4), filtered, and concentrated.Intermediate Structure Synthetic procedure YieldScheme 6XIII a NyO 73%Step laScheme 6XIII b 99% Step lbWSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldScheme 6XIII c 31%Step lbScheme 6XIII d 70%1 Step la0^Scheme 6XIII e 70%1 o Step la0^z ' — AC^z~V~ A Scheme 6XIII f 91%Step 1cScheme 6XIII g 82%Step laScheme 6XIV a 68% steps lb and la^Ny\Scheme 6XIV b N^Af? 74% steps lb and 2a0^WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldScheme 6XIV c 95%steps lb and 2aScheme 6XIV d 96%1 steps lb and 2a0^Br / Scheme 6XIV e - steps la and 2bCrfl Scheme 6XIV f - steps la and 2aScheme 6XIV g 83%Step 2aBrScheXIV h f^V^ me 685%Step 2bN| VSynthesis of intermediate XIV a

[0282] Step lb: The title compound was prepared as described in the Scheme above using III e (416 mg, 1.86 mmol) to afford 4-methyl-5-(oxetan-3-ylmethyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-10%) to provide the title compound as a solid (XIII b, 375 mg, 99%).

[0283] Step 2a: The title compound was prepared as described in the Scheme above using XIII b via step lb (367 mg, 1.81 mmol) and DMF. The mixture was stirred at 23 °C for 18 h to afford 7-iodo-4-methyl-5-(oxetan-3-ylmethyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 gWSGR Docket No. 57050-708.601cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (402 mg, 68%).Synthesis of intermediate XIV b

[0284] Step lb: The title compound was prepared as described in the Scheme above using III b (372 mg, 1.66 mmol) to afford 4-methyl-5-[(3R)-tetrahydrofuran-3-yl]pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-6%) and by ACCQ eluting with water [10 mM (NH4XHCO3)] and MeCN (10-20%) to provide the title compound as a solid (XIII c, 104 mg, 31%).

[0285] Step 2a: The title compound was prepared as described in the Scheme above using XIII c via step lb (104 mg, 0.512 mmol) and DMF. The mixture was stirred at 23 °C for 18 h to afford 7-iodo-4-methyl-5-[(3R)-tetrahydrofuran-3-yl]pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (124 mg, 74%).Synthesis of intermediate XIV c

[0286] Step 1c: The title compound was prepared as described in the Scheme above using III f (0.700 g, 3.10 mmol), to afford 5-[(2R)-2-methoxypropyl]-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using MeOH in MeCN (9%) to provide the title compound as a solid (XIII d, 447 mg, 70 %).

[0287] Step 2a: The title compound was prepared as described in the Scheme above using XIII d step 1c (447 mg, 2.18 mmol) and MeCN at 0 °C under nitrogen. The mixture was stirred at 50 °C for 5 h to afford 7-iodo-5-[(2R)-2-methoxypropyl]-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (24 g cartridge) using the MeCN to provide the title compound as a solid (686 mg, 95%).Synthesis of intermediate XIV d

[0288] Step lc: The title compound was prepared as described in the Scheme above using III g (0.700 g, 3.10 mmol), to afford 5-[(2S)-2-methoxypropyl]-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using MeOH in MeCN (9 %) to provide the title compound as a solid (XIII e, 443 mg, 70 %).

[0289] Step 2a: The title compound was prepared as described in the Scheme above using XIII e step 1c (443 mg, 2.16 mmol) and MeCN at 0 °C under nitrogen. The mixture was stirred at 50 °C for 5 h to afford 7-iodo-5-[(2S)-2-methoxypropyl]-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (24 g cartridge) using the MeCN to provide the title compound as a solid (682.8 mg, 96%).Synthesis of intermediate XIV e

[0290] Step la: The title compound was prepared as described in the Scheme above using III d (5.15 g, 24.8 mmol) to afford 5-(cyclopropylmethyl)-4-methyl-pyrrolo[3,2-d]pyrimidine. The residue was decolorized (activated charcoal powder, 100 mesh) filtered, and concentrated to provide the title compound as a solid (XIII f, 4.21 g, 91%).WSGR Docket No. 57050-708.601

[0291] Step 2b: The title compound was prepared as described in the Scheme above using XIII f step la (4.21 g, 22.5 mmol) to afford 7-bromo-5-(cyclopropylmethyl)-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (80 g cartridge) using MeOH in DCM (5 %) to provide the title compound as a solid (3.60 g, 48 %).Synthesis of intermediate XIV f

[0292] Step la: The title compound was prepared as described in the Scheme above using 7-chloro-l-isopropyl-pyrrolo[2,3-c]pyridine (CAS: 1150617-64-3, 1.50 g, 7.71 mmol) to afford l-isopropyl-7-methyl-pyrrolo[2,3-c]pyridine. Purification by chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XIII g, 1.20 g, 82%).

[0293] Step 2a: The title compound was prepared as described in the Scheme above using XIII g step la (600 mg, 3.24 mmol) and MeCN. The mixture was stirred at 23 °C for 18 h to afford 3-iodo-l-isopropyl-7-methyl-pyrrolo[2,3-c]pyridine. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in DCM (0-50%) to provide the title compound as a solid (1.00 g, quant). Synthesis of intermediates XIV g

[0294] Step la: The title compound was prepared as described in the Scheme above using 4-chloro-5-isopropyl-pyrrolo[3,2-d]pyrimidine (CAS: 919278-25-4, 4.64 g, 23.7 mmol) to afford 5 -isopropyl -4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (120 g cartridge) using a gradient of MeOH in DCM (1-5%), and then by neutral alumina chromatography (2 x 80 g, stacked) using a gradient of EtOAc in hexanes (0-60%). The product was diluted with Et2O (10.0 mL) and hexanes (100 mL) and concentrated to provide the title compound as a solid (XIII a, 3.05 g, 73%).

[0295] Step 2a: The title compound was prepared as described in the Scheme above using XIII a (593 mg, 3.38 mmol) to afford 7-iodo-5 -isopropyl -4-methyl-pyrrolo [3, 2-d]pyrimidine. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (844 mg, 83%).Synthesis of intermediates XIV h

[0296] Step 2b: The title compound was prepared as described in the Scheme above using XIII a (2.78 g, 15.9 mmol) to afford 7-bromo-5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (80 g cartridge) using MeOH in MeCN (20%) to provide the title compound as a solid (3.60 g, 85%).Scheme 7Synthesis of Intermediates XVIWSGR Docket No. 57050-708.601XIVBoronic acid CsF, RuPhos, Pd MeMgBr, RuPhos, Pd2(dba)31,4-Dioxane 2-Me-THF Step le Step la SeO3w„fA)— (R'j,, 2,4,6-trimethyl-l,3,5,2,4,6- 1,4-dioxane R5X J trioxatriborinane Step 2a Rt -X. J. TT YV - K2CO3, Pd(dppf)CI2-DCMCl1,4-dioxane I, PISA V Step lb XV XVI DMSOMeB(OH)2Step 2b K2CO3, Pd(dppf)Cl2·DCM 1,4-dioxane Step 1c OsO4, NalOs1,4-dioxane, H2O Step Idxvn

[0297] Step la: MeMgBr (3.4 M in 2-Me-THF, 1.5 eq.) was added to a mixture of intermediate V or the suitable starting material (1 eq.), RuPhos (0.08 eq.) and Pd(OAc)2 (0.05 eq.) in 2-Me-THF (13 mL / g of V) at 23 °C. The mixture was stirred at 23 °C for 16 h and diluted with sat. aq. NH4CI. H2O was added, and the organic phase was separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (Na2SO4), filtered, and concentrated.

[0298] Step lb: 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (1.3 eq.) was added to a solution of the suitable intermediate V (1 eq.), K2CO3 (2.5 eq.) and Pd(dppf)C12-DCM (0.1 eq.) in 1,4-dioxane (25 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 4 h, cooled to 23 °C, and filtered over Celite. The filtrate was diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with sat. aq. NaHCOs, brine, dried (Na₂SO₄), filtered, and concentrated.

[0299] Step 1c: 1,4 -Dioxane (16 mL / g starting material) was added to a mixture of the suitable intermediate V (1 eq.), methylboronic acid (CAS: 13061-96-6, 10 eq.), K3PO4 (2 eq.) and Pd(dppf)Cl₂·DCM (0.1 eq.) at 23 °C under nitrogen. The mixture was stirred at 80 °C for 16 h and diluted with water. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO4), filtered, and concentrated.

[0300] Step Id: OsO4(0.12 eq.) was added to a mixture of NaIO4 (2 eq.) and the suitable intermediate XVII (1 eq.) in 1,4-dioxane (32 mL / g starting material) and water (16 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and diluted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated to provide the title compound as a solid.

[0301] Step le: 1,4 -Dioxane (8 mL / g starting material) and water (0.8 mL / g starting material) were added to a mixture of the suitable intermediate XIV (1 eq.), the suitable boronic acid (1.5 eq.), CsF (3WSGR Docket No. 57050-708.601eq.), RuPhos (0.1 eq.) and Pd2(dba)s (0.03 eq.) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h and diluted with EtOAc and aq. NaOH. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (Na2SO4), filtered, and concentrated.

[0302] Step 2a: 1,4 -Dioxane (8 mL / g starting material) was added to a mixture of XV (1 eq.) and selenium dioxide (1.1 eq.) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 3 h and diluted with DCM and sat. aq. NaHCCE. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO4), filtered, and concentrated.

[0303] Step 2b: Molecular iodine (0.4 eq.) was added to a mixture of XV (1 eq.) and p-toluenesulfonic acid monohydrate (1 eq.) in DMSO (34 mL / g starting material) at 23 °C. The mixture was bubbled with air, stirred at 120 °C for 1 h and cooled to 23 °C. DCM and sat. aq. NH4CI were added. The aqueous phase was extracted with DCM, and the combined organic extracts were washed with sat. aq. NaHCOs, dried, filtered, and concentrated.Yield Intermediate Structure Synthetic procedure(step b)=N / N. Scheme 7XV a 99% 05 Step lbr^N ^NFScheme 7XV b 76%Step lb47O Scheme 7XV c 68%Step lbScheme 7XV d 96%Step lbFScheme 7XV e 75%Step 1c5 / ^WSGR Docket No. 57050-708.601Yield Intermediate Structure Synthetic procedure(step b)Scheme 7XV f 62%Step laScheme 7XV g 70%Step laF.Scheme 7XV h J Steps 1cNyQ5 <-, N. _ IScheme 7XV i 89%Step lbScheme 7XV j 61 C r>N'^ %NIX<F< UV Step lbo~."_N. Scheme 7XV k 80%Ny^N Step lbo—yy, N. T Scheme 7XV IN^XN 78%Step lb0-WSGR Docket No. 57050-708.601Yield Intermediate Structure Synthetic procedure(step b) yr Scheme 7XV m 70%Step leTvj / Scheme 7XVI a? Tv 50%Steps 2bCHO / ^-FScheme 7XVI b t* T v 53%Step 2aCHO } —JScheme 7XVI c 39%Step 2bN<=jT~NCHO } - N.Scheme 7XVI d, N _ / I361%Step 2bCHO } — - FScheme 7XVI e 79%N^TV Step 2aCHOxT Scheme 7XVI f 64%N< PV Step 2aCHO } -WSGR Docket No. 57050-708.601Yield Intermediate Structure Synthetic procedure(step b)Scheme 7XVI g 66%Step 2aCHOE WScheme 7XVI h 69%N? TvY^N?Step 2aCHO / 7==r\ _ r=^NScheme 7XVI i 70%Step 2aCHO°^ / N\Scheme 7XVI j 70%05 Step 2a'S^^NCHOO^ / •^\_-^NN. 7 Scheme 7XVI k 48%Ny^N Step 2bCHO0— / ^N -^NScheme 7XVI I NyO 99%Steps IdCHO / =S\=^NScheme 7XVI m 76%N^XN Step 2aCHOO—WSGR Docket No. 57050-708.601Yield Intermediate Structure Synthetic procedure(step b)Scheme 7XVI n 43%Steps lb, 2afi I DCHOSynthesis of Intermediate XVI a

[0304] XV a: The title compound was prepared as described in the Scheme above using V d (120 mg, 0.384 mmol) via step lb, to afford 3-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV a, 105 mg, 99%).

[0305] XVI a: The title compound was prepared as described in the Scheme above using XV a (987 mg, 3.39 mmol) via step 2b to afford 3-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (513 mg 50%).Synthesis of Intermediate XVI b

[0306] Step lb: The title compound was prepared as described in the Scheme above using V e (114 mg, 0.344 mmol), to afford 2-fluoro-3-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV b, 81.3 mg, 76%).

[0307] Step 2a: The title compound was prepared as described in the Scheme above using XV b (81.3 mg, 0.262 mmol) to afford 2-fluoro-3-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (45.5 mg, 53%).Synthesis of Intermediate XVI c

[0308] Step lb: The title compound was prepared as described in the Scheme above using V f (167 mg, 0.535 mmol) to afford 4-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile.Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (XV c, 106 mg, 68%).

[0309] Step 2b: The title compound was prepared as described in the Scheme above using XV c (106 mg, 0.364 mmol) to afford 4-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile.Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (43.3 mg, 39%).Synthesis of Intermediate XVI dWSGR Docket No. 57050-708.601

[0310] Step lb: The title compound was prepared as described in the Scheme above using intermediate V h (55.0 mg, 0.166 mmol), to afford 4-fluoro-3-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV d, 49.4 mg, 96%).

[0311] Step 2b: The title compound was prepared as described in the Scheme above using XV d (87.7 mg, 0.283 mmol) to afford 4-fluoro-3-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (55.8 mg, 61%).Synthesis of Intermediate XVI e

[0312] Step 1c: The title compound was prepared as described in the Scheme above using V g (90% purity, 289 mg, 0.826 mmol) to afford 2-fluoro-5-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound as a solid (XV e, 217 mg, 84% purity, 75%);

[0313] Step 2a: The title compound was prepared as described in the Scheme above using XV e (79% purity, 248 mg, 0.669 mmol) to afford 2-fluoro-5-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile (223 mg, 79% purity, 85%).Synthesis of Intermediate XVI f

[0314] Step la: The title compound was prepared as described in the Scheme above using V i (131 mg, 0.434 mmol) to afford 5 -isopropyl -4-methyl-7-(p-tolyl)pyrrolo [3, 2-d]pyrimidine. Purification by by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV f, 75.5 mg, 62%).

[0315] Step 2a: The title compound was prepared as described in the Scheme above using XV f (75.5 mg, 0.270 mmol) to afford 5-isopropyl-7-(p-tolyl)pyrrolo[3,2-d]pyrimidine-4-carbaldehyde. Purification by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (50.7 mg, 64%).Synthesis of Intermediate XVI g

[0316] Step la: The title compound was prepared as described in the Scheme above using intermediate V j (77.0 mg, 0.256 mmol) to afford 5-isopropyl-4-methyl-7-(o-tolyl)pyrrolo[3,2-d]pyrimidine. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV g, 50.0 mg, 70%).

[0317] Step 2a: The title compound was prepared as described in the Scheme above using XV g (50.0 mg, 0.179 mmol) to afford 5-isopropyl-7-(o-tolyl)pyrrolo[3,2-d]pyrimidine-4-carbaldehyde. Purification by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-15%) to provide the title compound as a solid (36.8 mg, 66%).Synthesis of Intermediate XVI h

[0318] Step 1c: The title compound was prepared as described in the Scheme above using V o (90% purity, 289 mg, 0.826 mmol) to afford 3-fluoro-5-(5-isopropyl-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile (XV h, 217 mg, 80% purity, 75%).WSGR Docket No. 57050-708.601

[0319] Step 2a: The title compound was prepared as described in the Scheme above using XV h (80% purity, 217 mg, 0.585 mmol) to afford 3-fluoro-5-(4-formyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-10%) to provide the title compound as a solid (128 mg, 69%).Synthesis of Intermediate XVI i

[0320] Step lb: The title compound was prepared as described in the Scheme above using V 1 (480 mg, 1.17 mmol) to afford 3-[5-(2-isopropoxyethyl)-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV I, 335 mg, 89%).

[0321] Step 2a: The title compound was prepared as described in the Scheme above using XV I (325 mg, 1.01 mmol) to afford 3-[4-formyl-5-(2-isopropoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile, by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (238 mg, 70%).Synthesis of Intermediate XVI j

[0322] Step lb: The title compound was prepared as described in the Scheme above using intermediate V m (0.287 g, 0.868 mmol) to afford 4-fluoro-3-[5-(2-methoxyethyl)-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and MeOH in DCM (0-30%) to provide the title compound as a solid (XV j, 0.219 g, 75% purity, 61%).

[0323] Step 2a: The title compound was prepared as described in the Scheme above using XV j (219 mg, 75% purity, 0.529 mmol) to afford 4-fluoro-3-[4-formyl-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (63.0 mg, 70% purity, 26%). Synthesis of Intermediate XVI k

[0324] Step lb: The title compound was prepared as described in the Scheme above using V n (181 mg, 0.550 mmol) to afford 3-[5-(2-methoxyethyl)-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV k, 135 mg, 80%).

[0325] Step 2b: The title compound was prepared as described in the Scheme above using XV k (10.0 mg, 0.0325 mmol) to afford 3-[4-formyl-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (58.0 mg, 48%).Synthesis of Intermediate XVI 1

[0326] The title compound was prepared as described in the Scheme above using XVII c (50.0 mg, 0.160 mmol) via step Id to afford 3-{4-formyl-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}benzonitrile as a solid (56.0 mg, 99%).Synthesis of Intermediate XVI mWSGR Docket No. 57050-708.601

[0327] Step lb: The title compound was prepared as described in the Scheme above using V c (218 mg, 0.667 mmol) to afford 3-[5-(2-methoxypropyl)-4-methyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XV 1, 159 mg, 78%).

[0328] Step 2a: The title compound was prepared as described in the Scheme above using XV 1 (159 mg, 0.519 mmol) to afford 3-[4-formyl-5-(2-methoxypropyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (127 mg, 76%).Synthesis of Intermediate XVI n

[0329] Step le: The title compound was prepared as described in the Scheme above using XIV f (260 mg, 0.823 mmol) and (5-cyano-2-fluoro-phenyl)boronic acid (204 mg, 1.24 mmol), to afford 4-fluoro-3-(l-isopropyl-7-methyl-pyrrolo[2,3-c]pyridin-3-yl)benzonitrile. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in DCM (0-100%) to provide the title compound as a solid (XV m, 178 mg, 70%).

[0330] Step 2a: The title compound was prepared as described in the Scheme above using XV m (178 mg, 0.576 mmol) to afford 4-fluoro-3-(7-formyl-l-isopropyl-pyrrolo[2,3-c]pyridin-3-yl)benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in DCM (0-30%) to provide the title compound as a solid (80.6 mg, 43%).Scheme 8Synthesis of Intermediates XVII4,4,5,5-Tetramethyl-2- vinyl-l,3,2~dioxaboro!ane- ►Cs2CO3, Pd(dppf)Cl2-DCM1,4-dioxane, H2OStep 1V XVII

[0331] Step 1: Pd(dppf)C12-DCM (0.05 eq.) was added to a mixture of the suitable intermediate V (1 eq.), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (1.2 eq.) and CS2CO3 (2 eq.) in 1,4-dioxane (4.5 mL / g starting material) and water (1.1 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h and filtered through Celite, washed with EtOAc (25.0 mL). The filtrate was concentrated.Intermediate Structure Synthetic procedure Yield=NScheme 8XVII a 05 75%Step 1WSGR Docket No. 57050-708.601 / c=\— =NScheme 8XVII b \ D A 70%Step 1Scheme 8XVII c 62%Step 1

[0332] Synthesis of intermediate XVII a: The title compound was prepared as described in the Scheme above using V k (224 mg, 0.690 mmol) to afford 3-[5-(cyclopropylmethyl)-4-vinyl-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography (25 g cartridge) using a gradient of EtOAc in hexanes (0-60%) to provide the title compound as a solid (164 mg, 75%).

[0333] Synthesis of intermediate XVII b: The title compound was prepared as described in the Scheme above using intermediate V d (250 mg, 0.800 mmol), to afford 3 -(5 -isopropyl -4-vinyl-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (171 mg, 70%).

[0334] Synthesis of intermediate XVII c: The title compound was prepared as described in the Scheme above using intermediate V b (419.0 mg, 1.27 mmol) to afford 3-{4-ethenyl-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}benzonitrile. Purification by silica gel chromatography (24 g cartridge) with heptane and EtOAc (0-20%) to provide the title compound as a solid (255 mg, 62%).Scheme 9Synthesis of Intermediates XXMeMgBr DMP. X, ' ~- *" v xT V" H115THF DCM H X RStep la Step 22XV! XIX XX Tributyl(l-ethoxyvinyl)stannanePd(PPh3)2CI21,4-dioxane Step lb

[0335] Step la: MeMgBr (1.2 eq.) was added to a mixture of the suitable intermediate XVI (1 eq.) in THF (20 mL / g starting material) at 0 °C. The mixture was stirred at 23 °C for 30 min and sat. aq. NH4CI was added. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to provide the title compound as a solid.WSGR Docket No. 57050-708.601

[0336] Step lb: Tributyl(l-ethoxyvinyl)stannane (2 eq.) was added to a mixture of the suitable intermediate V (1 eq.), Pd(PPh3)2Cl2 (0.2 eq.) in 1,4-dioxane (17 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 18 h and concentrated. The residue was dissolved in 1,4-dioxane (17 mL / g starting material). HC1 (35% aq. 8.5 mL / g starting material) and H2O (30 mL / g starting material) were added. The mixture was stirred at 23 °C for 18 h and diluted with brine. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (MgSO4). filtered, and concentrated.

[0337] Step 2: DMP (1.2 eq.) was added to a mixture of XIX (1 eq.) in DCM (0.4 mL / g starting material) at 23 °C. The mixture was stirred at 23 °C for 2 h and concentrated.Intermediate Structure Synthetic procedure YieldAScheme 9XIX a 80%Step la2NXJZ / Scheme 9XIX b 91%Step la^0HVkJ / "Scheme 9XX a 90%Step 2 / AANXJ / Scheme 9XX b 98%Step 2AVANScheme 9XX c 83%Step lbSynthesis of Intermediate XX a:WSGR Docket No. 57050-708.601

[0338] Step la: The title compound was prepared as described in the Scheme above using XVI i (100 mg, 0.299 mmol) to afford 3-[4-(l-hydroxyethyl)-5-(2-isopropoxyethyl)pyrrolo[3,2-d] pyrimidin-7-yl] benzonitrile as a solid (XIX a, 105 mg, 80%, 80% purity).

[0339] Step 2: The title compound was prepared as described in the Scheme above using XIX a (80% purity, 90.0 mg, 0.205 mmol), to afford 3-[4-acetyl-5-(2-isopropoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (65.8 mg, 90% purity, 83%).Synthesis of Intermediate XX b:

[0340] Step la: The title compound was prepared as described in the Scheme above using XVI k (155 mg, 0.506 mmol) to afford 3-[4-(l-hydroxyethyl)-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile as a solid (XIX b, 166 mg, 91%).

[0341] Step 2: The title compound was prepared as described in the Scheme above using XIX b (166 mg, 0.490 mmol), to afford 3-[4-acetyl-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (171 mg, 98%).Synthesis of Intermediate XX c:

[0342] Step lb: The title compound was prepared as described in the Scheme above using V d (593 mg, 2.00 mmol), to afford 3-(4-acetyl-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl) benzonitrile.Purification by reverse phase chromatography (C18, 50 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (10-100%) to provide the title compound as a solid (503 mg, 83%).;Scheme 10Synthesis of Intermediates XXIINaBH3CN, Sc(OTf)3AcOH, DMSO Step lb

[0343] Step la: AcOH (3.5 mL / g starting material) was added to a mixture of XVI a (1 eq.), the suitable tert-butyl amine-1-carboxylate (1.2 eq.), Sc(OTf)3 (0.25 eq.) and NaBFhCN (1.5 eq.) in DMSO (25 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and dilutedWSGR Docket No. 57050-708.601with EtOAc. The organic phase was washed with sat. aq. NaHCOs, brine, dried (Na2SO4), filtered, and concentrated.

[0344] Step lb: AcOH (3 mL / g starting material) was added to a mixture of XVI a (1 eq.), the suitable amine, Sc(OTf)3 (0.25 eq.) and NaBH3CN (1.5 eq.) in DMSO (20 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 3 h and diluted with EtOAc. The organic phase was washed with sat. aq. NaHCOs, brine, dried (Na₂SO₄), filtered, and concentrated.

[0345] Step 2: HC1 (4 M in 1,4-dioxane, 19 eq.) was added to a mixture of XXI (1 eq.) in DCM (57 mL / g starting material) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and concentrated to provide the title compound as a solidIntermediate Structure Synthetic procedure Yield ZT\—Scheme 10XXI a 75%Step laM _ rScheme 10XXI b 55%Step laA0Scheme 10XXII a 05 99%Step 2Hc>r^NHN— 'VScheme 10XXII b Ov 83%Step 2HC1WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldScheme 10XXII c 05 57%Step lbHN^> ISynthesis of Intermediate XXII a:

[0346] Step la: The title compound was prepared as described in the Scheme above using (2S,5R)- 2,5-dimethylpiperazine-1-carboxylate (35.4 mg, 0.165 mmol), to afford tert-butyl (2S,5R)-4-[[7-(3-cyanophenyl)-5-isopropyl-pyrrolo[3,2-d] pyrimidin-4-yl]methyl]-2,5-dimethyl-piperazine-l-carboxylate. Purification by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%) to provide the title compound as a solid (XXI a, 52.9 mg, 75%).

[0347] Step 2: The title compound was prepared as described in the Scheme above using XXI a (52.9 mg, 0.103 mmol) to afford 3-[4-[[(2R,5S)-2,5-dimethylpiperazin-l-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile hydrochloride as a solid (43.7 mg, 99%).Synthesis of Intermediate XXII b:

[0348] Step la: The title compound was prepared as described in the Scheme above using tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate (35.4 mg, 0.165 mmol), to afford tert-butyl (2R,5S)-4-[[7-(3-cyanophenyl)-5-isopropyl-pyrrolo[3,2-d] pyrimidin-4-yl]methyl]-2,5-dimethyl-piperazine-l-carboxylate. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NTUXHCOs)] and MeCN (5-80%) to provide the title compound as a solid (XXI b, 39.2 mg, 55%).

[0349] Step 2: The title compound was prepared as described in the Scheme above using XXI b (39.2 mg, 0.103 mmol) to afford 3-[4-[[(2S,5R)-2,5-dimethylpiperazin-l-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile hydrochloride as a solid (83% purity, 32.4 mg, 83%).Synthesis of Intermediate XXII c:

[0350] Step lb: The title compound was prepared as described in the Scheme above using (2S,6R)- 2,6-dimethylpiperazine (29.5 mg, 0.258 mmol), to afford 3-[4-[[(3S,5R)-3,5-dimethylpiperazin-l-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%) to provide the title compound as a solid (75% pure, 25.2 mg, 57%).Scheme 11Synthesis of Intermediates XXVIIWSGR Docket No. 57050-708.601XXXXicNaBH3CN, Sc(OTf|,AcOH, DMSOStep 2a Br / i Br / i R® X 7 c nR- ^.x. -I XXXXic H ■ A— RR- ■ - ► Il £ Rw.4A MS, STAB | 1,4-dioxane 'HO step 2|jStep 1XIVXXViXXXXicXXVii NaBH3CN, Sc(OTf)3 NEt3AcOH, DMSOStep 2c

[0351] Step 1: SeO2 (1.1 eq.) was added to a mixture of XIV (1 eq.) in 1,4-dioxane (20 mL / g starting material) at 23 °C. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C and filtered through Celite, washed with DCM. The filtrate was concentrated to afford XXVI.

[0352] Step 2a: NaBH3CN (1.5 eq.) was added to a mixture of XXVI (1 eq.), XXXXI c (1 eq.), Sc(OTf)3 (0.25 eq.) and NEt3(1 eq.) in DMSO (4 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min and AcOH (3 eq.) was added. The mixture was stirred at 23 °C for 2 h and diluted with DCM and sat. aq. NaHCOs. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO4), fdtered, and concentrated.

[0353] Step 2b: XXXXI c (1.00 M in DCM, 1.5 eq.) (free-based from the HC1 salt by dissolving in MeOH and eluting through HCOs-SPE cartridge) was added to a mixture of XXVI ( 1 eq.) and 4A MS (3 mg / mmol starting material) in DCM (68 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 5 h. STAB (1.5 eq.) was added. The mixture was stirred at 23 °C for 18 h and fdtered through Celite, washed with DCM. The fdtrate was washed with sat. aq. NaHCOs, brine, dried (Na2SO4), fdtered, and concentrated.

[0354] Step 2c: NaBH3CN (1.5 eq.) was added to a mixture of XXVI (1 eq.), XXXXI c (1 eq.), Sc(OTf)3 (0.25 eq.) and NEt3 (1 eq.) in DMSO (4 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min and AcOH (3 eq.) was added. The mixture was stirred at 23 °C for 2 h and diluted with DCM and sat. aq. NaHCOs. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO4), fdtered, and concentrated.WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldScheme 11XXVI aNY^-N 76%Step 1CHO / ^—BrScheme 11XXVI b 100%Step 1CHO ) —Scheme 11XXVI c 71%Step 1CH0Scheme 11XXVI d 78%CHO V^, Step 10^Scheme 11XXVI e 92%1 \ Step 1CHOScheme 11XXVI f rit Tv 92%Step 1CHO0—WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure Yield BrScheme 11XXVI g 98%Step 1CHOScheme 11XXVII a 59%Step 2a. / oBr X-°. N, Yz'"■' / zr''' “0 v\y- 5" Scheme 11XXVII b ^QZ" 50%Step 2ao o9r °oScheme 11XXVII c 28%Step 2a_N. 7Ov Scheme 11XXVII d I ^5*^l^rr 43%0Step 2bScheme 11XXVII e 53%Step 2cWSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldScheme 11XXVII f J 53%0^ N J °- Step 2cy;BrX 7Scheme 11XXVII g 64%Step 2bSynthesis of intermediate XXVII a

[0355] Step 1: The title compound was prepared as described in the Scheme above using XIV g (300 mg, 0.996 mmol) to afford 7-iodo-5-isopropyl-pyrrolo[3,2-d]pyrimidine-4-carbaldehyde. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XXVI a, 238 mg, 76%).

[0356] Step 2: The title compound was prepared as described in the Scheme above using XXVI a (purity 57 %, 0.744 g, 1.35 mmol), to afford (8aS)-2-[(7-iodo-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl)methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by reverse phase chromatography (Cl 8, 60 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (10-100%) to provide the title compound as a solid (418 mg, 59%, 88% purity).Synthesis of intermediate XXVII b

[0357] Step 1: The title compound was prepared as described in the Scheme above using XIV h (85% purity, 1.30 g, 4.35 mmol) to afford 7-bromo-5-isopropyl-pyrrolo[3,2-d]pyrimidine-4-carbaldehyde. Purification by silica gel chromatography (48 g cartridge) using MeCN in DCM (10%) to provide the title compound as a solid (XXVI b, 1.21 g, 100 %).

[0358] Step 2: The title compound was prepared as described in the Scheme above using XXVI b (300 mg, 0.839 mmol), to afford (8aS)-2-[(7-bromo-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl)methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (176 mg, 50%).Synthesis of intermediate XXVII c

[0359] Step 1: The title compound was prepared as described in the Scheme above using XIV a (200 mg, 0.608 mmol) to afford 7-iodo-5-(oxetan-3-ylmethyl)pyrrolo[3,2-d]pyrimidine-4-carbaldehyde.WSGR Docket No. 57050-708.601Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (50-100%) to provide the title compound as a solid (XXVI c, 148 mg, 71%).

[0360] Step 2a: The title compound was prepared as described in the Scheme above using XXVI c (148 mg, 0.431 mmol) to afford (8aS)-2-[[7-iodo-5-(oxetan-3-ylmethyl)pyrrolo[3,2-d]pyrimidin-4-yl] methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and by ACCQ eluting with water [10 mM (NH4)(HCO3) | and MeCN (22-32%) to provide the title compound as a solid (60.5 mg, 28%).Synthesis of intermediate XXVII d

[0361] Step 1: The title compound was prepared as described in the Scheme above using XIV b (122 mg, 0.371 mmol) to afford 7-iodo-5-[(3R)-tetrahydrofuran-3-yl]pyrrolo[3,2-d]pyrimidine-4-carbaldehyde. Purification by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (XXVI d, 99.0 mg, 78%).

[0362] Step 2b: The title compound was prepared as described in the Scheme above using XXVI d (74.0 mg, 0.216 mmol) to afford (8aS)-2-[[7-iodo-5-[(3R)-tetrahydrofuran-3-yl]pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-6%) to provide the title compound as a solid (45.9 mg, 43%).Synthesis of intermediate XXVII e

[0363] Step 1: The title compound was prepared as described in the Scheme above using XIV c (343 mg, 1.04 mmol) to afford 7-iodo-5-[(2R)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidine-4-carbaldehyde as a solid (XXVI e, 330 mg, 92%).

[0364] Step 2c: The title compound was prepared as described in the Scheme above using XXVI e (165 mg, 0.478 mmol) to afford (8aS)-2-[[7-iodo-5-[(2R)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (126 mg, 53%).Synthesis of intermediate XXVII f

[0365] Step 1: The title compound was prepared as described in the Scheme above using XIV d (342 mg, 1.03 mmol) to afford 7-iodo-5-[(2S)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidine-4-carbaldehyde as a solid (XXVI f, 330 mg, 92%).

[0366] Step 2c: The title compound was prepared as described in the Scheme above using XXVI f (160 mg, 0.464 mmol) to afford (8aS)-2-[[7-iodo-5-[(2S)-2-methoxypropyl]pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (118 mg, 51%).Synthesis of intermediate XXVII gWSGR Docket No. 57050-708.601

[0367] Step 1: The title compound was prepared as described in the Scheme above using XIV e (3.05 g, 11.5 mmol) to afford 7-bromo-5-(cyclopropylmethyl)pyrrolo[3,2-d]pyrimidine-4-carbaldehyde (XXVI g, 3.14 g, 98%).

[0368] Step 2b: The title compound was prepared as described in the Scheme above using XXVI g (500 mg, 1.78 mmol) to afford (8aS)-2-[[7-bromo-5-(cyclopropylmethyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound as a solid (497 mg, 64%).Scheme 12Synthesis of intermediate XXXVIIImethylboronic acidPd(dppf)Cl2·DCM, K, CO’3NIS - - - ► - ► 1,4-dioxane DMF Step 2a Step 1a 4-chloro-5H- XXVIII XXIX pyrrolo[3,2- d]pyrimidine boron ic acid II Pd(dppf)Cl2-DCM K3PO4, 1,4-dioxane, H2OTFA Step 6DCMWSGR Docket No. 57050-708.601III c NaBH3CN, Sc(OTf)3 NEt3, AcOH DMSO XXXVStep 4b SeO21,4-dioxane Step 3bTrimethylboroxine NIS - ► Pd(dppf)Cl2, * DMF K2CO31,4-dioxane Step 2b4-chloro-5-{[2- Step 1b XXXIII(trimethylsilyl)ethoxyjmethyl}-5H- pyrrolo[3,2-d]pyrimidineXXXIISynthesis of intermediate XXXVIII a:

[0369] Step la: Pd(dppf)C12-DCM (0.2 eq.) was added to a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (CAS: 84905-80-6, 5.00 g, 30.9 mmol), methylboronic acid (9.26 g, 155 mmol) and K2CO3 (8.55 g, 61.9 mmol) in 1,4-dioxane (150 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 20 h, cooled to 23 °C and diluted with MeOH (100 mL). The mixture was filtered through Celite, washed with MeOH (300 mL), and the filtrate was concentrated. Purification by silica gel chromatography (80 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (XXVIII, 2.15 g, 52%).

[0370] Step 2a: NIS (3.40 g, 15.1 mmol) was added to a mixture of 4-methyl-5H-pyrrolo[3,2-d]pyrimidine (2.12 g, 15.1 mmol) in DMF (50.0 mL) at 23 °C. The mixture was covered with aluminium foil and stirred at 23 °C for 1 h. The mixture was concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of MeOH in EtOAc (0-25%) to provide the title compound as a solid (XXIX, 3.30 g, 80%).

[0371] Step 3a: A solution of 7-iodo-4-methyl-5H-pyrrolo[3,2-d]pyrimidine (1.50 g, 5.50 mmol) in 1,4-dioxane (60.0 mL) and water (12.0 mL) was added to a mixture of (3-cyanophenyl)boronic acid (CAS: 150255-96-2, 0.889 g, 6.05 mmol), K3PO4 (2.34 g, 11.0 mmol) and Pd(dppf)Cl2·DCM (0.449 g, 0.550 mmol) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h, cooled to 23 °C, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (XXX, 1.09 g, 63%, 75% purity).

[0372] Step 4a: Molecular iodine (290 mg, 1.14 mmol) was added to a mixture of 3-(4-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile (705 mg, 1.14 mmol) and p-toluene sulfonic acid monohydrateWSGR Docket No. 57050-708.601(544 mg, 2.86 mmol) in DMSO (30.0 mL) at 23 °C. The mixture was bubbled with air, stirred at 120 °C for 1 h and cooled to 23 °C. DCM (100 mL) and sat. aq. NH4CI (50.0 mL) were added. The aqueous phase was extracted with DCM (2 x 50.0 mL), and the combined organic extracts were washed with sat. aq. NaHCOs (20.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of MeOH in DCM (0-40%) to provide the title compound as a solid (XXXI, 630 mg, 48%, 50% purity).

[0373] Step 5a: NaBH3CN (75.9 mg, 1.21 mmol) was added to a mixture of 3-(4-formyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)benzonitrile (50% purity, 500 mg, 1.01 mmol), III c (309 mg, 1.51 mmol) and Sc(OTf)3 (124 mg, 0.252 mmol) in DMSO (6.00 mL) and AcOH (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 2 h and concentrated. The residue was purified by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) to provide the title compound as a solid (XXXVIII, 70.8 mg, 17%).Synthesis of intermediate XXXVIII b:

[0374] Step lb: Trimethylboroxine (758 uL, 50% w / w soln, in THF, 2.70 mmol) was added to a mixture of 4-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine (511 mg, 1.80 mmol), K2CO3 (622 mg, 4.50 mmol) and Pd(dppf)Cl2(198 mg, 0.27 mmol) in 1,4-dioxane (13.5 mL) at 23 °C under argon atmosphere. The mixture was stirred at 100 °C for 16 h then cooled to 23 °C, filtered over Celite and 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 sat. aq. NaHCO3(30.0 mL), brine (30.0 mL), dried (MgSO4). filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in heptane (50-100%) to provide the title compound as a solid (XXXIII, 235 mg, 50%).

[0375] Step 2b: N-Iodosuccinimide (263 mg, 1.17 mmol) was added to a mixture of 4-methyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (205 mg, 0.78 mmol) in MeCN (5.00 mL) at 23 °C. The mixture was stirred at 23 °C for 14 h and diluted with EtOAc (80.0 mL), washed with water (20.0 mL) and brine (20.0 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (10-60%) to provide the title compound as a solid (XXXIV, 277 mg, 91%).

[0376] Step 3b: 1,4-Dioxane (50.0 mL) was added to a mixture of 2-[(7-iodo-4-methyl-pyrrolo[3,2-d]pyrimidin-5-yl)methoxy]ethyl-trimethyl-silane (2.00 g, 5.14 mmol) and selenium dioxide (599 mg, 5.39 mmol) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 4 h, cooled to 23 °C and filtered over Celite. The solid was washed with DCM (100 mL) and the filtrate was concentrated to provide the title compound as a solid (XXXV, 2.05 g, 94%).

[0377] Step 4b: NEt3(0.681 mL, 4.89 mmol) was added to a mixture of 7-iodo-5-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-d]pyrimidine-4-carbaldehyde (2.28 g, 5.37 mmol), III c (1.00 g, 4.89 mmol), Sc(OTf)3 (601 mg, 1.22 mmol) in DMSO (15.0 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min. NaCNBH3(460 mg, 7.33 mmol) and acetic acid (0.839 mL, 14.7 mmol) were added at 23 °C. The mixture was stirred at 23 °C for 4 h and diluted with DCM (50.0 mL) and sat.WSGR Docket No. 57050-708.601aq. NaHCOs (50.0 mL). The aqueous phase was extracted with DCM (2 x 50.0 mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexane (0-100%) to provide the title compound as a solid (XXXVI, 1.85 g, 68%).

[0378] Step 5b: H2O (1.50 mL) was added to a mixture of (8aS)-2-[[7-iodo-5-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one (800 mg, 1.44 mmol), (5-cyano-2-fluoro-phenyl)boronic acid (475 mg, 2.88 mmol), RuPhos (67.3 mg, 0.144 mmol), Pd2(dba)s (39.6 mg, 0.0432 mmol), CsF (656 mg, 4.32 mmol) in 1,4-dioxane (15.0 mL) at 23 °C 0 under nitrogen. The mixture was stirred at 95 °C for 18 h, cooled to 23 °C, diluted with EtOAc (50.0 mL) and sat. aq. NaHC’CF (30.0 mL). The aqueous phase was extracted with EtOAc (2 x 50.0 mL), and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The residue was purified by silica gel chromatography (40 g cartridge) using a gradient of EtOAc in hexane (0-100%) to provide the title compound as a solid (XXXVII, 637 mg, 81%).\\ \z

[0379] Step 6: TFA (5.00 mL, 67.3 mmol) was added to a mixture of3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3, 4,8, 8a-tetrahydro-lH-pyrrolo[ l,2-a]pyrazin-2 -yl]methyl]-5-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-d]pyrimidin-7-yl]-4-fluoro-benzonitrile (0.637 g, 1.16 mmol) in DCM (2.50 mL) at 0 °C under nitrogen. The mixture was stirred at 60 °C for 18 h, cooled to 23 °C and concentrated. The residue was dissolved in DCM (40.0 mL) and sat. aq. NaHCOs (30.0 mL) was added. The aqueous phase was extracted with DCM (2 x 30.0 mL), and the combined organic extracts were washed with water (50.0 mL), dried (MgSO₄), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide the title compound as a solid (XXXVIII, 492 mg, 96%).Intermediate Structure Synthetic procedure YieldScheme 12XXXVIII a 17%Step 5aScheme 12XXXVIII b 96%Step 6WSGR Docket No. 57050-708.601Scheme 13Synthesis of Intermediates XXXIXboronic acid, K3PO4, Pd(dtbpf)Cl2, DMF, H2OStep 1XXVIIn=l,2

[0380] Step 1: DMF (15 mL / g starting material) and water (0.6 mL / g starting material) were added to a mixture of the suitable intermediate XXVII (1 eq.), the suitable boronic acid (2 eq.), K3PO4 (3 eq.) and Pd(dtbpf)C12 (0.1 eq.) at 23 °C under nitrogen. The mixture was stirred at 80 °C for 2 h and diluted with EtOAc and aq. NaOH. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, dried (MgSO4), fdtered, and concentrated.Intermediate Structure Synthetic procedure YieldXXXIX a N^-N Scheme 13 30% Example 116 f -nr.— 0r n AXXXIX b Scheme 13 91%? VAXXXIX c Scheme 13 88%XXXIX d Scheme 13 86%WSGR Docket No. 57050-708.601

[0381] Synthesis of intermediate XXXIX a (Example 116): The title compound was prepared as described in the Scheme above using XXVII b (100 mg, 0.238 mmol) and (4,4-difluorocyclohexen-l-yl)boronic acid (77.1 mg, 0.476 mmol), to afford (8aS)-2-[[7-(4,4-difluorocyclohexen-l-yl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (24 g cartridge) using MeOH in DCM (20%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (48-58%) to provide the title compound as a solid. Example 116, Intermediate XXXIX a (9.00 mg, 30%).

[0382] Synthesis of intermediate XXXIX b: The title compound was prepared as described in the Scheme above using XXVII a (150 mg, 0.321 mmol) and 3,6-dihydro-2H-pyran-4-ylboronic acid (82.1 mg, 0.642 mmol) to afford (8aS)-2-[[7-(3,6-dihydro-2H-pyran-4-yl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (24 g cartridge) using MeOH in DCM (20%) to provide the title compound as a solid (124 mg, 91%).

[0383] Synthesis of intermediate XXXIX c: The title compound was prepared as described in the Scheme above using XXVII a (150 mg, 0.321 mmol) and cyclohexen-l-ylboronic acid (80.9 mg, 0.642 mmol), to afford (8aS)-2-[[7-(cyclohexen-l-yl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (24 g cartridge) using MeOH in DCM (20%) to provide the title compound as a solid (119 mg, 88%).

[0384] Synthesis of intermediate XXXIX d: The title compound was prepared as described in the Scheme above using XXVII a (150 mg, 0.321 mmol) and cyclopenten-l-ylboronic acid (71.9 mg, 0.642 mmol), to afford (8aS)-2-[[7-(cyclopenten-l-yl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (24 g cartridge) using MeOH in DCM (20%) to provide the title compound as a solid (113 mg, 86%). Scheme 14Synthesis of intermediates XXXXI a-d:n-BuLi, DI PEA, CHJ HCi - ► - ► -78“C -» RT, THF, lh. 1,4-dioxane, RT, 4hStep 1 Step 2XXXIX XXXX XXXXia-d

[0385] Step 1: w-BuLi (2.50 M in hexanes, 4.4 eq.) was added to a mixture of diisopropylamine (4.8 eq.) in THF (12 mL / g starting material) at -78 °C. The mixture was stirred at -78 °C for 20 min and added to a mixture of the suitable starting material XXXIX (1 eq.) and iodomethane (5.7 eq.) in THF (7 mL / g starting material) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 h, and at 25 °C for 1 h. The mixture was diluted with sat. aq. NH4CI. The aqueous phase was extracted with EtOAc, and the combined organic extracts were dried (MgSO4), filtered, and concentrated (XXXX).

[0386] Step 2: HCI (4 M in 1,4-dioxane, 8.5 eq.) was added to intermediate XXXX (1 eq.) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 4 h and diluted with MeCN. The mixture was concentrated to provide the title compound as a solid (XXXXI).WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure Yield HC1HIST XXXXI a Scheme 14 92%0HCI XXXXI b Scheme 14 99%O HC1HN^ Y'V / XXXXI c Scheme 14 88%O HClXXXXI d f y Scheme 14 99%OSynthesis of intermediate XXXXI a

[0387] Step 1: The title compound was prepared as described in the Scheme above using tert-butyl (9aS)-6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine-2-carboxylate (0.720 g, 2.83 mmol) to afford tert-butyl (9aS)-7,7-dimethyl-6-oxo-l,3,4,8,9,9a-hexahydropyrido[l,2-a] pyrazine-2 -carboxylate. Purification by reverse phase chromatography (Cl 8, 86 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (0-100%) to provide the title compound as a solid (XXXX a, 622 mg, 76%)Step 2: The title compound was prepared as described in the Scheme above using XXXX a (0.720 g, 2.83 mmol) to afford (9aS)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (XXXXI a, 516 mg, 92%).Synthesis of intermediate XXXXI b

[0388] Step 1: The title compound was prepared as described in the Scheme above using tert-butyl (9aR)-6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazine-2-carboxylate (0.441 g, 1.73 mmol) to afford tert-butyl (9aR)-7,7-dimethyl-6-oxo-l,3,4,8,9,9a-hexahydropyrido[l,2-a] pyrazine-2 -carboxylate. Purification by reverse phase chromatography (Cl 8, 86 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (0-100%) to provide the title compound as a solid (XXXX b, 306 mg, 63%).

[0389] Step 2: The title compound was prepared as described in the Scheme above using XXXX b (306 mg, 1.20 mmol), to afford (9aR)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (238 mg, 99%).WSGR Docket No. 57050-708.601Synthesis of intermediate XXXXI c

[0390] Step 1: The title compound was prepared as described in the Scheme above using tert-butyl (8aS)-6-oxo-l,3,4,7,8,8a-hexahydropyrrolo[l,2-a]pyrazine-2-carboxylate (2.0 M in THF, 1.32 g, 5.49 mmol), to afford tert-butyl (8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazine-2-carboxylate. Purification by reverse phase chromatography (C18, 30 g cartridge) with water [10 mM (NH4)(HCO3)] and MeCN (5-80%) to provide the title compound as a solid (XXXX c, 862 mg, 59%).

[0391] Step 2: The title compound was prepared as described in the Scheme above using XXXX c (1.99 g, 7.41 mmol), to afford (9aS)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (XXXXI c 1.34 g, 88%).Synthesis of intermediate XXXXI d

[0392] Step 1: The title compound was prepared as described in the Scheme above using tert-butyl (8aR)-6-oxo-l,3,4,7,8,8a-hexahydropyrrolo[l,2-a]pyrazine-2-carboxylate (1.32 g, 5.50 mmol), to afford tert-butyl (8aR)-7,7-dimethyl-6-oxo-3, 4, 8, 8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazine-2 -carboxylate.Purification by reverse phase chromatography (Cl 8, 86 g cartridge) with [10 mM (NH4)(HCO2)] and MeCN (30-100%) to provide a title compound as a solid (XXXX d, 700 mg, 96%)

[0393] Step 2: The title compound was prepared as described in the Scheme above using XXXX d (870 mg, 3.24 mmol), to afford (9aR)-7,7-dimethyl-2,3,4,8,9,9a-hexahydro-lH-pyrido[l,2-a]pyrazin-6-one hydrochloride (680 mg, 99%).Scheme 15Synthesis of Intermediate XXXXIVLDA, CH3I HCI THF 1,4-dioxaneStep 1 Step 2 XXXXII XXXXIII XXXXIV tert-Butyl (3aS)-l,l-dioxo-lX‘- thia-5,7a-diazaoctahydro-5- indenecarboxylate

[0394] Step 1: Freshly prepared LDA (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 mb) 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. NH4CI (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 tert-Butyl (3aS)-2,2-dimethyl-l,l-dioxo-1λ6-thia-5,7a-diazaoctahydro-5-indenecarboxylate the title compound as a solid (XXXXIII 1.60 g, 79%).

[0395] Step 2: HCI (4 M in 1,4-dioxane, 6.00 mL, 24.0 mmol) was added to XXXXIII (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 (3aS)-2,2-Dimethyl- 1λ6-thia-5,7a-diazahexahydro-1,1(2H)-indenedione hydrochloride as a solid (XXXXIV, 1.12 g, 89%).WSGR Docket No. 57050-708.601Scheme 16Synthesis of Intermediate XXXXVIIXXXXV XXXXVI XXXXVII(3S,8aS)-2-benzyl-3- methyl-l,3,4,7,8,8a- hexahydropyrrolo[l,2- a]pyr3zin-6-one

[0396] Step 1: n-BuLi (2.50 M in hexanes, 4 eq.) was added to a mixture of diisopropylamine (4 eq.) in THF (1.5 mL / mmol starting material) at -78 °C. The mixture was stirred at -78 °C for 20 min and the suitable starting material (2.00 M in THF, 1 eq.) was added. The mixture was stirred at -78 °C for 15 min and iodomethane (2.5 eq.) was added. The mixture was stirred at -78 °C for 8 h and diluted with sat.aq. NH4CI. The aqueous phase was extracted with DCM, and the combined organic extracts were, dried (MgSO4), filtered, and concentrated (XXXXVI).

[0397] Step 2: MeOH (10 mL / g starting material) was added to a mixture of the suitable intermediate XXXXVI (1 eq.) and wet Pd / C (10 % on charcoal, 0.4 eq.) at 23 °C under nitrogen. The mixture was stirred under H2 atmosphere at 23 °C for 48 h and filtered through Celite, washed with MeOH, and the filtrate was concentrated (XXXXVII).Synthesis of intermediate XXXXVII a:

[0398] Step 1: The title compound was prepared as described in the Scheme above using (3S,8aS)-2-benzyl-3-methyl-l,3,4,7,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one (2.00 M in THF, 2.05 mb, 4.09 mmol) to afford (3S,8aS)-2-benzyl-3,7,7-trimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-6-one (XXXXVI a, 0.785 g, 80% purity, 56%).

[0399] Step 2: The title compound was prepared as described in the Scheme above using XXXXVI a (80 % purity, 0.785 g, 2.31 mmol) to afford (3S,8aS)-3,7,7-trimethyl-l,2,3,4,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one. XXXXVII a (382 mg, 79% purity, 72%).Synthesis of intermediate XXXXVII b:

[0400] Step 1: The title compound was prepared as described in the Scheme above using (3R,8aS)-2-benzyl-3-methyl-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-6-one (300 mg, 1.11 mmol) to afford (3R,8aS)-2-benzyl-3,7,7-trimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one (XXXXVI b, 125 mg, 37%).

[0401] Step 2: The title compound was prepared as described in the Scheme above using XXXXVI b (125 mg, 0.459 mmol) to afford (3R,8aS)-3,7,7-trimethyl-l,2,3,4,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one. XXXXVI b (83.0 mg, 89%).WSGR Docket No. 57050-708.601Intermediate Structure Synthetic procedure YieldHXXXXVII a Scheme 16 72%0H.: / A:'111XXXXVII b Scheme 16 89%0Scheme 17Synthesis of Intermediate LIStep 1 Step 2 Step 3XXXXVIH XXXXIX L LI

[0402] Step 1: TBDPS-C1 (0.456 mL, 1.75 mmol) was added to a mixture of 7 -hydroxy-2, 5, 6, 7, 8, 8a-hexahydro-lH-indolizin-3-one (261 mg, 1.59 mmol) and imidazole (326 mg, 4.78 mmol) in DMF (6.00 mL) at 0 °C under nitrogen. The mixture was stirred at 23 °C for 18 h and diluted with sat. aq. NH4CI (25.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (0 30%) to provide 7-[tert-Butylbis(phenyl)siloxy]hexahydro-3(lH)-indolizinone as an oil (XXXXIX, 567 mg, 86%).

[0403] Step 2: Freshly prepared LDA (1 M in THF: Hexanes, 2.48 mL, 2.48 mmol) was added to a mixture of XXXXIX (517 mg, 1.18 mmol) and iodomethane (0.184 mL, 2.96 mmol) in THF (4.00 mL) at -78 °C under nitrogen. The mixture was stirred at -25 °C for 18 h and diluted with sat. aq. NH4CI (25.0 mL) and water (25.0 mL). The aq. phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The residue was diluted with THF (4.00 mL). Freshly prepared LDA (1 M in THF: Hexanes, 2.48 mL, 2.48 mmol) and iodomethane (0.184 mL, 2.96 mmol) were added at -78 °C under nitrogen. The mixture was stirred at -78 °C for 2 h and diluted with sat. aq. NH4CI (25.0 mL) and water (25.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The residue was purified by silica gel chromatography (24 g cartridge) using a gradient of EtOAc in DCM (0-100%)WSGR Docket No. 57050-708.601to provide 7-[tert-Butylbis(phenyl)siloxy]-2,2-dimethylhexahydro-3(lH)-indolizinone as an oil (L, 382 mg, 73%);

[0404] Step 3: AcCl (4.22 pL, 0.0591 mmol) was added to a mixture of L (175 mg, 0.394 mmol) in MeOH (2.00 mL). The mixture was stirred at 23 °C for 24 h and diluted with DCM (20.0 mL) and sat. aq. NaHCOs (25.0 mL). The aqueous phase was extracted with DCM (3 x 20.0 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-30%) to provide 7 -hydroxy-2, 2-dimethyl-l,5,6,7,8,8a-hexahydroindolizin-3-one as a solid (LI, 43.0 mg, 57%).Scheme 18Synthesis of Intermediate LIV1,3,2-dioxathiolaneAmmonium formate 2,2-dioxide Pd(OH)2, EtOHLDA, THFStep 1 Lili Step 2 LIV

[0405] Step 1: A mixture of (8aS)-2-benzyl-l,3,4,7,8,8a-hexahydropyrrolo[l,2-a]pyrazin-6-one (405 mg, 1.49 mmol) in THF (5.00 mL) was added dropwise to freshly prepared LDA (1.0 M in THF, 3.29 mL, 3.29 mmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 h. A mixture of 1,3,2-dioxathiolane 2,2-dioxide (241 mg, 1.94 mmol) in THF (5.00 mL) was added dropwise at -78 °C and the mixture was stirred at -25 °C for 1 h. Another portion of LDA (1.0 M in THF, 1.64 mL, 1.64 mmol) was added dropwise at -78 °C. The mixture was stirred at -25 °C for 3 h diluted with sat. aq. NFLC1 (25.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated. The residue was purified by reverse phase chromatography (30 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (5-100%) to provide 7'aS)-6'-Benzyl-3'a,6'-diazahexahydro-3'H-spiro[cyclopropane-l,2'-inden]-3'-one as a solid (LIII, 125 mg, 31%).

[0406] Step 2: Ammonium formate (49.1 mg, 0.778 mmol) was added to a mixture of LIII (70.0 mg, 0.259 mmol) and Pd(OH)2 (20% on charcoal, 36.4 mg, 0.0519 mmol) in EtOH (1.50 mL). The mixture was stirred under nitrogen at 70 °C for 2 h, filtered through Celite, washed with MeOH (3 x 20.0 mL), and concentrated to provide (7'aS)-3'a,6'-Diazahexahydro-3'H-spiro[cyclopropane-l,2'-inden]-3'-one as a solid (LIV, 44.0 mg, 92%).Scheme 19Synthesis of intermediate LVIWSGR Docket No. 57050-708.601

[0407] Step 1: DIAD (86.7 pL, 0.440 mmol) was added to a mixture of LI (38.6 mg, 0.200 mmol), 4-nitrobenzoic acid (66.9 mg, 0.400 mmol) and PPhs (115 mg, 0.440 mmol) in THF (0.800 mL) at 0 °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 hexanes (0-100%) to provide (7R,8aS)-2,2-Dimethyl-3-oxooctahydro-7-indolizinyl p-nitrobenzoate as a solid (LV, 68.5 mg, 93%).

[0408] Step 2: LiOH monohydrate (13.8 mg, 0.330 mmol) was added to LV (68.5 mg, 0.165 mmol) in MeOH (1.00 mL) and water (0.800 mL) at 23 °C. The mixture was stirred at 23 °C for 18 h and diluted with 1 M aq. HC1 to pH = 4-5 and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-20%) to provide (7R,8aS)-7-Hydroxy-2,2-dimethylhexahydro-3(lH)-indolizinone as an oil (LVI, 47.0 mg, 60% pure, 99%).Scheme 20Synthesis of intermediate LVIIIZn, LiCI1,2-dibromoethaneBr-<. I| _ _ Br-Zn-v {S'"'2-Me-THF, 90 ’C, 16hLVIISteP1LVIII

[0409] Step l: 2-Bromo-4-methyl-thiazole (181 pL, 1.68 mmol) was added to a mixture of zinc (205 mg, 3.14 mmol), LiCI (133 mg, 3.14 mmol), 1,2-dibromoethane (7.38 pL, 0.0856 mmol) and 1,2-dibromoethane (7.38 pL, 0.0856 mmol) in 2-Me-THF (2.00 mL) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 16 h and the solution of Bromo-(4-methylthiazol-2-yl)zinc (LVIII) was used without isolation.Scheme 21Synthesis of Examples 1-24-(Aminomethyl)-N, N- dimethylbenzenesulfonarnideRS, X ' / _Ti J V-R’0K CO,I L-. 1,4-dioxaneClR‘Step 1VExamples1-2Synthesis of Example 1

[0410] 4-(Aminomethyl)-A, A-dimethylbenzenesulfonamide (CAS: 210918-25-5, 50.0 mg, 0.234 mmol) and K2CO3 (46.0 mg, 0.335 mmol) were added to a mixture of V p (45.0 mg, 0.167 mmol) in 1,4-dioxane (1.20 mL) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 18 h, fdtered, and theWSGR Docket No. 57050-708.601filtrate was evaporated. The residue was purified by preparative HPLC (Waters SunFire prep C-18 OBD, 5 um, 50 x 50 mm) with water [20 mM NH4HCO3] and MeCN (5-100%) to provide the title compound.Example 1 (15.0 mg, 20%).Synthesis of Example 2

[0411] 4-(Aminomethyl)- V,jV-dimethylbenzenesulfonamide (CAS: 210918-25-5, 39.8 mg, 0.190 mmol) and K2CO3 (36.7 mg, 0.270 mmol) was added to a mixture of V a (44.0 mg, 0.130 mmol) in 1,4-dioxane (0.940 m ) at 23 °C under nitrogen. The mixture was stirred at 110 °C for 16 h. After cooling to 23 °C, the mixture was filtered though Celite and washed with EtOAc (25.0 mL). The filtrate was washed with water (10.0 mb), dried (MgSO₄), filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Gemini Prep C18 5um, 50 x 50 mm, AXIA) with water [0.1% NH4OH] and MeCN (50-100%) to provide the title compound. Example 2 (41.0 mg, 61%).Scheme 22Synthesis of Examples 3-5NHPdCI2(PPh3)2, Na2CO3DMF1,4-dioxane, H2O O-S! -0 Step 1 Step 2O-S=oA vm Examples 3-4 Example 5

[0412] Step 1: Na2CO3 (2 eq.) and PdCl2(PPh3)2 (0.05 eq.) were added to a mixture of VIII (1 eq.) and the suitable boronic acid (6.3 eq.) in 1,4-dioxane (17 mL / g starting material) and water (5 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 18 h and filtered through Celite. The filtrate was concentrated and diluted with water. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine, water, dried (MgSO4), filtered, and concentrated.Synthesis of example 3

[0413] Step 1: The title compound was prepared as described in the Scheme above using VIII (150 mg, 0.28 mmol) and 3-cyanophenylboronic acid (CAS: 150255-96-2, 218 mg, 1.76 mmol) to afford 4-( { [7 -(3 -Cyanophenyl) -5 -phenyl-5H-pyrrolo [3,2-d]pyrimidin-4-yl] amino [ meth l )- '. '-di meth l bcnzcnc-1 -sulfonamide. The residue was purified by preparative HPLC (Phenomenex Gemini Prep C18 5 um, 50 x 50 mm, AXIA) with water [20 mM NH4HCO3] and MeCN (20-100%) to provide the title compound.Example 3 (22.1 mg, 15%).Synthesis of example 4WSGR Docket No. 57050-708.601

[0414] Step 1: The title compound was prepared as described in the Scheme above using VIII (80.0 mg, 0.150 mmol) and 4-cyanophenylboronic acid (CAS: 126747-14-6, 46.4 mg, 0.320 mmol) to afford 4-({[7-(4-Cyanophenyl)-5-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl] aminolmcthyl)- '. '-dimethylbenzene-l-sulfonamide. The residue was purified by preparative HPLC (Phenomenex Gemini Prep C18 5 um, 50 x 50 mm, AXIA) with water [20 mM NH4HCO3] and MeCN (20-100%) to provide the title compound. Example 4 (23.7 mg, 31%).Synthesis of example 5

[0415] Step 2: NaH (60% in oil; 3.10 mg, 0.0800 mmol) was added to a mixture of Example 3 (30.0 mg, 0.0600 mmol) in DMF (0.260 m ) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 30 min. Mel (10.0 mg, 1.20 mmol) was added. The mixture was stirred at 23 °C for 1 h and diluted with water (2.00 m ). The aqueous phase was extracted with EtOAc (2 x 1.00 mb), and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex Gemini Prep C18 5 um, 50 x 50 mm, AXIA) with water [20 mM NH4HCO31 and MeCN (40-100%) to provide the title compound. Example 5 (18.5 mg, 60%).Scheme 23Synthesis of Examples 6-7NaH, Alky! iodideDMFStep 1XII Examples 6-7

[0416] Step 1: NaH (60% in mineral oil, 1.3 eq.) was added to a mixture of XII (1 eq.) in DMF (10 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 30 min. The suitable alkyl iodide ( 1.2) was added, and the mixture was stirred at 23 °C for 1 h. The mixture was poured into water. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed with brine (3.00 mb), dried (MgSO4), filtered, and concentrated.Synthesis of Example 6

[0417] The title compound was prepared as described in the Scheme above using 2-Iodopropane (CAS: 75-30-9, 28.2 mg, 0.17 mmol) to afford 4-({[7-(3-Cyanophenyl)-5 -(propan-2 -yl)-5H-pyrrolo [3,2-d]pyrimidin-4-yl]oxy}methyl)-N, N-dimethylbenzene-l-sulfonamide. The residue was purified by preparative HPLC (Phenomenex Gemini Prep C18 5 um, 50 x 50 mm, AXIA) with water [20 mM NH4HCO3] and MeCN (20-100%) to provide the title compound. Example 6 (14.0 mg, 21%).Synthesis of Example 7

[0418] The title compound was prepared as described in the Scheme above using Mel (19.6 mg, 0.0140 mmol) to afford 4-({[7-(3-Cyanophenyl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl]oxy}WSGR Docket No. 57050-708.601mcthyl)-N. N-dimcthylbcnzcnc- 1 -sulfonamide. Purification by preparative HPLC. Example 7 (13.0 mg, 25%).Scheme 24Synthesis of Examples 8-32R3NHR4NaBH3CN, Sc(OTf)3R® X,AcOH, DM SOR®,>%. J J T 'y-R-®J T V- R10Step laR2OHO RSNHR4N XVI NaBH(OAc)3, Sc(OIf)3, AcOH Examplesmolecular sieves, DCM ’ 8-32Step lbStep la: NaBH3CN (0.64 eq.) was added to a mixture of the suitable intermediate XVI (1 eq.), the suitable amine (1.5 eq.) and Sc(OTf)s (0.25 eq.) in DMSO (20 mL / g starting material) and AcOH (1.7 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and concentrated.

[0419] Step lb: AcOH (3 eq.) was added to a mixture of the suitable Intermediate XVI (1 eq.), the suitable amine (2 eq.), Sc(OTf)3 (1.5 eq.) and 3Å molecular sieves in DCM (62.5 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min. NaBH(OAc)3 (1.5 eq.) was added. The mixture was stirred at 23 °C for 2 h and diluted with DCM and H2O. The aqueous phase was extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated. Synthesis of Example 8

[0420] Step lb: The title compound was prepared as described in the Scheme above using XVI l (74.0 mg, 0.220 mmol) and Ethyl- 1 -piperazinecarboxylate (54.2 mg, 0.34 mmol) to afford Ethyl-4-{[7-(3 -cyanophenyl) -5 -phenyl-5H-pyrrolo [3,2-d]pyrimidin-4-yl] methyl (piperazine- 1 -carboxylate.Purification by preparative HPLC (Phenomenex Gemini Prep C18 5 urn, 50 x 50 mm, AXIA) with water [20 mM NH4HCO3] and MeCN (5-95%) to provide the title compound. Example 8 (17.2 mg, 16%). Synthesis of Example 9

[0421] Step lb: The title compound was prepared as described in the Scheme above using XVI a (32.5 mg, 0.106 mmol) and XXXXI a (20.4 mg, 0.106 mmol) to afford 3-[4-[[(9aS)-7,7-dimethyl-6-oxo- 1,3,4, 8,9,9a-hexahydropyrido [ 1,2-a] pyrazin-2-yl]methyl] -5 -isopropyl -pyrrolo [3,2-d]pyrimidin-7 -yl] benzonitrile. Purification by silica gel chromatography (12 g cartridge) with hexanes and EtOAc (0- 100%), then by preparative HPLC (BEH, C18, 30 xl50 mm) with water [10 mM (NH4XHCO3)] and MeCN (50-60%) to provide the title compound. Example 9 (5.47 mg, 11%).Synthesis of Example 10

[0422] Step lb: The title compound was prepared as described in the Scheme above using XVI a (16.0 mg, 0.0524 mmol) and XXXXI b (20.1 mg, 0.105 mmol), to afford 3-[4-[[(9aR)-7,7-dimethyl-6-oxo-l,3,4,8,9,9a-hexahydropyrido[l,2-a] pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-WSGR Docket No. 57050-708.601yl] benzonitrile. Purification by reverse phase chromatography (Cl 8, 13 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (5-100%) and by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (48-58%) to provide the title compound. Example 10 (3.00 mg, 13%).Synthesis of Example 11

[0423] Step la: The title compound was prepared as described in the Scheme above using XVI a (40.0 mg, 0.138 mmol) and tert-butyl piperazine -1 -carboxylate (38.5 mg, 0.207 mmol), to afford tert-butyl-4-[[7-(3-cyanophenyl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]piperazine-l-carboxylate. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%), then by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (60-70%) to provide the title compound. Example 11 (13.5 mg, 21%).Synthesis of Example 12

[0424] Step la: The title compound was prepared as described in the Scheme above using XVI a (150 mg, 0.517 mmol) and XXXXI c (159 mg, 0.775 mmol) to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (44-54%) to provide the title compound. Example 12 (73.0 mg, 32%).Synthesis of Example 13

[0425] Step la: The title compound was prepared as described in the Scheme above using XVI a (50.0 mg, 0.172 mmol) and XXXXIV (49.8 mg, 0.207 mmol), to afford 3-[4-[[(3aS)-2,2-dimethyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-isothiazolo [2,3-a]pyrazin-5-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%), then by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (46-56%) to provide the title compound. Example 13 (21.2 mg, 26%).Synthesis of Example 14

[0426] Step la: The title compound was prepared as described in the Scheme above using XVI a (50.0 mg, 0.172 mmol) and XXXXVII b (56.5 mg, 0.258 mmol), to afford 3-[4-[[(3R,8aS)-3,7,7-trimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (53-63%) to provide the title compound. Example 14 (28.4 mg, 36%).Synthesis of Example 15

[0427] Step la: The title compound was prepared as described in the Scheme above using XVI a (40.0 mg, 0.138 mmol) and 2-methyl-l -piperazin- 1-yl-propan-l -one hydrochloride (39.8 mg, 0.207 mmol), to afford 3-[5-isopropyl-4-[[4-(2-methylpropanoyl)piperazin-l-yl]methyl]pyrrolo [3,2-d]pyrimidin-7-yl]benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 15 (25.8 mg, 42%). Synthesis of Example 16WSGR Docket No. 57050-708.601

[0428] Step la: The title compound was prepared as described in the Scheme above using XVI a (80.0 mg, 0.262 mmol) and LIV (51.7 mg, 0.295 mmol), to afford 3-[4-[[(8aS)-6-oxospiro[3,4,8,8a-tetrahydro- lH-pyrrolo[ 1,2-a]pyrazine-7, 1 '-cyclopropane] -2-yl]methyl] -5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 16 (44.8 mg, 39%). Synthesis of example 17

[0429] Step la: The title compound was prepared as described in the Scheme above using XVI b (45.5 mg, 0.148 mmol) and XXXXI c (45.3 mg, 0.221 mmol), to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]-2-fluoro -benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 17 (26.9 mg, 39%).Synthesis of example 18

[0430] The title compounds were prepared as described in the Scheme above using XVI k (62.7 mg, 0.205 mmol) and XXXXI c (62.8 mg, 0.307 mmol), to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 18 (41.6 mg, 44%).Synthesis of example 19

[0431] The title compounds were prepared as described in the Scheme above using XVI i (55.0 mg, 0.164 mmol) and XXXXI c (50.5 mg, 0.247 mmol), to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl]-5-(2-isopropoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (10-100%) to provide the title compound. Example 19 (39.2 mg, 49%).Synthesis of example 20

[0432] The title compounds were prepared as described in the Scheme above using XVI k (40.0 mg, 0.131 mmol) and XXXXIV (47.2 mg, 0.196 mmol), to afford 3-[4-[[(3aS)-2,2-dimethyl-l,l-dioxo-3a,4,6,7-tetrahydro-3H-isothiazolo[2,3-a]pyrazin-5-yl]methyl]-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and MeOH in EtOAc (0-100%) to provide the title compound.Example 20 (19.5 mg, 29%).Synthesis of example 21

[0433] The title compounds were prepared as described in the Scheme above using XVI a (150 mg, 0.517 mmol) and XXXXVII a (79% purity, 155 mg, 0.672 mmol), to afford 3-[4-[[(3S,8aS)-3,7,7-trimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by neutral alumina chromatography (40 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NEEXEICOs)] and MeCN (50-60%) to provide the title compound. Example 21 (101 mg, 43%).Synthesis of example 22WSGR Docket No. 57050-708.601

[0434] The title compounds were prepared as described in the Scheme above using XVI j (63.0 mg, 70% purity, 0.136 mmol) and XXXXI c (41.8 mg, 0.204 mmol), to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl]-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]-4-fluoro-benzonitrile. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-100%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (38-48%) to provide the title compound. Example 22 (34.8 mg, 54%).Synthesis of example 23

[0435] The title compounds were prepared as described in the Scheme above using XVI k (37.0 mg, 0.121 mmol) and XXXXVII a (31.7 mg, 0.145 mmol), to afford 3-[4-[[(3S,8aS)-3,7,7-trimethyl-6-oxo-3,4,8, 8a-tetrahydro- IH-pyrrolo [ 1,2-a]pyrazin-2-yl]methyl] -5 -(2-methoxyethyl)pyrrolo [3,2-d]pyrimidin-7-yl] benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 23 (35.0 mg, 61%).Synthesis of example 24

[0436] The title compounds were prepared as described in the Scheme above using XVI c (43.3 mg, 0.149 mmol) and XXXXI c (45.8 mg, 0.224 mmol), to afford 4-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl] -5 -isopropyl -pyrrolo [3, 2-d]pyrimidin-7-yl] benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 24 (32.3 mg, 48%).Synthesis of example 25

[0437] The title compounds were prepared as described in the Scheme above using XVI e (79% purity, 70.0 mg, 0.180 mmol) and XXXXI c (55.3 mg, 0.270 mmol), to afford 5-[4-[[(8aS)-7,7-dimethyl- 6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin- 7-yl] -2 -fluoro-benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeOH (58-68%) to provide the title compound. Example 25 (6.05 mg, 7%).Synthesis of example 26

[0438] The title compounds were prepared as described in the Scheme above using XVI d (55.8 mg, 0.181 mmol) and XXXXI c (55.6 mg, 0.271 mmol) to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl] -5 -isopropyl -pyrrolo [3, 2-d]pyrimidin-7-yl] -4-fluoro-benzonitrile. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 26 (39.8 mg, 47%).Synthesis of example 27

[0439] The title compounds were prepared as described in the Scheme above using XVI f (48.7 mg, 0.166 mmol) and XXXXI c (37.3 mg, 0.182 mmol) to afford (8aS)-2-[[5-isopropyl-7-(p-tolyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc inWSGR Docket No. 57050-708.601hexanes (0-100%) and by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NEEXHCOs)] and MeCN (53-63%) to provide the title compound. Example 27 (21.6 mg, 30%).Synthesis of example 28

[0440] The title compounds were prepared as described in the Scheme above using XVI g (36.8 mg, 0.125 mmol) and XXXXI c (28.2 mg, 0.138 mmol) to afford (8aS)-2-[[5-isopropyl-7-(o-tolyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in DCM (0-100%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (42-52%) to provide the title compound. Example 28 (18.3 mg, 33%).Synthesis of example 29

[0441] The title compounds were prepared as described in the Scheme above using XVI h (79% purity, 70.0 mg, 0.180 mmol) and XXXXI c (55.3 mg, 0.270 mmol) to afford 3-[4-[[(8aS)-7,7-dimethyl- 6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a] pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin- 7-yl] -5 -fluoro-benzonitrile. Purification by neutral alumina chromatography (48 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (51-61%) to provide the title compound. Example 29 (37.0 mg, 45%).Synthesis of examples 30-31

[0442] The title compounds were prepared as described in the Scheme above using XVI m (127 mg, 0.396 mmol) and XXXXI c (122 mg, 0.595 mmol) to afford 3-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-(2-methoxypropyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by neutral alumina chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-5%), and by ACCQ eluting with water [10 mM (NH4XHCO3)] and MeCN (45-55%) to provide a mixture of both isomers of the title compound as a solid (37.7 mg, 20%). The isomers were separated by chiral SFC (ChiralPak ID 5to60 IPA lOmM AmFor 2 min) to provide both isomers of the title compound. Isomer 1 (Example 30, 13.0 mg). SFC (ChiralPak ID 5to60 IPA lOmM AmFor 2 min) tR = 5.57 min. Isomer 2 (Example 31, 16.2 mg, 43%). Stereochemistry was arbitrarily assigned.Synthesis of Example 32

[0443] The title compounds were prepared as described in the Scheme above using XVI n (80.6 mg, 0.210 mmol) and XXXXI c (47.2 mg, 0.231 mmol), to afford 3-[7-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro- lH-pyrrolo[ 1,2-a]pyrazin-2-yl]methyl] - 1 -isopropyl -pyrrolo [2,3 -c]pyridin-3 -yl] -4-fluoro-benzonitrile. Purification by silica gel chromatography (12 g gold cartridge) using a gradient of EtOAc in DCM (0-100%), by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (50-60%), by neutral alumina chromatography (24 g cartridge) using a gradient of EtOAc in hexanes (0-100%) and by ACCQ eluting with water [10 mM (NH4XHCO3)] and MeCN (47-67%) to provide the title compound. Example 32 (10.7 mg, 11%).Scheme 25Synthesis of Example 33WSGR Docket No. 57050-708.601Vk Example33

[0444] Step 1: XXXXI c (41.3 mg, 0.198 mmol) was added to a mixture of V k (53.5 mg, 0.165 mmol) and NEt3(0.0688 mL, 0.494 mmol) in MeCN (1.00 mL) at 23 °C under nitrogen. The mixture was refluxed for 1 week, concentrated and diluted with water (20.0 mL) and EtOAc (25.0 mL). The aqueous phase was extracted with EtOAc (3 x 20.0 mL), and the combined organic extracts were washed with brine (60.0 mL), dried (Na₂SO₄), filtered, and concentrated. The residue was purified by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (50-60%) to provide the title compound. Example 33 (33.6 mg, 46%).Scheme 26Synthesis of Examples 34-39J""kr u VY TVRW NaBH3CN, Ti(OtPr)4XEton / -AAstep lO O:'-Y;XX Examples' \ 34-39

[0445] Step 1: Ti(OiPr)4 (15 eq.) was added to a mixture of the suitable intermediate XX (1 eq.) and XXXXI c (2 eq.) in EtOH (31 mL / g starting material) at 23 °C. The mixture was stirred at 90 °C for 3 h, cooled to 23 °C and NaBH3CN (1.5 eq.) was added. The mixture was stirred at 90 °C for 3 h, fdtered and concentrated.Synthesis of Examples 34 and 35

[0446] The title compounds were prepared as described in the Scheme above using XX c (100 mg, 0.329 mmol), to afford 3-[4-[l-[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]ethyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc / EtOH (3: 1) in hexanes (0-100%), and by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeOH (63-73%) to provide both isomers of the title compound. Isomer 1 (Example 34): (16.4 mg, 11%). Isomer 2 (Example 35): (17.3 mg, 12%). Stereochemistry was arbitrarily assigned.Synthesis of Examples 36 and 37WSGR Docket No. 57050-708.601

[0447] The title compounds were prepared as described in the Scheme above using XX a (65.0 mg, 0.187 mmol), to afford 3-[4-[l-[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]ethyl]-5-(2-isopropoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl] benzonitrile. Purification by reverse phase chromatography (C18, 12 g cartridge) with water [10 mM (NH4)(HCO2)] and MeCN (10-100%) and by preparative HPLC (BEH Phenyl, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeOH (65-75%) to provide both isomers of the title compound. Isomer 1 (Example 36): (7.7 mg, 8%). Isomer 2 (Example 37): (8.8 mg, 9%). Stereochemistry was arbitrarily assigned.Synthesis of Examples 38 and 39

[0448] The title compounds were prepared as described in the Scheme above using XX b (171 mg, 0.480 mmol), to afford 3-[4-[l-[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]ethyl]-5-(2-methoxyethyl)pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by silica gel chromatography (12 g cartridge) using a gradient of EtOAc in hexanes (0-100%), and by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (43-53%) to provide both diastereomers of the title compound: Isomer 1: (Example 38, 27.7 mg, 12%). Isomer 2: (Example 39, 31.9 mg, 14%). Stereochemistry was arbitrarily assigned.Scheme 27Synthesis of Example 40Synthesis of Example 40

[0449] NatBuO (70.0 mg, 0.728 mmol) was added to a mixture of XVII b (85.0 mg, 0.280 mmol) and XXXXI d (76.0 mg, 0.364 mmol) in THF (1.00 mb) at 23 °C under nitrogen. The mixture was stirred at 80 °C for 18 h and diluted with DCM (50.0 mL) and water (20.0 mb). The aqueous phase was extracted with DCM (3 x 20.0 mb), and the combined organic extracts were washed with brine (60.0 mb), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (12 g cartridge) using a gradient of MeOH in DCM (0-30%) and by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (41-51%) to provide the title compound. Example 40 (48.1 mg, 38%).Scheme 28Synthesis of Examples 41-43WSGR Docket No. 57050-708.601

[0450] Step 1: 2-Methylpropanoyl 2-methylpropanoate (50.6 pL, 0.449 mmol) was added to a mixture of the suitable intermediate XXII (43.7 mg, 0.0977 mmol), DIEA (83.6 pL, 0.488 mmol) and DMAP (2.98 mg, 0.0244 mmol) in 1,4-dioxane (3.00 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and concentrated.Synthesis of Example 41

[0451] The title compounds were prepared as described in the Scheme above using XXII a (43.7 mg, 0.0977 mmol), to afford 3-[4-[[(2R,5S)-2,5-dimethyl-4-(2-methylpropanoyl)piperazin-l-yl] methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%) to provide the title compound. Example 41 (34 mg, 73%).Synthesis of Example 42

[0452] The title compounds were prepared as described in the Scheme above using XXII b (32.4 mg, 0.0724 mmol), to afford 3-[4-[[(2S,5R)-2,5-dimethyl-4-(2-methylpropanoyl)piperazin-l-yl] methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%) to provide the title compound. Example 42 (26.9 mg, 79%).Synthesis of Example 43

[0453] The title compounds were prepared as described in the Scheme above using XXII c (25.0 mg, 0.0611 mmol) to afford 3-[4-[[(3R,5S)-3,5-dimethyl-4-(2-methylpropanoyl)piperazin-l-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzonitrile. Purification by reverse phase chromatography (Cl 8, 12 g cartridge) with water [10 mM (NH4XHCO3)] and MeCN (5-80%), then by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (56-66%) to provide the title compound. Example 43 (11.3 mg, 39%).Scheme 29Synthesis of Example 44WSGR Docket No. 57050-708.601trideuteriomethyl boronic acid XXXXIc Pd(dppf)Cl₂·DCM NaBD₃CN, Sc(OTf)₃ NEt₃, DMSO 1,4-dioxane Step 1 Step 2 Step 3 V d XXIV XXV Example44

[0454] Step 1: V d (0.980 M in 1,4-dioxane, 4.00 mL, 3.92 mmol) was added over a period of 5 h to a mixture of trideuteriomethylboronic acid (0.184 mL, 3.92 mmol), Pd(dppf)Cl₂·DCM (41.3 mg, 0.0505 mmol) and K3PO4 (386 mg, 1.82 mmol) in 1,4-dioxane (1.00 mL) at 60 °C under nitrogen. The mixture was stirred at 60 °C for 1 h after addition was completed. The mixture was diluted with water (10.0 mL) and DCM (25.0 mL). The aqueous phase was extracted with DCM (2 x 25.0 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 MeOH in DCM (0-5%) to provide the title compound as a solid (XXIV, 86.0 mg, 6%).

[0455] Step 2: 1,4-Dioxane (0.500 mL) was added to a mixture of XXIV (72% purity, 85.0 mg, 0.218 mmol) and SeO₂ (30.3 mg, 0.273 mmol) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 2 h and concentrated to provide the title compound as a solid (XXV, 88.6 mg). It was used as such for the next step without purification.

[0456] Step 3: NaBD3CN (21.6 mg, 0.327 mmol) was added to a mixture of XXV (72% purity, 88.6 mg, 0.218 mmol), XXXXI c (90.0 mg, 0.440 mmol), Sc(OTf)3(26.9 mg, 0.0546 mmol) and NEt3(30.4 pL, 0.218 mmol) in deuterated DMSO (0.500 mL) at 23 °C under nitrogen. The mixture was stirred at 23 °C for 15 min and deuterated acetic acid (132 pL, 2.18 mmol) was added at 23 °C under nitrogen. The mixture was stirred at 23 °C for 1 h and diluted with sat. aq. NaHCOs (5.00 mL) and DCM (10.0 mL). The aqueous phase was extracted with DCM (2 x 25.0 mL), and the combined organic extracts were washed with brine (10.0 mL), dried (MgSO₄), filtered, and concentrated. The residue was purified by neutral alumina chromatography (48 g cartridge) using a gradient of EtOAc in hexanes (0-100%) to provide the title compound. Example 44 (11 mg, 11%).Scheme 30Synthesis of Examples 45-93 and Intermediate LIXWSGR Docket No. 57050-708.601boronic acid, K3PO4Pd(dppf)Cl₂·DCM1,4-dioxaneStep laboronic acid, CsFRuPhos, Pd2(dba)31,4-dioxaneStep lbXXVH Examples 45-93Bromo-zinc reagent Intermediate LIXorboronic acidXPhos Pd G32-Me-THFStep 1c

[0457] Step la: 1,4 -dioxane (10 mL / g starting material) and H2O (9 eq.) were added to a mixture of the suitable intermediate XXVII (1 eq.), the suitable boronic acid (1.5 eq.), Pd(dppf)C12-DCM (0.25 eq.) and K3PO4 (2.5 eq.) at 23 °C under nitrogen. The mixture was stirred at 100 °C for 16 h and diluted with water and DCM. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (MgSO₄), filtered, and concentrated.

[0458] Step lb: H2O (1.2 mL / g starting material) was added to a mixture of the suitable intermediate XXVII (1 eq.), the suitable boronic acid (2 eq.), RuPhos (0.1 eq.), Pd2(dba)s (0.025 eq.), CsF (3 eq.) in 1,4-dioxane (12 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 90 °C for 16 h and diluted with 2 M aq. K2CO3. The aqueous phase was extracted with DCM, and the combined organic extracts were dried (Na₂SO₄), filtered, and concentrated.

[0459] Step 1c: The suitable boronic acid or Bromo-zinc reagent ( 1.1 eq.) was added to a mixture of XXVII b (1 eq.) and XPhos Pd G3 (0.07 eq.) in 2-Me-THF (0.7 mL / g starting material) at 23 °C under nitrogen. The mixture was stirred at 45 °C for 2 h and diluted with MeOH and MeCN. The mixture was concentrated and diluted with MeCN. The mixture was filtered through Celite, washed with MeCN, and the filtrate was concentrated.

[0460] Synthesis of Intermediate LIX: The title compounds were prepared as described in the Scheme above via step lb, using XXVII a [2-fluoro-5-(hydroxymethyl)phenyl]boronic acid (CAS: 1072952-25-0, 36.4 mg, 0.214 mmol), to afford (8aS)-2-[[7-[2-fluoro-5-(hydroxymethyl)phenyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (12 g gold cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound. LIX (40.5 mg, 81%).Synthesis of Example 45WSGR Docket No. 57050-708.601

[0461] The title compounds were prepared as described in the Scheme above via step la, using XXVII a (88% purity, 80.0 mg, 0.151 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (CAS: 660867-80-1, 49.5 mg, 0.226 mmol), to afford (8aS)-2-[[5-isopropyl-7-(2-methyl-4-pyridyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (24 g cartridge) using a gradient of MeOH in DCM (3-9%) and by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (20-30%) to provide the title compound. Example 45 (11.3 mg, 17%).Synthesis of Example 46

[0462] The title compounds were prepared as described in the Scheme above via step la, using 3-pyridylboronic acid (CAS: 1692-25-7, 27.8 mg, 0.226 mmol), to afford (8aS)-2-[[5-isopropyl-7-(4-methylthiazol-2-yl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NELXHCOs)] and MeCN (32-42%) to provide the title compound. Example 46 (35.6 mg, 57%).Synthesis of Example 47

[0463] The title compounds were prepared as described in the Scheme above via step lb, using XXVII a (43.0 mg, 0.0920 mmol) and (4-cyano-2-fluoro-phenyl)boronic acid (CAS: 1150114-77-4, 30.3 mg, 0.184 mmol), to afford 4-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl] -5 -isopropyl -pyrrolo[3,2-d]pyrimidin-7 -yl] -3 -fluoro-benzonitrile. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (45-55%) to provide the title compound. Example 47 (16.0 mg, 38%).

[0464] Synthesis of Example 48: The title compounds were prepared as described in the Scheme above via step lb, using XXVII a (43.0 mg, 0.0920 mmol) and (3-methoxyphenyl)boronic acid (CAS:10365-98-7, 28.0 mg, 0.184 mmol), to afford (8aS)-2-[[5-isopropyl-7-(3-methoxyphenyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (43-53%) to provide the title compound. Example 48 (15.5 mg, 38%).

[0465] Synthesis of Example 49: The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (CAS: 1036990-42-7, 50.2 mg, 0.184 mmol), to afford (8aS)-2-[[5-isopropyl-7-[2-(trifluoromethyl)-4-pyridyl]pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (52-62%) to provide the title compound. Example 49 (21.1 mg, 47%).Synthesis of Example 50

[0466] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and (4-chloro-3-cyano-phenyl)boronic acid (CAS: 871332-95-5, 33.4 mg, 0.184 mmol) to afford 5-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-WSGR Docket No. 57050-708.601yl]methyl] -5 -isopropyl -pyrrolo [3,2-d]pyrimidin-7 -yl] -2 -chloro-benzonitrile. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH₄)(HCO₃)] and MeCN (50-60%) to provide the title compound. Example 50 (4.80 mg, 11%).Synthesis of Example 51

[0467] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (20.0 mg, 0.0428 mmol) and (3,5-dicyanophenyl)boronic acid (CAS: 1212021-54-9, 14.7 mg, 0.0856 mmol), to afford 5-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-7-yl]benzene-l,3-dicarbonitrile. Purification by preparative HPLC (BEH, C18, 30x100 mm) with water [10 mM (NH4XHCO3)] and MeCN (45-55%) to provide the title compound. Example 51 (8.50 mg, 43%).Synthesis of Example 52

[0468] The title compounds were prepared as described in the Scheme above via step lb using XXVII b (88.2 mg, 0.210 mmol) and phenylboronic acid (CAS: 98-80-6, 38.4 mg, 0.315 mmol) to afford (8aS)-2-[(5-isopropyl-7-phenyl-pyrrolo[3,2-d]pyrimidin-4-yl)methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo [l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (48-58%) to provide the title compound. Example 52 (56.4 mg, 64%).Synthesis of Example 53

[0469] The title compounds were prepared as described in the Scheme above via step 1c using XXVII b (70.0 mg, 0.167 mmol) and freshly prepared chloro-(4-methyl-2-pyridyl)zinc (419 mM in Et2O: THF; 1: 1.4, 795 pL, 0.333 mmol) to afford (8aS)-2-[[5-isopropyl-7-(4-methyl-2-pyridyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (39-49%) to provide the title compound. Example 53 (7.00 mg, 10%).Synthesis of Example 54

[0470] The title compounds were prepared as described in the Scheme above via step lb using XXVII b (88.2 mg, 0.210 mmol) and [3-(difluoromethyl)phenyl]boronic acid (CAS: 854690-87-2, 54.1 mg, 0.315 mmol), to afford (8aS)-2-[[7-[3-(difluoromethyl)phenyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4)(HCO2)] and MeCN (49-59%) to provide the title compound. Example 54 (17.0 mg, 17%).Synthesis of Example 55

[0471] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (CAS: 1193104-53-8, 54.6 mg, 0.214 mmol), to afford (8aS)-2-[[7-[2-(difluoromethyl)-4-pyridyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (40-50%) to provide the title compound. Example 55 (29.6 mg, 59%).Synthesis of Example 56WSGR Docket No. 57050-708.601

[0472] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and (4-fluorophenyl)boronic acid (CAS: 1765-93-1, 29.9 mg, 0.214 mmol), to afford (8aS)-2-[ [7 -(4-fluorophenyl)-5 -isopropyl -pyrrolo [3,2-d]pyrimidin-4-yl]methyl] -7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (49-59%) to provide the title compound.Example 56 (27.4 mg, 59%).Synthesis of Example 57

[0473] The title compounds were prepared as described in the Scheme above via step la using XXVII a (88% purity, 55.0 mg, 0.104 mmol) and [3-(trifluoromethyl)phenyl]boronic acid (CAS: 1423-26-3, 29.5 mg, 0.155 mmol), to afford (8aS)-2-[[5-isopropyl-7-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-d] pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (59-69%) to provide the title compound. Example 57 (24.0 mg, 48%).Synthesis of Example 58

[0474] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and (3-methylsulfonylphenyl)boronic acid (CAS: 373384-18-0, 36.8 mg, 0.184 mmol) to afford (8aS)-2-[[5-isopropyl-7-(3-methylsulfonylphenyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (41-51%) to provide the title compound. Example 58 (20.7 mg, 45%).Synthesis of Example 59

[0475] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and (3-cyano-4-methoxy-phenyl)boronic acid (CAS: 911210-48-5, 36.6 mg, 0.184 mmol) to afford 5-[4-[[(8aS)-7,7-dimethyl-6-oxo-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-2-yl]methyl] -5 -isopropyl -pyrrolo [3,2-d]pyrimidin-7 -yl] -2 -methoxy-benzonitrile. Purification by preparative HPLC (BEH, C18, 30 x 150 mm) with water [10 mM (NH4XHCO3)] and MeCN (50-60%) to provide the title compound. Example 59 (14.5 mg, 33%).Synthesis of Example 60

[0476] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (40.0 mg, 0.0856 mmol) and m-tolylboronic acid (CAS: 17933-03-8, 23.3 mg, 0.171 mmol), to afford (8aS)-2-[[5-isopropyl-7-(m-tolyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (47-57%) to provide the title compound. Example 60 (6.20 mg, 7%).Synthesis of Example 61

[0477] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (CAS: 179113-90-7, 37.9 mg, 0.184 mmol), to afford (8aS)-2-[[5-isopropyl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparativeWSGR Docket No. 57050-708.601HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (53-63%) to provide the title compound. Example 61 (17.0 mg, 37%).Synthesis of Example 62

[0478] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (43.0 mg, 0.0920 mmol) and 4-pyridylboronic acid (CAS: 1692-15-5, 22.6 mg, 0.184 mmol), to afford (8aS)-2-[[5-isopropyl-7-(4-pyridyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro- lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 100 mm) with water [10 mM (NH4XHCO3)] and MeCN (30-40%) to provide the title compound. Example 62 (12.2 mg, 36%).Synthesis of Example 63

[0479] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (65.0 mg, 0.139 mmol) and (2,4-difluorophenyl)boronic acid (CAS: 144025-03-6, 43.9 mg, 0.278 mmol), to afford (8aS)-2-[[7-(2,4-difluorophenyl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (12 g gold cartridge) using a gradient of MeOH in DCM (0-5%) and by ACCQ eluting with water [10 mM (NH4XHCO3)] and MeCN (53-63%) to provide the title compound. Example 63 (49.4 mg, 78%).Synthesis of Example 64

[0480] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (150 mg, 0.321 mmol) and (2-fluoro-5-hydroxy-phenyl)boronic acid (CAS: 1150114-52-5, 100 mg, 0.642 mmol), to afford (8aS)-2-[[7-(2-fluoro-5-hydroxy-phenyl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by silica gel chromatography (12 g gold cartridge) using a gradient of MeOH in DCM (0-5%) to provide the title compound. Example 64 (110 mg, 72%).Synthesis of Example 65

[0481] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) 2-[4-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (CAS: 2410032-62-9, 58.2 mg, 0.214 mmol), to afford (8aS)-2-[[7-[4-(difluoromethyl)-2-fluoro-phenyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (49-59%) to provide the title compound. Example 65 (30.0 mg, 58%).Synthesis of Example 66

[0482] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and (2-methoxy-4-pyridyl)boronic acid (CAS: 762262-09-9, 32.7 mg, 0.214 mmol) to afford (8aS)-2-[[5-isopropyl-7-(2-methoxy-4-pyridyl)pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (35-45%) to provide the title compound. Example 66 (22.5 mg, 47%).Synthesis of Example 67WSGR Docket No. 57050-708.601

[0483] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and 2-[5-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS: 1142228-23-6, 58.2 mg, 0.214 mmol), to afford (8aS)-2-[[7-[5-(difluoromethyl)-2-fluoro-phenyl]-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-1H-pyrrolo[1,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH₄)(HCO₃)] and MeCN (52-62%) to provide the title compound. Example 67 (24.1 mg, 46%).Synthesis of Example 68

[0484] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and (3-chlorophenyl)boronic acid (CAS: 63503-60-6, 33.5 mg, 0.214 mmol), to afford (8aS)-2-[[7-(3-chlorophenyl)-5-isopropyl-pyrrolo[3,2-d]pyrimidin-4-yl]methyl]-7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (51-61%) to provide the title compound.Example 68 (26.7 mg, 55%).Synthesis of Example 69

[0485] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and (3-cyclopropylphenyl)boronic acid (CAS: 1049730-10-0, 34.7 mg, 0.214 mmol) to afford (8aS)-2-[ [7 -(3 -cyclopropylphenyl) -5 -isopropyl -pyrrolo[3,2-d]pyrimidin-4-yl]methyl] -7,7-dimethyl-3,4,8,8a-tetrahydro-lH-pyrrolo[l,2-a]pyrazin-6-one. Purification by preparative HPLC (BEH, C18, 30 x 250 mm) with water [10 mM (NH4XHCO3)] and MeCN (52-62%) to provide the title compound. Example 69 (10.7 mg, 22%).Synthesis of Example 70

[0486] The title compounds were prepared as described in the Scheme above via step lb using XXVII a (50.0 mg, 0.107 mmol) and [3-(difluoromethoxy)phenyl]boronic acid (CAS: 866607-09-2, 40.2 mg, 0.214 mmol), to afford (8aS)-2-[[7-[3-(dif...

Claims

WSGR Docket No. 57050-708.601CLAIMS 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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 C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R2is C1-C6alkyl 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. 57050-708.601each 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)-, or -CH2CH2-;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C6alkyl, 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, C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independentlyWSGR Docket No. 57050-708.601optionally 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, C1-C6alkyl, 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 C1-C3alkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHC1-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, -OC1-C3alkyl, -S(=O)C1-C3alkyl, -S(=O)2C1-C3alkyl, - S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(C1-C3alkyl)2, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)C1-C3alkyl, -C(=O)OH, -C(=O)OC1-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHC1-C3alkyl, C1-C3alkyl, or C1-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;provided that the compound is not:Cl2. 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 C1-C6alkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen.WSGR Docket No. 57050-708.6015. 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 CRY7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen, halogen, or C1-C6alkyl.

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 C1-C6alkyl.

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 C1-C6alkyl.

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 C1-C6alkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, orWSGR Docket No. 57050-708.601stereoisomer thereof, wherein:R12is -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, or C1-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 C1-C6alkyl.

20. 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 any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (I) is of Formula (la):WSGR Docket No. 57050-708.601Formula (la);wherein:each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C6alkyl; 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, orWSGR Docket No. 57050-708.601stereoisomer thereof, wherein:each R14is independently C1-C6alkyl 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, or stereoisomer 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, orWSGR Docket No. 57050-708.601stereoisomer thereof, wherein:

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

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

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

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R11is independently halogen, -CN, C1-C6alkyl, C2-Cealkenyl, or C2-Cealkynyl.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R11is independently C1-C6alkyl.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:q is 0, 1, or 2.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:q is 0 or 1.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z1is -CH2- or -CH(CH3)-.

48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z1is -CH2-.WSGR Docket No. 57050-708.60149. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is C1-C6alkyl independently optionally substituted with one or more R3.

50. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is C1-C6alkyl.

51. The compound of any one of claims 1-49, 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”.

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

53. 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.

54. The compound of any one of claims 1-48, 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”.

55. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

56. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is heterocycloalkyl or aryl.

57. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

58. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-708.601O —, or N.

59. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

60. The compound of any one of claims 1-48, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is.

61. The compound of any one of claims 1 -60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl or heteroaryl.

62. The compound of any one of claims 1-61, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.

63. The compound of any one of claims 1 -62, 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.

64. The compound of any one of claims 1-62, 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.

65. The compound of any one of claims 1 -62, 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.

66. The compound of any one of claims 1-65, 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, C1-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, andWSGR Docket No. 57050-708.601heteroaryl is independently optionally substituted with one or more R”.

67. The compound of any one of claims 1-66, 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”.

68. The compound of any one of claims 1-67, 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’.

69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen or -CN.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0, 1, or 2.

71. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1 or 2.

72. The compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

73. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-708.601F74. The compound of any one of claims 1-60 or 73, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

75. The compound of any one of claims 1-60 or 73 or 74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-708.60176. The compound of any one of claims 1-60 or 73-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

77. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WH AR® 7 ' — •Y X / R1°R7O 72 R\ ii / 2 / N-S II— ( V C J )R8O(R6)PFormula (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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R9is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;R10is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl independently optionally substituted with one or more R’;W is absent or -C(=O)-;R2is C1-C6alkyl independently optionally substituted with one or more R3;WSGR Docket No. 57050-708.601or 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 C1-C6alkyl independently optionally substituted with one or more R’;each R5is independently hydrogen or C1-C6alkyl 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, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, -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 hydrogen, C1-C6alkyl, 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, C1-C6alkyl, 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 C1-C6alkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionallyWSGR Docket No. 57050-708.601substituted 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, C1-C6alkyl, 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, C1-C6alkyl, 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)C1-C3alkyl, - S(=O)2Ci-C3alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-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)2NHC1-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi- C3alkyl, -N(C1-C3alkyl)2, -NHC(=O)OC1-C3alkyl, -C(=O)C1-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.

78. The compound of claim 77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is CRX.

79. The compound of claim 77 or 78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen, halogen, or C1-C6alkyl.

80. The compound of any one of claims 77-79, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Rxis hydrogen.

81. The compound of claim 77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X is N.

82. The compound of any one of claims 77-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:WSGR Docket No. 57050-708.601Y is CRY83. The compound of any one of claims 77-82, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen, halogen, or C1-C6alkyl.

84. The compound of any one of claims 77-83, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:RYis hydrogen.

85. The compound of any one of claims 77-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

86. The compound of any one of claims 77-85, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is absent.

87. The compound of any one of claims 77-85, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -C(=O)-.

88. The compound of any one of claims 77-87, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen, halogen, or C1-C6alkyl.

89. The compound of any one of claims 77-88, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.

90. The compound of any one of claims 77-89, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen, halogen, or C1-C6alkyl.

91. The compound of any one of claims 77-90, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R10is hydrogen.

92. The compound of claim 77, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (II) is of Formula (Ila):Formula (Ila).WSGR Docket No. 57050-708.60193. The compound of any one of claims 77-92, 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.

94. The compound of any one of claims 77-93, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Z2is -C(R5)2C(R5)2-, *-C(R5)2NR4-, *-NR4C(R5)2-, *-C(R5)2O-, or *-OC(R5)2-; wherein * is the attachment point to Ring C.

95. The compound of any one of claims 77-94, 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.

96. The compound of any one of claims 77-95, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen or C1-C6alkyl.

97. The compound of any one of claims 77-96, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen.

98. The compound of any one of claims 77-97, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R5is independently hydrogen.

99. The compound of any one of claims 77-98, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring C is aryl or heteroaryl.

100. The compound of any one of claims 77-99, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring C is phenyl.

101. The compound of any one of claims 77-100, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R6is independently halogen, -CN, -OH, -ORa, -NRcRd, or C1-C6alkyl.

102. The compound of any one of claims 77-101, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R6is independently halogen or C1-C6alkyl.

103. The compound of any one of claims 77-102, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:p is 0 or 1.

104. The compound of any one of claims 77-103, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:p is 0.WSGR Docket No. 57050-708.601105. The compound of any one of claims 77-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7is hydrogen or C1-C6alkyl.

106. The compound of any one of claims 77-105, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7is C1-C6alkyl.

107. The compound of any one of claims 77-106, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R8is hydrogen or C1-C6alkyl.

108. The compound of any one of claims 77-107, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R8is C1-C6alkyl.

109. The compound of any one of claims 77-104, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R7and R8are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”.

110. The compound of any one of claims 77-109, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is C1-C6alkyl independently optionally substituted with one or more R3.

111. The compound of any one of claims 77-110, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is C1-C6alkyl.

112. The compound of any one of claims 77-111, 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”.

113. The compound of any one of claims 77-112, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

114. The compound of any one of claims 77-113, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is aryl, or heteroaryl.

115. The compound of any one of claims 77-114, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl or heteroaryl.

116. The compound of any one of claims 77-115, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.WSGR Docket No. 57050-708.601117. The compound of any one of claims 77-116, 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, C1-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”.

118. The compound of any one of claims 77-117, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently halogen or -CN.

119. The compound of any one of claims 77-118, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R1is independently -CN.

120. The compound of any one of claims 77-119, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0, 1, or 2.

121. The compound of any one of claims 77-120, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 1 or 2.

122. The compound of any one of claims 77-120, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

123. A compound, selected from a compound found in the specification and in Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

124. A pharmaceutical composition comprising a compound of any one of claims 1-123, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

125. 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 1-123, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

126. The method of claim 125, 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.

127. The method of claim 125, wherein the TRPML1 -mediated disorder or disease is Aicardi- Goutieres syndrome, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ataxia-WSGR Docket No. 57050-708.601telangiectasia, 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.

128. The method of claim 125, 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, pancreatitis, retinal detachment, type 2 diabetes mellitus, ulcerative colitis, or sarcopenia.

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