HTT modulators for treating Huntington's disease

Abstract

Provided herein are certain compounds useful as HTT modulators. Such compound are useful in the treatment of Huntington's disease.

Description

HTT MODULATORS FOR TREATING HUNTINGTON'S DISEASE CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of United States Provisional Application No. 63 / 024,052 filed May 13, 2020, which is hereby incorporated by reference in its entirety. FIELD The present disclosure relates to methods of preventing and / or treating a neurodegenerative disease or condition. BACKGROUND Huntington's disease (HD) is a dominant inherited progressive neurodegenerative disorder, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. HD has a prevalence of 5-10 cases per 100,000 worldwide, which makes it the most common inherited monogenetic neurodegenerative disease. Neurodegenerative diseases and conditions, such as Huntington's disease, have a profound negative impact on the lives of those effected. Current treatments for Huntington's disease are palliative, aimed at lessening the severity of symptoms. There is no disease modifying treatment available. Huntington's disease is caused by the expansion of a CAG repeat domain in Exon 1 of the huntingtin gene (HTT), which is expressed as mutant huntingtin protein (mHTT), containing an expanded polyglutamine tract in the amino terminal domain of the protein. The molecular route of pathogenesis is not entirely understood even though HD is monogenic and autosomal dominant. Therefore, mHTT lowering is a clear therapeutic strategy targeting the gene products of the causative gene. In fact, several therapeutic strategies targeting mHTT lowering via antisense oligionucleotide (ASO) or AAV-miR mediated HTT RNA degradation are advancing through clinical trials in HD and have demonstrated lowering of mHTT levels in the CSF of treated patients. ‘While these modalities show great promise, they are invasive (involving repeated intrathecal injections); their distribution throughout the brain to all affected regions is not certain; and they do not address any peripheral dysfunction the ubiquitously distributed mHTT may be responsible for. Therefore small molecule HTT lowering agents that can be delivered systemically and non-invasively would be an attractive HTT lowering therapy to pursue. Thus, there is a need for small molecule modulators of HTT protein. Such molecules may find use in treating the symptoms and / or delaying the disease progression of Huntington's disease. SUMMARY The present disclosure relates generally to small molecule modulators of HTT, and use thereof as therapeutic agents, for example, in treating diseases such as Huntingtons disease. Thus, provided herein are compounds, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers of the compounds, that are useful in treating Huntington's disease. In certain embodiments, provided are compounds that modulate a protein or a protein fragment implicated in neurodegenerative disease, for example, HTT protein. In certain embodiments, provided is a pharmaceutical composition comprising a compound described herein, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient. The disclosure also provides compositions, including pharmaceutical compositions, kits that include the compounds, and methods of using (or administering) and making the compounds. The disclosure further provides compounds or compositions thereof for use in a method of treating a disease or condition that is mediated, at least in part, by a protein, or a protein fragment, implicated in neurodegenerative disease. Moreover, the disclosure provides uses of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease or condition that is mediated, at least in part, by a protein, or a protein fragment, implicated in neurodegenerative disease. DETAILED DESCRIPTION The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. Definitions As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise. A compound described herein refers to a compound, or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, of any formula described herein, including those of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula Ila, Formula IIIb, Formula IIIc, Formula ITId, Formula ITTe, Formula IIIf, or a compound described anywherein herein including the Examples, or a compound of Table 1 or Table 1A. A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment to a parent structure for a substituent. For example, -C(O)NH; is attached to a parent structure through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a bond in a structure indicates a specified point of attachment. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named. The prefix “Cu.” indicates that the following group has from u to v carbon atoms, exclusive of further substitution. For example, “C1. alkyl” indicates an alkyl group having from 1 to 6 carbon atoms. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount + 10%. In other embodiments, the term “about” includes the indicated amount + 5%. In certain other embodiments, the term “about” includes the indicated amount + 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art. “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C120 alkyl), 1 to 12 carbon atoms (i.e., Ci.12 alkyl), 1 to 9 carbon atoms (i.e., Cig alkyl), 1 to 8 carbon atoms (i.e., C1.s alkyl), 1 to 6 carbon atoms (i.e., Ci. alkyl) or 1 to 4 carbon atoms (i.e., C1 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3- methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2);CHs), sec-butyl (i.e., - CH(CH3)CH:CHj), isobutyl (i.e., -CHCH(CHs),) and tert-butyl (i.e., -C(CHs)s); and “propyl” includes n-propyl (i.e., -(CH2).CHs) and isopropyl (i.e., -CH(CHz)2). Alternative chemical names known to those of skill in the art may be used in lieu of the terms provided herein. For example, a divalent group such as a divalent “alkyl” group or a divalent “aryl” group, etc., may also be referred to as an “alkylene” or an “arylene” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2. alkenyl), 2 to 8 carbon atoms (i.e., Cz alkenyl), 2 to 6 carbon atoms (i.e., C26 alkenyl) or 2 to 4 carbon atoms (i.e., C24 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and isoprenyl. “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., Ca.20 alkynyl), 2 to 8 carbon atoms (i.e., C2 alkynyl), 2 to 6 carbon atoms (i.e., Cz.¢ alkynyl) or 2 to 4 carbon atoms (i.e., C24 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond. “Alkoxy” refers to a group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2- dimethylbutoxy. “Alkylamino” refers to a group “alkyl-NH-". Examples of alkylamino groups include, e.g., methylamino, ethylamino, iso-propylamino, tert-butylamino, and n-hexylamino. “Dialkylamino” refers to a group “(alkyl);N-". Examples of dialkylamino groups include, e.g., dimethylamino, diethylamino, (iso- propyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and di-n-hexylamino. “Alkylthio” refers to a group “alkyl-S-". “Alkylsulfinyl” refers to a group “alkyl-S(O)-". “Alkylsulfonyl” refers to a group “alkyl-S(0),-”". “Acyl” refers to a group -C(O)R?Y, wherein RY is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl. “Amido” refers to both a “C-amido” group which refers to a group -C(O)NR’R* and an “N- amido” group which refers to a group -NR'C(O)R?, wherein R” and R* are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or R” and R” are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein. “Amino” refers to a group -NRYR” wherein R* and R* are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. In some embodiments, “amino” refers to a group NH,. “Amidino” refers to a group -C(NR”)(NR?%), wherein RY and R* are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., Ce.20 aryl) or 6 to 10 carbon ring atoms (i.e., Cs.10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl. “Arylalkyl” or “Aralkyl” refers to a group “aryl-alkyl-". “Carbamoy!” refers to both an “O-carbamoyl” group which refers to a group -O-C(O)NR’R* and an “N-carbamoyl” group which refers to a group -NR*C(O)OR?, wherein RY and R* are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Carboxyl ester” or “ester” refer to both -OC(O)R* and -C(O)OR*, wherein R* is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp ring carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., Cs.20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C312 cycloalkyl), 3 to 10 ring carbon atoms (i.e., Ca.;0 cycloalkyl), 3 to 8 ring carbon atoms (i.e., Cas cycloalkyl), or 3 to 6 ring carbon atoms (i.e., Cs. cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring system which may include a fused aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl,” for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5Jundecanyl. When there are two positions for substitution on a carbon atom in a parent structure, cycloalkyl as a substituent group may include spirocycloalkyl. A cycloalkyl may be substituted at its carbon atom of attachment to a parent structure. “Cycloalkoxy” refers to a group “-O-cycloalkyl.” “Cycloalkylalkyl” refers to a group “cycloalkyl-alkyl-". “Guanidino” refers to -NRYC(=NR?*)(NR*R?), wherein each RY and R* are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Imino” refers to a group -C(NRY)R?, wherein RY and R* are each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Imido” refers to a group -C(O)NR¥C(O)R?, wherein R¥ and R* are each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Halogen” or “halo” refers to a substituent atom of group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo. “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms, up to and including all hydrogen atoms, are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. A perhaloalkyl group is a haloalkyl group in which every hydrogen substituent is replaced by halo. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like. “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms, up to and including all hydrogen atoms, are replaced by a halogen. “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group. “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms of the alkyl chain (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR>-, -O-, -S-, -S(0)-, -S(0)2-, and the like, wherein RY is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCHs3, -CH(CH3)OCHs, -CH,CH;0OCHjs, -CH,CH,OCH,CH,OCHj, etc.), thioethers (e.g., -CH.SCH3, -CH(CH3)SCH3, -CH,CH,SCH3, -CH,CH,SCH>CH,SCHj, etc.), sulfones (e.g., -CH2S(0).CHs, -CH(CH3)S(0).CHs, -CH2CH,S(0):CHs, -CH.CH,S(0),CH,CH,OCH3, etc.) and aminoalkyls (e.g., -CH,NRYCHs, -CH(CH3)NRYCH3, -CH.CH2NRYCHs, -CH2CHNRYCHCH2NRYCHj, etc., where RY is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. “Heteroaryl” refers to an aromatic group having a single ring or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, and may comprise one or more (e.g., 1 to 3) N-oxide (-O°) moieties. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C120 heteroaryl), 3 to 12 ring carbon atoms (i.e., Cs.i2 heteroaryl), or 3 to 8 carbon ring atoms (i.e., Ca heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, ‘benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring system, having a single or multiple fused rings containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. “Heteroarylalkyl” refers to a group “heteroaryl-alkyl-". “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen or sulfur atoms are optionally oxidized to form an N-oxide, a sulfinyl (-S(O)-), or a sulfoxide (-S(0O)2-). The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., a heterocyclyl group having at least one endocyclic or exocyclic double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups, oxo- heterocyclyl (i.e., a heterocyclyl including at least one oxo) and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro. Regardless of substituent groups listed, a heterocyclyl may comprise one or more (e.g., 1 to 3) oxo (=0) or N-oxide (-O°) moieties unless stated otherwise. A heterocyclyl can be bound through a carbon atom or a heteroatom as valency permits. Further, the term heterocyclyl encompasses any ring system including a non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. A heterocyclyl may have a charged resonance structure that is aromatic (e.g., pyridin-2(1H)-on-1-yl). As used herein, a heterocyclyl may include 3 to 14 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms, or 5 to 6 ring atoms, and / or 2 to 12 ring carbon atoms (i.e., Cs.12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., Cs.10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., Cas heterocyclyl), 3 to 12 ring carbon atoms (i.e., Ca.12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., Css heterocyclyl), or 3 to 6 ring carbon atoms (i.e., Cs. heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. The term “heterocyclyl” also includes “spiroheterocyclyl.”. Examples of the spiroheterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of bridged-heterocyclyl rings include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptanyl. When there are two positions for substitution on a carbon atom in a parent structure, heterocyclyl as a substituent group may include spiroheterocyclyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4- tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system. “Heterocyclylalkyl” refers to a group “heterocyclyl-alkyl-.” “Oxime” refers to a group -CR¥(=NOH) wherein R? is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. “Sulfonyl” refers to a group -S(O):RY, where RY is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl. “Sulfinyl” refers to a group -S(O)RY, where RY is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl. “Sulfonamido” refers to the groups -SO;NR'R* and -NR’SO2R?, where R” and R* are each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. The terms “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. Also, the term “optionally substituted” refers to a group which is unsubstituted or substituted. The term “substituted” used herein refers to a group in which any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms is replaced by a non-hydrogen group such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, arylalkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkoxy, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH,, =NNH,, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(0)20H, sulfonamido, thiol, thioxo, N-oxide or -Si(RY)3, wherein each RY is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. In certain embodiments, “substituted” refers to a group in which one or more (e.g., 1 to Sor I to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, hydroxyl, imino, nitro, azido, oxo, thioxo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkyl, haloalkoxy, cycloalkyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRERY, -NREC(=O)R", -NREC(=0)NRER", -NREC(=0)OR", -NR&S(=0)12R", -C(=0)RE, -C(=0)ORE, -OC(=0)ORE, -OC(=O)R¢, -C(=O)NRER", -OC(=O)NRFR", -OR, -SRE, -S(=0)RE, -S(=0)R¢, -0S(=0)12R¢, -S(=0):20R¢, -NR8S(=0),2NRER", =NSO:RE, =NOR¢, -S(=0),.2NR#R", -SFs, or -SCFs. In certain embodiments, “substituted” also means a group in which one or more (e.g., 1 to 5 or I to 3) hydrogen atoms are replaced with -C(=O)RE, -C(=0)ORS, -C(=0)NRER", -CH,SO:R8, or -CH,SO,NRER". In the foregoing, RE and R" are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of R& and R® and R' are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to arise from the above definitions. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to encompass compounds having chemically unfeasable or unisolable substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having three consecutive oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to three. Any compound or structure given herein is intended to represent unlabeled forms as well as “isotopically enriched analogs” of the compounds. Isotopically enriched forms of compounds may also be referred to as “labeled.” Isotopically enriched analogs have structures depicted herein, except that one or more atoms are enriched in an isotope having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as 2H, °H, !'C, *C, *C, “N, IN, 150, 70, #0, 3'P, 3p, 3, BF, *Cl, '21, and '¥, respectively. Generally, an isotopically enriched analog includes compounds having any isotopic enrichement above the natural abundance of the isotope (e.g., at Earth’s surface). Various isotopically labeled compounds are included in the present disclosure, for example those into which radioactive isotopes such as *H, '*F, !'C, '*C and "“C are incorporated. Compounds labeled with °F, *H, or 'C may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds may exhibit increased resistance to metabolism and are thus may be useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium. Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Where a compound is described as a deuterated analog, the compound may be drawn with deuterium as a substituent. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen and its isotopes at their natural abundances. In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Provided also are isotopically enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use. The term “pharmaceutically acceptable salt” of a compound described herein refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” of compounds described herein include, for example, acid addition salts obtained by interacting a compound with a basic functional group with an acid, and base addition salts obtained by interacting a compounds with an acidic functional group with a base. If the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base (e.g., of an amine), an addition salt may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts of compounds described herein may be prepared from inorganic and organic acids. Suitable inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Suitable organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NHx(alkyl)), dialkyl amines (i.e., HN(alkyl),), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NHx(substituted alkyl)), disubstituted alkyl) amines (i.e., HN(substituted alkyl),), tri(substituted alkyl) amines (i.e., N(substituted alkyl)s), alkenyl amines (i.e., NHz(alkenyl)), dialkenyl amines (i.e., HN(alkenyl),), trialkenyl amines (i.e., N(alkenyl)s), substituted alkenyl amines (i.e., NHz(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)z), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)s, mono-, di- or tri- cycloalkyl amines (i.e., NHa(cycloalkyl), HN(cycloalkyl), N(cycloalkyl)s), mono-, di- or tri- arylamines (i.e., NHy(aryl), HN(aryl),, N(aryl)s), cyclic amines (e.g., piperidine, piperazine, 1,4- diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like. Some compounds described herein may exist as tautomers. For example, where a compound is drawn as including an amide, the compound may exist as an imidic acid tautomer, and where a compound is drawn as including a ketone, the compound may also exist as an enol tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both tautomers. Thus, for example, the amide containing compounds are understood to include their imidic acid tautomers, and the imidic acid containing compounds are understood to include their amide tautomers. The compounds described herein may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. Compounds described herein are meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both cis- and trans- or E- and Z- geometric isomers. A “stereoisomer” refers to one of a set of compounds made up of the same atoms bonded by the same bonds but having different three-dimensional structures. Various stereoisomers and mixtures thereof are contemplated including “enantiomers,” which refers to stereoisomeric compounds that are non-superimposable mirror images of one another. A “diastereomer” is one of a set of stereoisomers that have at least two asymmetric atoms that are not mirror-images of each other. A “prodrug” is any molecule which releases a putatively active parent drug according to a compound described herein in vivo when such prodrug is administered to a mammalian subject. A prodrug may be a form of a compound described herein modified in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compound described herein in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety. As used herein the terms “group,” “moiety,” “radical,” “substituent,” and “fragment” are synonymous and are intended to indicate portions of molecules attachable to other portions of molecules, e.g., through an indicated attachment point or bond. The term “active agent” is used to indicate a compound which has biological activity in the treatment, amelioration, or prevention of a disease or condition. In some embodiments, an “active agent” is a compound or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof, having pharmaceutical utility. For example an active agent may be an anti-neurodegenerative therapeutic. The term “effective amount” means an amount, for example, of a compound described herein, sufficient to bring about a desired response in an individual or patient. The term “therapeutically effective amount” means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease e.g., a therapeutically effective amount may be an amount sufficient to decrease the symptoms of a disease described herein. The (therapeutically) effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can be determined by one of ordinary skill in the art. The term “huntingtin protein” or “HTT protein” as used herein, refers to the protein encoded by the human huntingtin gene (HTT gene) located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the IT:s gene coding for the HTT protein is located from base pair 3,076,407 to base pair 3,245,686 on chromosome 4. The term “protein aggregate,” as used herein refers to an aggregation of protein which may be, for example, an insoluble fibrous amyloid comprising mis-folded HTT protein molecules (“HTT protein aggregate”) or mis-folded B-amyloid protein molecules (“B-amyloid aggregate”). A “protein implicated in neurodegenerative disease” may be a protein that is capable of forming such aggregates, in its wild type or in a mutated form, or may be a protein that participates in a pathological process related to a neurodegenerative disease. In some embodiments, the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of neurodegenerative diseases include those described herein. “Treatment” or “treating” means any treatment of a disease state in a patient, including a) inhibiting the disease (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life and / or prolonging survival). “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk (e.g., carries a genetic or epigenetic marker, has engaged in an activity, or has been exposed to an environmental condition, associated with the disease or condition) or has a family history of the disease or condition. “Subject” or “patient” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments the subject or patient is human. The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art. It is appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features described herein, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables contained within Formula I are specifically embraced herein just as if each and every combination was individually and explicitly recited, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, are also specifically embraced herein just as if each and every subcombination of chemical groups and subcombination of uses and medical indications was individually and explicitly recited herein. In addition, some embodiments include every combination of one or more additional agents disclosed herein just as if each and every combination was individually and explicitly recited. List of Abbreviations and Acronyms Chemical shift Acetate Addition Approximately Aqueous Aryl 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl Terr-butyloxycarbonyl Broad 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6"- triisopropyl-1,1'-biphenyl Column volumes Doublet Doublet of doublets Dibenzylideneacetone Dichloromethane Dimethoxyethane N,N’ -Dimethylethylenediamine N,N-dimethylformamide Dimethyl sulfoxide Equivalent Electrospray positive ionization Ethyl Ethyl acetate Hour(s) N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate ‘N-oxide HBTU N,N,N’,N’-Tetramethyl-O-(1 H-benzotriazol-1-yljuronium hexafluorophosphate High performance liquid chromatography Homogeneous time resolved fluorescence Liquid chromatography-mass spectrometry Coupling constant Multiplet Methyl Acetonitrile Methanol Minute(s) Mass spectrometry Mass to charge ratio Nuclear magnetic resonance Para Phenyl Part(s) per million Preparative Quartet Reaction mixture Retention time Room temperature 2nd Generation RuPhos Precatalyst, Chloro(2- dicyclohexylphosphino-2’,6°-diisopropoxy-1,1’-biphenyl)[2- (2’-amino-1,1’-biphenyl)]palladium(II) [s— Singlet Saturated Strong cation exchange Supercritical fluid chromatography Nucleophilic substitution, aromatic Triplet terr-Butyl Chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate Trifluoroacetic acid Tetrahydrofuran p-Toluenesulfonyl Compounds Provided herein are compounds for modulating HTT. In certain embodiments, provided is a compound of Formula I: "a Q 2 . 5 Ix | 5 . Ja rd R! : or \ A Rr? or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein: X!, X2, X3, and X* are CR? or N, wherein at least two but no more than three of X!, X2, X?, and X*are N; each R* is independently hydrogen, halo, hydroxy, Cu.ealkyl, Ci.shaloalkyl, or Ci. salkoxy; Y!isCRorN; R® is hydrogen, cyano, halo, hydroxy, Ci.alkyl, C1.¢haloalkyl, C1.salkylthio, Cy.ealkoxy, C1ehaloalkoxy, heterocyclyl, -NHa, -NHRY, or -N(R!7),, and optionally substituted on an available nitrogen atom with C,salkyl or C,shaloalkyl; Y2is absent, CR or N: R® is hydrogen, cyano, halo, hydroxy, Ci.alkyl, Cy.chaloalkyl, Ci.salkylthio, Cy.ealkoxy, Ci shaloalkoxy, heterocyclyl, -NHz, -NHR', or -N(R'7),, and optionally substituted on an available nitrogen atom with C;salkyl or C;¢haloalkyl; and Y3isCR3orN; R? is hydrogen, cyano, halo, hydroxy, Cr.ealkyl, C.shaloalkyl, Cy.ealkylthio, Cy.alkoxy, Cishaloalkoxy, heterocyclyl, -NHa, -NHR', or -N(R'7),, and optionally substituted on an available nitrogen atom with C,salkyl or C,shaloalkyl; each R'is independently C)alkyl, or two R' join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl; each of Z' and Z2is Cor N: Ring A and Ring B together form a 9- or 10-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms; Ring B contains 1 to 3 heteroatoms selected from N, O, and S, and is optionally substituted on available carbon atom(s) with 1 to 3 substituents independently selected from halo, hydroxy, Cisalkyl, Ci¢haloalkyl, C;.¢alkoxy, and C;haloalkoxy, and optionally substituted on an available nitrogen atom with Cisalkyl or Cishaloalkyl; R'is -L'-R!}, wherein L! is -O-, -S-, -S(0)-, -S(0)2-, -N(R'?)-, -Cysalkylene-, -O-C;.salkylene-, -N(R'?)-Cysalkylene-, or absent, and R'! is Cz.alkynyl, Cs.1ocycloalkyl, Ce.oaryl, heteroaryl, or heterocyclyl, wherein R!! is optionally substituted with 1 to 4 R3 groups; R!?is hydrogen or Ci.salkyl; each R'is independently selected from halo, cyano, hydroxy, Ci.salkyl optionally substituted with R'6, C ¢haloalkyl, C,¢hydroxyalkyl, Cs.iocycloalkyl optionally substituted with R!6, Cs. jocycloalkyl-Ci.galkyl optionally substituted with R'6, Ce.j0aryl optionally substituted with R!®, Cs. 10aryl-Cialkyl optionally substituted with R'6, heteroaryl optionally substituted with R'6, heteroaryl-Csalkyl optionally substituted with R'6, heterocyclyl optionally substituted with R'S, heterocyclyl-C,salkyl optionally substituted with R'6, OR!, -NH,, -NHRY, -N(R™),, -C1. salkylene-NH,, -Cysalkylene-NHR!, -C)_salkylene-N(R#),, -C(O)R!3, -C(O)OR'3, -C(O)NHR'S, -C(O)N(C14alkyD)R"3, -S(0):R", -S(O)R', -NHC(O)R*, -N(C4alkyl)C(O)R'*, -NHS(O)R"?, -N(C;4alkyl)S(O)R', -NHS(0),R", and -N(Calky])S(O);R!5; each R'* is independently selected from C.¢alkyl, Ca.iocycloalkyl, Ce 1aryl, heteroaryl, and heterocyclyl; and each R' is optionally substituted with one to six halo, C}.aalkyl, C,. salkoxy, Ca.jocycloalkyl, or -NHSO,-aryl-N(CHa)y; each R'® is independently hydrogen, -OH, C)salkyl, Cy.haloalkyl, Ca.iocycloalkyl, Ce.10aryl, heteroaryl, or heterocyclyl; each R!® is independently halo, cyano, hydroxy, -NHa, -NHR2, -N(R?"),, Crealkyl, C1. haloalkyl, OR?!, or Cs.jocycloalkyl; each R?' is independently selected from C.ealkyl, Cs.iocycloalkyl, Ceoaryl, heteroaryl, and heterocyclyl, and each R?! is optionally substituted with one to six halo or Ciaalkoxy; and R?is hydrogen or Cysalkyl. In certain embodiments, provided is a compound of Formula I: 2 , 2, 0 yr>z JAF AA x A x ae Rx or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein: X* are N. . , X?, , and X' 4 are CRS or N, 2 hes rein at I ea: st two bu t 1 0 me ore tha n thr ee of Xx! , X2 , X32 , an d Y!is CR? or N: Y2is CRé or N: Y3is CR? or N: each of Z! and Z2is C or N: Ring A and Ring B together form a 9- or 10-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms; and Ring B contains 1 to 3 nitrogen atoms and is optionally substituted on an available carbon atom with halo, hydroxy, Ci.salkyl, Ci.shaloalkyl, or C1.salkoxy and optionally substituted on an available nitrogen atom with C,salkyl or C,shaloalkyl; R'is -L'-R", wherein L! is -O-, -S-, -S(0)-, -S(0)2-, -N(R')-, or absent, and R'! is Cs. 1ocycloalkyl, Ce.ioaryl, heteroaryl, or heterocyclyl, wherein R'! is optionally substituted with 1 to 4 R*® groups, R!?is hydrogen or Cysalkyl; each R'? is independently selected from halo, cyano, hydroxy, Ci.salkyl optionally substituted with R!6, Cghaloalkyl, C,shydroxyalkyl, Cs.iecycloalkyl optionally substituted with R'®, Cs.iocycloalkyl-Ci.salkyl optionally substituted with R*, Ce.i0aryl optionally substituted with R'®, Cs. j0aryl-Cialkyl optionally substituted with R'6, heteroaryl optionally substituted with R'6, heteroaryl-Csalkyl optionally substituted with R'6, heterocyclyl optionally substituted with R'6, heterocyclyl-C salkyl optionally substituted with R'6, OR, -NHa, -NHRY, -N(R™),, -C1. ealkylene-NH», -Cisalkylene-NHR", -Cjgalkylene-N(R'),, -C(O)R'®, -C(O)ORY, -C(O)NHRY, -C(O)N(C14alkyl)R"3, -S(0);R", -S(O)R', -NHC(O)R, -N(C).salkyl)C(O)R', -NHS(O)R'3, -N(C14alky])S(O)R 5, -NHS(0),R", and -N(C)4alkyl)S(O).R'S; each R'* is independently selected from Ci.salkyl, Cs.iocycloalkyl, Cs.ioaryl, heteroaryl, and heterocyclyl, and each R!* is optionally substituted with one to three halo; each R'® is independently hydrogen, -OH, C;alkyl, Ci.¢haloalkyl, C.iocycloalkyl, Cs-10aryl, heteroaryl, or heterocyclyl; each R'® is independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, or C. ealkyl; R2? is hydrogen or Cysalkyl; Ris hydrogen, cyano, halo, hydroxy, Ci.salkyl, C1.chaloalkyl, Ci.salkylthio, Ci.alkoxy, heterocyclyl, -NHa, -NHR'7, or -N(R')2; wherein each R" is independently Ci alkyl, or two R! join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl; each R* is independently hydrogen, halo, hydroxy, C\.salkyl, C,.shaloalkyl, or Cy6alkoxy; R* is hydrogen, cyano, halo, hydroxy, Ci.salkyl, Cy.haloalkyl, Cy.salkylthio, Cy.ealkoxy, heterocyclyl, -NHa, -NHR'7, -N(R'7)2; and R® is hydrogen, halo, hydroxy, Ci.salkyl, Ci.¢haloalkyl, or Cyalkoxy. In certain embodiments, Ring B is a 5-membered heteroaryl containing 1 to 3 nitrogen atoms. In certain embodiments, Ring B is a 6-membered heteroaryl containing 1 to 3 nitrogen atoms. In certain embodiments, Ring B is selected from R10 rR R® NN XY R® R? N Je Jw nn 1 gr RY N Gr , and wherein each of R7, R%, and RY is independently hydrogen, halo, hydroxy, Ci.salkyl, Ci.shaloalkyl, or Ci. salkoxy; and R'is hydrogen, C1salkyl, or C shaloalkyl. In certain embodiments, Ring B is selected from RE 7 At rR? R® LL oe R10 %... N ’ 1 \ oO & 4 (nx RO { n No ROA ee Lg Fr ar NN XY wy R® rR? O N AN J R® L- R® Lo 1 oR? RI N ( J 0 RE rR RK I \ : i CLT , and I wherein each of R7, R®, and R%is independently hydrogen, halo, hydroxy, Ci.ealkyl, C1.shaloalkyl, or Ci. salkoxy; and R'° is hydrogen, C; alkyl, or C;shaloalkyl. In certain embodiments, Ring B is selected from RT R® m7 R" R® RY rR? FR = N Or N N | ) i» BB I on JL (Lh Je Ae J NN XY R® rR’ N Je Hw nn nn 2 » x ® 1 x 7 -L Pn ibn — = wherein each of R7, R®, and Ris hydrogen, halo, hydroxy, Cisalkyl, Ci.¢haloalkyl, or Cisalkoxy; and R'is hydrogen, Cisalkyl, or Ci.shaloalkyl. In certain embodiments, Ring B is selected from RE A | Al rR? R N ht le x AA and i wherein each of R” and R¥is hydrogen, halo, hydroxy, Cialkyl, C1.chaloalkyl, or C.salkoxy; and R'is hydrogen, Cysalkyl, or C;.haloalkyl. In certain embodiments, Ring B is selected from and wherein each of R7, R®, and R? is hydrogen, halo, hydroxy, Cisalkyl, Cishaloalkyl, or Cisalkoxy. In certain embodiments, provided is a compound of Formula Ia: ~~ Ia i = JE ° Yat” NX A A N Y'© Re AA rR PAY R? I: or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where Ring A, Ring B, R, R% R?, Y!, Y?, Z' and 7? are as defined herein. In certain embodiments, provided is a compound of Formula Ib: sy b 4 = J 0 For AL | | A Re I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where Ring A, Ring B, R', R% R?, Y', Y2, Z! and Z? are as defined herein. In certain embodiments, provided is a compound of Formula Ic: Ic Q 2 vis J ~ Jat R! ’ N R? ” Ic or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where Ring A, Ring B, R', R% R?, Y', Y2, Z' and Z? are as defined herein. In certain embodiments, provided is a compound of Formula IIa: ol oN la 9 I y R? R! = Re I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R% R?, R7, R®, X!, X2, X? X*, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula IIb: 1b IN R10 / N i \ 0 2 RO | or R! * Re or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R% R%, R7, R'%, X', X2, X? X*, and Y' are as defined herein. In certain embodiments, provided is a compound of Formula IIc: Re I RL R® NP 9 ox XZ Z x1 A Pgs A ox Rr R X Ic de i sD it cid or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R% R3, R7, R®, R®, X!, X2 X3, X*, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula IId: Td R® LN } ZN I A } 3S R® x | Va Rr? " hut or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R%, R*, R7, R%, R®, X!, X2, X?, X*, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula IIa: ol . Ta | A LCL R ZN R? " I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R%, R? R?, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula IIIb: ot . Ib ] [on = 7 | A k 1 X I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R%, R?, R%, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula IIIc: pol . lec IN o N UN ort x R! Na nT I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R?, R3, R®, and Y! are as defined herein. In certain embodiments, provided is a compound of Formula ITId: R10 / 11d / N Ty IN 1 or Ye 1 ZN RZ R® RON I SG or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R%, R?, R?, and R!° are as defined herein. In certain embodiments, provided is a compound of Formula Ile: R10 2 Ile £ A 0 2 NN = 0 | N R?2 RS hr or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R2, R3, RS, and R!? are as defined herein. In certain embodiments, provided is a compound of Formula IIIf: R10 / If or 2 R’ - Ne 4 R? RS ¥ I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, where R!, R2, R3, R%, and R!? are as defined herein. In certain embodiments, L! is absent or -N(R'?)-. In certain embodiments, L! is absent. In certain embodiments, R! is heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, Ci.salkyl, Cighaloalkyl, Cs.iocycloalkyl, heteroaryl, heterocyclyl, heterocyclyl-Chsalkyl, -NH,, -NHR', -N(R'),, -C\salkylene-NHa, -Cy.salkylene-NHR, -C\.salkylene- N(R"), and -C(O)OR*; wherein each R* is independently selected from C.calkyl, Ca.iocycloalkyl, and heterocyclyl, and each R™ is optionally substituted with one to three halo; and wherein R is Cj.¢alkyl. In certain embodiments, R is unsubstituted heterocyclyl. In certain embodiments, R* is heterocyclyl substituted by methyl. 1 \_ / Na In certain embodiments, R"! is N wherein Ring C is a 3- to 10-membered heterocyclyl containing 0, 1 or 2 additional ring nitrogen atoms optionally substituted with 1 to 4 R** N groups. In certain embodiments, Ring C is < substituted with 1 to 4 R' groups. In certain ", - embodiments, Ring C is [Nv substituted with 1 to 4 R" groups. In certain embodiments, Ring C is \ MH / substituted with 1 to 4 R' groups. In certain embodiments, Ring C is a 5- to 10-membered bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'? groups. In certain embodiments, Ring Cis a 5- to 10-membered spirobicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'3 groups. In certain embodiments, Ring Cis a 5- to 10-membered fused bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'? groups. wO>- On [a oH J In certain embodiments, R!! is selected from (10H ™ a WOO WOH FH wl CoH rN ot HN} N / V HN NA N~~ ' H H HOT qe Ie OO) oH oN} / \ sn O~\ 5H <0 Bq H N = Lo" ° , and HN N 1 + each of which is optionally substituted with 1 to 4 R!? groups. \ n> Cr N In certain embodiments, R'! is selected from - — = NA a A A A 5 Ew RT WOO H Mya A oN YH SN H H H NT nH ' H S25 H . Jo ou i IN H AA CLA OH JOH “= mV Sy A H SN H Fao x nN NN N \ CN AST ~L ™ HN. _~ pS OF A o="T 0H =) C NN N~ yA (BO HN N—| H —NH ,and HN , each of which is optionally substituted with 1 to 4 R!3 groups. In certain embodiments, R!! is optionally substituted with 1 to 4 groups independently selected from fluoro, methyl, ethyl, trifluoromethyl, cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolidinyl, N- pyrrolidinylmethyl, cyclopropylamino, amino, aminomethyl, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3- difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, and tert-butoxycarbonyl. In certain embodiments, R!! is optionally substituted with 1 to 4 groups independently selected from fluoro, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl- 2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1-ylamino)methyl, cyclopropyl, 1- (cyclopropylamino)-1-cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, 2- pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperdinyl, 1-cyclopropyl-2-piperdinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert- butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N- dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl-N- methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylaminomethyl, N-isopropyl-N-aminomethyl, tert-butylamino, n-butylamino, N- methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, (3-methoxy-1-azetidinyl)methyl, (3-methoxy-1-pyrrolidinyl) methyl, (3-fluoro-1- pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, 4-morpholinylmethyl, and tert- butoxycarbonyl. In certain embodiments, R!! is optionally substituted with 1 to 4 groups independently selected from 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1- ylamino)methyl, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert- butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N- dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl-N- methylamino, N-cyclopropyl-N-methylaminomethyl, isopropylaminomethyl, N-isopropyl-N- aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, (3-methoxy-1-azetidinyl)methyl, (3- methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1- pyrrolidinyl)methyl, and 4-morpholinylmethyl. In certain embodiments, R!! is optionally substituted with 1 to 4 groups independently selected from amino, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, and oxetanylamino. In certain embodiments, two of X!, X2, X3, and X* are N. In certain embodiments, one of X!, X2, X3, and X* are N. In certain embodiments, Y? is absent, CR® or N. In certain embodiments, R' is -L!-R!!, wherein L! is -O-, -S-, -S(0)-, -S(O)2-, -N(R'?)-, -C1. salkylene-, -O-C).salkylene-, -N(R'2)-C;.salkylene-, or absent, and R" is Czsalkynyl, Cs.iocycloalkyl, Ce. 10aryl, heteroaryl, or heterocyclyl, wherein R'! is optionally substituted with 1 to 4 R'? groups. In some embodiments, each R* is independently selected from halo, cyano, hydroxy, Cy.ealkyl optionally substituted with R'6, Ci shaloalkyl, Ci.shydroxyalkyl, Ca.ocycloalkyl optionally substituted with RS, Cs.jecycloalkyl-Cyealkyl optionally substituted with R', Ce.i0aryl optionally substituted with RS, Cs. 10aryl-Cy.ealkyl optionally substituted with R'®, heteroaryl optionally substituted with R'¢, heteroaryl-Csalkyl optionally substituted with R'6, heterocyclyl optionally substituted with R'6, heterocyclyl-Cisalkyl optionally substituted with R'6, OR, -NH,, -NHR', -N(R'#),, -Cysalkylene-NH,, -Cialkylene-NHR', -C\.6alkylene-N(R'4),, -C(O)R', -C(O)OR*, -C(O)NHR®, -C(O)N(C1alkyR?, - S(0):RY, -S(O)R', -NHC(O)R', -N(C1alky)C(O)RY, -NHS(O)R', -N(Cialkyl)S(O)RY, - NHS(O)2R*, and -N(Ci4alkyl)S(0)2R'S; each R'* is independently selected from C.calkyl, Ca.iocycloalkyl, Ce.oaryl, heteroaryl, and heterocyclyl; and each R' is optionally substituted with one to six halo, C1.aalkyl, Cisalkoxy, Ca.iocycloalkyl, or -NHSO:-aryl-N(CHa)z; each R' is independently hydrogen, -OH, Cyalkyl, C1shaloalkyl, Ca.iocycloalkyl, Ceoaryl, heteroaryl, or heterocyclyl; each R'® is independently halo, cyano, hydroxy, -NHa, -NHR?, -N(R?'),, Csalkyl, Cishaloalkyl, OR?, or Ca.iocycloalkyl; and each R? is independently selected from Cisalkyl, Caiocycloalkyl, Ceioaryl, heteroaryl, and heterocyclyl, and each R?! is optionally substituted with one to six halo or Ci.3alkoxy. In certain embodiments, R? is hydrogen. In certain embodiments, R? is hydrogen. In certain embodiments, R* is halo. In certain embodiments, R? is fluoro. In certain embodiments, R? is Ci .salkyl. In certain embodiments, R? is methyl. In certain embodiments, R? is C;.¢alkoxy. In certain embodiments, R? is methoxy. In certain embodiments, each R* is hydrogen. In certain embodiments, one R* is halo and the rest are hydrogen. In certain embodiments, R® is hydrogen. In certain embodiments, R® is Cyalkoxy. In certain embodiments, R® is methoxy. In certain embodiments, R® is hydrogen. In certain embodiments, R is hydrogen. In certain embodiments, R® is Cy salkyl. In certain embodiments, R® is methyl. In certain embodiments, R® is C.salkyl. In certain embodiments, R® is methyl. In certain embodiments, R!° is Cgalkyl. In certain embodiments, R° is methyl. In certain embodiments, L! is absent. In certain embodiments, Y' is CR®. In certain embodimnets, Y' is N. In certain embodiments, Y* is CH. In certain embodiments, Y? is CR®. In certain embodiments, Y? is N. In certain embodiments, Y? is CH. In certain embodiments, Y? is CR. In certain embodiments, Y?3 is CH. In certain embodiments, Ring B contains 1 to 3 heteroatoms independently selected from N, O, and S, and is optionally substituted on available carbon atom(s) with 1 to 3 substituents independently selected from halo, hydroxy, Cisalkyl, Ci.¢haloalkyl, Cisalkoxy, and C;shaloalkoxy, and optionally substituted on an available nitrogen atom with C; alkyl or C;¢haloalkyl. R® rR? R Y= NN XY In certain embodiments, Ring B is In certain embodiments, Ring B is In certain embodiments, Ring B is In certain embodiments, each R'? is independently selected from halo, Crealkyl, Cs.iocycloalkyl optionally substituted with RS, heterocyclyl optionally substituted with R'®, -NH,, -NHR™, -N(R*),, -C1. salkylene-NH,, -Cisalkylene-NHR', -C).salkylene-N(R 4), wherein R'6 and R'* are as defined herein. In certain embodiments, each R'? is independently selected from -NH,, -NHR™, -N(R'),, -C .¢alkylene- NHa, -Ch.calkylene-NHR', and -Ci.salkylene-N(R'*),, wherein R* is as defined herein. In certain embodiments, each R" is independently selected from halo, Ci .salkyl, -NH3, -NHR', -N(R')3, -C1. salkylene-NHa, -Cyealkylene-NHR', and -C.salkylene-N(R'4), wherein R* is as defined herein. In certain embodiments, the heterocyclyl of R'? includes one ring nitrogen atom. In certain embodiments, R!¥ is heterocyclyl optionally substituted with R'®, wherein the heterocyclyl includes one ring nitrogen atom. In certain embodiments, R'* is -NHz, -NHR!* or -C1calkylene-NHR, and R** is as defined herein. In certain embodiments, R'* is -NHR™ or -C;.salkylene-NHR', and R* is as defined herein. In certain embodiments, R'? is -NHR'* or -Cy.salkylene-NHR'4, and R** is Cs.jocycloalkyl. In certain embodiments, R'? is -NH-cyclopropyl. In certain embodiments, R*? is -NH-methyl. In certain embodiments, R* is <CH,-NH-cyclopropyl. In certain embodiments, R'? is -CH,-NH-methyl. In certain embodiments, R'? is —<CH,-heterocyclyl optionally substituted with R'6, where R€is as defined herein. In certain embodiments, R' is Cialkyl. In certain embodiments, R' is C1salkyl substituted by one to six fluoro. In certain embodiments, R'* is methyl. In certain embodiments, R** is C.jocycloalkyl. In certain embodiments, R'* is cyclopropyl. In certain embodiments, R' is hydrogen or C;.salkyl. In certain embodiments, R'® is amino, alkylamino, or dialkylamino. In certain embodiments, each R'¢ is independently -NH;, -NHR?, or -N(R?),; and each R? is independently selected from C.calkyl, Cishaloalkyl, or Cs.jocycloalkyl. In certain embodiments, each R'6 is independently halo, Cy.salkyl, or OR?! and R?! is as defined herein. In certain embodiments, provided is a compound of Formula I: 1G ; ot B) Nad 2 R 2 - or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein: X!, X% X3, and X* are CR? or N, wherein at least two but no more than three of X*, X?, X3, and X* are N: Y!is CR or N: Y2is CRS or N; Y3is CR?or N: each of Z! and Z2is C or N: Ring A and Ring B together form a 9-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms; and Ring B is selected from RL RE R7 R™ R8 Fl of wf 5 \ mn \ w= SN Rr TN NN XY R® R? RT FR N Le Le Jb 1 nn A and R'is -L-R'}, wherein L' is -O-, -S-, -S(O)-, -S(O)2-, -N(R'?)-, or absent, and R"' is Cs. 1cycloalkyl, Ce oaryl, heteroaryl, or heterocyclyl, wherein R'! is optionally substituted with 1 to 4 R'? groups; R!?is hydrogen or Ci.salkyl; each R'? is independently selected from halo, cyano, hydroxy, Ci.salkyl optionally substituted with R', Cy.chaloalkyl, C1.shydroxyalkyl, Ca.iacycloalkyl optionally substituted with R'S, Cs.i0cycloalkyl-C alkyl optionally substituted with R'¢, Cs.j0aryl optionally substituted with RS, Ce.j0aryl-C alkyl optionally substituted with R'¢, heteroaryl optionally substituted with R'®, heteroaryl-C)salkyl optionally substituted with R'6, heterocyclyl optionally substituted with R'6, heterocyclyl-C salkyl optionally substituted with R'6, OR, -NH,, -NHRY, -N(R™),, -C. salkylene-NHa, -Cyalkylene-NHR!, -Cysalkylene-N(R4),, -C(O)R!S, -C(O)OR!3, -C(O)NHRS, -C(O)N(Ci4alkyl)R'3, -S(0)2R", -S(O)R 5, -NHC(O)R, -N(C14alkyl)C(O)R', -NHS(O)R 5, -N(C;4alkyl)S(O)R'S, -NHS(0),R", and -N(C;alkyl)S(O):R!5; each R'* is independently selected from Ci.6alkyl, Cs.1ocycloalkyl, Ce-ioaryl, heteroaryl, and heterocyclyl, and each R" is optionally substituted with one to three halo; each R" is independently hydrogen, -OH, Ciealkyl, C1.shaloalkyl, Cs.iocycloalkyl, Ce.10aryl, heteroaryl, or heterocyclyl; each R'® is independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, or C1. salkyl; R?is hydrogen or Cisalkyl; Ris hydrogen, cyano, halo, hydroxy, Ciealkyl, C1.chaloalkyl, Cyealkylthio, Cyealkoxy, heterocyclyl, -NHz, -NHR!, or -N(R")z; wherein each R" is independently C) alkyl, or two R" join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl; each R* is independently hydrogen, halo, hydroxy, C\.salkyl, Cishaloalkyl, or Cyealkoxy; R® is hydrogen, cyano, halo, hydroxy, Ci.alkyl, C1 ¢haloalkyl, Cialkylthio, Ci ealkoxy, heterocyclyl, -NH,, -NHR!, -N(R')z; R® is hydrogen, halo, hydroxy, Ci.salkyl, Ci.ehaloalkyl, or Cyalkoxy; each of R7, R%, and R®is independently hydrogen, halo, hydroxy, C1.ealkyl, Ci.chaloalkyl, or Ci. salkoxy; and R'is hydrogen, C;salkyl, or Ci.shaloalkyl. In certain embodiments, provided is a pharmaceutical composition comprising a compound described herein, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient. In certain embodiments, provided is a method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutical composition described herein. In certain embodiments, provided is a method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein in combination with a second active agent. Structure Structure = ° Noy £Y N x ~A hg y 2 She GQ. J fe at? . pu HN ~ =~ z | N J ” iW N s RS An Ah . & a, 0 : -_— ” Enantiomer 1 + Enantiomer 2 = 21 ears wv = Le a / ol o & Lr [og A B ah Fig 2 N ON 4 Pi o (J Hn 20) 8 1X 5 I$ d A Enantiomer 1 + Enantiomer 2 = 2 | _ ALL NN PE AnH » Oy N. Mr ts =~ ° ip! ON > Enantiomer 1 Enantiomer 2 ~ 3 o NN WN ~~ 1X NAA i NN F & H SN HN, J % Enantiomer 1 Enantiomer 2 o Oh my LL or —N o = ILL or HN, ry —d > d Cis Isomer, Enantiomer 1 Enantiomer 2 & 7 9 s j . NN $ ort r L nd r= HN, h — -0 Enantiomer 1 Enantiomer 1 Enanfiomer 1 a TC = o Leg AL 9 oh & lh i Pa ° y LL o = Enantiomer 2 [ mole ITH Xi N [ite SY 0 r ee i» ed = NN ZF F 2 0 cs fas = i IX TN F Sead ye i" Cis Isomer, Enantiomer 1 as oT Cis Isomer, Enantiomer 1 HN Cis Isomers, Enantiomer 1 + Enantiomer Lf [somers, Enantiomer 1 + Enantiomer ~ ~ Rae a ~N NH ui Cis Isomer, Enantiomer 2 NN NN 0 NEN F ] | H AN H HSN vs H WS HN TT —_— ) Cis Isomer, Enantiomer 2 Cis Isomer, Enantiomer 1 ~ = o LL YY wT YN FZ F WANN H NAAN 5 HN. \ H Cis Isomer, Enantiomer 1 id Cis Isomer, Enantiomer 1 Cis Isomer, Enantiomer 2 { Cis Isomer, Enantiomer 2 ~ NN # AL = ve a IL _— A oO or : NH, HN. gee _{ ~ ol =u 0 Mv Ped ~NA NE Ze XX N * ot er AN 3 - w NHz NS \ wo NH, NN = Q NN ~Io lL {CY - ry CR N’ = WAN HN. af ¥ —— rr = Ne NN a 10 © NEY F i; : In" Enantiomer 1 + Enantiomer 2 o HN, > Enantiomer 1 + Enantiomer 2 0 ( wv ” = =~ Enantiomer 1 + Enantiomer 2 [ ~ SC KAY NE NON J = or HN, o NN > LL Sy F Enantiomer 1 + Enantiomer 2 oH > x AL Ay F Enantiomer 1 + Enantiomer 2 AA H | = Al & = Crs mK wn i al od a oJ eee 2,0 L, W ot LE i Cr : 3 or ory ZF Enantiomer 1 + Enantiomer 2 NN a h —NH Q M Y NTE = pe ods ot H ZN H i) i & 3 & - Lr [J HN, ¥ r HN, Enantiomer 1 > Enantiomer 2 =~ ~ AK fT A yr AL I OSA H ’ wo Enantiomer 2 > = Enantiomer 1 ig i LJ Q HN > we a ~O mr Enantiomer 1 + Enantiomer 2 NH / = LAX wy N aa HN. NN LJ ON v ok = 2 1) = ove LL ky . or Nr i ~ F <r N o Noy HN A N 3 A I NN Trans Isomers, Enantiomer 1 + NF | HN Enantiomer 2 . & UX ) ny (7 a [ / —NH > a CY o (YX ~ yoru — [eae wh " a Seg ‘ mJ hg Hn { [ NTS 1, - 'e uJ mil 0 = 2 oh ~All ~All AN n yo ’ ¢ g = 21 HA ° 3 fale over a Enantiomer 1 = 21 HA I = =~ NN I il NTS LAL % Ww 0 > Enantiomer 2 Cs (L 2 AX Cr od = Zh pe o Fup) 4 A A « a > Cis Isomer, Enantiomer 1 nd — HN A Zh pe Cis Isomer, Enantiomer 2 / = ry N N ° Nz o 7 [. yw YW y Cr : cr oN HN, HN, \ \ in Yer aes Tonnidicrmde {nm Cha Temmars Tnantimmiie do Baa niiamb Trans Isomers, Enantiomer 1 and Cis Isomers, Enantiomer 1 + Enantiomer Enantiomer 2 2 = $y Aen F QQ, ~~) NT HN, N Trans Isomers, Enantiomer 1 and Enantiomer 2 NH BY NSO Ae A Q, 7 x = Z SO . NSP Lr or! ! YO HN, HN \ Cg Cis Isomer, Enantiomer 1 a 5 Ao ld or —NH N o & NT N CO Ea oO / = lh N —NH — / Ch Oo oO z 9 {2h 0 nel o 3 CENTS 2 iv AN Ed > P g HN 2 ol ™ ” 1 oF NN o ( NTN Fo Lor OEt Aa ! A a —NH HN = HN 7 = : % (5 NTS Li | - § —NH HN— / ’ Me = 9 & ZN N or pS. > , HN— SN 7 N o n WYN or OMe HA, \ = SP Zp C or H HN HN Cis Isomer, Enantiomer 1 + Enantiomer 2 | Fy! = 21 1 1 ol od — HN, \—CF, =~ pel ~ ALL o MN or A LL 2 . or H > q rN gt L 0 H Cis Isomer, Enantiomer 1 NY Cr IN MOF NN oY =) Mr HN, ° & Ye YW Enantiomer 1 + Enantiomer 2 E {3 AN / ™N id r 7 N = o Ln Oo NP or i Cis Isomer, Enantiomer 2 HN NO J Enantiomer 1 + Enantiomer 2 a NN Or ory HN HN, NI Cis Isomer, Enantiomer 1 ~ & AF r Ww gl / "> q hy 21 FEnantiomer 1 + Enantiomer 2 yt J) N 0 & ASA La. HN NN o = wold o NN NSN NY AL J pe H HA, NW \ O) —NH . = a Lx} ~All op? 2 > ¥ ~ ” as > AFH N NON O 3 | 3 —NH oo = - = 2 1) X oi 9 & Fi) a HN. or N 3 NN C 1X Enantiomer 1 + Enantiomer 2 Si Pee wl x mJ A AL AJ rN NZ o = oJ iS SN oY . = or Nz LX - oye r / N nN” Enantiomer 1 + Enantiomer 2 j=! ) / NTONT Enantiomer 1 + Enantiomer 2 jul HN, ~ \ N. UN | LJ ~ 8 N NN 4 8 CX z NN F o 7 LJ H Ww” oN YT F ye Cis Isomer - \ / oN / = Cis Isomer, Enantiomer 1 Nos Q — & F NT N F pact ot B NN Sr LAL AN jen Ae Je nH Me—NH Me o Oh ht & N od Go NN J ws x xX LN IQ oe a =I Me—NH = NY NTN NE XH at HN, 5 WS a | H NAN AD roa Nd Cis Isomer, Enantiomer 1 Enantiomer 1 A iw! ~~ & oO Z Z ol eh ’ re NA I" BY HN, \ Enantiomer 1 + Enantiomer 2 Cis Isomer, Enantiomer 2 i | y Wa ~~ o 1X YW Sn wo f Enantiomer 2 4 =e Enantiomer 1 NN § AL NOY FZ E anPaeN I Enantiomer 1 HN A ~~ & ~~ ( AN H ne — =~ HN— ° NN = | Enantiomer 1 A l Ya pL ° ig! (X Da Enantiomer 2 Re HN uN o< Enantiomer 2 A & oy ( NAN H ne =X 2 ) NZ ; Bg! : A 5 Enantiomer 2 Pe W NZ NNN a All J ot = of = = 0 of Enantiomer 1 YY 4 N o 4 / Wo endo Le \ y- NAN A -— W 0 4 ii | NNO ~ nN id 1 Ade — an PB ne Enantiomer 1 — Enantiomer 2 =H = N o hrs IA | H lL Ca ' 2 3 / Enantiomer 2 ° = = o ono As oA H NAN AnH N & 7 HN L Stereoisomer 3 o i J . & ~~ ~ Oo ! nN 0 ot Z Enantiomer 1 5 HN: = © = 7 o TL Stereoisomer 4 ~~ a NY ON I H = a o A Ao LL HN oy ATH NY NTF IT h = - RAL Ao Ba Stereoisomer 1 og Enantiomer 1 @ = | node JH 5 NN NT N F or of ~NTNZ ° NN LX NY INN Ne ; or H Stereoisomer 2 HN Enantiomer 2 i 7 o NN N or § CX Aen NN a: pe AnH Wo ~~ — J SN” H Enantiomer 1 io = o or ° NN 2 | N 1 — Enantiomer 2 = NN =~ ZN RS . =X WE 0 AN Ly SS FZ | N F NT ~~ j= 4 fo) INS YY A A $4 Aon 1 PR 4 1 YS yo AN or —NH = 4 x NS ZF no 5 P NY JA fF ™ “P= ~N =~ OMe ON “a” N j= NP SL #: OMe HN. HN, \ ” pt 3 r Yas ALT HN, - or YL, le we \_ Fp y ory - 3 a. ’ HN NZ i 5 LO A UN > “ - OMe HN, \ HN, N SO A < OFEt 8 HN N HN, N 0 ( pr WY Cy AN OCHF, HN A " noo © OMe ~~ _N —F = al & | Q i I; nes OMe v = = 3 ; ° NN =~ z LL 0 NN meg tS = 5 ° Z o 4 Ils ol ot ; SNL - § ~~ NN 0 I® Fan fog A QL " he? ° NN C A Sr + : Tao ~ 1% & = wy Le ~ o NN 0 WI soe v a =N Enantiomer 1 ) ~ + = 3 ° NN 4" Co ol ov / =~ o Jn a A ay o lw! ae 2s A A gsi 2 : _ EL NSS aor ° oh 7 zN Qo Sean AA = = 0 ag TE SE oo ASEH | NJ a Fu] ~All UH NT + HN— 7 / FiC 3) ar. oo Nolet F Ny - 5 La A _N ~~ i! IX oy ory r o Mv AE lo ie =\ ? LX NY NZ Some JOH WH = 0Y - 0 oH H XL LO v H NN ~\ a LLY Enantiomer 1 Sy NZ oMe = on ~All v Seas o v rex AL Fo Enantiomer 2 3 & ° NN “ oh apni T / N Ln o / on JUN Wo, cre 7 AL . 5 N AL XY F on =~ Noid Ngo A oh . ool yo Aen a N Fu, A § ® HoN N — . = = Zh res Yo Bog At HF . Ne A y Sy H HN— i! / NF (5 0 (7 LJ [ Lx > . p-? H yor F =~ o 4 i J > HN— / H > = 3 HN—" of =, | = Ww Jor or ort a pL od Raz =o J Sn / FiC | | 0 OH Ae ps JC ~ AL \ Enantiomer 2 SF 2 (J oS = ° = ~o CdR AL Sp NZ Enantiomer 1 Oh aq LL AD LA. Enantiomer 1 ° = Joke , hen AL J NZ Enantiomer 2 ly! Y rp Xo he A aR Y NAN ~ Enantiomer 1 SARE " or o ’ Hoe Weng oh Is Q f CLS CIC Enantiomer 1 | Jor or o Stereoisomer 1 lo! Q Fol Vpn” Xo No Enantiomer 2 = ° = o IN ZN N ol d Enantiomer 2 Stereoisomer 2 yg A Stereoisomer 3 oy N 7 2 LL = Z = Wl F N | 3 OY ANH a e se wn A \ LL" Enantiomer 1 + Enantiomer 2 ~ Stereoisomer 4 0 = =~ A LL { or A ’ or A, oy NTE pv es Enantiomer 1 + Enantiomer 2 / > ~ J Ox 0 Me oh Co N’ Sf ~ N NUN qd oo =~ nantiomer o™ NN wn TNS HN— o 5 o » oe SPY “ NAAN Anan LN A 4 > HN —i a =~ NH o 5 Cs o $2 ; SPY an Hoo Oo ~ N—NH ~ NN ~ ) Sr H ~ y OMe vv F JY = Enantiomer 1 + Enantiomer 2 N RX ° SP Ae o L Aan F PR: NTE 2 Home H NON A pe F \ Crantinmiar 1 1 Ernant:armar NH Lnantiomer 1 + £nantomer by ; 4 [Nn ° 4 ~~ ~ oO SN | / N = {NN h 1 1, 2 WN F SP F H PPG! Home ine Fu, A wt ( A H . og NN o 4 CY [ SL ’ SO 4 r r Ni 4 4 = o— NN " LLL 9 N A oe ” rye oN 3 oo Ls HN, Abs) > & oo yr ) ly ' a A ANA 3 Aa - AE = ° Ft AN @ ~All ¥ SAN Ho ome Nr mn Nec ow oll HE 22 Se =k = 2M 0 Mv or AL ros ¢ oe NH v va = H 2N A 7 H 4 0, H or z & NH v AT N og te : HN- =~ Jor ™ A =~ N 0 Gh or wd” 4 / 3 ~~ LX os aT NON [ A A Lxs O DH Fi Be A He EF ~~ F ~ AT NN RL 2 v A Ch A o AH A i ln H boo NV [N AL - ” 5 = N’ a5 ASS = = o { 1 a Noy NSP NZ { 1 AnH NSNON o H A 4 55 Cis Isomer. Enantiomer 1 Fi) 2 5 oh Cr = J! ZF NTN pe HN, 0 Cis Isomer. Enantiomer 1 4, Cis Isomer, Enantiomer 1 N o or RO ~ Vv _— = g I AF NSN H ee Cis Isomer. Enantiomer 2 ] A = TY HT he 1 of Cis [somer, Enanti | OX 4 ntiomer 2 nd AN F i ; _ oN" HN or r oi a to v ao re o ih ao 0 4 UN AL CY raat q YC Gol hoo / =~ f- ° NN N OE ag A NN F NN SPN a oo fog FE NN —t LL A WYN Pg v or ed ~~ ’ a o Wei STs \ a Wr z > ALL te! OF ¥ Al ¥ oo ST) Diastereoisomer 1 Nn 2 ™ ZN Lr = Hd NTF A F IN, ONS E RY 5 mL N vA F 2 LX Enantiomer 1 + Enantiomer 2 SP ZF Sh ! 0 Al N T ZN 3 ~~ ISNA or 0 H Z ih : Diastereoisomer 2 Enantiomer 1 i 7 AL o 5 | N £ 4 LL fe ON Enantiomer 2 a ol A o NN a I Enantiomer 1 + Enantiomer 2 NT N cl oT ~ » NN Enantiomer 1 Cre r H NN NN AH 0 IX WNP F ~ “ASN H NN JX @ ~My Z Nowe < or wv » Enantiomer 1 NH d oo | 0 ( J N H or o % SH 3 Enantiomer 2 XN o NA / r N 0 AN ax i r o AN 2x OT vv" = AT 0 AM ¢ at ! . = = ~ (AN 0 0 ~ x = OL be / Pe A Z H N NON o : N ; ro oy > BE or Enantiomer 1 yl WNP Ls 0” OY L- F WAN i) yo ’ NE 3 N NS Cis Isomer Enantiomer 1 Enantiomer 2 = = 0 [o LL ALL NSONTON Yo TN Aon YY F N ~<) HN HN, HN, N\ . . Pie femrnar Cis Isomer, Enantiomer 1 Cis Isomer Enantiomer 2 =Haiiiitist < =~ 0 1,00 Lr NN ~~) HN HN, y Cis Isomer, Enantiomer 2 y Cis Isomer, Enantiomer 2 Cis Isomer, Enantiomer 1 Fi ii] i 0X 2.) oY ZF ~A z LJ H N N F Cr en HN Fs HN: Cis Isomer, Enantiomer 1 oA 4 0 eg (1 — os = cr (XY ; NA Sy oA A Cis Isomer, Enantiomer 1 Sy H = o o—( pets & ~~ N ry F HN, rN oz ¥ HN. + Cis Isomer, Enantiomer 2 Bh fwd Ease oA o Zh HN a Fg! o Zh rg ws og ll | H [ H cl NAN ort A © HN A > 4 Enantiomer 1 oe Qo fare) (Abs) ~ 5 on oN ® 3 oi 1, H VO H a ’ ALC J N, ? { | od yp & 1 = H _ NA 4 NN oY 1 J NTN -~ . \ Nu J hl 5 Ie! = Ae ~& XL NY ON F Ow NAN ZF A cel H a" “o \ HH oo NRA So” Enantiomer 1 = NN 2 LL =~ Sy ZF | YY # Lx | H a N N EL - So H he 0 IZ o nN F = ¢ NN — ot a N ~ Ly v Hy . u NO A 4 AJ H RN & = 4 ole NL =~ N 5 =~ Z N WAI ~\ NA fo ’ SH N Zz = ro N | 2 2 LL ~~ ZF Sy F Ln A =~ NN a NN 4 fo NU WW = a NN a 0 N x N F Enantiomer 1 + Enantiomer 2 wold X “o_o pos Enanf ~ oh “1 LF oN ; on ~~ NN i “CZ Ar HN = 2 LX oreo Sung C HN: ae Enantiomer 1 + Enantiomer 2 O / / . A x o SPY F SY | H 373 ot Aen To _ HN—<] df [ 369 |

[374] = 1, 3 oo N il SP Zo HN A | NAN h ! I ° i! Ad LL NAN a v Li HN A Me jo] yw = = " F a ar 3 o | NH | 375 | be = J Me—NH

[571] ~~ wrapper opr HN ~~

[372] | SP PE opr MeHN Also is provided a compound, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, selected from Table 1A: Structure Structure | = = Q 7 oh Hl x WA SP F I” yr si HN - NS = HN__~ ~ Ayn << my 4 SNH o I Ny aE ZN = o C Ns 3 NH lh } ) “AN Q NL NH Q. Oh NSP > F o ® Aen Lor = JO 4 _— = PL il oo ~ £2 rr ° io! 9 & ot AL or yo A = NAN Ap ANH ~~) —N NL a ~~ 7 2 > Ad . > Nd Fy! § 1) " rd nn Nd oh a —N > . EE $ mA LL ZN Ih L ~y - nv] Nl Jey: Pols AN i) § oo oh mA LL or Oo HN, Nn = i! . or . } rN Ar Oo $5 HN HN. - "y— A o & abe A 3 A 0 = Pl re cre H WAN , ole ode Wm o \ fo [ ZZ ot 2 ’ = N Pet - SAL o&~ he . ~t Ned ~% nd Cyt o HJ Sy | H H Or Ze a5 H ode en AA - oh I! 0 o 7 i o i. / o oN q od SO LL ote AN # iQ pot x o WS = es = . 6 vr =~ Fa | Fy! he ~~ 5 ods he oe ! r 0 ed | vv ; & ~ Nee LO NL No oh =~ 2 P 0 NN or rd LF oF 4 N Ei oe 2 eles = ~~ / N ~~ An H ed CY —NH vv oo = io o ( 1 l { od oA 8 An 4 NH / & 2 fe) ( 3 NT i Zz [ Nee ye ee he Sf mS = » Ei) & ~All NZ i N N yt ’ ~ " ae 4 HN | = = fateh oO SN ZN hee) oO ° NN PURE be F: Aaa By vi A AL H ~r H.N ¢ . ~N HN § ll : HN, | - ~ Fd o NN 1 1 2 ~All oe Hn H ON Oy r AN HN ° Oh o eh N i abe Pa nen A x = 21 HN £ OF ~All Saal HN. J =~ Cy Zh ~, 'S or HN, \ = A NN {iN RAL 3 Oy 7 Cp yr [Ng HN, \ HN ] ) | NSP Ae Ao LL ! N | H or! 7 nl NH Nd ju Ww NH AN —_— - “N rf 2 CL ° NN WS FE LA aul NN a ~ | H N (1 HN HN, \ i & L / N wl / 2N N : H 4 0. — i ON wl ~ zN A : H 4 oN HN o = IR ot wl / I_Vv BB A & | NT N | i” —NH or a) w IN, o NIN - etd A oy ZN orld —NH SNS ™ L 0 Z & § LX HN A ZF PP H IA to or o I oN HN or SAN | | wo 0 AN oF; NAN ~ ASA Home 0 ANN LX y+ a a HN ae A Cg Oh Wy SLC / N Sy ie i) 2 0 7 fh older ~~) or jy —_— pe ) Ap rs AN = Ped T —_— ~ G Zh ; HE 5 oN NN A ho Pe F \ ] ory =~ » —NH 2 NZ Pe oo” J ! es "a ® 5 "i \ o rT IN ° ” iY oye ~ or No” 8 " . HN @ | rd Jo or oy es or HN a We! Fo oa ra be NTN FN = ~ HN, HN, — \ Cy =~ Fi) 2 & oO ZZ wer ol ne od I ~ =~ o MN" 0 NN N. X x ~ I LL ry HN. BSS iti Bh J idl. a ~ =k NN 0 x ZF AJL oa ae NTH i NN N” °N N. eS 7 _N he L. [ Jo " Net H 7 Ra Ra HN, N Le | y = & le peg 9 2 ~ 0 z or wl 4 a EN INE rr ; i % & 4 5 = 4 0 o po Res Hy Hey 2 = o hoger Sr A i AN dh ’ ead J 4 rr ‘ & Fi! oy > F oS AK 5 be, FA I) NN = NN old 1 IX N NSP ZF S$ AnH in ~~ — «J SN H = = o or é NN Z | N py — =~ NN =~ ZN x L =X, We 0 AN LB NN Z no Ny ? 4 = ° NN NC a nt 3 —NH ~~ H 0 N IN Sy A Aen ’ 0 (oN PY N Jon fH OMe NY A fF hg JOO a HN, \ [\ 0 N° 5 a 0 a oN IT VY NN A 0 SA Ho ome HN r HN A & or yy X o N HN, - he H 0 L / re & ’ nk g oy - \ 2 ON Ho lH AN OMe HN, \ v N - 0 Aun = Nos SS N OCHF, NSP . No ARN A HN, \ Aor yh gv o { PD 2) oY Th AL SN i » [\ 9 a 7 AK Ro Owe or Fi o 4 2 jeg pes of & oY NY NTN | Jam _{ SO Lv 4 H Ae i; ° oH = 2 sorb a No oye" = Yr wi Le Sue AT NNT 4 a o = = ~All ~All aor" ! nA ’ a" a! ~ ch pet Ch AL ~ NANA ~ = qd Ned N J LL N pt ] wr F oo AMAL = . 21 JN LT = Ped loWs; rete _ WA o MY 2 LX N ot a AD _ ° Ie! eS = ae ye Q & ° = A te NL ’ Aan | ~~ “NT Cl UN N N F i I PI NSP NZ OMe N rn ALD ag H ~ Hiv ou ON of = HN 1 of Pe F A Lr je ” oA N= ” =A F Sv I= \, Nn H ! FaC os a [ N H NS A yee AH H [TN n AH =~ =! NY ON NF 1X " NT N” °N” “OMe 5 AN N ot SI NF & rs sey Leom SALT LX > H Nr F = Yr i! nN NS Pp or " HN iy Nr Tr AN x ore Thc: sid wt Sn / FiC & we] J o Reg Cr eee AT HE ; ol HN. 5 NN = of os 8 RAT o & a Zh Sr rls A AL ni A ~ 0 ANN aq & ol noe or Lo ) “7 Dai NZ > = = ° oY H Hr ’ os A 4 A rr rey NN ! ALD FH J A v NN i ~ § LL YH PE frah al H — Bh = ~ Po pu! H AH Ww ~ t = ° dN N Qo = » oy SL - Al o™ NAN WAN ou LAA NH = v ° NN , ~All l i 4 Aen aq Is} PS NS vo et Hoo Fa: \ 4 ra 11 / ” or A 0 & SAA or Go ae — ~All ” Lo ye vk ~A y Co 5 No” BS IN oO 2 3 IL A i» AL Y N = oO & or Hl N, [ Z or N Jeane 0 Lo ys or Beas or F 0 (on Or J ae A ome YH \ NH 4 ~~ ~ —\ A N @ 0 ~ FZ NON F OMe HN NP Fu, A Se” H Ci AL 7 - pee ot A 4 CB LF AN NH 3 NBoc 4 4 0, = . o NN Set LL 0 oh 0 4.5 > 5 o o~ oy Lr N= y yen WE v oh = N LA Me ag TT nA i OMe Lv he ~ a2 NN NAN H “rr Qf N LA 0” N i OX 4d v" 7 ~ 9 1) NN 7 1 1 AH ™ or Na >—NH vv / =, Ch 0 ox A ) ore No” NAN [oN _N N qa v HN— / ™ G g ° NN og le! CO 4. a ~~ { & or N i lL . 0 pe ~t A A a N\A ee Aa aE ’ H AN Y ’ 22 or @ at ~~ A. NN ~Aarle 9. H aa § j LX MA Ny u keg N 7 a oh 5h 4 LO or 5 CL SON ZF HN: b © N [Nn o Su ho [Ny vv or ch 2 & hs ot = vo NN Ap LX = # _— Ml Lr ~ I AH 0 { I Qs =~ ° NN ju hello Se: ~~ & Oo " =~ = £Y NN 0 NN 0 AL xl “AL 1 SN n HNL NTH F = si v 0 o = pS RB N. - oh oF 3 NH A Va Fy Be! < = : =\ 7 0 ANN ° . 4 Penne H N R NSP F vv MoU ao I! PE A SA = Ch or ove F AA i N \ nL 4 ~ F o NN 5 N ? F Ih Se, J rr oe SAH daa : So ARE ALL = AN " 9 jd YY SO No HN een A —~) HN, \ 8 1 ZF NN H Ae aff = NY NN NE pees HN 9 3 spaglhs hen A A. Je ot / oT - ; Ann f od of oH NSA NZ x q & A Sy Bt Pe L Ap te So 7 Sah J I ad od ay SEE rr pe [mn HN Si vo ; or NT HN = Sy bod : ~N LX or An H Cl Cr HN Ny > = o WN zN TY QL v af vo | = = LL of oe mr 7 ° Nf AX 7 ey Ny | N° Ad = @ Zh Cy N | oO ~All AY op or Na Sy HN of | Z | H ; H So ~ = } = ° NN | N oN wo 4 \ = a oo = 0 A 0 XC ao ’ NN F Vv or ” ™ 0 Ny % NN R ~All 4 AnH a 4 ms oo r N AF | oh & % 7 aor oN f 5 ~~ ~zN = ¢ 0 lo! - SS Fig! Q NZ AL 0 oe " LO uy Cd = LN A I LL 3 h CN CX 70 ore NHH -° oak TL NRA Ny Ad lJ 2 NT N F A ~yAen bg NNO fo HN: N H < = < a Ih . of ~All ZN ess 0-2 NH ° J = AN " F a NH ye ae N ’ Vi NZ oN ~ = VN : (7 0X A OR >F 4 BOY H Sn? H-N Sv HN A ~~ ~ Zh % o a Nes | J LL NY ON F N 7 > oe MeHN HN 7 — iN ‘re MeHN HN _ —_ ol ’ N WN Ae Aut oO A HEE N o - ~~ BORD! HN—<] Py 1X 7 S NN Poe "a Indications and Treatment Methods A compound described herein may be useful for treating a disease or condition mediated, at least in part, by a protein implicated in neurodegenerative disease. In some embodiments, a compound described herein is useful for detecting diseases or conditions mediated, at least in part, by HTT protein. In some embodiments, treatment of a disease or condition mediated, at least in part, by a protein implicated in neurodegenerative disease may comprise administration of a compound described herein. Treatment may include coadministration of a compound described herein and one or more other active agents and / or therapies. In some embodiments, provided is a method of treating or preventing a disease or condition mediated, at least in part, by a protein implicated in neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein. Exemplary diseases or conditions are as follows. Huntington’s disease (HD) Huntington's disease (HD) is an inherited progressive neurodegenerative condition, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy. Atrophy may begin in the striatum and cortex and extend to other subcortical brain regions. HD belongs to a family of neurodegenerative diseases in which an expanded CAG repeat tract results in long stretches of polyglutamine (polyQ) in an encoded protein. The family also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and the spinocerebellar ataxias (SCAs). In HD, the selective neurodegeneration of the y-aminobutyric acid-releasing spiny-projection neurons of the striatum had been observed, although neuron loss in many other brain regions has also been reported. Symptoms of HD include loss of motor control, psychiatric symptoms, memory and / or cognitive impairment. Huntingtin protein (HTT protein) is a 348-kDa multidomain protein that contains a polymorphic glutamine / proline-rich domain at its amino-terminus. The number of CAG repeats in the IT}s gene that encodes them varies from 6 to 35 in healthy individuals; repeats of 36 or more define an HD allele. The length of the CAG expansion has been inversely correlated with age of disease onset, with cases of juvenile onset characterized by expansions of more than 60 repeats. Reduced penetrance is seen between 36 and 39 repeats. See McColgan P, et al., Huntington's disease: a clinical review, Eur. J. Neurology, 2017, Vol. 25, 24-34, which is incorporated by reference herein in its entirety. The longer polyQ domain is believed to induce conformational changes in the HTT protein, which causes it to form intracellular aggregates that, in many, manifest as nuclear inclusions. However, aggregates can also form outside the nucleus. HTT protein is present in the nucleus, cell body, dendrites and nerve terminals of neurons, and is also associated with a number of organelles including the Golgi apparatus, endoplasmic reticulum and ‘mitochondria. A diagnosis of Huntington's disease is based on a confirmed family history or positive genetic test and the onset of motor disturbance as defined by the Unified HD Rating Scale (UHDRS) total motor score (TMS) diagnostic confidence score. This score ranges from 0 (no motor abnormalities suggestive of HD) to 4 (299% to be due to HD), with a score of 4 defining motor onset or ‘manifest’ HD. However, subtle motor, cognitive and psychiatric deficits can be identified up to 10-15 before the onset of manifest disease and this is referred to as the pre-manifest stage of the disease. Huntington's disease (HD) stages are described in, e.g., Winder, J.Y. et al., Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP, Mov Disord Clin Pract. 2018 Sep-Oct; 5(5): 527-533, which is incorporated by reference herein in its entirety. HD may be classified as early stage (stage 1 or 2 TFC score), mid stage (stage 3 TFC score), or late stage (stage 4 or 5 TFC score). See, e.g., Shoulson, I. et al., Huntington disease: Clinical care and evaluation, Neurology, 1979, Vol. 29(1), 1; Shoulson, I., Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs, Neurology, 1981, Vol. 31(10), 1333-35.The part of the brain most affected by HD, and thus believed to be most likely to contain HTT protein abnormalities, is a group of nerve cells at the base of the brain known collectively as the basal ganglia. The basal ganglia organize muscle-driven movements of the body, or “motor movement.” The major components of the basal ganglia are the caudate and the putamen (together known as the striatum) and the globus pallidus (external and internal regions). The substantia nigra and the subthalamic nucleus are often included as part of the basal ganglia as well. Basal ganglia are a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions. Disruption of the basal ganglia network are believed to contribute to several movement disorders. Normal function of the basal ganglia requires fine tuning of neuronal excitability within each nucleus to determine the degree of movement facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where the excitability of medium spiny neurons is controlled by several pre- and postsynaptic mechanisms as well as interneuron activity, and secured by several recurrent or internal basal ganglia circuits. The motor circuit of the basal ganglia has two entry points, the striatum and the subthalamic nucleus, and an output, the globus pallidus pars interna, which connects to the cortex via the motor thalamus. A compound described herein, when administered to a subject, may inhibit neuron degeneration. In some embodiments, inhibiting neuron degeneration may include inhibiting axon or neuron degeneration in a neuron. Such inhibition with respect to the entire neuron or a portion thereof, such as the neuron cell body, axons and dendrites. This can be assessed, for example, by analysis of neurological function according to methods known in the art. The administration of a compound described herein may result in a rescue, for example, at least a 10% reduction (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 10%, 15% 80%, 85%, 90% or 100%) in one or more symptoms of a disease or condition described herein. The disease or condition may be a disorder of the nervous system that is secondary to a disease, condition, or therapy having a primary effect outside of the nervous system; an injury to the nervous system caused by physical, mechanical or chemical trauma; autoimmune neural degeration; neurodegeneration secondary to infection; and / or ocular neurodegeneration. Symptoms of nerve degeneration include, e.g., tremors, slowness of movement, ataxia, loss of balance, depression, decreased cognitive function, short term memory loss, long term memory loss, confusion, changes in personality, language difficulties, loss of sensory perception, sensitivity to touch, numbness in extremities, muscle weakness, muscle paralysis, muscle cramps, muscle spasms, significant changes in eating habits, excessive fear or worry, insomnia, delusions, hallucinations, fatigue, back pain, chest pain, digestive problems, headache, rapid heart rate, dizziness, blurred vision, shadows or missing areas of vision, metamorphopsia, impairment in color vision, decreased recovery of visual function after exposure to bright light, and loss in visual contrast sensitivity. The administration of a compound described herein may result in at least a 10% decrease (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 10%, 75%, 80%, 85%, 90%, 95%, or 100%) in the number of neurons (or neuron bodies, axons, or dendrites thereof) that degenerate in a neuron population or in a subject compared to the number of neurons (or neuron bodies, axons, or dendrites thereof) that degenerate in neuron population or in a subject that is not administered the one or more of the compounds described herein. Neurons can convey information from tissues and organs into the central nervous system (afferent or sensory neurons) and transmit signals from the central nervous systems to effector cells (efferent or motor neurons). Other neurons, designated interneurons, connect neurons within the central nervous system (the brain and spinal column). Certain specific examples of neuron types that may be subject to treatment according to the disclosure include cerebellar granule neurons, dorsal root ganglion neurons, PNS neurons (e.g. sensory neurons), and cortical neurons. Other examples of cell types that may be subject to treatment according to the disclosure include astrocytes and microglia. A neurodegenerative disease is a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of neurodegenerative diseases include, e.g., Alexander's disease, Alper’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick’s disease, Primary lateral sclerosis, Prion disease, Refsum’s disease, Sandhoff disease, Schilder’s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance or Tabes dorsalis. In some embodiments, the disease or condition is selected from Huntington's disease (HD), dentatorubropallidoluysian atrophy, spinal and bulbar muscular atrophy, spinocerebellar ataxia, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson’s disease, amyotrophic lateral sclerosis, cerebral cavernous malformation, cardiovascular disease, Alzheimer’s disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes, chronic and / or neuropathic pain, stroke, ischemia, retinopathy, spinal muscular atrophy (SMA), erectile dysfunction, nephropathy (non-hypertensive), hypertensive nephropathy, hypertension (high blood pressure), optic nerve lesion, hepatic fibrosis, lupus, liver failure after transplant, encephalomyelitis, epilepsy, and glioblastoma. Further, the compounds described herein can be used in the prevention or treatment of memory loss. Types of memory that can be affected by loss, and thus treated according to the disclosure, include episodic memory, semantic memory, short-term memory, and long-term memory. In some embodiments, the disease or condition is a neurodegenerative disease selected from Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Prion disease and spinocerebellar ataxias. In some embodiments, the neurodegnerative disease is classified as a trinucleotide repeat disorder. In some embodiments, the trinucleotide repeat disorder is classified as belonging to Category I, Category II, or Category III. In some embodiments, the neurodegenerative disease is Huntington's disease. Also provided is use of a compound described herein for the manufacture of a medicament for use in diagnosis, prevention, or treatment of a disease or condition described herein. For example, the disease or condition may be Huntington’s disease. Pharmaceutical Compositions and Administration Thereof Compounds provided herein may be administered in the form of a pharmaceutical composition. Thus, provided herein are also pharmaceutical compositions that contain a compound described herein and a pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). The pharmaceutical composition may be formulated for administration by various methods including, for example, oral, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. The pharmaceutical composition may be formulated for administration by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical excipients. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable vehicle, for example as a solution in 1,3- butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be useful in the preparation of injectables. Such solutions may be formulated as 0.01% -10% isotonic solutions, pH 5-7, with appropriate salts. The compound described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion techniques. The compound described herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration the carrier comprises at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is chosen from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. A pharmaceutical composition, for example, for injection, may comprise a cyclodextrin. The cyclodextrin may be, for example, a hydroxypropyl cyclodextrin or a sulfobutylether cyclodextrin. The cyclodextrin may be, for example, an a-cyclodextrin, a B-cyclodextrin, or a y-cyclodextrin. A compound described herein may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood. Suitable examples of sustained release carriers include semi-permeable polymer matrices in the form of shared articles, e.g., suppositories or microcapsules. Examples can be found, e.g., in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A. R., Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, N. C. et al. 7th Edition ISBN 0-683305-72-7, the entire disclosures of which are herein incorporated by reference. The pharmaceutical composition may be formulated for oral administration. The pharmaceutical composition may be in the form of, for example, a capsule or a tablet. The oral formulation may include an enteric coating. In making the pharmaceutical composition the compound described herein is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders. Some examples of suitable excipients include, e.g., lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methyl cellulose. The pharmaceutical composition can additionally include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents. The pharmaceutical composition can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. For preparing solid compositions such as tablets, the compound described herein may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture. When referring to these preformulation compositions as homogeneous, the compound may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the intestine, or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of ‘polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The compound described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Furthermore, pharmaceutical compositions containing the compound described herein can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methyl cellulose, glucose / sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifying agents (e.g., lecithin, sorbitan monooleate, or acacia), non- aqueous vehicles, which can include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol and ethyl alcohol), and preservatives (e.g., methyl or propyl p-hydroxybenzoate and sorbic acid). Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. A compound described herein, or a pharmaceutical composition thereof, may be administered in an appropriate dose as determined by an informed medical practitioner. The compound or pharmaceutical composition may be administered in a single dosage or in multiple dosages, and in a single dosage form or in a plurality of dosage forms (e.g., two tablets or three capsules). For any particular subject, an appropriate dose will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, active agents used in combination, and the severity of the particular disease or condition, of the subject. For example, a dose may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg) per day. A dose of about 0.1 to about 150 mg / kg may be appropriate. In some embodiments, a dose of about 0.1 to about 100 mg / kg may be appropriate. In some embodiments, a dose of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate. In some embodiments, a dose may be administered in multiple administrations per day, for example, in one administration per day, two administrations per day, or three administrations per day. In some embodiments, a dose may be administered once in two days, once in three days, once in four days, or once per week. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. Kits Also provided herein are kits that include a compound described herein and suitable packaging. In certain embodiments, a kit further includes instructions for use. In one aspect, a kit includes a compound described herein, and a label and / or instructions for use of the compound in the treatment of a disease or condition described herein. Also provided herein are articles of manufacture that include a compound described herein in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe and / or intravenous bag. Combination Therapy In some embodiments, a compound described herein is administered in combination with one or more additional active agents. The methods described herein include methods for detecting, treating or preventing a disease or condition described herein, for example, Huntington's disease, comprising administering to a subject, simultaneously or sequentially, a compound described herein and one or more additional active agents. In methods using simultaneous administration, the agents can be present in a combined composition or can be administered separately. When used in combination with one or more additional active agents, a compound described herein may be administered prior to, concurrently with, or following administration of the additional active agents. The administration can be by the some route or by different routes. Also provided is a pharmaceutical composition comprising a compound described herein and one or more additional pharmaceutical agents used in the treatment of Huntington's disease such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, ‘haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. Similarly, also provided is a packaged pharmaceutical composition containing a pharmaceutical composition comprising a compound described herein, and another composition comprising one or more additional pharmaceutical agents used in the treatment of Huntington's disease such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. In some embodiments, the active agent is carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, or risperidone. Also provided are methods for treating or preventing Alzheimer’s disease, including treating memory and / or cognitive impairment associated with Alzheimer’s disease, comprising administering to a subject, simultaneously or sequentially, a compound described herein and one or more additional agents. In some embodiments, the active agent is Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, Estrogen or Clioquinol. In some embodiments, compounds described herein can be administered with an active agent for treating Parkinson’s disease, for example, with L-dopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and lisuride), dopa decarboxylase inhibitors (e.g., levodopa, benserazide, and carbidopa), and / or MAO-B inhibitors (e.g., selegiline and rasagiline). In some embodiments, compounds described herein can be administered with an active agent for treating Alzheimer’s disease, for example, with acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and / or NMDA receptor antagonists (e.g., memantine). Synthesis of the Compounds A compound described herein may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of a typical compound described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. A compound described herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006), Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and references cited therein. Furthermore, a compound described herein may contain one or more asymmetric (“chiral”) centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like. When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in the Examples. The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Sigma Aldrich, Alfa Aesar, and the like. Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The terms “solvent,” “inert organic solvent” and “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like). Generally, the term inert, as used herein with respect to a solvent, refers to a material that does not undergo reaction to form the target compound of interest though carbon-carbon bond forming reactions. Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon. The term “q.s.” means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%). It will also be appreciated that in each of the below schemes, the addition of any substituent may result in the production of a number of isomeric products (including, but not limited to, enantiomers or one or more diastereomers) any or all of which may be isolated and purified using conventional techniques. Incorporation of an isotopical label, e.g., a deuterium atom, into a compound described herein may be conducted by reacting an appropriate starting material(s) with a reagent including a radioactive isotope. Methods typically follow the same principles as standard organic chemical reactions, and may be carried out by any method known to those of skill in the art, including those provided in the present disclosure. Scheme 1 provides exemplary synthetic routes for the synthesis of compounds provided herein (e.g., compounds of Formula I). The compounds of Formula I, or other formulas or compounds disclosed herein, are typically prepared by first providing Formulas Va and Vb and then attaching the desired substituents using suitable conditions (e.g., amide bond formation, nucleophilic aromatic substitution, or cross coupling). In some embodiments, synthesis of a compound of Formula I proceeds according to Scheme 1. Synthesis of a compound of Formula I may proceed by coupling Compound Va with Compound Vb to form Compound Vc, coupling Compound Vc with Compound Vd, and preparing a compound of Formula I by one or more subsequent steps. Scheme 1 5 24=Z pn; —— — 24-22 J % XL Hy EL R2 Vb Va xi ] A? | - x 1 Va 5 24=Z A — — Formula | rr vd zz 5 N ° SAY 7G x TX X N vs ~X3 . ” Fh Re Ve Veo In Scheme 1, R}, R4 R?, X!, X2, X3, X*, Y', and Y? are as defined herein. A’, A2 and A? are as defined below, and Z3-Z*-Z° is N-CR’=CR® or C=CR’-NR!?. In Scheme 1, Compound Va may be joined with Compound Vb by amide bond formation through a leaving group at A' and an amine in Compound Vb (as shown in Scheme 1). A' may be a suitable leaving group such as, for example, a halide, a pseudohalide, a carboxylic acid or carboylate. Compound Va may be activated at A' by an activating agent for activating a carboxylate group (e.g., chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, HATU, HBTU), optionally in the presence of a base (e.g., 1-methylimidazole, triethylamine, diisopropylethylamine), and in a suitable solvent (e.g., a polar aprotic solvent such as acetonitrile, DMF, or dichloromethane). Alternatively, a carboxylate at A' may be first activated by an activating agent (e.g., oxalyl chloride) and then combined with Compound Vb in the presence of a base (e.g., triethylamine, diisopropylethylamine). In such embodiments, an activated form of Compound Va (e.g., where A! is a halide such as a chloride) need not be isolated, and the reaction can be conducted in one pot. In Scheme 1, a compound of Formula I may be prepared. Thus, Compound Vc may be joined with Compound Vd in a coupling reaction, e.g., by nucleophlic addition such as nucleophilic aromatic substitution to Compound Vc at A2 In such embodiments, A> may be a suitable leaving group (e.g., a halide such as a chloride or a fluoride, or a pseudohalide such as a sulfonyl), and A® may be a hydrogen atom or, where R' is present as an anion, a cation (e.g., sodium ion, potassium ion). A nucleophilic aromatic substitution may be carried out heated (e.g., to a temperature of 50 to 200 °C) in the presence of a base (e.g., triethylamine, cesium carbonate, NaH, potassium carbonate, pyridine), and in a suitable solvent (e.g., dioxane, DMF, acetonitrile, DMSO). Alternatively, Compound Vc may be joined with Compound Vd in a coupling reaction (e.g., a metal-catalyzed coupling reaction). In such embodiments, for example, A? may be a leaving group (e.g., a halide such as a chloride or a bromide, or a pseudohalide such as a sulfonyl), and R! may comprise a suitable coupling functionality (e.g., a carbon-carbon double bond) and A? may be a complimentary coupling partner to A? (e.g., a hydrogen atom or a tin- or boron- containing group). The reaction may be conducted with a catalyst (e.g., bis(triphenylphosphine)palladium(IT) dichloride), and optionally in the presence of a base (e.g., sodium carbonate). In some embodiments, A> may be R', and Compound Vc may be converted to a compound of Formula I directly (without reaction with Compound Vd). In Compound Va, Vb, Vc, and / or Vd, any of R', R%, R?, X!, X2, X* X* Y', Y2 Z* and Z° may be present in a protected form, for example at an amine or hydroxyl group. Amine protecting groups include those known in the art and described herein, including, for example, the tert-butoxycarbonyl group. In such embodiments, an additional step of deprotection may be needed. For example, where the protecting group is a tert-butoxycarbonyl group, an acidic deprotection step (e.g., using HC in dioxane or TFA) may be needed to prepare the compound of Formula I. A person of skill in the art will appreciate that any of Compound Va, Vb, Vc, or Vd may be available from a commercial supplier for a particular embodiment. Alternative synthesis of Compound Va, Vb, Vc, or Vd may be as described herein or as known to those of skill in the art. EXAMPLES The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Analytical Methods Acidic QC methods AcHSSC18 - standard acidic UPLC-MS Instrumentation UPLC + Waters DAD + Waters SQD2, single quadrapole UPLC-MS MassLynx Files Column ‘Acquity UPLC HSS C18 1.8 um 100 x 2.1 mm. (Plus guard cartridge), maintained at temp Mobile Phase A Water (High purity via PureLab Option unit) with 0.1% formic acid _ Mobile Phase B Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid Flow 0.4 mL / min Gradient Program Time (mins) % A %B 0.0 95 05 0.4 95 05 05 95 05 95 95 05 95 05 6.0 05 95 6.8 05 95 7.0 95 05 8.0 95 05 Sample 0.5-2uL (concentration ~ 0.2 -1 mg / mL). Detectors UV, diode array 210nm-400nm Resolution 1.2nm Other wavelength traces are extracted from the DAD data MS, mass 100-700 (or —1500 for HM method) in ES+ & ES- (300puL / min split to MS) 10cm_Formic_AQ - standard acidic UPLC-MS Instrumentation UPLC + Waters DAD + Waters SQD2, single quadrapole UPLC-MS MassLynx Files Column ‘Acquity UPLC HSS C18 1.8 um 100 x 2.1 mm. (Plus guard cartridge), maintained at temp Mobile Phase A Water (High purity via PureLab Option unit) with 0.1% formic acid Mobile Phase B Acetonitrile (Far UV grade) with 0.1% (V / V) formic acid Flow 0.5 mL / min Gradient Program Time (mins) % A %B 0.0 95 05 12 95 05 35 0 100 49 0 100 5 95 05 6 95 05 Sample 0.5-2uL (concentration ~ 0.2 -1 mg / mL). Detectors UV, diode array 210nm-400nm Resolution 1.2nm Other wavelength traces are extracted from the DAD data MS, mass 100-700 (or —1500 for HM method) in ES+ & ES- (300pL / min split to MS) ‘Acidic 1 - standard acidic UPLC-MS Instrumentation UPLC + Shimadzu SQD2, single quadrapole UPLC-MS Column Phenomenex C18 Kinetex column, 5 pm (4.6 x 150 mm) (Plus guard cartridge), maintained at temp Mobile Phase A Water with 0.1% v / v trifluoroacetic acid Mobile Phase B Acetonitrile with 0.1% v / v trifluoroacetic acid Flow 2.0 mL / min Gradient Program Time (mins) % A %B 0.0 95 5 10.0 0 100 13.0 0 100 14.0 95 5 Sample 0.5-2uL (concentration ~ 0.2 -1 mg / mL). Detectors UV, 254 nm and 215 nm MS, mass 100-700 in ES+ & ES- (300uL / min split to MS) Basic QC methods BicarbBEHC18 - standard basic UPLC-MS Mobile Phase A Instrumentation UPLC + Waters DAD + Waters SQD2, single quadrapole UPLC-MS MassLynx Files Column Acquity UPLC BEH Shield RP18 1.7 um 100 x 2.1 mm. (Plus guard cartridge), maintained at temp Mobile Phase A Water (High purity via PureLab Option unit) with 10 mM ammonium bicarbonate (ammonium hydrogen carbonate) Mobile Phase B Acetonitrile (Far UV grade) Flow 0.4 mL / min Gradient Program Time (mins) % A %B 0.0 95 05 0.4 95 05 6.0 05 95 6.8 05 95 7.0 95 05 8.0 95 05 Sample 0.5-2uL (concentration ~ 0.2 -1 mg / mD). Detectors UV, diode array 210nm-400nm Resolution 1.2nm Other wavelength traces are extracted from the DAD data MS, mass 100-700 (or —1500 for HM method) in ES+ & ES- (300pL / min split to MS) 10cm_Bicarb_AQ - standard basic UPLC-MS Instrumentation UPLC + Waters DAD + Waters SQD?2, single quadrapole UPLC-MS MassLynx Files Column Acquity UPLC BEH Shield RP18 1.7 um 100 x 2.1 mm. (Plus guard cartridge), maintained at temp Mobile Phase A ‘Water (High purity via PureLab Option unit) with 10 mM ammonium bicarbonate (ammonium hydrogen carbonate) Mobile Phase B Acetonitrile (Far UV grade) Flow 0.5 mL / min Gradient Program Resolution 1.2nm Sample Detectors Time (mins) % A %B 0.0 95 05 1.2 95 05 35 0 100 4.9 0 100 5 95 05 6 25 05 0.5-2uL (concentration ~ 0.2 -1 mg / mL). UV, diode array 210nm-400nm __ Resolution 120m Other wavelength traces are extracted from the DAD data MS, mass 100-700 (or —1500 for HM method) in ES+ & ES- (300uL / min split to MS) General Procedures Compounds were named with the Chemdraw 18.1 structure naming tool. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware. Examples 1-140 Examples 1-140 were conducted in accordance with the following: Method A Ester hydrolysis Ester, methanol (11 mL / mmol), water (1.08 mL / mmol) and LiOH-H,O (1 eq.) were combined and stirred at room temperature for 17 hours, then at 50 °C for 3 days. The reaction mixture was evaporated to dryness to give the corresponding lithium carboxylate salt. Method B HBTU coupling Lithium carboxylate salt, amine (1.0 eq), HBTU (1.0 eq), triethylamine (12 eq.) and DMF (7 mL / mmol) were combined and stirred at r.t. for 19 hours. The reaction mixture was filtered and purified by preparative HPLC. Method C HCI Boc deprotection Boc protected amine, methanol (20 mL / mmol) and 4N HCl in dioxane (20 mL / mmol) were combined and stirred at r.t. for 2 - 17 hours. Reaction mixture was evaporated to dryness and purified by preparative HPLC. Method D S~Ar displacement Substituted aryl halides, amine (1 eq), cesium carbonate (1.1 eq) and DMF (5 mL / mmol) were combined in a sealed tube and heated to 100 °C for 1-5 days. The reaction mixture was cooled to room temperature. The cesium salts were removed by filtration and the filtrate evaporated to dryness to give crude product which was used directly in next step. Method D2 SxAr displacement Substituted aryl halides, amine (1 eq), triethylamine (1.1 eq) and MeCN (5 mL / mmol) were combined in a sealed tube and heated to 60 °C for 1-5 days. The reaction mixture was evaporated to dryness to give crude product, which could be purified or used directly in the next step. Method E TFA Boc deprotection Boc protected amine, dichloromethane (4 mL / mmol) and TFA (23 eq) were combined and stirred for 1 day. Reaction mixture was evaporated to dryness and purified by preparative HPLC. Method F Cul coupling conditions Benzamide, aryl halide (1.05 eq.), copper (I) iodide (0.10 eq.), potassium carbonate (1.5-2.5 eq.) and DMEDA (0.20 eq.) in toluene (2 mL / mmol) was degassed, sealed and heated at 100 °C for 20-114 hours. After this time the reaction mixture was filtered through celite and concentrated under reduced pressure. Method G t-BuBrettPhos conditions Benzamide, aryl halide (1.05 eq.) terr-BuBrettPhos-Pd-G3 (0.10 eq.) and K3POy4 (1.4-2.4 eq.) were placed in a stem block tube. Toluene (3 mL / mmol) was added and the reaction degassed. The reaction mixture was heated at 110 °C for 18-114 hours. After this time the reaction mixture was filtered through celite and concentrated under reduced pressure. Method H TCFH coupling TCFH (1.20 eq.) was added to acid (1.0 eq.), amine (1.30 eq.) and 1-methylimidazole (2.5-3.5 eq.) in MeCN (3 mL / mmol) at room temperature with stirring for 16 h. Method I tri-tert-butylphosphine Buchwald conditions Aryl bromide, amine (2 eq), Pd(PtBus), (0.2 eq) and Cs2COs (3 eq) were suspended in dioxane (3 mL / mmol) and the mixture purged with N; for 10 minutes. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washing with DCM, and the filtrate was concentrated to dryness. Method J Pd,(dba)s Buchwald conditions Aryl bromide, amine (1 eq), Pd2(dba)s (0.1 eq), rac-BINAP (0.2 equiv) and Cs2COs (4 eq) were suspended in DMF (3 mL / mmol) and the mixture purged with N; for 10 minutes. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washing with MeOH, and the filtrate was concentrated to dryness. Method K RuPhos Pd G2 Buchwald conditions Aryl bromide, amine (2 eq), RuPhos Pd G2 (0.1 eq), and Cs>COs (3 eq) were suspended in '‘BuOH (20 mL / mmol) and the mixture purged with N; for 10 minutes. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washing with MeOH, and the filtrate was concentrated to dryness. Method L Boc protection Aryl amine (1 eq), di-rerr-butyl dicarbonate (1.3 eq) and EtOAc (0.298 M) were combined and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with water and the layers separated, The aq. layer was washed with EtOAc (x2), and the combined organics washed with brine, dried (phase separating filter paper) and concentrated in vacuo. Method M Amino pyridinium salt formation Substituted pyridine (1 eq) was dissolved in DMF (0.13 M) and O-(2,4-dinitrophenyl)hydroxylamine (1.1 eq) was added. The reaction mixture was stirred at r.t. for 16 h. Method N 1,3 dipolar addition Amino pyridinium salt (1 eq), ethyl 2-butynoate (1.1 eq), K2COs (1.5 eq) were dissolved in DMF (0.088 M) and the reaction mixture was stirred at r.t. overnight. Method O HBr Decarboxylation Ester (1 eq) was dissolved in 48 wt. % in HO Hydrobromic acid (0.2 M) and the reaction mixture stirred at 100°C for 4 h. Method P Pd catalyzed amidation Lactam (1 eq), heteroaryl chloride (1 eq) and Cs,COs (1.5 eq) were suspended in dioxane (0.2 M) and the mixture purged with N> for 10 minutes. Pd2(dba)s (0.2 eq), Xantphos (0.2 equiv) were then added, the tube was sealed and heated to 100 °C for 16 h. After cooling to RT the mixture was evaporated to dryness, loaded onto silica in DCM / MeOH and purified by silica gel chromatography. Method Q Formaldehyde reductive amination Amine (1 eq), formaldehyde (37% solution, 50 eq), methanol (1 mL), and sodium triacetoxyborohydride (2 eq) (1.5 eq) were combined and the resulting mixture was stirred at rt for 16h. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried and evaporated. The crude material was purified by achiral SFC or prep HPLC. Intermediate 1: 5-Chloro-N-(8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)pyrazine-2-carboxamide = 0 COH NT > - ° NN Ny FZ AN ; ’ 5-Chloro-2-pyrazinecarboxylic acid (960 mg, 6.05 mmol), 8-fluoro-2-methylimidazo[1,2- alpyridin-6-amine (1000 mg, 6.05 mmol), Chloro-N,N,N,N-tetramethylformamidinium hexafluorophosphate (2038 mg, 7.25 mmol), 1-methylimidazole (1.49 mL, 18.16 mmol) and acetonitrile (25 mL) were combined and stirred at room temperature for 18 hours. Water (50 mL) was added and the reaction mixture was filtered and the solid dried in vacuo to give 5-chloro-N-(8-fluoro-2- methylimidazo[ 1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step. MS (ES+) 306 (M+H), *H NMR (400 MHz, CDCl;) 9.37 (1H, 5), 9.26 (1H, d, J=1.4 Hz), 9.08 (1H, d, J=1.8 Hz), 8.60 (1H, d, J=1.4 Hz), 7.46 (1H, d, J]=2.8 Hz), 6.87 (1H, dd, J=1.8, 10.8 Hz), 2.49 (3H, 5). Intermediate 2: 5-Chloro-N-(2,8-dimethylimidazo[ 1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide = COH NY : 0 —— | _ or " 5-Chloro-2-pyrazinecarboxylic acid (1466 mg, 9.25 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin- 6-amine (1500 mg, 9.25 mmol), Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3114 mg, 11.10 mmol), 1-methylimidazole (2.20 mL, 27.74 mmol) and acetonitrile (25 mL) were combined and stirred at room temperature for 2 hours.Water (50 mL) was added and left to stir for 16 h, before the reaction mixture was filtered and the solid dried in vacuo to give 5-Chloro-N-(2,8-dimethylimidazo[1,2- alpyrazin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step. MS (ES+) 302 (M+H), 'H NMR (400 MHz, CDCls) 9.82 (s, 1H), 9.25 (d, J=1.4 Hz, 1H), 9.14 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 7.50 (s, 1H), 2.85 (s, 3H), 2.52 (s, 3H). Intermediate 3: 6-Ethoxy-2-methyl-2H-indazol-5-amine a + OEt 6-Ethoxy-5-nitro-1H-indazole (3.12 g, 15.07 mmol), DMF (30 mL), potassium carbonate (2.29 g, 16.58 mmol) and Mel (1.03 mL, 16.58 mmol) were combined and stirred at room temperature for 20 hours. The reaction was then diluted with EtOAc, washed with water (3x), brine (1x), evaporated to dryness onto silica and purified by flash chromatography, with the minor of the two main peaks being 6- ethoxy-2-methyl-5-nitro-2 H-indazole, which was used directly in the next step. 6-Ethoxy-2-methyl-5-nitro-2H-indazole (117 mg, 0.53 mmol), EtOAc (15 mL) and methanol (15 mL) were combined and pumped through an H-cube with 10% Pd / C cartridge at 1 mL per minute flow rate, 40 °C, 40 bar pressure. Evaporation of reaction mixture to dryness gave 6-ethoxy-2-methyl-2H- indazol-5-amine, which was used crude in the next step. Intermediate 4: 6-Methoxy-2-methyl-2H-indazol-5-amine of / OMe OMe N | % N ON OMe 6-Methoxy-5-nitro-1H-indazole (1 g, 5.18 mmol), potassium carbonate (0.79 g, 5.7 mmol), DMF (10 mL) and MeI (0.35 mL, 5.7 mmol) were combined at room temperature under a nitrogen atmosphere and stirred for 3 days. The reaction mixture was then diluted with EtOAc, washed with water (x3), brine (x1), evaporated to dryness onto silica and purified by flash chromatography to give two regioisomeric products. The minor regioisomer corresponds to 6-methoxy-2-methyl-5-nitro-2H-indazole. MS (ES+) 208 (M+H). 'H NMR (400 MHz, DMSO) & 8.56 (s, 1H), 8.42 (s, 1H), 7.25 (s, 1H), 4.18 (s, 3H), 3.92 (s, 3H). 6-Methoxy-2-methyl-5-nitro-2H-indazole (224 mg, 1.08 mmol), EtOAc (15 mL) and MeOH (15 mL) were combined and then pumped at 1 ml per min through an H-Cube with 10% Pd / C cartridge at 50 bar of hydrogen and 40 °C. The reaction mixture was evaporated to dryness to give 6-methoxy-2-methyl- 2H-indazol-5-amine, which was used crude in next reaction. MS (ES+) 178 (M+H). Intermediate 5: N-Isopropylpyrrolidin-3-amine-2HCl Boc Boc Boc H NC —N rN No ~ TY ~ po pm ~~ =f tert-butyl 3-oxopyrrolidine-1-carboxylate (1.31 g, 7.07 mmol), isopropylamine (0.67 mL, 7.78 mmol), dichloromethane (10 mL) and sodium triacetoxyborohydride (3.15 g, 14.85 mmol) were combined and stirred at room temperature for 3 days. The reaction mixture was then quenched with sat. aq. NaHCO, extracted with dichloromethane, dried (MgSQ.) and evaporated to dryness to give terr- butyl 3-(isopropylamino)pyrrolidine- 1-carboxylate, which was used crude in next step. tert-butyl 3-(isopropylamino)pyrrolidine- 1-carboxylate (1.53 g, 6.7 mmol), MeOH (5 mL) and 4N HCl in dioxane (20 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound, which was used crude in next step. Intermediate 6: N-(3,3-difluorocyclobutyl)pyrrolidin-3-amine- 2HC1 Boc H Boc NO NO SN ~N +» 2HCI ~ TY ~ F © tert-butyl 3-oxopyrrolidine-1-carboxylate (1310 mg, 7.07 mmol, 1 equiv) was dissolved in DCM (80 mL) and 3,3-difluorocyclobutan-1-amine (1120 mg, 7.78 mmol, 1.10 equiv) and sodium triacetoxyborohydride (4650 mg, 21.9 mmol, 3.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO; (aq) and extracted with DCM three times. The combined organics were dried (MgSO) and concentrated in vacuo to give crude rert-butyl 3- ((3,3-difluorocyclobutyl )Jamino)pyrrolidine- 1 -carboxylate, which was used without further purification. Crude tert-butyl tert-butyl 3-((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate (1910 mg, 6.92 mmol, 1 equiv) was dissolved in methanol (5 mL) and 4M HCl in dioxane (20 mL) was added and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude title compound, which was used without further purification. Intermediate 7: N-(oxetan-3-yl)pyrrolidin-3-amine- 2TFA Boc Boc H rr No NX AN rN ~N 2TFA ~ TY ~ tert-butyl 3-oxopyrrolidine-1-carboxylate (1310 mg, 7.70 mmol, 1 equiv) was dissolved in DCM (10 mL) and oxetan-3-amine (568 mg, 7.78 mmol, 1.10 equiv) and sodium triacetoxyborohydride (3140 mg, 14.84 mmol, 2.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aq) and washed with DCM three times. The combined organics were washed with saturated brine solution, dried (phase separating filter paper) and concentrated in vacuo to give crude rer-butyl 3-(oxetan-3-ylamino)pyrrolidine- 1-carboxylate, which was used without further purification. Crude rert-butyl 3-(oxetan-3-ylamino)pyrrolidine-1-carboxylate (1.69 g, 7 mmol, 1 equiv) was dissolved in dichloromethane (5 mL) and TFA (4 mL) was added and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude title compound, which was used without further purification. Intermediate 8: (3R*,45%)-N-cyclopropyl-4-fluoro-N-methylpyrrolidin-3-amine- 2HCI 2HCI (eos HO Si ye FC on — — — ON 4 tert-Butyl (1R*,55%)-6-oxa-3-azabicyclo[3.1.0]Thexane-3-carboxylate (896 mg, 4.69 mmol), N- methylcyclopropanamine (1 g, 14.08 mmol) and water (1 mL) were combined in a sealed tube and heated to 50 °C for 2 days. The reaction was cooled to room temperature, quenched with sat. aq. NaHCO3, extracted with dichloromethane (2x), dried (MgSO) and evaporated to dryness to give zerr-butyl (3R*,4R*)-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine- 1-carboxylate, which was used crude in next step. tert-Butyl (3R*4R*)-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate (200 mg, 0.78 mmol) and dichloromethane (10 mL) were combined. Deoxo-Fluor® 50% in THF (0.32 mL, 0.86 mmol) was added dropwise at r.t. and the reaction stirred overnight. The reaction was quenched by addition of saturated sodium hydrogen carbonate and extracted with DCM (x2). The organic layer was dried (MgSQ,) and the solvent removed in vacuo to give tert-butyl (3R*,45%)-3- (cyclopropyl(methyl)amino)-4-fluoropyrrolidine- 1-carboxylate, which was used crude in next step. tert-Butyl (3R*,45*)-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine- 1 -carboxylate, MeOH (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a brown oil, which was used crude in next step. Intermediate 9: (3aR*,6a5*)-3-cyclopropylhexahydro-2 H-pyrrolo[3,4-dJoxazol-2-one hydrochloride Lp on Z-one hydrochloride NB @ ~) oc oY A HO. NBoc HO. NBoc —_ "> he o NH A tert-Butyl (1R* 55*)-6-0xa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.25 g, 6.75 mmol), cyclopropylamine (8.0 mL, 95.84 mmol) and water (12 mL) was added to a reaction tube. The reaction tube was sealed and heated to 50 °C for 48 h. The reaction was cooled to r.t. and quenched by addition of saturated sodium hydrogen carbonate. The aqueous layer was extracted with DCM (x2) and the organic layer dried (MgSO4). The solvent was removed in vacuo to give crude zerr-butyl (3R*,4R*)-3- (cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylate, which was used in the next step without further purification. Crude material from the previous step rerr-butyl (3R*,4R*)-3-(cyclopropylamino)-4- hydroxypyrrolidine-1-carboxylate was dissolved in DCM (40 mL) and di-zerr-butyl dicarbonate (1.62 g, 7.43 mmol) was added followed by triethylamine (2 mL, 14.35 mmol). The reaction was stirred overnight at r.t.. The solvent was removed in vacuo to give crude rerr-butyl (3R*,4R*)-3-((tert- butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine- 1-carboxylate, which was used in the next step without further purification. Crude rert-butyl (3R*,4R*)-3-((rert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine- 1-carboxylate (342 mg, 1.00 mmol) was dissolved in DCM (10 mL). Deoxo-Fluor® 50% in THF (487 mg, 1.10 mmol) was added dropwise at r.t. and the reaction stirred overnight. The reaction was quenched by addition of saturated sodium hydrogen carbonate and extracted with DCM (x2). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give tert-butyl (3aR*,6aS5*)-3-cyclopropyl-2- oxohexahydro-5H-pyrrolo[3,4-dJoxazole-5-carboxylate. The material was used without further purification. Crude rert-butyl (3aR*,6a5*)-3-cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazole-5- carboxylate (239 mg, 0.69 mmol) was dissolved in methanol (3 mL) and 4 N HCl in dioxane (3 mL) was added dropwise. The reaction was stirred at r.t. overnight and the solvent removed in vacuo to give the title compound. The material was used in the next step without further purification. Intermediate 10: 8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-amine-2HCI Jo Br SN No” xX (x Br” “NZ No” 3 JA eo 2HCI OX (L HN” NZ No 1-Bromo-2,2-dimethoxypropane (4.2 mL, 31.0 mmol) was added to 2-amino-5-bromo-3- methoxypyrazine (3.96 g, 19.4 mmol) and pyridinium p-toluenesulfonate (0.51 g, 1.94 mmol) in iso- propanol (60 mL). The reaction mixture was heated at 65 °C for 66 hours. The reaction mixture was cooled to room temperature and diluted with DCM and saturated sodium bicarbonate solution. The layers were separated and the DCM layer dried (phase separator). The solvents were removed under reduced pressure and the crude material purified by silica gel column chromatography (gradient elution 0-100% ethyl acetate in cyclohexane) to afford the title compound. ‘H NMR (400 MHz, CDCl) 6 7.82 (d, J=1.6 Hz, 1H), 6.49 (d, J=1.5 Hz, 1H), 3.99 (s, 3H), 2.43 (s, 3H). LCMS (ES+) 244 (M+H)+, RT 3.07 min (Analytical method AcHSSC18). 6-Bromo-8-methoxy-2-methylimidazo[ 1,2-a]pyrazine (1 g, 4.13 mmol), acetamide (240 mg, 4.13 mmol), Cul (79 mg, 0.413 mmol), K2COs (1.71 g, 12.39 mmol), N, N’-dimethylethylenediamine (73 mg, 0.826 mmol), and toluene (11 mL) were placed in a sealed tube, de-gassed by bubbling nitrogen through for 5 mins, then hot block heated to 100 °C for 42 hours. After cooling to room temperature, LCMS analysis indicated partial conversion. The reaction mixture was evaporated to dryness onto silica and purified by flash chromatography, eluting with 1-9% MeOH in EtOAc to give N-(8-methoxy-2- methylimidazo[ 1,2-a]pyrazin-6-yl)acetamide. MS (ES+) 221 (M+H). H NMR (400 MHz, de-DMSO) 10.20 (s, 1H), 8.79 (s, 1H), 7.88 (s, 1H), 4.04 (s, 3H), 2.32 (s, 3H), 2.10 (s, 3H). HCI (4 M in dioxane, 4.3 mL, 17.25 mmol) was added to N-(8-methoxy-2-methylimidazo[1,2- alpyrazin-6-yl)acetamide (380 mg, 1.73 mmol) in methanol (11 mL) at room temperature with stirring. After 18 hours the reaction mixture was concentrated under reduced pressure to afford the ritle compound. Intermediate 11: N-(rert-butyl)pyrrolidin-3-amine-2HCI Boc Boc Boc H No —N_ rN ~N_ « 2HCI ~ ~ ~ 3 NH tert-butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv) was dissolved in DCM (10 mL) and tert-butylamine (0.62 mL, 5.94 mmol, 1.10 equiv) and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO; (aq) and washed with DCM three times. The combined organics were washed with saturated brine solution, dried (phase separating filter paper) and concentrated in vacuo to give crude rert-butyl 3-(rerr-butylamino)pyrrolidine-1-carboxylate, which was used without further purification. Crude tert-butyl 3-(terr-butylamino)pyrrolidine-1-carboxylate (1310 mg, 5.41 mmol, 1 equiv) was dissolved in methanol (10 mL) and 4M HCl in dioxane (13.5 mL, 54.05 mmol, 10 equiv) was added and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude N-(rert-butyl)pyrrolidin-3-amine- 2HCI, which was used without further purification. Intermediate 12: N-cyclopropylpyrrolidin-3-amine-2HC1 Boc Boc Boc H ~NO RX —~N aN ~N, * 2HCI ~ TY ~ tert-butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv) was dissolved in DCM (10 mL) and cyclopropylamine (0.41 mL, 5.94 mmol, 1.10 equiv) and sodium triacetoxyborohydride (2400 g, 11.34 mmol, 2.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO; (aq) and washed with DCM three times. The combined organics were washed with saturated brine solution, dried (phase separating filter paper) and concentrated in vacuo to give crude tert-butyl 3-(cyclopropylamino)pyrrolidine- 1-carboxylate, which was used without further purification. Crude tert-butyl 3-(cyclopropylamino)pyrrolidine- 1-carboxylate (1220 mg, 5.39 mmol, 1 equiv) was dissolved in methanol (10 mL) and 4M HCl in dioxane (13.5 mL, 53.91 mmol, 10 equiv) was added and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude N-cyclopropylpyrrolidin-3-amine- 2HCI, which was used without further purification. Intermediate 13: N-(cyclopropylmethyl)pyrrolidin-3-amine Boc Boc Boc H No NO ~N No ~ TY ~ NH NH a N tert-butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv) was dissolved in DCM (10 mL) and cyclopropanemethylamine (0.42 mL, 5.94 mmol, 1.10 equiv) and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equiv) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO; (aq) and extracted with DCM three times. The combined organics were washed with saturated brine solution, dried (phase separating filter paper) and concentrated in vacuo to give crude tert-butyl 3-((cyclopropylmethyl)amino)pyrrolidine-1- carboxylate, which was used without further purification. Crude tert-butyl 3-((cyclopropylmethyl)amino)pyrrolidine- 1-carboxylate (1340 mg, 5.58 mmol, 1 equiv) was dissolved in methanol (10 mL) and 4M HCl in dioxane (13.9 mL, 55.75 mmol, 10 equiv) was added and the reaction mixture stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue loaded in MeOH onto a 10 g SCX cartridge (pre-conditioned with MeOH), eluting with MeOH (2 CV) then 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated in vacuo to give crude N-(cyclopropylmethyl)pyrrolidin-3-amine, which was used without further purification. Intermediate 14: 4-(pyrrolidin-3-yl)morpholine / NBoc / NH y = N, N rN Yo— Yo— tert-Butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.4 mmol) and morpholine (0.52 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at r.t. and the reaction was stirred for 18 h. The reaction was diluted with DCM and washed with water and brine, separating the layers using a phase separator. The solvent was removed in vacuo to give the crude tert-butyl 3-morpholinopyrrolidine-1-carboxylate, which was used without further purification. terr-Butyl 3-morpholinopyrrolidine-1-carboxylate (1.38 g, 5.40 mmol) was dissolved in methanol (10 mL) and 4M HCl in dioxane (13.5 mL, 53.99 mL) was added at r.t.. The reaction was stirred for 18h and the solvent removed in vacuo to give crude product, which was purified by SCX 10 g cartridge (pre- conditioned with MeOH), eluting with MeOH (2 CV) then 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated in vacuo to give crude 4-(pyrrolidin-3-yl)morpholine, which was used without further purification. Intermediate 15: N-butylpyrrolidin-3-amine-2HCI / NH y = 2HCI ¥: 1 HN. HN, N \ tert-Butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.4 mmol) and butylamine (0.59 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at r.t. and the reaction was stirred for 18 h. The reaction was diluted with DCM and washed with water and brine, separating the layers using a phase separator. The solvent was removed in vacuo to give crude rert- butyl 3-(butylamino)pyrrolidine- 1-carboxylate, which was used without further purification. tert-Butyl 3-(butylamino)pyrrolidine-1-carboxylate (1.31 g, 5.41 mmol) was dissolved in methanol (10 mL) and 4M HCl in dioxane (13.5 mL, 13.5 mL) was added at r.t.. The reaction was stirred for 18 h and the solvent removed in vacuo to give crude N-butylpyrrolidin-3-amine, which was used without further purification. Intermediate 16: N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine- 2HCI / NBoc / ~NBoc / NH yA +» J « 2HCI r HN HN, NY ham / —0 gd tert-Butyl 3-oxopyrrolidine-1-carboxylate (1.31 g, 7.07 mmol) and tetrahydro-2H-pyran-4-amine (787 mg, 7.78 mmol) were dissolved in DCM (50 mL). Sodium triacetoxyborohydride (3.14 g, 14.84 mmol) was added at r.t. and the reaction was stirred for 18 h. The reaction was diluted with DCM and washed with water and brine, separating the layers using a phase separator. The solvent was removed in vacuo to give the crude rerr-butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine-1-carboxylate, which was used without further purification. tert-butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine- 1-carboxylate (1.82 g, 4.74 mmol) was dissolved in methanol (5 mL) and 4M HCl in dioxane (20.0 mL, 80 mmol) was added at r.t.. The reaction was stirred for 18h and the solvent removed in vacuo to give crude N-(tetrahydro-2H-pyran-4- yl)pyrrolidin-3-amine- 2HCI, which was used without further purification. Intermediate 17: 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine = = NN — NN J LX EN ao” Sodium hydride (60% dispersion in mineral oil, 256 mg, 6.4 mmol) was added portionwise to a mixture of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine (1.69 g, 5.8 mmol) in methanol (30 mL) and the reaction stirred for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water and brine. The organics were concentrated in vacuo to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine, which was used without further purification. Intermediate 18: N-(Pyrrolidin-3-ylmethyl)cyclopropanamine.2HC1 yl)cyclopropanamine.2ZHCl NE NH2HCI wt” wt” A A 4 4 tert-Butyl 3-formylpyrrolidine-1-carboxylate (2 g, 10 mmol), cyclopropylamine (630 mg, 11 mmol), dichloromethane (60 mL) and sodium triacetoxyborohydride (4.45 g, 21 mmol) were combined and stirred at room temperature for 18 hours. Reaction mixture was then quenched with sat. aq. NaHCO3, extracted with dichloromethane, dried (MgSO) and evaporated to dryness to give rerr-butyl 3- ((cyclopropylamino)methyl)pyrrolidine-1-carboxylate (2.29 g) as a clear oil which was used crude in next step. tert-Butyl 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylate (2.29 g, 9.54 mmol), MeOH (20 ml) and 4N HCI in dioxane (10 ml) were combined and stirred at room temperature for 16 hours. Reaction mixture was then evaporated to dryness to give the title compound as a clear oil, which was used crude in next step. Intermediate 19: N-methyl-N-(pyrrolidin-3-ylmethyl)propan-2-amine.2HCI 2HCI & Boc Boc & 8 4 / , HN, —N —N NN NN tert-Butyl 3-((isopropylamino)methyl)pyrrolidine-1-carboxylate (200 mg, 0.83 mmol) was dissolved in DMF (3 ml), then sodium hydride (60%, 50 mg, 1.24 mmol) and iodomethane (51 ul, 0.83 mmol) were added atr.t., and stirred for 65 h. Reaction mixture was then quenched with LiCl aqueous solution (4%), extracted with ethyl acetate (x2), dried over a phase separator paper and evaporated to dryness to give tert-butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate (190 mg) as a clear oil which was used crude in next step. tert-butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate (190 mg, 0.74 mmol), MeOH (3 ml) and 4N HCl in dioxane (1.9 ml) were combined and stirred at room temperature for 19 hours. Reaction mixture was then evaporated to dryness to give the title compound as an oil, which was used crude in next step. Intermediate 20: N-(pyrrolidin-3-ylmethyl)propan-2-amine.2HC1 2HCI & / L 7’ HN HN I~ ~ tert-Butyl 3-((isopropylamino)methyl)pyrrolidine- 1-carboxylate (300 mg, 1.24 mmol), MeOH (5 ml) and 4N HCI in dioxane (4 ml) were combined and stirred at room temperature for 16 hours. Reaction mixture was then evaporated to dryness to give the title compound as a white solid, which was used crude in next step. Intermediate 21: 6-methoxy-2-methylpyrazolo[1,5-alpyridin-5-amine. 2HBr ® NHBoc * X : OAH NO; BocHN” OMe NO, EO,C \ [ N (oN BocHN” OMe Following Method L Boc protection from 3-methoxypyridin-4-amine (370 mg, 2.98 mmol, 1 eq). The crude was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert-butyl (3-methoxypyridin-4-yl)carbamate (590 mg, 88%) as a white solid LCMS (ES+) 225 (M+H)+ Following Method M Amino pyridinium salt formation from rerr-butyl (3-methoxypyridin-4- yl)carbamate (590 mg, 2.63 mmol, 1 eq). LCMS showed consumption of starting material and new peak with correct target mass ion (240). The reaction mixture was taken forward to next step without work up (assumed 100% yield). Following Method N 1,3 dipolar addition from 1-amino-4-((zert-butoxycarbonyl)amino)-3- methoxypyridin-1-ium 2,4-dinitrophenolate (1114 mg, 2.63 mmol, 1 eq). The reaction mixture was concentrated in vacuo onto silica and the crude purified by silica chromatography, elution gradient 0- 75% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give ethyl 5-((rert-butoxycarbonyl)amino)-6-methoxy-2-methylpyrazolo[1,5- a]pyridine-3-carboxylate (169 mg, 18%) as an off white solid LCMS (ES+) 350 (M+H)+ ‘H NMR (400 MHz, CDCI3) 68.69 (s, 1H), 7.93 (s, 1H), 7.20 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 2.62 (s, 3H), 1.55 (s, 9H), 1.44 (t, J=7.1 Hz, 3H). Following Method O HBr Decarboxylation from ethyl 5-((tert-butoxycarbonyl)amino)-6- methoxy-2-methylpyrazolo[1,5-alpyridine-3-carboxylate (169 mg, 0.484 mmol, 1 eq). The reaction mixture was concentrated in vacuo to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine. 2HBr as a brown oil. Taken forward to the next step without further purification. Intermediate 22: ethyl 5-((zerr-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3- carboxylate and Intermediate 23: ethyl 5-((zerr-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5- alpyridine-3-carboxylate o° EOC, EtO,C, \ I \ ~ NH. NO; [N N hs — — NT — on Nw oF PF BocHN~Y BocHN BooHN” 7 NH, NHBoc & NO, T Product 1 Product 2 Following Method L Boc protection from 3-fluoropyridin-4-amine (925 mg, 8.25 mmol, 1 eq). The crude was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to tert-butyl (3-fluoropyridin-4-yl)carbamate (1453 mg, 83%) as a white solid LCMS (ES+) 213 (M+H)+ Following Method M Amino pyridinium salt formation from terr-butyl (3-fluoropyridin-4- yl)carbamate (503 mg, 2.37 mmol, 1 eq). LCMS showed consumption of starting material and new peak with correct target mass ion (228). The reaction mixture was taken forward to next step without work up (assumed 100% yield). Following Method N 1,3 dipolar addition from 1-amino-4-((zert-butoxycarbonyl)amino)-3- fluoropyridin-1-ium 2,4-dinitrophenolate (1278 mg, 3.11 mmol, 1 eq). The reaction mixture was concentrated in vacuo onto silica and the crude purified by silica chromatography, elution gradient 0- 20% EtOAc in cyclohexane. Fractions containing target mass combined and the solvent removed in vacuo to give mixture of ethyl 5-((rerr-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5- a]pyridine-3-carboxylate and ethyl 5-((zerr-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5- a]pyridine-3-carboxylate. The crude was re-purified using silica chromatography, elution gradient 0-18% EtOAc in cyclohexane to give title compounds ethyl 5-((zert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (Product 1) as a yellow solid (127 mg, 12%) LCMS (ES+) 338 (M+H)+ Ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[ 1,5-a]pyridine-3-carboxylate (Product 2) as a yellow soild (265 mg, 25%) LCMS (ES+) 338 (M+H)+ ‘H NMR (400 MHz, CDCI3) 68.20 - 8.18 (m, 1H), 7.90 (dd, J=7.0, 7.0 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.55 (s, 9H), 1.40 (t, J=7.3 Hz, 3H). Intermediate 24: 6-fluoro-2-methylpyrazolo[1,5-alpyridin-5-amine. 2HBr HBr Following Method O HBr Decarboxylation from ethyl 5-((rerr-butoxycarbonyl)amino)-6- fluoro-2-methylpyrazolo[ 1,5-a]pyridine-3-carboxylate (127 mg, 0.376 mmol, 1 eq). The reaction mixture was concentrated in vacuo to give crude 6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-amine. 2HBr as a brown solid. Taken forward to the next step without further purification. Intermediate 25: ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-alpyridine-3- carboxylate and Intermediate 26: ethyl 5-((tert-butoxycarbonyl)amino)-2,4-dimethylpyrazolo[1,5-alpyridine-3- carboxylate EOC, rs N : oN BocHN” = EtO:C, EtO,C, 1 3 OO NH, NO, [ [N LL ~~ 0 & —- @ 7 d BocHN” BocHN” BocHN” NH. NHBoc NO, Product 1 Product 2 Following Method L Boc protection 3-methylpyridin-4-amine (600 mg, 5.55 mmol, 1 eq). The crude was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert- butyl (3-methylpyridin-4-yl)carbamate (939 mg, 81%) as a white solid LCMS (ES+) 209 (M+H)+ Following Method M Amino pyridinium salt formation from tert-butyl (3-fluoropyridin-4- yl)carbamate (939 mg, 4.51 mmol, 1 eq). LCMS showed consumption of starting material and new peak with correct target mass ion (224). The reaction mixture was taken forward to next step without work up (assumed 100% yield). Following Method N 1,3 dipolar additionfrom 1-amino-4-((tert-butoxycarbonyl)amino)-3- methylpyridin-1-ium 2,4-dinitrophenolate (1835 mjg, 4.51 mmol, 1 eq). The reaction mixture was concentrated in vacuo onto silica and the crude purified by silica chromatography, elution gradient 0- 50% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give title compounds ethyl 5-((zert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-alpyridine-3-carboxylate (Product 1) as a yellow oil (516 mg, 34%) LCMS (ES+) 334 (M+H)+ 'H NMR (400 MHz, CDCl) 6 8.67 (s, 1H), 8.15 (s, 1H), 6.45 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 2.26 (s, 3H), 1.56 (s, 9H), 1.44 (dd, J=7.2, 7.2 Hz, 3H). Ethyl 5-((tert-butoxycarbonyl)amino)-2,4-dimethylpyrazolo[1,5-alpyridine-3-carboxylate (Product 2) as a yellow solid (253 mg, 18%) LCMS (ES+) 334 (M+H)+ 'H NMR (400 MHz, CDCl) 6 8.23 (d, J=7.4 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 6.54 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 2.57 (s, 3H), 1.54 (s, OH), 1.40 (t, J=7.1 Hz, 3H). Intermediate 27: 2,6-dimethylpyrazolo[1,5-alpyridin-5-amine. 2HBr EtO,C, A [N\ ( N BocHN Z HBr Following Method O HBr Decarboxylation from ethyl 5-((rerr-butoxycarbonyl)amino)-2,6- dimethylpyrazolo[1,5-alpyridine-3-carboxylate (250 mg, 0.750 mmol, 1 eq). The reaction mixture was concentrated in vacuo to give crude 2,6-dimethylpyrazolo[1,5-a]pyridin-5-amine 2HBr as a brown oil. Taken forward to the next step without further purification. Intermediate 28: 6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine N, » NHBoc &° SNH NO; y 8 2 2 BocHN” OEt NO; Following Method L Boc protection from 3-ethoxypyridin-4-amine (2200 mg, 15.9 mmol, 1 eq). tert-butyl (3-ethoxypyridin-4-yl)carbamate as a yellow solid. Taken forward to next step without further purification. Following Method M Amino pyridinium salt formation from rerr-butyl (3-ethoxypyridin-4- yl)carbamate (4200 mg, 17.6 mmol, 1 eq). LCMS showed consumption of starting material and new peak with correct target mass ion (254). The reaction mixture was taken forward to next step without work up (assumed 100% yield). Following Method N 1,3 dipolar addition from 1-amino-4-((tert-butoxycarbonyl)amino)-3- ethoxypyridin-1-ium 2,4-dinitrophenolate (7702 mg, 17.626 mmol, 1 eq). The reaction mixture was concentrated in vacuo onto silica and the crude purified by silica chromatography, elution gradient 0- 60% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5- alpyridine-3-carboxylate (380 mg, 5%) as a yellow solid LCMS (ES+) 364 (M+H)+ ‘H NMR (400 MHz, DMSO) 88.53 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 4.16 (dt, J=7.5, 14.6 Hz, 2H), 1.52 (s, 9H), 1.50 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.37 - 1.33 (m, 3H). Following Method O HBr Decarboxylation from ethyl 5-((rerr-butoxycarbonyl)amino)-6- ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 0.941 mmol, leq). The reaction mixture was concentrated in vacuo to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine. 2HBr as a brown oil. The crude was loaded onto a 5 g SCX cartidge (pre-conditioned with MeOH). The residue was eluted with MeOH then 7M NH3 in MeOH. The ammonia fraction was concentrated in vacuo to give 6- ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine as a tan oil. Taken forward without further purification to next step. Intermediate 29: 6-(difluoromethoxy)-2-methyl-2H-indazol-5-amine 5-Bromo-1H-indazol-6-o0l (900 mg, 4.22 mmol, 1 eq), sodium chlorodifluoroacetate (1288 mg, 8.45 mmol, 2 eq), Cs2C0s (2065 mg, 6.34 mmol, 1.5 eq) were dissolved in DMF (10 mL) and the reaction mixture stirred at 100°C in a sealed tube for 18 h. EtOAc and H;O were added and the layers separated. The aq. layer was washed with EtOAc (x2) and the combined organics were washed with brine, dried (phase separating filter paper) and concentrated in vacuo. The crude was purified by silica chromatography, elution gradient 5-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give 5-bromo-6-(difluoromethoxy)-1H- indazole (490 mg, 44%) as a yellow solid LCMS (ES+) 253, 265 (M+H)+ (Br) 5-Bromo-6-(difluoromethoxy)-1H-indazole (490 mg, 1,86 mmol, 1 eq) was dissolved in EtOAc (50 mL) and trimethyloxonium tetrafluoroborate (413 mg, 2.79 mmol, 1.5 eq) was added and the R.M stirred at r.t for 16 h. EtOAc and H,O were added and the layers separated. The aq. layer was washed with EtOAc (x2) and the combined organics were washed with brine, dried (phase separating filter paper) and concentrated in vacuo to give 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 77%) LCMS (ES+) 277, 279 (M+H)+ (Br) 'H NMR (400 MHz, DMSO) 6 8.40 (s, 1H), 8.18 (s, 1H), 7.50 (s, 1H), 7.34 (t, J=74.6 Hz, 1H), 4.18 (s, 3H). 5-Bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 1.44 mmol, 1 eq), diphenylmethanimine (0.24 mL, 1.44 mmol, 1 equiv) Cs;COs (706 mg, 2.16 mmol, 1.5 eq), Pd(OAc); (32 mg, 0.14 mmol, 0.1 equiv) rac-BINAP (90 mg, 0.14 mmol, 0.1 equiv) were combined in THF (5 mL) and the mixture purged with N; for 15 minutes. The reaction mixture was stirred at 80°C for 18 h in a sealed tube. The reaction mixture was allowed to cool to r.t. and the mixture was diluted with water and the aqueous phase was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (phase separating filter paper) and the solvent was removed in vacuo. The crude was purified using silica chromatography, elution gradient 0-75% EtOAc in cyclohexane. Fractions containing the desired materials were combined and the solvent removed in vacuo to give N-(6-(difluoromethoxy)-2-methyl- 2H-indazol-5-yl)-1,1-diphenylmethanimine. Still impurities present, therefore taken forward to next step without further purification. N-(6-(difluoromethoxy)-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (220 mg, 0.48 mmol, 1 eq) was dissolved in MeOH (10 mL) and 4M HCl in dioxane (0.48 mL, 1.91 mmol, 4 eq) was added. The reaction mixture was stirred at r.t. for 16 h. The reaction mixture was concentrated in vacuo to give 6- (difluoromethoxy)-2-methyl-2H-indazol-5-amine. 2HClI as a red solid. Taken forward to next step without further purification. Intermediate 30: 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide HBr [\ a oN . YN A o Py OMe A 0 we 1 ‘OH AK Following Method H TCFH coupling from 5-chloropyrazine-2-carboxylic acid (321 mg, 2.02 mmol, 1 eq) and 6-methoxy-2-methylpyrazolo[ 1,5-a]pyridin-5-amine. 2HBr (858 mg, 2.02 mmol, 1 eq). The reaction mixture was diluted with H>O and the solid filtered. Thae solid was washed with MeCN:H,O (1:2) (x3) to give 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (327 mg 80% pure, 40%) as a yellow solid LCMS (ES+) 318 (M+H)+ Intermediate 31: (6-bromo-8-fluoroimidazol[ 1,2-a]pyridin-2-yl)methanol Br FZ 'F wl | Br” NF Np 5-Bromo-3-fluoropyridin-2-amine (2 g, 10.47mmol) and ethyl bromopyruvate (1.4 mL, 11.52 mmol) was dissolved in ethanol (50 mL) and heated at reflux for 18 h. The reaction was cooled to r.t. and the solvent removed in vacuo to give a residue. The residue was dissolved in EtOAc and washed with saturated sodium hydrogencarbonate. The EtOAc layer was dried (MgSQs) and the solvent removed in vacuo to give a residue, which was purified using silica chromatography, elution gradient 0-50% EtOAc / cyclohexane to give the title compound as an off-white solid (1.76g, 59%). Methyl 6-bromo-8-fluoroimidazo[1,2-a]pyridine-2-carboxylate (1.76 g, 6.13 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. IM DIBAL in toluene (12.88 mL, 12.88 mmol) was added dropwise and the reaction allowed to warm to r.t. over 18 h. The reaction was cooled to 0 °C in an ice-bath and quenched by addition of water. The aqueous layer was extracted with EtOAc x3 and the organic layer dried (MgSOx). The solvent was removed in vacuo to give a residue, which was purified using silica chromatography, elution gradient 0-100% EtOAc / cyclohexane to give the title compound as a clear oil (1.1 g,73%). Intermediate 32: Lithium (S)-5-(3-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)pyrrolidin-1- yl)pyrazine-2-carboxylate (mare \ NH, TMS > Q Poor ' 0° aro? (ane! N= =< 4 4 whe Ao PS wh Ana AN — WAN — WAN SAEs & o x o& £ 1 4 hg a N-Boc (R)-3-(Aminomethyl)- 1-Boc-pyrrolidine (1000 mg, 4.99 mmol, 1.00 eq), (1- ethoxycyclopropoxy)trimethylsilane (1.0 mL, 4.99 mmol, 1.00 eq) and methyl alcohol (50.00 mL) were combined. Sodium cyanoborohydride (345 mg, 5.49 mmol, 1.10 eq) was added followed by acetic acid (0.20 mL). Reaction was then hot block heated to 55°C for 2 days. Reaction was cooled to room temperature. Diluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO4) and concentrated in vacuo to give a mixture of rert-butyl (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1- carboxylate and tert-butyl (R)-3-((dicyclopropylamino)methyl)pyrrolidine- 1-carboxylate as a clear oil (1.29¢), which was used crude in next step. Mixture of tert-butyl (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1-carboxylate and rert-butyl (R)-3- ((dicyclopropylamino)methyl)pyrrolidine-1-carboxylate (1.20 g, 4.99 mmol, 1.00 eq), methyl alcohol (10 mL) and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.01 eq) were combined and stirred at room temperature for 23 hours. Reaction was then concentrated in vacuo and partitioned between dichloromethane and 15% Aq NaOH soln. The organic layer concentrated in vacuo to give a mixture of N-[[(3S)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride and (S)-N-cyclopropyl-N-(pyrrolidin- 3-ylmethyl)cyclopropanamine dihydrochloride as a clear gum (718 mg), which was used directly in the next step. A mixture of N-[[(35)-pyrrolidin-3-ylJmethyl]cyclopropanamine and (S)-N-cyclopropyl-N-(pyrrolidin-3- ylmethyl)cyclopropanamine dihydrochloride (700 mg, 4.99 mmol, 1.00 eq), methyl 5-chloro-2- pyrazinecarboxylate (861 mg, 4.99 mmol, 1.00 eq), N,N-diisopropylethylamine (2.0 mL, 11.5 mmol, 2.30 eq) and 1,4-dioxane (100.00 mL) were combined and hot block heated to 100°C for 16 hours. The reaction was cooled to room temperature and used reaction mixture directly in next step. Di-rert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.00 eq) was added to the reaction mixture from previous step and stirred at room temperature for 2 hours. The crude reaction was concentrated in vacuo onto silica and purified by flash chromatography to give methyl 5-[(35)-3-[[zert- ‘butoxycarbonyl(cyclopropyl)amino]methyllpyrrolidin- 1-yl]pyrazine-2-carboxylate as a clear gum (682 mg). Used directly in next step. LCMS (ES+) 377 (M+H)+ Methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidin-1-yl]pyrazine-2- carboxylate (682 mg, 1.81 mmol, 1.00 eq), lithium hydroxide monohydrate (76 mg, 1.81 mmol, 1.00 eq), methyl alcohol (30.00 mL) and water (3.00 mL) were combined and hot block heated to 50°C for 16 hours. Concentrated in vacuo to give [5-[(3S)-3-[[tert- ‘butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidin- 1-yl]pyrazine-2-carbonylJoxylithium as a white solid (672mg). LCMS (ES+) 363 (M+H)+ as acid. Intermediate 33: N-[[(3R)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride _Boc ore Cr Cow 2HCI > & 3g Taney £ OTMS \ >< NHz \OEt <4 qd N= 4 N-[[(3R)-Pyrrolidin-3-ylJmethyl]cyclopropanamine dihydrochloride was made using the same chemistry as its enantiomer N-[[(35)-pyrrolidin-3-ylJmethyl]cyclopropanamine dihydrochloride and was used directly in next steps. Intermediate 34: Lithium (R)-5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine- 2-carboxylate pane -Boc CY Boc Cy HN OTMS XX. Ig NT | vr aN o 0 N WAN - AN Ae “ — ae Barn—N Boo, J > gh (R)-(+)-1-Boc-3-aminopyrrolidine (1000 mg, 5.37 mmol, 1.00 eq), (1- ethoxycyclopropoxy)trimethylsilane (1.1 mL, 5.37 mmol, 1.00 eq) and methyl alcohol (50.00 mL) were combined. Sodium cyanoborohydride (371 mg, 5.91 mmol, 1.10 eq) was added followed by acetic acid (0.20 mL). Reaction was then hot block heated to 55°C for 20 hours. The reaction was cooled to room temperature anddiluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO.) and concentrated in vacuo to give tert-butyl (3R)-3-(cyclopropylamino)pyrrolidine- I-carboxylate as clear oil (1.11g), which was used directly in next step. tert-Butyl (3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate (1.11 g, 4.91 mmol, 1.00 eq), methyl alcohol (10.00 mL) and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.07 eq) were combined and stirred at room temperature for 20 hours. The reaction was concentrated in vacuo to give (3R)-N- cyclopropylpyrrolidin-3-amine;dihydrochloride as a white semi-solid (985mg), which was used directly in next step. (3R)-N-Cyclopropylpyrrolidin-3-amine; dihydrochloride (985 mg, 4.95 mmol, 1.00 eq), methyl 5-chloro- 2-pyrazinecarboxylate (854 mg, 4.95 mmol, 1.00 eq), 1,4-dioxane (100.00 mL) and N,N- diisopropylethylamine (2.0 mL, 11.5 mmol, 2.32 eq) were combined and hot block heated to 100°C for 3 days. The reaction was cooled to room temperatureand used crude in the next step. Di-rert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.01 eq) was added to the reaction mixture from the previous step and stirred for 3 days. The reaction was concentrated in vacuo onto silica and purified by flash chromatography to give methyl 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1- yllpyrazine-2-carboxylate as a pale yellow gum (436mg), which was used directly in the next step. LCMS (ES+) 363 (M+H)+ Methyl 5-[(3R)-3-[rerr-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylate (436 mg, 1.20 mmol, 1.00 eq), lithium hydroxide monohydrate (50 mg, 1.20 mmol, 1.00 eq), methyl alcohol (30.00 mL) and water (3.00 mL) were combined and hot block heated to 55°C for 20 hours. The reaction was concentrated in vacuo to give [5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1- yl]pyrazine-2-carbonyl]oxylithium as a tan glass (349mg). LCMS (ES+) 349 (M+H)+ as acid. Intermediate 35: N-(azetidin-3-ylmethyl)cyclopropanamine = [I NH ,Boc JS [a Cyclopropylamine (2.1 mL, 29.7 mmol) rert-butyl 3-formylazetidine-1-carboxylate (5.00 g, 27.0 mmol) and sodium triacetoxyborohydride (12.59 g, 59.4 mmol) were combined in dichloromethane (50.00 mL) and stirred at r.t. for 17 h. Saturated aqueous sodium hydrogen carbonate solution (200 mL) was added to the reaction mixture and stirred vigorously for 10 mins. The organics were collected and washed with water and brine, before passing through a phase separator and concentrating to dryness to give the ritle compound as a clear oil (5.1 g, 83%) which was progressed to the next step directly. tert-Butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate (3.00 g, 13.3 mmol, 1.00 eq) and trifluoroacetic acid (5.1 mL, 66.3 mmol, 5.00 eq) were combined in dichloromethane (30 mL) and stirred atr.t. for 72 h. The reaction mixture was concentrated in vacuo and loaded onto an SCX cartridge and washed with DCM / MeOH (1:1). The compound was realeased using DCM / MeOH / 7M ammonia in MeOH (5:5:1) and concentrated to dryness to give N-(azetidin-3-ylmethyl)cyclopropanamine as a colourless oil (1.19 g, 71%). NB: multiple elutions were required to release product from SCX cartridge. 'H NMR (400 MHz, CDCI3) §, 3.74 (dd, J=7.8, 7.8 Hz, 2H), 3.44 - 3.35 (m, 2H), 2.94 - 2.91 (m, 2H), 291-283 (m, 1H), 2.13 - 2.05 (m, 1H), 0.46 - 0.40 (m, 2H), 0.33 - 0.28 (m, 2H). Intermediate 36: 3-(azetidin-3-yl)-1-methylpiperidine hydrochloride Hale 50. S-{azelidin-o-yl)- 1 -MCUlyipPIpEridine nydrocrioriac NBoc NBoc NH HN — ON — ON \% \ Ho / NN ~~ Hal A mixture of rert-butyl 3-(piperidin-3-yl)azetidine- 1-carboxylate (250 mg, 1.04 mmol), formaldehyde (37% solution, 3.9 mL, 52.0 mmol) and sodium triacetoxyborohydride (441 mg, 2.08 mmol) in methanol 1 mL) was stirred for 20 hours. Water was added and the organics were extracted with DCM. The combined organics were passed through a phase separator and concentrated under reduced pressure yielding the crude material as an off-white gum, which was taken on without further purification (rerr- butyl 3-(1-methylpiperidin-3-yl)azetidine-1-carboxylate; 330 mg). A solution of tert-butyl 3-(1-methylpiperidin-3-yl)azetidine-1-carboxylate (265 mg, 1.04 mmol) in 4 M HCl in dioxane (8.7 mL, 34.7 mmol) and methanol (8.7 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to yield the crude material as a colourless oil which was used without further purification (3-(azetidin-3-yl)-1-methylpiperidine hydrochloride; 310 mg). MS (ES+) 155.1 [M-HCI1+H]*. Intermediate 37: 3-(azetidin-3-yl)-1-cyclopropylpiperidine hydrochloride RE or Ln ad eS Md ML ‘NBoc NBoc NH wn _— AA p— AA \ \ ( Ha NN NZ ’ Hal A mixture of rert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (250 mg, 1.04 mmol), 1- (ethoxycycloproxy)trimethylsilane (0.23 mL, 1.14 mmol) and sodium cyanoborohydride in methanol (10 mL) and acetic acid (0.1 mL) was heated to 50 °C for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organics were separated and washed with brine and dried over sodium sulfate, decanted and concentrated under reduced pressure to yield the crude material as an orange gum, which was taken forward without further purification (tert-butyl 3-(1-cyclopropylpiperidin-3-yl)azetidine- 1 -carboxylate; 224 mg). MS (ES+) 281.2 [M+H]*. A solution of rerr-butyl 3-(1-cyclopropylpiperidin-3-yl)azetidine-1-carboxylate (224 mg, 0.799 mmol) in 4 M HCl in dioxane (6.7 mL, 26.6 mmol) and methanol (6.7 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to yield the crude material as a colourless oil, which was used without further purification (3-(azetidin-3-yl)-1-cyclopropylpiperidine hydrochloride; 144 mg). MS (ES+) 181.1 [M-HCI+H]*. Intermediate 38: 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide = I 4 [ ! [ bi 1 Wel - J oo Be oo A ov oo or ANN tooo To a suspension of 6-ethoxy-5-nitro-1H-indazole (2.30 g, 11.1 mmol) and potassium carbonate (1.69 g, 12.2 mmol) in N,N-dimethylformamide (20 mL) was added iodomethane (0.76 mL, 12.2 mmol) as drops and the reaction was stirred overnight. The reaction mixture was diluted with EtOAc and water and the organics separated and further extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, decanted and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0 to 100% EtOAc in cyclohexane; 80 g column). The product containing fractions were concentrated under reduced pressure to yield the title compound as a tan solid (586 mg; 23% yield). MS (ES+) 222.2 [M+H]*. *H NMR (400 MHz, CDCl;) 3 8.16 (s, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 4.21 - 4.15 (m, 5H), 1.49 (t, J=7.0 Hz, 3H). To a thoroughly degassed suspension of 6-ethoxy-2-methyl-5-nitro-indazole (580 mg, 2.62 mmol) and 1- methyl-1,4-cyclohexadiene (2.9 mL, 26.2 mmol) in ethanol (25 mL) was added 10% palladium on carbon (279 mg, 2.62 mmol) and the reaction was heated to 70 °C overnight. After 24 hours, the reaction was allowed to cool to room temperature and filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to yield a brown gum and the crude material was used directly in the next step without further purification (460 mg; 92% yield). MS (ES+) 192.2 [M+H]*. ‘H NMR (400 MHz, CDCls) 6 7.54 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 4.09 (s, 3H), 3.72 (q, J=7.0 Hz, 2H), 1.49 (t, J=7.0 Hz, 3H). A suspension of 6-ethoxy-2-methyl-indazol-5-amine (460 mg, 2.41 mmol), 5-chloro-2- pyrazinecarboxylic acid (381 mg, 2.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (810 mg, 2.89 mmol) and 1-methylimidazole (0.58 mL, 7.22 mmol) in acetonitrile (12 mL) was stirred under nitrogen over the weekend. The reaction mixture was diluted with water and stirred for 15 minutes. The reaction mixture was filtered and the filtercake taken and dried under reduced pressure yielding 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide as a yellow powder (410 mg; 51% yield). MS (ES+) 332.2 [M+H]*. '"H NMR (400 MHz, CDCl) 6 10.39 (s, 1H), 9.27 (d, J=1.4 Hz, 1H), 8.81 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 7.82 (s, 1H), 7.02 (s, 1H), 4.22 (q, J=7.0 Hz, 2H), 4.16 (s, 3H), 1.57 (t, J=7.0 Hz, 3H). Intermediate 39: N-(azetidin-3-ylmethyl)cyclopropanamine dihydrochloride i fe a A LN Ro —- 0g - — - — v Y F F aur «2HCI A suspension of rerr-butyl 3-fluoro-3-(hydroxymethyl)azetidine- 1-carboxylate (500 mg, 2.44 mmol) and Dess-Martin periodinane (1.24 g, 2.92 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous sodium thiosulfate (10% w / v) and sat. aqueous sodium hydrogen carbonate and stirred for 20 minutes. The mixture was passed through a phase separator and the organics concentrated under reduced pressure yielding a colourless oil, which was taken on without further purification (480 mg; 97% yield). A mixture of rer-butyl 3-fluoro-3-formyl-azetidine-1-carboxylate (240 mg, 1.18 mmol), sodium triacetoxyborohydride (526 mg, 2.48 mmol) and cyclopropylamine (0.090 mL, 1.30 mmol) in dichloromethane (10 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with water and stirred for 10 minutes. The mixture was passed through a phase separator and the organics concentrated under reduced pressure yielding the crude material as a pale yellow gum (250 mg; 87% yield). A solution of rerr-butyl 3-[(cyclopropylamino)methyl]-3-fluoro-azetidine- 1-carboxylate (250 mg, 1.02 mmol) in 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) and methanol (5 mL) was stirred at room temperature for three days. The reaction mixture was concentrated under reduced pressure to yield the crude material as a tan solid, which was used without further purification (210 mg; 95% yield). Intermediate 40: 1-(Azetidin-3-ylmethyl)-3-methoxy-azetidine “he ! o AI ) - “XO Ae ) — “XO Pa tert-Butyl 3-formylazetidine-1-carboxylate (0.50 g, 2.70 mmol), sodium triacetoxyborohydride (1.26 g, 5.94 mmol) and 3-methoxyazetidine hydrochloride (334 mg, 2.70 mmol) were combined in dichloromethane (50 mL) and stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture and stirred vigorously for 10 mins. The organics were collected and washed with water and brine, before passing through a phase separator and concentrating to dryness to give tert-butyl 3-[(3-methoxyazetidin-1-yl)methylJazetidine-1- carboxylate as a clear oil (700 mg), which was used without further purification. tert-Butyl 3-[(3-methoxyazetidin- I-yl)methyl]azetidine- 1-carboxylate (700 mg, 2.73 mmol) and trifluoroacetic acid (1.0 mL, 13.7 mmol) were combined in dichloromethane (30 mL) and stirred at room temperature for 21 hours. The reaction mixture was concentrated in vacuo, then dissolved in DCM:MeOH (1:1, 20 mL) and passed through an SCX cartridge. The column was eluted with DCM:MeOH (1:1) to remove TFA and the product was released using DCM:MeOH:7M NHs in MeOH (5:5:1). The product containing fraction was concentrated to dryness to give 1-(azetidin-3-ylmethyl)-3- methoxy-azetidine as a colourless oil (400 mg). Intermediate 41: 1-cyclopropyl-3,3'-biazetidine \ Boc Boc [IR N [IR iH HN=d trert-Butyl [3,3'-biazetidine]-1-carboxylate (80mg, 0.38 mmol), (1-ethoxycyclopropoxy)trimethylsilane (0.15 mL, 0.75 mmol), methanol (2.5 mL), acetic acid (0.01 ml) and sodium cyanoborohydride (47 mg, 0.75 mmol) were combined and stirred at 50 °C for 18 hours. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried and evaporated to afford rerz-butyl 1'-cyclopropyl-[3,3'- biazetidine]-1-carboxylate (103mg) as a colorless oil which was used crude in the next step. tert-Butyl 1'-cyclopropyl-[3,3'-biazetidine]-1-carboxylate (100 mg, 0.38 mmol), DCM (1 ml) and TFA (1 ml) were combined and stirred at room temperature for 65 hours. The reaction mixture was purified by SCX to give 1-cyclopropyl-3,3'-biazetidine as a crude yellow oil (56 mg) which was used as such in next step. Intermediate 41a: 2,8-dimethylimidazo[1,2-alpyrazin-6-amine =~ NN LI Br 'N Fy) HN LL A mixture of 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (prepared according to WO 2015 / 197503, 991 mg, 4.38 mmol) and CuSO4 (401 mg, 2.51 mmol) in 35% aqueous ammonia solution (8 mL) was heated to 90 "C under microwave irradiation for 3 h. After cooling to rt, the material was filtered through Celite, washing with water and methanol. The filtrate was acidified to pH 4 with 2 M HCI, then concentrated. The residue was applied to a 70 g SCX cartridge, eluting with 100 mL MeOH, then 150 mL 2.3 M NH3 / MeOH. The ammonia fraction was concentrated and the residue purified by silica gel column chromatography (gradient elution, 0-20% MeOH / DCM) to give 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine as a brown powder (450 mg, 2.77 mmol, 63%). Intermediate H1: 5-Chloro-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide OMe ” a Br Cl ON A NN — NN IL onde HN” NP Na) ; po rte aA 3-Chloro-5-nitro-pyridin-2-amine (0.0010 g, 5.76 pmol), 1-bromo-2,2-dimethoxypropane (0.0012 mL, 9.22 pmol), pyridinium p-toluenesulfonate (0.00014 g, 0.576 pmol) and IPA (10.00 mL) were combined and the R.M was stirred at 95°C for 4.5 h. The reaction mixture was filtered and washed with IPA to give the desired product (91% purity, 1.5 g, quantitative). LCMS (ES*) 212 (M+H)*, RT 1.35 min. 8-Chloro-2-methyl-6-nitro-imidazo[ 1,2-a]pyridine (300 mg, 1.42 mmol) and iron (396 mg, 7.09 mmol) in acetic acid (1 mL) were stirred at 60°C for 1 h. The reaction mixture was loaded onto an SCX cartridge and passed through using NH; (7 M) in MeOH. The filtrate was concentrated, diluted with DCM and washed with aqueous 15 mol% NaOH. The organic layer was concentrated in vacuo to give the desired product (211 mg, 82%). LCMS (ES*) 181 (M+H)*, RT 1.05 min. 8-Chloro-2-methyl-imidazo[ 1,2-a]pyridin-6-amine (211 mg, 1.16 mmol), 5-chloro-2-pyrazinecarboxylic acid (184 mg, 1.16 mmol), chloro-N,N,N',N -tetramethylformamidinium hexafluorophosphate (489 mg, 1.74 mmol) and 1-methylimidazole (0.28 mL, 3.49 mmol) in acetonitrile (8.00 mL) was stirred under nitrogen for 16 h at RT.The reaction mixture was concentrated, diluted with DCM and washed with aqueous sodium bicarbonate. The organic layer was concentrated onto silica and purified by column chromatography, eluting with cylcohexane / EtOAc (0-100% gradient). The appropriate fractions were combined and concentrated in vacuo to give the desired product (211 mg, 75%). LCMS (ES*) 322 (M+H)*, RT 1.23 min. 'H NMR (400 MHz, CDCl) 8 9.36 (s, 1H), 9.26 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 7.47 (s, 1H), 7.19 (d, J=1.6 Hz, 1H), 2.51 (s, 3H). Intermediate H2 (5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2- carboxamide) Br OMe Me io) = ° NN © . a — 4 — — (J NZ NH, MeO’ | SON OMe Br OMe HN Me _ . . A 5-Bromo-3-methoxy-pyridin-2-amine (3.57 g, 17.6 mmol), 1-bromo-2,2-dimethoxypropane (3.8 mL, 28.1 mmol), pyridinium p-toluenesulfonate (0.44 g, 1.76 mmol) and IPA (10.00 mL) were combined. The R.M was stirred at 95°C for 5 h. The reaction mixture was diluted with 3:1 DCM / IPA and washed with brine. The organic layer was concentrated in vacuo to afford 6-bromo-8-methoxy-2- methylimidazo[1,2-a]pyridine (4.2 g, 96%). LCMS (ES*) 242 (M+H)*, RT 1.02 min. ‘H NMR (400 MHz, DMSO) 6 8.44 (1H, d, J=1.6 Hz), 7.66 (1H, s), 6.81 (1H, d, J=1.5 Hz), 3.95 (3H, s), 2.32 (3H, s). 6-Bromo-8-methoxy-2-methyl-imidazo[1,2-a]pyridine (1.01 g, 4.19 mmol), copper(I) iodide (0.16 g, 0.838 mmol), potassium carbonate (0.87 g, 6.28 mmol), ammonium hydroxide solution (0.26 mL, 6.28 mmol), L-proline (0.19 g, 1.68 mmol) and DMSO (10.00 mL) were added to the reaction flask. The reaction vessel was sealed and heated at 90°C for 16 h. The reaction mixture was passed through an SCX cartridge with MeOH and NH; (7 M) in MeOH and the appropriate fraction was concentrated in vacuo to give the desired product (1.19 g, 99%). LCMS (ES*) 179 (M+H)*. 8-Methoxy-2-methyl-imidazo[ 1,2-a]pyridin-6-amine (326 mg, 1.84 mmol), 5-chloro-2- pyrazinecarboxylic acid (292 mg, 1.84 mmol), chloro-N,N,N',N"-tetramethylformamidinium hexafluorophosphate (774 mg, 2.76 mmol) and 1-methylimidazole (0.44 mL, 5.52 mmol) in acetonitrile (8.00 mL) was stirred under nitrogen for 16 h at RT. The reaction mixture was concentrated, diluted with 3:1 DCM:IPA and washed with brine. The crude product was purified by column chromatography eluting with cyclohexane / EtOAc (0-100% gradient) to give 5-chloro-N-(8-methoxy-2- methylimidazo[ 1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (909 mg, 87%). LCMS (ES*) 317 (M+H)*. Intermediate H3: 5-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(7-fluoro-2-methyl-2H-indazol-5- yl)pyrazine-2-carboxamide o£ o BA IX HN F 7 Ss cl 2 T > N HBTU (1.88 g, 4.96 mmol, 1.00 eq), triethylamine (3.5 mL, 24.8 mmol, 5.00 eq), 5-chloro-2- pyrazinecarboxylic acid (0.79 g, 4.96 mmol, 1.00 eq), N,N-dimethylformamide (10.00 mL) and 7-fluoro- 2-methyl-indazol-5-amine; hydrochloride (1.00 g, 4.96 mmol, 1.00 eq) were combined and stirred at room temperature for 17 h. LCMS indicated none of the expected chlorinated material present, and instead the HOBt adduct was formed. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed multiple times with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo. NB. Significant quantities of the HOBt adduct remained in the aqueous layer. The material was purified by flash silica chromatography (gradient elution c-hex to EtOAc) to give 5-(benzotriazol-1-yloxy)-N-(7-fluoro-2-methyl-indazol-5-yl)pyrazine-2- carboxamide as a pale yellow solid (586 mg, 28%). LCMS (ES+) 405 (M+H)*. 'H NMR (400 MHz, DMSO) 38 10.81 (s, 1H), 9.16 (s, 1H), 8.82 (s, 1H), 8.48 (d, J=2.7 Hz, 1H), 8.25 - 8.20 (m, 2H), 7.87 (d, J=8.3 Hz, 1H), 7.71 (dd, J=7.6, 7.6 Hz, 1H), 7.62 - 7.57 (m, 2H), 4.20 (s, 3H). Intermediate 42: 7-fluoro-2-methyl-2H-indazol-5-amine hydrochloride / N NH N Ng H { x J LN {n ’ F — Br F gi 5 Br’ F Br’ F N N [Ln [n Ph 4 — 7 A PRN F HN’ F HCI 5-Bromo-2,3-difluoro-benzaldehyde (5 g, 22.6 mmol), methoxyamine hydrochloride (2.27 g, 27.1 mmol) and potassium carbonate (6.88 g, 49.8 mmol) were added to ethylene glycol dimethyl ether (100 mL). The reaction was heated to 45 °C for 18h. The reaction was cooled to r.t. and filtered through a glass sinter and the collected solid was washed with EtOAc. The collected liquid was concentrated in vacuo to give 5-bromo-2,3-difluorobenzaldehyde O-methyl oxime as a pale yellow solid (6.82 g, 100%). 5-Bromo-2,3-difluorobenzaldehyde O-methyl oxime (5.66 g, 22.6 mmol) was dissolved in 1,4-dioxane (150 mL) and hydrazine (3.6 mL, 0.113 mol) was added. The reaction was heated at 90 °C for 5 days. The reaction was cooled to r.t. and concentrated in vacuo. The residue was purified by silica chromatography EtOAc / cyclohexane 0-40% to give 5-bromo-7-fluoro-2H-indazole as an off-white solid (3.83 g, 711%). 5-Bromo-7-fluoro-1 H-indazole (3.83 g, 17.8 mmol) was dissolved in ethyl acetate (100 mL) and cooled to 0 °C using an ice-bath. Trimethyloxonium tetrafluoroborate (3.95 g, 26.7 mmol) was added portion wise and once addition was complete the reaction was warmed to r.t.. The reaction was stirred for 18 h at r.t.. The reaction was quenched with water, extracted with EtOAc and the layers separated. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel, eluting with 0-50 % EtOAc in cyclohexane to give 5-bromo-7-fluoro-2-methyl-2H-indazole as an off-white solid (2.42 g, 55%). 5-Bromo-7-fluoro-2-methyl-indazole (2.42 g, 10.6 mmol) was dissolved in degassed tetrahydrofuran (100 mL) and cesium carbonate (5.16 g, 15.8 mmol), palladium(II) acetate (0.24 g, 1.06 mmol), (rac)- 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.66 g, 1.06 mmol) and benzophenone imine (1.8 mL, 10.6 mmol) was added. The reaction tube was purged with nitrogen and sealed. The reaction heated at 80 °C for 18 h. The reaction was cooled to r.t. and the solids filtered and washed with EtOAc. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel, eluting with EtOAc / cyclohexane 0-100 % to give an oil (3 g). 'H NMR analysis showed predominantly starting material, 5-Bromo-7-fluoro-2-methyl-indazole, with 35% conversion to N-(7- fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. The impure material (3.00 g, 4.58 mmol, assume 35% purity) was dissolved in degassed tetrahydrofuran (80 mL) and cesium carbonate (2.24 g, 6.88 mmol), palladium(II) acetate (0.21 g, 0.917 mmol), (rac)- (+)-2,2"-bis(diphenylphosphino)-1,1'-binaphthalene (0.57 g, 0.917 mmol) and benzophenone imine (0.92 mL, 5.50 mmol) was added. The reaction tube was purged with nitrogen and sealed. The reaction was heated at 80 °C for 24 h. The reaction was cooled to r.t. and the solids filtered and washed with EtOAc. The filtrate was concentrated in vacuo to give a residue oil. The residue was purified by column chromatography on silica gel, eluting with EtOAc / cyclohexane 0 -100 % to give N-(7-fluoro-2-methyl- 2H-indazol-5-yl)-1,1-diphenylmethanimine as an off-white solid (2.56 g, >100%). N-(7-Fluoro-2-methyl-indazol-5-yl)-1,1-diphenyl-methanimine (2.56 g, 7.77 mmol) was suspended in methyl alcohol (10 mL) and 4 N hydrogen chloride in dioxane (19 mL, 77.7 mmol) was added at r.t. The reaction was stirred at r.t. for 18 h. The solvent was removed in vacuo to give a pale yellow solid. EtOAc was added and the formed slurry was stirred for ~10 minutes. The solid was filtered and washed with further EtOAc to give the title compound as an off-white solid (1.66 g, 95%). LCMS (ES+) 166 M+H)+ Intermediate 43: tert-butyl cyclopropyl((2-oxopyrrolidin-3-yl)methyl)carbamate NH NH _ NH _ Aw NH Ho~ / — MsO— = HN— ~~ a 7% 5 4 To a stirred solution of 3-(hydroxymethyl)pyrrolidin-2-one (780 mg, 6.77 mmol) in dichloromethane (50 mL) and triethylamine (1.9 mL, 13.5 mmol) at r.t. was added methanesulfonyl chloride (0.58 mL, 7.45 mmol) dropwise. The reaction was stirred for 18 h at r.t.. The reaction was quenched by addition of water and the layers separated using a phase separator. The DCM was removed in vacuo to give (2- oxopyrrolidin-3-yl)methyl methanesulfonate as a white solid (800 mg, 61%). (2-Oxopyrrolidin-3-yl)methyl methanesulfonate (800 mg, 4.14 mmol) was dissolved in acetonitrile (15 mL) and triethylamine (1.7 mL, 12.4 mmol) was added followed by cyclopropylamine (1.7 mL, 24.8 mmol). The reaction tube was sealed and heated in a microwave at 120°C for 2 h. The solvent was removed in vacuo to give a residue, which was purified by SCX chromatography (5 g, eluting with MeOH / DCM 50% and then 10% 7N NH3 in MeOH / MeOH). The ammonical fractions were combined and the solvent removed in vacuo to give 3-((cyclopropylamino)methyl)pyrrolidin-2-one as a yellow oil (438 mg, 69%). 3-[(Cyclopropylamino)methyl]pyrrolidin-2-one (438 mg, 2.84 mmol) was dissolved in dichloromethane (30 mL). Di-tert-butyl dicarbonate (0.72 mL, 3.12 mmol) and 4-(dimethylamino)pyridine (17 mg, 0.142 mmol) was added. The reaction was stirred at r.t. for 18 h. The solvent was removed in vacuo to give a residue, which was purified by silica chromatography (10g, eluting with EtOAc) to give the title compound as a clear oil (420 mg, 58%). Intermediate 44: 5-chloro-N-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide N nA GAN o oo AN 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 7-fluoro-2-methyl-indazol-5-amine hydrochloride (254 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.53 mL, 3.78 mmol) was added and the reaction stirred at r.t. for 3 h. The reaction was quenched by addition of water and the aqueous layer extracted with DCM. The layers were separated using a phase separator and the DCM removed in vacuo to give the title compound as a light tan solid (280 mg, 65%). Used in next step without further purification. Intermediate 45: 5-chloro-N-(1H-indazol-5-yl)pyrazine-2-carboxamide o ~~ aA =N a NH YH An " 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 2H-indazol-5-amine (168 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.53 mL, 3.78 mmol) was added at 1.t. and the reaction was stirred for 3h at r.t. The reaction was quenched with water and the aqueous extracted with DCM x3. The layers were separated using a phase separator and solvent removed in vacuo to give the title compound as brown solid (305 mg, 79%). Used in the next step without further purification. Intermediate 46: 5-chloro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)pyrazine-2-carboxamide og fod HN 0 N 1 CX = Sy F ae i; 4-Fluoro-2-methyl-1,3-benzoxazol-6-amine (200 mg, 1.20 mmol), 5-chloro-2-pyrazinecarboxylic acid (191 mg, 1.20 mmol) and 1-methylimidazole (0.29 mL, 3.60 mmol) were suspended in acetonitrile (10 mL). Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (400 mg, 1.43 mmol) was added and the suspension stirred at r.t. for 18 h. The formed solid was collected by filtration and washed with acetonitrile and water. The solid was dried overnight in a vacuum oven to give the title compound as an off-white solid (250 mg, 67%). Used in the next step without further purification. Intermediate 47: 5-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)azetidin-1-yl)pyrazine-2-carboxylic acid o a ZN 0 0 or or - H N — , ey poy A o ; NTN Sep tert-Butyl N-(azetidin-3-ylmethyl)carbamate (675 mg, 3.62 mmol), methyl 5-chloro-2- pyrazinecarboxylate (625 mg, 3.62 mmol), cesium carbonate (2373 mg, 7.28 mmol) and 1,4-dioxane (25 mL) were combined and heated at reflux overnight. The reaction was cooled to r.t. and the solvent removed in vacuo. Residue taken up in DCM and washed with water, the layers were separated using a phase separator. The DCM was removed in vacuo to give a residue. The residue was purified by column chromatography on silica gel (25 g, eluting with EtOAc in cyclohexane 0-100 %) to give a yellow oil (870 mg, 74%). Methyl 5-[3-[(tert-butoxycarbonylamino)methyl]azetidin-1-yl]pyrazine-2-carboxylate (250 mg, 0.776 mmol) was dissolved in N,N-dimethylformamide (5 mL) and sodium hydride (60%, 34 mg, 0.853 mmol) was added. The reaction was stirred at r.t. for 1 h. Iodomethane (0.048 mL, 0.776 mmol) was added and the reaction stirred for 18 h at r.t. The reaction was quenched with MeOH (to avoid ester hydrolysis) and the solvent removed in vacuo to give a residue oil. Used in the next step without further purification. Methyl 5-[3-[[tert-butoxycarbonyl(methyl)amino]methyl]azetidin- 1-yl]pyrazine-2-carboxylate (261 mg, 0.776 mmol) was dissolved in methyl alcohol (2 mL) and water (1 mL) and lithium hydroxide monohydrate (33 mg, 0.776 mmol) was added. The reaction was stirred at r.t. for 18 h. The solvent was removed in vacuo and the residue dissolved in water (2 mL). The pH was adjusted to pH=3 with IM HCl and the aqueous layer extracted with EtOAc x4. The organic layer was separated and dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give the title compound as a clear oil (155 mg, 61%). Used in the next step without further purification. Intermediate 48: 7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-amine. HCI =~ o NN LT] Ln NN A = AL of HzN . F Ph” "Ph F 1227586-61-8 plus bromide imp. plus bromide imp. ~ usedimpure used impure 4-Fluoro-3-methyl-pyridin-2-amine (500 mg, 3.96 mmol, 1.00 eq), N-bromosuccinimide (706 mg, 3.96 mmol) and dichloromethane (20 mL) were combined and stirred at r.t. for 2 h. Reaction mixture was then evaporated to dryness to give a brown solid, which was used crude in next step. LCMS (ES+) 205 / 207 (M+H)+. 5-Bromo-4-fluoro-3-methyl-pyridin-2-amine (813 mg, 3.96 mmol) (crude from previous step), 1-bromo- 2,2-dimethoxypropane (0.80 mL, 5.95 mmol), pyridinium p-toluenesulfonate (100 mg, 0.396 mmol) and 2-propanol (15 mL) were combined in a sealed tube and hot block heated to 85°C overnight. Off- white precipitate was observed. The reaction mixture was cooled to r.t., concentrated in vacuo, partitioned between ~10% aq. NaOH soln. and dichloromethane. The organic phase was dried (MgSOa) and concentrated in vacuo to give 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine (856 mg) as a brown solid. LCMS (ES+) 243 / 245 (M+H)+. 'H NMR (400 MHz, CDCls) 3 8.09 (d, J=6.3 Hz, 1H), 7.25 (s, 1H), 2.53 (d, I=2.5 Hz, 3H), 2.44 (s, 3H). Cesium carbonate (1721 mg, 5.28 mmol), palladium(II) acetate (79 mg, 0.352 mmol), (+)-2,2'- bis(diphenylphosphino)-1,1'-binaphthalene (219 mg, 0.352 mmol), 6-bromo-7-fluoro-2,8-dimethyl- imidazo[1,2-a]pyridine (856 mg, 3.52 mmol) and tetrahydrofuran (20 mL) were combined and the reaction mixture was degassed by bubbling through nitrogen for 5 mins. Reaction tube was sealed and hot block heated to 85°C over weekend. The reaction mixture was filtered through a Celite plug to remove Cesium salts, rinsing through with EtOAc. The organic phase was concentrated in vacuo onto silica and purified by flash chromatography. Starting material and target seemed to co-run. 622 mg, tan solid. LCMS basic, RT = 1.42 mins, 243 / 245 M+H starting material, RT = 1.70 mins, 344 M+H target. Used as is in next step. A mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine and N-(7-fluoro-2,8-dimethyl- imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (622 mg, from previous step), methyl alcohol (5 mL) and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) were combined and stirred atr.t. for 1 h. Reaction mixture was evaporated to dryness to give 767 mg, tan solid. LCMS analysis showed a mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-alpyridine and 7-fluoro-2,8-dimethyl-imidazo[1,2- alpyridin-6-amine. HCl. LCMS basic RT = 1.04 mins, 180 M+H target, RT = 1.42 mins, 243 / 245 bromide in starting material. Used as is in next step. Example 1: (R)-5-(2-ethylpiperazin- 1-yl)-N-(8-fluoro-2-methylimidazo[ 1,2-alpyridin-6-yl )pyrazine-2- carboxamide % = A LL oA 8 0o i P oy SED At 1 WO To a solution of Intermediate 1 (150 mg, 0.49 mmol) in dioxane (1 mL) was added rerr-butyl (R)- 3-ethylpiperazine-1-carboxylate (263 mg, 1.23 mmol). Triethylamine (0.1 mL, 0.74 mmol) was added and the reaction was heated in a microwave at 140 °C for 30 minutes. The solvent was removed in vacuo and the residue purified using silica chromatography elution gradient 0-10% ethyl acetate / cyclohexane to give tert-butyl (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yl)piperazine-1-carboxylate. MS (ES+) 484 (M+H). To a solution of rerr-butyl (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)pyrazin-2-yl)piperazine- 1 -carboxylate (140 mg, 0.29 mmol) in methanol (2 mL) was added 4M hydrochloric acid in dioxane (10 mL). The reaction was stirred at r.t. for 1 h. The solvent was removed in vacuo, and the crude product provided was purified by reverse phase HPLC to give a TFA salt of the target. The TFA salt was dissolved in methanol / DCM 1:1 and MP-carbonate was added. The mixture was left standing for 18 h. The MP-carbonate was filtered and the solvent removed in vacuo to give the title compound. LCMS (ES+) 384 (M+H)+, RT 1.85 min (Analytical method AcHSSC18); 'H NMR (400 MHz, DMSO) § 10.44 (s, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.60 (dd, J=1.1, 12.7 Hz, 1H), 4.47 - 4.44 (m, 1H), 4.32 (d, J=12.9 Hz, 1H), 3.14 - 2.98 (m, 3H), 2.81 (dd, J=2.9, 12.5 Hz, 1H), 2.70 - 2.64 (m, 1H), 2.39 (s, 3H), 1.92 - 1.74 (m, 2H), 0.89 (t, J=7.5 Hz, 3H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. | Ex. | Structure | Amine | Analytical data =~ 2 .| aL NT JOT Ie ol NT N’ ANE 1G LCMS (ES+) 398 (M+H)+, RT 1.89 min (Analytical method AcHSSC18) 'H NMR (400 MHz, DMSO) 3 10.32 (s, 1H), 9.11 (4, J=1.5 Hz, 1H), 8.65 (d, tert-butyl J=1.3 Hz, 1H), 8.16 (d, J=1.3 Hz, 1H), (28,5R)-2-ethyl- | 7.82 (d, J=2.5 Hz, 1H), 7.48 (dd, J=1.6, 5- 13.2 Hz, 1H), 4.46 - 4.41 (m, 1H), 4.07 methylpiperazin | (dd, J=1.6, 13.3 Hz, 1H), 3.39 (dd, J=4.2, e-l-carboxylate | 13.3 Hz, 1H), 3.04 (dd, J=4.8, 13.1 Hz, 1H), 2.85 - 2.80 (m, 1H), 2.52 (dd, J=2.6, 13.1 Hz, 1H), 2.28 (s, 3H), 1.48 - 1.33 (m, 2H), 1.19 (d, J=6.6 Hz, 3H), 0.82 (t, J=7.5 Hz, 3H). LCMS (ES+) 370 (M+H)+, RT 1.69 min (Analytical method AcHSSCI18) 'H NMR (400 MHz, DMSO) 8 10.97 (s, tert-butyl (R)-3- 1H), 9.76 (s, 1H), 9.66 (s, 1H), 9.62 (d, (methylamino)p J=1.4 Hz, 1H), 8.85 (d, J=1.3 Hz, 1H), yrrolidine-1- 8.34 (s, 1H), 8.30 - 8.25 (m, 2H), 5.49 - carboxylate 5.39 (m, 1H), 3.48 - 3.37 (m, 2H), 3.27 - 3.14 (m, 5H), 2.51 (s, 3H), 2.27 - 2.18 (m, 1H), 2.17 - 2.06 (m, 1H). NT Jor |W NTN | JT Ls = ney | Hn o ho! A or A yo |G a ZF aa o£ 5 Fi) ~All SUH NS rT oo | Enantiomer 1 + Enantiomer 2 [1 | [RS ethylpyrrolidin- 3-amine = o Ta H 0.5 eq formate salt LCMS (ES+) 408 (M+H)+, RT 1.76 min | (Analytical method AcHSSC18); ~ 1H NMR (400 MHz, DMSO) 5 10.41 (s, NN 2-cyclopropyl- 0 OX 26 1H), 9.15 (4, J=1.6 Hz, 1H), 8.69 (d, | 10 | WS NF i J=1.3 Hz, 1H), 8.18 (s, 0.5H), 7.87 (d, NAN diazaspiro[3.3]h + J=2.8 Hz, 1H), 7.84 (d, J=1.4 Hz, 1H), N. eptane.2TFA | 7 7.53 (dd, J=1.9, 12.9 Hz, 1H), 4.23 (s, 4H), 3.39 (s, 4H), 2.32 (s, 3H), 1.87 - 1.80 (m, 1H), 0.34 - 0.29 (m, 2H), 0.22 - 0.25 (m, 2H). LCMS (ES+) 384 (M+H)+, RT 1.69 min (Analytical method AcHSSC18) =~ 1H NMR (400 MHz, DMSO) 88.95 (s, 0 NM Sn 1H), 8.64 (s, 1H), 7.94 (s, 1H), 7.78 (d, | SA or 322.0 Hz, 1H), 7.42 (d, J=12.7 He, 1H), 1 | N ¥ ethylpyrrolidin- Aaah ’ 3.72 - 3.60 (m, 2H), 3.52 - 3.47 (m, 1H), 3-amine o 3.41 (s, 1H), 3.31 - 3.27 (m, 1H), 2.58 | re (d, J=6.8 Hz, 2H), 2.32 (s, 3H), 2.21 - 2.15 (m, 1H), 1.84 - 1.84 (m, 1H), 1.02 (dd, J=7.1,7.1 Hz, 3H). Example 12: 5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[ 1,2- alpyridin-6-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2) ~~ ~~ H [7 \ ° NN on rw are H F d Fp) ~IAL Pe No wt 4 Prepared using general Method D and the following quantities: Intermediate 1 (127 mg, 0.41 mmol), N-(pyrrolidin-3-ylmethyl)cyclopropanamine dihydrochoride (87 mg, 0.41 mmol), cesium carbonate (487 mg, 1.5 mmol) and DMF (3 mL). The crude material was purified by preparative HPLC to give the title compound. LCMS (ES+) 410.2 (M+H)+, RT 3.59 min (Analytical method BicarbBEHC18). 'H NMR (400 MHz, DMSO) 8 10.17 (s, 1H), 8.95 (d, J=1.7 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.1 Hz, 1H), 7.65 (dd, J=0.8, 3.1 Hz, 1H), 7.33 (dd, J=1.6, 13.1 Hz, 1H), 3.51 - 3.40 (m, 2H), 3.32 - 3.24 (m, 1H), 3.03 - 2.95(m, 2H), 2.49 - 2.36(m, 2H), 2.10 (s, 3H), 1.90 - 1.82 (m, 2H), 1.55-1.46 (m, 1H), 0.17 - 0.12(m, 2H), 0.04 - -0.04 (m, 2H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure Amine Analytical data LCMS (ES+) 393 Sterile) Sd (M+H)+, RT 3.43 min | (Analytical method BicarbBEHC18) 1H NMR (400 MHz, o VN DMSO) 810.53 (s, 1x 1H), 9.20 (d, J=1.6 Hz = | EY Ap 5,6,7,8-tetrahydroimidazo[1,5- 1H), 8.82 (d, J=1.1 Hz or Pio cari 1H), 8.43 (d, J=1.1 Hz alpyrazine 9 ol | IW ee 12.8 Hz, 1H), 6.86 (s, SANIT OD SMe) AS, 1H), 9.20 (&, J=1.6 Hz, 1H), 8.82 (d, J=1.1 Hz, 1H), 8.43 (d, J=1.1 Hz, 1H), 8.19 (s, 1H), 791 (d, ¥=2.6 Hz, 1H), 7.68 (s, 1H), 7.58 (dd, J=16, 12.8 Hz, 1H), 6.86 (5, | 1H), 498 (s, 2H), 4.28 - 4.23 (m, 2H), 4.18 - 4.13 (m, 2H), 2.35 (s, 3H). LCMS (ES+) 440 Ae2VAD ALOT) ES (M+H)+, RT 2.02 min | VIHEDF, RT 2.02 mi (Analytical method AcHSSC18); 1H NMR (400 MHz, DMSO) 6 10.44 (s, =~ 1H), 7.58 (dd, J=1.8, \ NY NNN 1 oR F | 2methy1-2,7-diazaspirof4 4lnonane 1H), 9.20 (d, J=1.6 Hz = 1H), 8.75 (d, J=1.0 Hz oY 1H), 7.98 (d, J=1.1 Hz ~A Zz 1H), 7.90 (d, J=2.7 Hz 4 | 0 N F | 2-methyl-2,7-diazaspiro[4.4]nonane 1H), 7.58 (dd, J=1.8, ON 13.0 Hz, 1H), 3.65 - ~~ 3.56 (m, 3H), 3.48 (4, J=10.8 Hz, 1H), 2.69 N , 1H), Ad 2.54 (m, 1H), 2.54-2.4 Enantiomer 2 !" (m, 2H, obscured by Hz, 1H), 2.35 (s, 3H), AdRL, &24, ULLAL VY water), 2.42 (d, J=9.2 Hz, 1H), 2.35 (s, 3H), 2.27 (s,3H),2.03- 1.97 (m, 2H), 1.86 - 1.80 (m, ATTY 2H). LCMS (ES+) 398 Ate VLD Aad) 2S (M+H)+, RT 191 min | MID, RT 1.9] mo (Analytical method AcHSSC18): 1H NMR (400 MHz, DMSO) 5 10.44 (s, =~ 2-methyl-2,7-diazaspiro[4.4Jnonane | 1) 7.58 (dd, J=1.8, 1H), 9.20 (d, J=1.6 Hz = 1H), 8.75 (d, J=1.0 Hz of Ny 1H), 7.98 (d, J=1.1 Hz ~ALL sp methvl2 7 diazacoirold4 1H), 7.90 (d, J=2.7 Hz al N -methyl-2,7-diazaspiro[4.4]nonane 1H), 7.58 (dd, J=1.8, oN 13.0 Hz, 1H), 3.65 - x 3.56 (m, 3H), 3.48 (d, J=10.8 Hz, 1H), 2.69 - A 2.54 (m, 1H), 2.54-2.4¢ Enantiomer 1 !" (m, 2H, obscured by Hz, 1H), 2.35 (s, 3H), AL &24, ULLAL VY water), 2.42 (d, J=9.2 Hz, 1H), 2.35 (s, 3H), 2.27 (s, 3H), 2.03 - 1.97 (m, 2H), 1.86 - 1.80 (m, ALY 2H). LCMS (ES+) 428 iar tprli lan) A Lind) 2 ly (M+H)+, RT 2.25 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, SSIS, LES ASy 1H), 9.20 (d, J=1.6 Hz, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.09 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 433 T—m1 € 12 1 Wa (dd, J=1.6, 13.1 Hz, 1H), 5.57 (td, J=3.0, tur An fey: ~~ DMSO) 510.47 (s, 0 MN 1H), 9.20 (d, J=1.6 Hz XL 1H), 8.79 (d, J=1.3 Hz YY ZF ) 1H), 8.09 (s, 1H), 7.9( NAAN Intermediate 8 (d, J=2.8 Hz, 1H), 7.5 ~) (dd, J=1.6, 13.1 Hz, J 1H), 5.57 (td, J=3.0, 51.6 Hz, 1H), 4.03 - 3.78 (m, 4H), 3.49 - Vv | FOAM, FALL LST 3.38 (m, 1H), 2.36 (d, Cis Isomer, Enantiomer 1 Se Hy 2 os - 1.85 (m, 1H), 0.53 - 0.48 (m, 2H), 0.39 - 0.27 (m, 2H). LCMS (ES+) 438 AeA Ao) Fae (M+H)+, RT 2.46 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, Intermediate 9 | DM IS 0) 3 10.54 Gs, (s, 1H), 8.27 (s, 1H), 1H), 5.26 -5.21 (m, ! (Analytical method | = ACHSSCIS) 2 JL 1H NMR (400 MHz, NP i ! DMSO) 510.54 s, ANT Intermediate 9 | 110,923 (5, 1], 8.85 | Jed (s, 1H), 8.27 (s, 1H), oN | 7.94 ¢,3=25 He, 18D, A 7.62 (4, J=13.1 Hz, 1H), 526-521 (m, LAB) wield = Jue LAL | 1H), 4.55 (t, J=6.6 Hz, | fa as) ' 1H), 430-4.19(m, ' 2H), 3.71 (dd, J=5.3, LiL} Jo £1 AU, JJ | 13.1 Hz, 1H), 3.56 (dd, | 1-243 172 WW» 110 J=5.9, 12.3 Hz, 1H), 2.74 - 2.63 (m, 1H), due V0 dahl? Ay LLL Jy | 239 (s, 3H), 0.91 - 0.72 | (m, 4H). LCMS (ES+) 428 Tarte MVILID A utr] rl) | (M+H)+, RT 1.99 min | Vb Lp (Analytical method AcHSSCIB); ~ 'H NMR (400 MHz, \ TRAC £ 1A AD ro DMSO) 6 10.43 (s, 2-methyl-2,6-diazaspiro[3.4]octane LANRIAST A) AW She? Ay 1H), 9.20 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 7.98 (d, J=1.9 Hz, 1H), 7.89 (d, J=3.1 Hz, 1H), 7.57 31 T—1 © 13 7 1 (dd, J=1.5, 13.2 Hz, Ay » F wen 1 § NN 1 AU, umloady Lodo S14, / 1H), 3.68 (s, 2H), 3.58 Enantiomer 1 + Enantiomer 2 (dd, J=6.9, 6.9 Hz, 2H), AAD BA For AAR 3.19-3.12 (m, 4H), 2.35(s, 3H), 2.25 (s, 3H), 2.16 (dd, J=6.5, 6.5 Hz, 2H). LCMS (ES+) 446 eaVAD ALT) (M+H)+, RT 3.63 min | VIHEDF, RT 5.05 mu (Analytical method BicarbBEHC18) 1H NMR (400 MHz, DMSO) § 10.42 (s, 333: SINS. BTML NS, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.75 (d, J=1.3 Hz, 3G 1H), 7.98 (d, J=1.4 Hz, . > . La 1H), 7.90 (d, J=2.8 Hz, | difluorocyclobutyl)ammonio)pyrrolidin- m Loh T=1.6, wavy jal AAU 1-ium dichloride | 1H), 7.57 (dd, J=L.6, 13.1 Hz, 1H), 3.73 - aaeatiacans Chiu Rutile | 3.53 (m, 3H), 3.34 (s, 3H), 3.41 -3.22 (m, pe 3H), 3.32- 3.30 (m, Enantiomer 1 3H), 2.86 - 2.75 (m, 2H), 2.42-2.27 (m, 2.09 (m, 1H), 1.87 (s, Ad lly lend = Anil 2H), 2.35 (s, 3H), 2.19 - 2.09 (m, 1H), 1.87 (s, TITY 1H). LCMS (ES+) 446 Tu tyr Wha Afni] SD (M+H)+, RT3.63 min | (Analytical method BicarbBEHC18 333 ~ BicarbBEHCI8) 1H NMR (400 MHz, WTA y= | difluorocyclobutyl)ammonio)pyrrolidin- ig wy ay 1-ium dichloride 1H), 9.19 (d, J=1.6 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.6, 13.1 Hz, 1H), 3.73 - hagdaiioann Sing > Thoth Sl | 3.53 (m, 3H), 3.34 (s, 3H), 3.41-3.22 (m, 3H), 3.32-3.30 (m, 3H), 2.86 - 2.75 (m, 2H), 242-227 (m, ay Atl Luk] WJ | 2H), 2.35 (s, 3H), 2.19 - 2.09 (m, 1H), 1.87 (s, Fe 1H). Enantiomer 2 LCMS (ES+) 440 (M+H)+, RT 3.4 min (Analytical method BicarbBEHC18) 1H NMR (400 MHz, DMSO) $10.42 (s, JH INS JE 8 JAYS AS) 1H), 9.19 (d, J=1.5 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.90 (d, J=2.8 Hz, TTYE A Bm § Na} dichloride 1H), 3.85(d,J=114 = a Nr 3-((tetrahydro-2H-pyran-4- WAN yl)ammonio)pyrrolidin-1-jum < dichloride rr ALAS Ty DJ Lyd i, Hz, 2H), 3.79 - 3.51 (m, Ny 4H), 3.34 (s, 3H), 3.36 - 7 N\ 3) 2i2% 45, 20, Du nd | 3.27 (m, 3H), 2.76 - | 2.68 (m, 1H), 2.35 (s, Enantiomer 2 AIIY 3 3 1A fan 3H),2.20-2.14 (m, 1H), 1.84 - 1.76 (m, 3H), 1.32- 1.20 (m, 2H). LCMS (ES+) 440 foi amish ie (M+H)+, RT 3.39 min (Analytical method BicarbBEHC18) 1H NMR (400 MHz, DMSO) 610.42 (s, 3-((tetrahydro-2 H-pyran-4- yl)ammonio)pyrrolidin- 1-ium 1H NMR (400 MHz, ~ DMSO) 51042 (s, er 1H), 9.19 d, J=1.5 Hz, XL 1H), 8.75 (d, J=13 Hz, a . 3-((tetrahydro-2H-pyran-4- 1H), 7.98 (d, J=13 Hz, ASA yhammoniopyrrolidin-1-ium 1H), 7.90 (d, J=2.8 Hz, oO dichloride 1H), 3.85 (d, I=114 il Hz, 2H), 3.79 - 3.51 (m, — 4H), 3.34 (s, 3H), 3.36 - wd 1327 (m, 31), 276 - - | 2.68 (m, 1H), 2.35 (s, Enantiomer 1 AIIY A I 1A fn 3H), 2.20- 2.14 (m, 1H), 1.84 - 1.76 (m, 3H), 1.32-1.20 (m, 2H). LCMS (ES+) 412 niin ab inh Sind (M+H)+, RT 1.62 min | MiyIh+, RT 1,62 mn (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) $10.42 (s, Intermediate 7 “0 INMIK (UU Mz, DMSO) 510.42 (s, = 1H), 9.19 (d, J=1.6 Hz, ° 7 1H), 8.75 (d,J=1.3 Hz, ype 1H), 7.97 (d, J=1.3 Hz, Asn tiiommedive? 1H), 7.90 (d,J=2.8 Hz, <) 1H), 4.70 - 4.65 (m, Li 2H), 4.39 - 4.32 (m, 0 2H), 4.04 - 3.96 (m, Enantinmar 1 4 Enantinmar J 1H), 3.71 - 3.51 (m, 0 2H), 4.04 - 3.96 (m, Enantiomer 1 + Enantiomer 2 1H), 371 “ 3.51 (m, 3H), 3.43 -3.38 (m, 1H), 3.32-3.28 (m, 1H), 292-292 (m, 2.06 (m, 1H), 1.82 (d, 11h £74 ~ £2.04 \WL, 1H), 2.35 (s, 3H), 2.10 - 2.06 (m, 1H), 1.82 (d, Tod © IIe TTI J=4.5 Hz, 1H). LCMS (ES+) 382 ter™Y a) Tn Te De | (M+H)+, RT 1.64 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) $10.44 (s, 6-methyl-2,6-diazaspiro[3.3]heptane; dihydrochloride oo LF ASN] OU nL, 1H), 9.18 (d, J=1.6 Hz, 1H), 8.72 (d, J=1.4 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.86 (d, J=1.4 Hz, TITY MEL Ad T—1 Q 1H), 7.56 (dd, J=1.8, 12.9 Hz, 1H), 4.26 Gs, | am), 3.31 (s, 4H), 2.35 Hh 00 15, Btls od © (s,3H),2.20(s, 3H). LCMS (ES+) 374 (M+H)+, RT 1.6 min (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 610.46 (s, ANS) D. IT) Ay 1H), 9.20 (d, J=1.5 Hz, 1H), 8.77 (d, J=1.3 Hz, 1H), 8.02 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 34 T—m1 £€ 12 1 Wa (dd, J=1.6, 13.1 Hz, ON ZF tert-butyl (3R*,45%)-3-amino-4- ” or fluoropyrrolidine- 1-carboxylate HN HN 1H), 5.09 (d, J=54.4 i } | Hz, 17), 3.98 - 3.86 (m Cis Isomers, Enantiomer 1+ 13H). 3.79 - 3.60 (m, &rtdly SiS SARS | 2H), 3.17 @d, }=102, 10.2 Hz, 1H), 2.35 (s, 3H), 1.86- 1.83 (m, 2H). LCMS (ES+) 384 (M+H)+, RT 1.7 min (Analytical method AcHSSC18 1H NMR (400 MHz, Hz, 1H), 7.57 (dd, J=1.5, 13.2 Hz, 1H), 3.73 -3.54 (m, 3H), 'H NMR (400 MHz, = DMSO) 510.41 (s, » 7 1H), 9.19 (d, J=1.4 Hz, rod 1H), 8.74 (s, 1H), 797 Ih H (R)-N-ethylpyrrolidin-3-an (s, 1H), 7.89 (d, J=2.6 Cy Hz, 1H), 7.57 (dd, wl J=15, 13.2 Hz, 1H), % 3.73 -3.54 (m, 3H), 3.42 (m, 2H), 2.60 - eb Willy Le Thy for IMLS | 2.60 (m, 2H), 2.35 (s, 3H), 2.19-2.08 (m, 1H), 1.89 - 1.88 (m, 1H), 1.04 (dd, J=7.0, 7.0 Hz, 3H). LCMS (ES+) 398 Tr terlWian A Lond) 3 AY (M+H)+, RT 1.72 min VI RT 172m (Analytical method AcHSSC18) 1H NMR (400 MHz, AL eNAVLIN LOAN die: =~ DMSO) 310.44 (s, (s, 1H), 8.01 (s, 1H), 7.61 (dd, J=0.9, 13.4 LAL AM, JUL, LST | Hz, 1H), 3.83 - 3.68 (m, EAT ry INTs a eT = DMSO) 510.44 (s, oY | 1H), 9.23 (s, 1H), 8.79 oO (s, 1H), 8.01 (s, 1H), TN Intermediate 5 7.93 (d, J=2.8 Hz, 1H), SAN 7.61 (dd, J=09, 13.4 NA | Hz, 1H), 3.83 - 3.68 (m, i, 2, [2 SOs SB HN, © 2H), 3.63-3.52 (m, bai 2H). 3.34 - 3.26 (m, 1H), 2.93 - 2.85 (m, . Addly &edo = LOS ly Enantiomer 1 | 1H), 2.39 (s, 3H), 2.23 - £0, £0 (8, ST Los 2.14 (m, 1H), 1.86 - de Lip AL, L115 LO | 1.86 (m, 2H), 1.06 (dd, Bo (m, 2H), L061 J=5.9, 59 Hz, 6H). LCMS (ES+) 398 Tutte iWin nd") 2 EY (M+H)+, RT 1.87 min (Analytical method AcHSSC18) = *H NMR (400 MHz, DMSO) 610.44 (s, Intermediate 5 7.61 (dd, J=0.9, 13.4 = *H NMR (400 MHz, 0 NN DMSO) 10.44 (s, ~~ LL | 18,923 (5, 1H), 8.79 NN i (s, 1H), 8.01 (s, 1H), ran Toerfistes | 7.930, 3-28 He, 18D, J 7.61 (dd, 1=09, 13.4 om | Ho THD. 3.83. 3.68 (m Jal), AMSyalssitdedy Jon | Hz, 1H), 3.83 - 3.68 (m, HN, Rs eo ME r 2H),3.63-3.52 (m, 2H), 3.34-3.26 (m, Enantiomer 2 ~~ 1H),2.93-2.85(m, Sildfy desd = ds OI NTy | 1H), 2.39 (5, 3H), 2.23 - 2.14 (m, 1H), 1.86 - dae Let ALL, ALT 1.00 1.86 (m, 2H), 1.06 (dd, J=5.9,5.9 Hz, 6H). LCMS (ES+) 382 Soto VIS LIT JD 0L (M+H)+, RT 1.68 min (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 81045 (s, = SSDS] ISL Dy | 1H), 9.23 (s, 1H), 8.78 (s, 1H), 8.01 (s, 1H), tert-butyl hexahydropyrrolo[3,4- 7.94 & 7.91 (m, 1H), J=6.2,11.7 Hz, 1H), DMSO) 0 10.45 (s, =, | 1H), 9.23 (s, 1H), 8.78 o Of (s, 1H), 8.01 (s, 1H), NAN Ap tert-butyl hexahydropyrrolo[3,4- 12 o = 1 H fo - - h J=10. H " IN blpyrrole-1(2H)-carboxylate 1H), 3.88 dd. 19, | 20.7 Hz, 2H), 3.74 (dd, NH J=6.2, 11.7 Hz, 1H), 256d T=116 Hr = 3.56 (d,J=11.6 Hz, Cis Isomer, Enantiomer 1 1H), 2.99 - 2.88 (m, 3H), 2.75-2.68 (m, D1 fs &elad = £2.90 LIM, | 1H), 2.39 (s, 3H), 2.00 - 1.89 (m, 1H), 1.73 - 1.71 (m, 1H). LCMS (ES+) 382 VAD ALOT) S04 (M#H)+, RT 1.68 min VIHE)+, RT 1.08 mu (Analytical method AcHSSCI18) 1H NMR (400 MHz, DMSO) 6 10.45 (s, =~ TAINS YL Ley | 1H), 9.23 (s, 1H), 8.78 (s, 1H), 8.01 (s, 1H), tert-butyl hexahydropyrrolo[3,4- 7.94 -7.91 (m, 1H), J=6.2, 11.7 Hz, 1H), DMJ0Q) 0 10.45 (s, = | 1H), 9.23 (s, 1H), 8.78 0 1 (s, 1H), 8.01 (s, 1H), NA a tert-butyl hexahydropyrrolo[3,4- Ei - 20 ne H >: - - , J=13.. Hy PS blpyrrole-1(2H)-carboxylate LED, 3.88 (0d 19.3, | 20.7 Hz, 2H), 3.74 (dd, Nu J=6.2, 11.7 Hz, 1H), 286 (d T=116 Hz Cis Isomer, Enantiomer 2 ae or Eg 3H), 2.75 - 2.68 (m, WAL] eld = EOL | 1H), 2.39 (s, 3H), 2.00 - 1.89 (m, 1H), 1.73 - 1.71 (m, 1H). LCMS (ES+) 396 mii me ra] (M+H)+, RT 1.67 min =~ + (Analytical method AcHSSC18) Y 400 MHz, -methyloctahydropyrrolo[3,4-b]pyrrole | ‘HNMR (¢ 00 MHz ~ ! (Analytical method 0 NM ACHSSC18) ey .methyloctahydropyrrolo[3,4-blpyrrole | 1H NMR (400 MHz, " Ih H DMSO) 810.42 (s, N 1H), 9.19 (d, J=1.5 Hz oS 1H), 8.75 (d, J=1.3 Hz NH 1H), 7.99 (s, 1H), 7.9 dd T= f Hy 1H) 7 5 Cis Isomer, Enantiomer 1 (dd, J=1.6, 13.0 Hz, 1H), 3.89 -3.76 (m, 2H), 3.51 (dd, J=4.6, 12.0 Hz, 1H), 3.40 - 3.36 (m, 1H), 3.10 - 3.03 (m, 1H), 2.94 - 2.88 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.32 - 2.26 (m, 1H), 2.10 - 2.03 (m, 1H), 1.73 - 1.63 (m, 1H). LCMS (ES+) 396 (M+H)+, RT 1.67 min (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 61042 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 12.0 Hz, 1H), 3.40 - 1H), 9.19 (d, J=1.5 Hz = 1H), 8.75 (d, J=1.3 Hz 0 Nv 1H), 7.99 (s, 1H), 7.9( mA LL (d, J=2.8 Hz, 1H), 7.5" " pg H -methyloctahydropyrrolo[3,4-blpyrrole (dd, J=1.6, 13.0 Hz, N 1H), 3.89 - 3.76 (m, Cs 2H), 3.51 (dd, J=4.6, { H 12.0 Hz, 1H), 3.40 - 226 (m THY 210 - 3.36 (m, 1H), 3.10 - Cis Isomer, Enantiomer 2 3.03 (m, 1H), 2.94 - 2.88 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.32 - 2.26 (m, 1H), 2.10 - 2.03 (m, 1H), 1.73 - 1.63 (m, 1H). LCMS (ES+) 382 (M+H)+, RT 1.68 min (Analytical method AcHSSC18) 1H NMR (400 MHz, ~ DMSO) 310.43 (s, \ 1 6 10 (4d T—1 £ Ia 1H), 9.19 (d, J=1.6 Hz, 1H), 7.57 (dd, J=1.8, ~ LDIMISU) 0 1U.52 5, = y 1H), 9.19 (d, J=1.6 Hz, o [ tert-butyl hexahydropyrrolo[3,4- 1H), 875(d, J=13 Hz, Yu Py clpyrrole-2(1H)-carboxylate 1H), 7.99 (d, J=1.3 Hz, ANH Turpin Y 1H), 7.89 (d, J=2.6 Hz, 3 5 1H), 7.57 (dd, J=18, 13.1 Hz, 1H), 3.82 (dd, 13.1 Hz, 1H), 3.82 (dd, J=7.2,11.2 Hz, 2H), 3.43 (dd, J=2.6, 11.0 Hz, 2H), 2.97 - 2.88 (m, 4H), 2.70 (d, J=8.4 Hz, 2H), 2.35 (s, 3H). LCMS (ES+) 396.2 ter VD Aus) wT ad (M+H)+, RT 164 min | MoI, RT 1,64 mn (Analytical method AcHSSC18) 1H NMR (400 MHz, LIMIOU) 0 1U.S% (5, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H), 8.00 (d, J=1.3 Hz, | 2-methyloctahydropyrrolo[3,4-clpyrrole | 1H), 7.89 (d, J=2.8 Hz, ATA: RY EAE Vid 13.2 Hz, 1H), 3.85 - DMSO) 510.44 (s, 1H), 9.19 (d, J=1.5 Hz = 1H), 8.75 (d, J=1.1 Hz 0 1H), 8.00 (d, J=1.3 Hz roel | 2-methyloctahydropyrrolo[3,4-cJpyrrole | 1H), 7.89 (d, J=2.8 Hz on 1 1H), 7.57 (dd, J=1.6, $s 13.2 Hz, 1H), 3.85 - Lo | 3.78 (m, 2H), 3.49 (dd Ltede dLdey LL0}y WIebinl | 3.78 (m, 2H), 3.49 (dd, | {3 (Mm, 2), 34% (0) J=2.9,11.5 Hz, 2H), 2.99 - 2.99 (m, 2H), id d = dard \ Ny &lL]y | 2.58.44, J=1.8, 96 Hz, | ALIN YEN IY AE (+n 2H), 2.50-2.45 (m, dll fg deend') = Lent Ry 2H), 2.35 (s, 3H), 2.24 | s, 3H). LCMS (ES+) 368 (M+H)+, RT 1.6 min (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 610.45 (s, carboxylate son DMSO) 310.45 (s, | tert-butyl StSagnaglulS Kagel Ros hh y 1H), 8.72 (d, J=1.3 Hz, TIN TON ™ QL (+ 1H), 7.90 - 7.86 (m, 2H), 7.56 (dd, J=1.6, ls oa HN. 13.0 Hz, 1H), 4.28 (s, | 4H), 3.64 (s, 4H), 2.35 re TT (s, 3H). LCMS (ES+) 412 AVI ALOT) Fle (M+H)+, RT 1.94 min | MID RT 194m (Analytical method AcHSSC18) Intermediate 15 ! Hz, 1H), 7.32 (dd, 'H NMR (400 MHz, = MeOD) 88.98 (d, J=1.¢ 1 Hz, 1H), 8.69 (d, J=1. oy ey Hz, 1H), 7.89 (d, J=1.0 wos Hz, 1H), 7.66 (d, J=2." oO Intermediate 15 Hz, 1H), 7.32 (dd, LIN I-15 172 Hs 1H) J=1.5,12.2 Hz, 1H), HN, J=1.0, 12.2 1z, 11), Ny 3.82 -3.67 (m, 2H), 3.58 - 3.47 (m, 2H), 3.41 -3.34 (m, 1H), Enantiomer 1 + Enantiomer 2 . 2.70-2.62 (m, 2H), ae FY = Lull AL, ALL), 2.41 (s,3H),2.36- 2.26 (m, 1H), 2.02 - 1.89 (m, TI 1 £0 1 27 (em 1H), 1.59 - 1.37 (m, 4H), 0.98 (dd, J=7.3, 7.3 Hz, 3H). LCMS (ES+) 382 nine a minh id ond (M+H)+, RT 1.63 min | MoI, RT 1,63 mn (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 610.42 (s, SSYESA], WLU de ANY 1H), 9.20 (d, J=1.6 Hz, 1H), 8.76 (d, J=1.1 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.90 (d, J=2.6 Hz, TTIN A AQ A AD fren 1H), 4.48 - 4.42 (m, 1H), 3.91 - 3.79 (m, ° Fi! Aue tert-butyl hexahydropyrrolo[3,2- ¥ JM H blpyrrole-1(2H)-carboxylate 3 H HN. ind 2H), 3.59 - 3.51 (m, Cis Isomer, Enantiomer 2 1H), 2.81 (dd, J=6.7, 6.7 Hz, 2H), 2.34 (s, 3H), 2.16 - 1.87 (m, 3H), 1.69 - 1.63 (m, 1H). LCMS (ES+) 382 fmt asi amin Ais dl (M+H)+, RT 162 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) § 10.42 (s, SALINE © ASL AS, 1H), 9.20 (d, J=1.6 Hz, 1H), 8.76 (d, J=1.1 Hz, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.90 (d, J=2.6 Hz, TLIN A AQ A AD foam 1H), 4.48 - 4.42 (m, 1H), 3.91 -3.79 (m, ry) o Ale tert-butyl hexahydropyrrolo[3,2- o JH H blpyrrole-1(2H)-carboxylate a H HN. and 2H), 3.59 - 3.51 (m, Cis Isomer, Enantiomer 1 1H), 2.81 (dd, J=6.7, 6.7 Hz, 2H), 2.34 (s, 3H), 2.16 - 1.87 (m, 3H), 1.69 - 1.63 (m, 1H). LCMS (ES+) 370 fr Vn ek TA PTA] | (M+H)+, RT 1.67 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 610.46 (s, (s, 1H), 8.01 (s, 1H), ~ | DMSO) 510.46 (s, Oh 1H), 9.24 (s, 1H), 8.79 | oy xX (s, 1H), 8.01 (s, 1H), NN F tert-butyl (R)-(pyrrolidin-3- | 7.93 (d, J=2.0 Hz, 1H), cyst ylmethyl)carbamate 7.61 (dd, J=1.3, 13.2 3 | Hz, 1H), 3.81 -3.70 (m, | I ALIN 2 80 TE (fn J CTT £8) ALL Jemlasdy LJvd \ | Hz, 1H), 3.81 - 3.70 (m, | { 2H), 3.59 - 3.53 (m, NHz [| urls a A 0 dd lv Dvd 2 = Sud AT | 1H), 3.35 (d, J=7.8 Hz, | 1 212 ADL {vn 1H), 3.13 -3.06 (m, 1H), 2.71 (dd, J=6.9, 6.9 Hz, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 2.15 (s, 1H), 1.82 - 1.82 (m, 1H). LCMS (ES+) 370 rl) Stra ) ot FU (M+H)+, RT 167 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 510.46 (s, =~ AHNSINS J LPL) Ly | 1H), 9.24 (s, 1H), 8.79 | Aa er Pt pe Aw (s, 1H), 8.01 (s, 1H), ~ | 1H), 9.24 (s, 1H), 8.79 or (s, 1H), 8.01 (s, 1H), ~~ . tert-butyl (S)-(pyrrolidin-3- Tis 20 He, TH; AN ylmethyl)carbamate | Hz 1H), 3.81 a 370 (m & | 2H),3.59-3.53 (m, NH oF oad EAL AUS ml 2d Cr AN ylmethyl)carbamate | Hz, 1H), 3.81 - 3.70 (m, | 2H), 3.59 - 3.53 (m, {. | 11),335(¢, 127.8 Ha, | Hr I Ped SR | 1H), 335 (4 J=7 8 Hz, | TEN T1312 {vr 1H), 3.13 - 3.06 (m, 1H), 2.71 (dd, J=6.9, 6.9 Hz, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 2.15 (s, 1H), 1.82 - 1.82 (m, TTI 1H). LCMS (ES+) 424.2 Trtprli ian. J feign) tle (M+H)+, RT 1.83 min | (Analytical method AcHSSCI18) 1H NMR (400 MHz, SANINS EO IAMS AS, 1H), 9.20 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.90 (d, J=2.8 Hz, TI 7 87 (Ad Tel £& ~ DMSO) 310.43 (s, NN 1H), 9.20 (d, J=1.6 Hz £1 1H), 874 (d, J=1.3 Hz rh ZF ry 1H), 7.98 (d, J=1.0 Hz NS i. Lo 1H), 7.90 (d, J=2.8 Hz J 1-(pyrrolidin-3-ylmethyl)pyrrolidine 1H), 7.57 (dd, I=1.6, 3 1T0d THY 270 13.0 Hz, 1H), 3.79 - \ 13.0 Hz, 1H), 3.79 - O 3.65 (m, 2H), 3.57 - 3.48 (m, 1H), 3.33 - Enantiomer 1 + Enantiomer 2 3.22 (m, 1H), 2.52 (t, J=1.9 Hz, 10H), 2.56 - 2.41 (m, 10H), 2.35 (s, AIIY DAN A AO Fan 3H), 2.20-2.09 (m, 1H), 1.70 (dd, J=2.8, 2.8 Hz, 6H). LCMS (ES+) 398 Adi Ao) S20 (M+H)+, RT 1.69 min | Ta yee Vl. we ~ | (a+t)+ RT 169 NN (Analytical meth FILL ACHSSCI8) Z or NT N,N-dimethyl-1-(pyrrolidin-3- *H NMR (400 M] N Ri ie DMSO) 510.46 ¥ 1H), 9.23 (d, J=1.5 NT AW, ¥=ULIICLLY I= 1=1 P y11011U1ll=0= DMSO) 810.46 (s & yhmethanamine 1H), 9.23 (d, J=1.5 Hz Nee 1H), 8.79 (d, J=1.3 Hz / THY R00 (4d T—1 2 H- Enantiomer 1 + Enantiomer 2 biocide iid vod 1H), 9.23 (d, J=1.5 Hz, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1TH 7 £1 (44 Tl & ' 1H), 7.61(dd,J=1.5, ' 13.1 Hz, 1H), 3.81 - 3.70 (m, 2H), 3.61 - 3.53 (m, 1H), 3.35 - add AS AEE eS 3.26 (m, 1H), 2.61 (m, 1H), 2.39 (s, 3H), 2.37 - 2.27 (m, 2H), 2.23 (s, 6H), 2.20 - 2.16 (m, 1H), 1.80- 1.73 (m, 1H). LCMS (ES+) 412 min mindbl Miia | (M+H)+, RT 1.87 min Vibrio Lib (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO) 61041 (s, Intermediate 11 SAVIN] Le Dy 1H), 9.19 (d, J=1.5 Hz, 1H), 8.74 (d, J=1.3 Hz, 1H), 7.95 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, LES mr AS 3 re 1H), 7.57 (dd, J=1.6, ARTs Ladd Ws 458 Lely | 13.1 Hz, 1H), 3.81 (dd, 2 V- ! ' 1=6.8,10.7 Hz, 1H), Enantiomer 1 + Enantiomer 2 3.73 -3.67 (m, 1H), 3.52 -3.44 (m, 2H), 3.12 (dd, J=17.1, 10.7 Hz, 1H), 2.35 (s, 3H), 2.19-2.16 (m, 1H), 1.77 - 1.77 (m, 2H), 1.09 (s, 9H). LCMS (ES+) 384 (M+H)+, RT 1.8 min (Analytical method AcHSSCI18) 1H NMR (400 MHz, LVI Ten) JW Sd DMSO) 510.42 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (s, 1H), 8.31 (s, Dufiy S0 L1Je Oud hey. | 1H), 7.90 (d, J=3.0 Hz, th, 1904, I=30F carboxylate ! 1H), 7.56 (ad, J: =1 5; 13.0 Hz, 1H), 4.43 - q Poe tert-butyl (5)-2-ethylpiperazine-1- NS H carboxylate Hi. 4.30 (m, 2H), 3.04 - 2.95 (m, 2H), 2.72 - 2.59 (m, 2H), 2.50 - Resa FN yh Lf Reel WL 2.35(m, 1H), 2.35, 3H), 2.19 (s, 1H), 1.47 - 1.34 (m, 2H), 0.95 (dd, Ne ry AT ry J=7.5,7.5 Hz, 3H). LCMS (ES+) 408 ThE AEE A EE | (M+H)+, RT 1.73 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, 8.27 (s, 1H), 8.07 (d, AE ANAEER LTA AYA DMSO) 61037 (s, 1H), 9.10 (d, J=1.5 Hz, 1H), tert-butyl (3aR 4S,7R,7aS)-octahydro- | 8:70 (d, J=1.3 Hz, 1H), 1H-4,7-epiminoisoindole-8-carboxylate | 8-27 (; 1H), 8.07 (d, J=1.3 Hz, 1H), 7.81 (d, | Hot HOH iLL AN Hl 5 H H a © J=2.5Hz, 1H), 7.48 Enantiomer 1 + Enantiomer 2 (dd, J=1.5, 13.1 Hz 1H), 3.89 -3.79 (m, 4H), 3.22-3.14 (m, 2H), 291-285 (m, fii Bait sida wd | 2H), 2.27 (s, 3H), 1.42 - | 1.34 (m, 4H). LCMS (ES+) 370.2 Cr torkVian fd) (wd Filude (M+H+, RT 165 min | (Analytical method AcHSSC18) 1H NMR (400 MHz, (8)-N-methylpyrrolidin-3-amine ! 9.19 (s, 1H), 8.74 (s, ALVOL 10) = 1H NMR (400 MHz, 2 TL | DMSO) 510.41 (s, 1H), 2 di i 9.19 (s, 1H), 8.74 (s, NSP F -N-methylpyrrolidin-3-amine 3 , , An" = Hipp 1H), 7.97 (s, 1H), 7.89 or (d,J=2.5 Hz, 1H), 7.56 RA (d, J=12.9 Hz, 1H), 3.69 - 3.57 (m, 2H), LNT! 1 Ny LlTh | 233 (d, 1-88 Hz, 6H), | M1EL4 I00 fw OLIN 2.16 - 2.09 (m, 2H), 1.93 - 1.87 (m, 2H). LCMS (ES+) 410 (M+H)+, RT 1.9 min (Analytical method AcHSSC18) 1H NMR (400 MHz, =~ CDCl3) 89.22 (s, 1H), 9.09 (s, 1H), 8.92 (s, ZadZ By LLL] s Odo, 1H), 7.76 (s, 1H), 7.41 (d, J=2.3 Hz, 1H), 6.81 Ad 11 & 11 6 Ts 1H), 3.80 (dd, J=8.2, fy QUAI J =0rkey | 11.0 Hz, 1H), 3.69 (dd, | 1-2 1"NW~» 1LIV J=8.5, 12.0 Hz, 1H), ~~ 'H NMR (400 MHz, WN | | CDCl) 89.22 (s, 1H), o IX 9.09 (s, 1H), 8.92 (s, SP Ap | ) 1H), 7.76 (s, 1H), 7.4] H Bg H 1,1-dimethyloctahydropyrrolo[3,4- (d, J=2.3 Hz, 1H), 6.8] N clpyrrole (dd, J=1.5, 11.0 Hz, 1H), 3.80 (dd, J=8.2, HNN | 11.0 Hz, 1H), 3.69 (dd J=8.5, 12.0 Hz, 1H), . ! 3.62 - 3.50 (m, 2H), Cis Isomers, Enantiomer 1 and | 3.40 (dd, J=8.6, 11.4 Enantiomer 2 Fis ess nm: a ra wel) Ay aed, Sd | Hz, 1H), 3.23- 3.15 (m, | 1 DP Q% AA T—A & 1H), 2.86 (dd, J=4.5, 11.6 Hz, 1H), 2.68 - asianicnanin Sisto: Samedi ll | 2.60 (m, 1H), 2.47 (s, 3H), 1.24 (s, 3H), 1.21 (s, 3H). LCMS (ES+) 436.2 (M+H)+, RT 3.9 min (Analytical method BicarbBEHC18): 1H NMR (400 MHz, DMSO) 6 10.15 (s, SAVIO IVa 13 | 1H), 9.07 (s, 1H), 8.73 | HD, 9.07 (s, 1H), 8.7 (s, 1H), 7.87 (s, 1H), 7-cyclopropyl-2,7- 38 dL), Fd A Sy LEL)y | 7.83 (0,327 He, 18D, | 5 Ar Ta | Sly 1] 7.52 (dd, J=1.3, 12.8 Hz, 1H), 3.92 (s, 4H), 2.58 - 2.52 (m, 4H), 4 A node 7-cyclopropyl-2,7- AN diazaspiro[3.5]nonane.2HC1 OF Vv dO Lda VI, RATS 2.37 (s, 3H), 1.78 (dd, J=5.4, 5.4 Hz, 4H), 1.65 - 1.59 (m, 1H), 0.47 - 0.41 (m, 2H), 0.35 - 0.30 (m, 2H). LCMS (ES+) 421 Tr tyrlW ing A fini) taal | (M+H)+, RT 3.71 min | (Analytical method BicarbBEHC18). 1H NMR (400 MHz, AAAI) LO AVAO AD, 1H), 9.20 (s, 1H), 8.77 (s, LH), 8.43 (s, 1H), 7.91 (s, 1H), 7.76 (s, RAL Sth Sell 1H), 7.56 (dd, 1H), 7.31 (s, 1H), 6.90 (s, ~ 1H NMR (400 MHz, 0 NN DMSO) 3 1048 (s, ~ Ay LL oo Co | 1H), 9.20 (s, 1H), 8.77 AT N 4-(1H-imidazol- 1-yl)piperidine.2HC1 (s, 1H), 8.43 (s, 1H), IQ 7.91 (s, 1H), 7.76 (s, PN 1H), 7.56 (dd, 1H), N= 7.31 (s, 1H), 6.90 (s, 1H), 4.71 (m, 2H), By A Dy 4.45 (m, 1H), 3.15 (m, 2H), 2.35 (s, 3H), 2.11 (m, 2H), 1.94 (m, 2H). LCMS (ES+) 410 Sat torlWla Led") LY (M+H+, RT 176 min | (Analytical method =~ | (400 MHz, DMSO) 3 10.45 (s, 1H), 9.19 (d, Aa LY Legs 4 OA AcHSSC18); 'H NMR (400 MHz, DMSO) § 10.45 (s, 1H), 9.19 (d, | J=1.6 Hz, 1H), 8.72 (d, T—1 2 1 7 90 Hz, 1H), 3.90 (s, 4H), ~ | (400 MHz, DMSO) & WN 10.45 (s, 1H), 9.19 (d, 2 XL | 1=L6 Hz, 1). 872d, Su Pe 7-methyl-2,7-diazaspiro[3.5]nonane J=1.3 Hz, 1H), 7.89 Aan | (dd, J=1.8, 6.1 Hz, 2H), | 7.57 (dd, J=17, 13.0 oF He, 1H), 3.905, 4H), | 2.35 -2.35 (m. 4H). 2.35 -2.35 (m, 4H), 2.32-2.26 (m, 3H), 2.16 (s, 3H), 1.80 (t, J=5.0 Hz, 4H). LCMS (ES+) 410 (M+H)+, RT 1.9 min (Analytical method ASULALYLIL ab TIN LL | AcHSSCIS); 'H NMR | CHISSC 18) A NMI (400 MHz, DMSO) =~ 51 | AUS ELLIS LIVI 810.19 (s, 1H), 8.95 (d, J=1.6 Hz, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.33 33 T—m1 ™ 12 1 Wa 2H), 3.02 -2.94 (m, 2H), 2.64 - 2.57 (m, = J=1.6 Hz, 1H), 8.49 (s 2 Jol | 1H), 8.10 (s, 1H), 7.6¢ t | I | omen ine | 6735 0 ON 1H), 4.16 - 4.10 (m, [ AA 2H), 3.02 - 2.94 (m, A | 2H) 264-257(m, ll fy AI dn DA [Ly | 1H), 2.11 s, 3H), 1.92 - | ™), 2.11.08, 2H, 2S 1.86 (m, 1H), 1.76 - 1.69 (m, 3H), 1.14 - 1.02 (m, 2H), 0.18 - 0.13 (m, 2H), 0.01 - - 0.02 (m, 2H). Example 52: N-(2,8-dimethylimidazo[ 1,2-alpyrazin-6-yl)-5-(3-(pyrrolidin-1-ylmethyl)pyrrolidin-1- yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2) at at = 2h 1 x 2 I 1 _ YY N ol ml a N ¥ W — / Intermediate 2 (100 mg, 0.3 mmol), 1-(pyrrolidin-3-ylmethyl)pyrrolidine dihydrochloride (94 mg, 0.23 mmol), Cs;COs (487 mg, 1 mmol) and DMF (3 mL) were combined in a sealed tube and hot block heated to 100 °C for 16 hours. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration, and the reaction mixture was purified by Preparative HPLC to give the title compound. LCMS (ES+) 421.2 (M+H)+, RT 2.04 min (Analytical method AcHSSC18); '"H NMR (400 MHz, DMSO) § 9.66 (s, 1H), 9.15 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 3.79 - 3.66 (m, 2H), 3.57 - 3.49 (m, 1H), 3.33 - 3.24 (m, 1H), 2.71 (s, 3H), 2.52 (t, J=1.9 Hz, 6H), 2.50 - 2.42 (m, 6H), 2.40 (s, 3H), 2.15 - 2.13 (m, 1H), 1.71 (s, 6H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Structure | Amine | Analytical data 4-(1H-imidazol-1- yl)piperidine 0 7 NOON J (S)N- methylpyrrolidin-3- amine ok —NH | Intermediate 5 oo Ce Lyi Ne LT Enantiomer 1 | Intermediate 5 | -2.07 (m, 2H), 1.88 - 1.88 (m, 2H). LCMS (ES+) 395 (M+H)+, RT 1.99 min (Analytical method AcHSSC18) IH NMR (400 MHz, DMSO) & 9.68 (s, 1H), 9.17 (s, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.06 - 8.04 (m, 2H), 3.82 - 3.68 (m, 2H), 3.62 - 3.52 (m, 2H), | 3.31 (dd, J=5.1, 10.9 Hz, 1H), 2.94 - 2.83 (m, 1H), 2.74 (s, 3H), 2.44 (s, 3H), 2.20 (dd, J=5.6, 11.4 Hz, 1H), 1.85 - 1.85 (m, 2H), 1.06 (dd, J=5.7, 5.7 Hz, 6H). LCMS (ES+) 395 (M+H)+, RT 1.99 min (Analytical method AcHSSCI18) 'H NMR (400 MHz, DMSO) & 9.68 (s, 1H), 9.17 (s, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.06 - 8.04 (m, 2H), 3.82 - | 5 ey AEH oy a” ol 3.68 (m, 2H), 3.62 - 3.52 (m, 2H), 5 or 331 (dd, J=5.1, 10.9 Hz, 1H), 2.94 - YY 7 2.83 (m, 1H), 2.74 (s, 3H), 2.44 Gs, yo 3H), 2.20 (dd, J=5.6, 11.4 Hz, 1H), 1.85 - 1.85 (m, 2H), 1.06 (dd, J=5.7, - 5.7 Hz, 6H). Enantiomer 2 | Intermediate 11 = 3 Fnantiomer 1 + Enantiomer 2 = HI I~ { SH oS | Intermediate 12 (Analytical ~All SA by ee Enantiomer 2 (Analytical | Intermediate 12 pd Al es ee Enantiomer 1 (8)-N- ethylpyrrolidin-3- amine Fi) << 4 Vi N,N-dimethyl-1- (pyrrolidin-3- yl)methanamine a ON XL N M & » Enantiomer 1 + Enantiomer 2 (s, 3H), 2.40 - 2.32 (m, 2H), 2.26 (s, 6H), 2.20 (s, 1H), 1.85 - 1.78 (m, 1H). tert-butyl ©S) ethylpiperazine-1- carboxylate LCMS (ES+) 381 (M+H)+, RT 2.02 min (Analytical method AcHSSCI18); =~ H NMR (400 MHz, MeOD) 89.17 (s, Jo Lr tert-butyl ($)-2- | 1H), 8.81 (s, 1H), 8.30 (s, 1H), 7.82 | 64 | or ethylpiperazine-1- (s, 1H), 4.49 (dd, J=14.9, 40.1 Hz, wi) carboxylate 2H), 3.17 - 3.07 (m, 2H), 2.91 - 2.82 3 (m, 1H), 2.79 (s, 3H), 2.78 - 2.62 (m, 2H), 2.49 (s, 3H), 1.60 - 1.51 (m, 2H), 1.07 (dd, J=7.6, 7.6 Hz, 3H). Example 65: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(piperazin-1-yl)pyrazine-2-carboxamide ST o al zN oo Ko — Wr N - An wh ge = =~ NS i Le -~ or LN B A Pe Methyl 5-chloropyrazine-2-carboxylate (173 mg, 1 mol), N-Boc piperazine (186 mg, 1 mmol), Cs2CO;5 (650 mg, 2 mmol) and DMF (5 mL) were combined in a sealed tube and hot block heated to 100 °C for 4 hours. The reaction mixture was diluted with EtOAc, washed with water (x2), brine and evaporated to dryness to give methyl 5-(4-(rerr-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, which was used crude in next step. MS (ES+) 323 (M+H). Methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, LiOH- HO (50 mg), methanol (20 mL) and water (2 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness to give lithium 5-(4-(tert-butoxycarbonyl)piperazin-1- yl)pyrazine-2-carboxylate, which was used crude in next step. MS (ES+) 309 (M+H). Lithium 5-(4-(rert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate (157 mg, 0.5 mmol), 2,8-dimethylimidazo[ 1,2-alpyrazin-6-amine (81 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL) and DMF (2 mL) were combined and stirred at room temperature for 3 days. The reaction mixture was then purified by preparative HPLC to give tert-butyl 4-(5-((2,8- dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate. MS (ES+) 453 (M+H). tert-Butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1- carboxylate (10.6 mg), dichloromethane (2 mL) and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness then taken up in MeOH. Na,COs was added and stirred for 5 mins. The reaction was then filtered, the filtrate evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 353 (M+H)+, RT 1.86 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 3 9.68 (s, 1H), 9.15 (s, 1H), 8.75 (d, J=1.1Hz, 1H), 8.37 (d, J=1.1 Hz, 1H), 8.01 (s, 1H), 3.71 - 3.67 (m, 4H), 2.82 (dd, J=5.1, 5.1 Hz, 4H), 2.71 (s, 3H), 2.40 (s, 3H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure | Amine | Analytical data tert-butyl ~~ (2S,5R)-2 dimethylpiperazine-1- carboxylate LCMS (ES+) 381 (M+H)+, RT 2.05 min (Analytical method AcHSSC18) 'H NMR (400 MHz, DMSO) & 9.65 ~ (s, 1H), 9.15 (s, 1H), 8.74 (d, J=1.1 0 Jol tert-butyl ~~ (28,5R)-2,5- | Hz, 1H), 8.31 (d, J=1.1 Hz, 1H), 8.00 66 | or N dimethylpiperazine-1- (s, 1H), 4.55 - 4.49 (m, 1H), 4.04 (dd, a I; carboxylate J=2.0, 13.2 Hz, 1H), 3.38 (m, 1H), I 3.26 - 3.15 (m, 2H), 2.71 (s, 3H), 2.57 (dd, J=3.1, 12.6 Hz, 1H), 2.40 (s, 3H), 1.26 (d, J=6.7 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H). tert-butyl methyl(pyrrolidin-3- yl)carbamate NT J Ae O | —NH tert-butyl ethylpiperazine-1- carboxylate oh 0 j® LC X [mn tert-butyl ~~ (2S,6R)-2 dimethylpiperazine-1- carboxylate 4 "a | Swe | mS tert-butyl (i methylpiperazine-1- carboxylate NT J LJ Nes | Hd | ($)-1,3-bipyrrolidine & hy - Jor 7 © (Analytical tert-butyl ((3R*,4, fluoropyrrolidin-3- yl)carbamate HN = 0 LX oe Trans Isomers, Enantiomer 1 + Enantiomer 2 fol ; oN tert-butyl ethyl(pyrrolidin-3- yl)carbamate | N tert-butyl (25,65)-2 dimethylpiperazine-1- carboxylate RTs TE pS Further analogues were prepared using the same chemistry from commercially available or synthesized amines, however coupling with 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine in place of 2,8-dimethylimidazo[ 1,2-a]pyrazin-6-amine. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure | Amine | Analytical data Fg! J CF A | HN I 1.82 min (Analytical o NN tert-butyl (28,5R)-2,5- y @ i AcHSSCI18) 76 | NXYN F dimethylpiperazine-1- 1 I J H 1H NMR (400 MH> Th 76 | oS & Jor Le LCMS (ES+) 384 (M+H)+, RT 1.75 min (Analytical method AcHSSCI8) 1H NMR (400 MHz, DMSO) § 10.42 (s, 1H), 9.18 (d, J=1.6 Hz, tert-butyl (2S,6R)-2,6- | 1H), 8.73 (d, J=1.1 Hz, 1H), 8.33 dimethylpiperazine-1- | (d, J=1.3 Hz, 1H), 7.90 (d, J=2.8 carboxylate Hz, 1H), 7.57 (dd, J=1.5, 13.2 Hz, 1H), 4.41 (dd, J=1.8, 12.4 Hz, 2H), 2.80 - 2.71 (m, 2H), 2.53 - 2.50 (m, 2H), 2.47 (dd, J=10.9, 13.0 Hz, 2H), 2.35 (s, 4H), 1.07 (d, J=6.1 Hz, 6H). LCMS (ES+) 384 (M+H)+, RT 1.82 min (Analytical method tert-butyl (25,5R)-2,5- ) | | AcHSSCI8) dimethylpiperazine-1- 'H NMR (400 MHz, DMSO) §& carboxylate 10.40 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.73 (d, J=1.1 Hz, 1H), 8.24 min (Analytical =~ tert-butyl (R methyl(pyrrolidin-3- yl)carbamate ON 1 or | —NH min (Analytical tert-butyl (R)- methylpiperazine-1- carboxylate 9 ( A aaa | Hi min (Analytical = tert-butyl (R ethylpiperazine-1- carboxylate = o ( P | Hi (Analytical | (8)-1,3bipyrrolidine ~~ F JO ¢ © (Analytical | (R)-1,3'-bipyrrolidine = 21 Cr cS 2.90 - 2.90 (m, 1H), 2.55 - 2.53 (m, 4H), 2.35 (s, 3H), 2.19 - 2.18 (m, 1H), 1.99 - 1.96 (m, 2H), 1.76 + 1.70 (m, 3H). = 82 or Nor LCMS (ES+) 384 (M+H)+, RT 1.79 min (Analytical method AcHSSC18) ‘H NMR (400 MHz, DMSO) & 10.39 (s, 1H), 9.18 (d, J=1.5 Hz, tert-butyl (25,65)-2,6- 1H), 8.70 (s, 1H), 8.31 (s, 1H), dimethylpiperazine-1- 7.90 (d, J=2.6 Hz, 1H), 7.55 (dd, carboxylate J=1.6, 13.1 Hz, 1H), 3.81 (dd, J=3.1, 12.7 Hz, 2H), 3.41 (dd, J=6.4, 12.7 Hz, 2H), 3.20 - 3.13 (m, 2H), 2.34 (s, 3H), 1.04 (d, J=6.5 Hz, 6H). Example 83 (R)-5-(3-(ethylamino)pyrrolidin-1-yl)-N-(8-methoxy-2-methylimidazo[ 1,2-a]pyrazin-6- yl)pyrazine-2-carboxamide oS ee o sii | _. o NEN _ SPY No” or le ort H a wl AN, \ 5-Chloropyrazine-2-carboxylic acid (246 mg, 1.55 mmol) and dichloromethane (10 mL) were combined at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.27 mL, 3.1 mmol) was added, followed by 1 drop of DMF. The reaction mixture was stirred for 21 hours and then evaporated to dryness. Intermediate 10 (276 mg, 1.55 mmol), dichloromethane (30 mL) and triethylamine (2 mL) were added and the reaction was stirred for 1 hour. The reaction mixture was evaporated to dryness to give 5- chloro-N-(8-methoxy-2-methylimidazo[ 1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step. 5-Chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide(125 mg, 0.28 mmol), (R)-N-ethylpyrrolidin-3-amine (32 mg, 0.28 mmol), cesium carbonate (325 mg, 1 mmol) and DMF (3 mL) were combined in a sealed tube and heated to 100 °C for 2 hours. The reaction mixture was then cooled to room temperature, the cesium salts were removed by filtration and the filtrate was purified by prep HPLC to give the title compound. LCMS (ES+) 397 (M+H)+, RT 1.9 min (Analytical method AcHSSC18). tH NMR (400 MHz, DMSO) $9.48 - 9.46 (m, 1H), 8.89 (s, 1H), 8.74 (d, J=1.1 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.94 (s, 1H), 4.07 (s, 3H), 3.71 - 3.52 (m, 3H), 3.43 - 3.38 (m, 2H), 2.64 -2.56 (m, 2H), 2.35 (s, 3H), 2.19 - 2.08 (m, 1H), 1.88 - 1.88 (m, 2H), 1.04 (dd, J=7.2, 7.2 Hz, 3H). Further analogues were prepared using the same chemistry and suitable amines. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure | Amine | Analytical data 84 | | Intermediate 12 o 0 [> _ oh ON "ul > Enantiomer 1 8s | | Intermediate 12 3 9 [ _ orth ON wo > Enantiomer 2 Example 86: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperazin-1-yl)pyrazine-2- carboxamide =~ 9 0 NM Fi) Nou a 1 1X oY TT ep ~ ree IL fogs gi Lithium 5-(4-(terr-butoxycarbonyl)piperazin- 1-yl)pyrazine-2-carboxylate (157 mg, 0.5 mmol), 8- fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (83 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL) and DMF (2 mL) were combine and stirred at room temperature for 2 hours. The reaction mixture was then purified by Preparative HPLC to give tert-butyl 4-(5-((2,8- dimethylimidazo[ 1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H). tert-Butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1- carboxylate (80 mg), dichloromethane (2 mL) and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness then taken up in MeOH. Na,COs was added and stirred for 5 mins. The reaction was then filtered, and the filtrate evaporated to dryness and purified by Preparative HPLC to give the title compound. LCMS (ES+) 356 (M+H)+, RT 1.67 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 8 10.45 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.0 Hz, 1H), 8.32 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.57 (dd, J=1.5, 13.0 Hz, 1H), 3.65 (dd, J=5.1,5.1 Hz, 4H), 3.41 (dd, J=5.1, 5.1 Hz, 4H), 2.35 (s, 3H). Example 87: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-((3R,45)-3-fluoro-4- (methylamino)pyrrolidin- 1-yl)pyrazine-2-carboxamide And Example 88: N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-((35,4R)-3-fluoro-4- (methylamino)pyrrolidin- 1-yl)pyrazine-2-carboxamide o PO OM y e aN 2 o Ls YY oe ’ ~ z — or : BocHN BocN BocN, Cis Isomers | N 3 oh 2 LX WS ou 0 ox NN N” H 7 NAN —r WNP NZ — NAN 15 - : NN BocN, HN, Cis Enantiomer 1 \ \ BocN_ ad BocN, $ MN NN LK le cr HN Cis Enantiomer 2 HN, XN Methyl 5-chloropyrazine-2-carboxylate (665 mg, 3.85 mmol), rert-butyl ((3R*,45%)-4- fluoropyrrolidin-3-yl)carbamate (786 mg, 3.85 mmol), cesium carbonate (1.25 g, 3.85 mmol) and DMF (10 mL) were combined in a sealed tube and heated to 100 °C for 18 hours. The reaction mixture was then diluted with EtOAc, washed with water (3x), brine (1x) and evaporated to dryness to give methyl 5- ((3R*,45%)-3((tert-butoxycarbonyl)amino)-4-fluoropyrrolidin- 1-yl)pyrazine-2-carboxylate, which was used crude without further purification. Methyl 5-((3R*,45*)-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2- carboxylate (630 mg, 1.85 mmol) and DMF (15 mL) were combined under a nitrogen atmosphere at room temperature. NaH (60% in oil, 89 mg, 2.22 mmol) was added to the stirred reaction mixture followed by Mel (0.14 mL, 2.22 mmol). The reaction mixture was stirred for 22 hours then diluted with EtOAc, washed with water (3x) and brine (1x). The organic layer was evaporated to dryness to give methyl 5-((3R*,45%)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin- 1-yl)pyrazine-2- carboxylate, solid which was used crude without further purification. Methyl 5-((3R*,45%)-3-((rert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine- 2-carboxylate, LIOH-H20 (85 mg, 2.03 mmol), methanol (20 mL) and water (2 mL) were combined and stirred at 45 °C for 23 hours. The reaction mixture was then evaporated to dryness to give lithium 5- ((3R*,45*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification. Lithium 5-((3R*,45%)-3-((rert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine- 2-carboxylate, 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (162 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL) and DMF (5 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was then purified by preparative HPLC to give tert-butyl ((3R*,45%)-4-fluoro-1-(5-((8- fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, which was used without further purification. terr-Butyl ((3R*,45%)-4-fluoro-1-(5-((8-fluoro-2-methylimidazo[ 1,2-alpyridin-6- yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, dissolved in MeOH, stirred with Na>COs for 5 mins, filtered through an Isolute NH; resin cartridge and the filtrate was evaporated to dryness. The crude solid was purified by preparative HPLC then chiral Preparative HPLC to give; Cis Isomer, Enantiomer 1 N-(2,8-dimethylimidazo[1,2-alpyrazin-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidin-1- yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analytical method AcHSSC18); 1H NMR (400 MHz, DMSO) 5 9.69 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 5.39 (d, J=52.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.81 (dd, J=12.7, 39.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.24 - 3.18 (m, 1H), 2.71 (s, 3H), 2.44 - 2.39 (m, 6H), 2.01 - 2.01 (m, 1H). Cis Isomer, Enantiomer 2 N-(2,8-dimethylimidazo[1,2-alpyridin-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidin-1- yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analytical method AcHSSC18); 1H NMR (400 MHz, DMSO) 3 9.69 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 5.39 (d, J=52.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.81 (dd, J=12.7, 39.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.24 - 3.18 (m, 1H), 2.71 (s, 3H), 2.44 - 2.39 (m, 6H), 2.01 - 2.01 (m, 1H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure | Amine | Analytical data HN, \ Trans Isomers, Enantiomer 1 and Enantiomer 2 LCMS (ES+) 385 (M+H)+, RT 3.19 min (Analytical method ~~ BicarbBEHC18) ° NN H NMR (400 MHz, DMSO) 89 | ~All tert-butyl ((3R*,4R*)-4- | 39.68 (s, 1H), 9.14 (s, 1H), 8.78 oN A 4H fluoropyrrolidin-3- (d, J=1.3 Hz, 1H), 8.09 (s, 1H), =< yl)carbamate 8.01 (s, 1H), 5.28 (d, J=50.6 Hz, HN 1H), 3.91 (s, 1H), 3.83 (s, 1H), Trans Isomers, Enantiomer 1 and 3.74 - 3.65 (m, 2H), 3.42 - 3.36 Enantiomer 2 (m, 1H), 2.71 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H), 2.24 - 2.19 Further analogues were prepared using the same chemistry with lithium 5-((3R*,45%)-3-((zert- butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate or lithium 5-((3R*,4R*)- 3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl )pyrazine-2-carboxylate and 8-fluoro-2- methylimidazo[1,2-a]pyridin-6-amine. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. | Ex. | Structure | Analytical Data min (Analytical 0 ox H NMR (400 MHz, | 2 310.45 (s, 1H), 9.19 (d, | 90 NSA F ~) NN HN, N Trans Isomers, Enantiomer 1 and Enantiomer 2 min (Analytical o NN |= NMR (400 MHz, 91 Ca 01 510.49 (s. 1H). 9.23 (d. ] =~ Sy Ap or HN HN, \ Cis Isomer, Enantiomer 1 3.42 (m, 1H), 3.25 (dd, J=10.2, 10.2 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.11 - 2.06 (m, 1H). Example 92: (5)-5-([1,3'-Bipyrrolidin]-1'-yl)-N-(6-methoxy-2-methyl-2 H-indazol-5-yl)pyrazine-2- carboxamide NN COMe IN NT COM Lor yo or 3 Jd Methyl 5-chloropyrazine-2-carboxylate (473 mg, 2.74 mmol), (5)-1,3-bipyrrolidine (384 mg, 2.74 mmol), cesium carbonate (1.14 g, 3.5 mmol) and DMF (10 mL) were combined in a sealed tube and heated to 100 °C for 16 hours. The reaction mixture was filtered to remove the cesium salts, rinsing with EtOAc. The combined organic filtrate was evaporated to dryness to give methyl (5)-5-([1,3"- bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification. Methyl (5)-5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, LIOH- H20 (126 mg, 3 mmol), MeOH (50 mL) and water (5 mL) were combined and heated to 45 °C for 16 hours. The reaction mixture was then evaporated to dryness to give lithium (S)-5-([1,3-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification. Lithium (S)-5-([1,3"-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate (161 mg, 0.6 mmol), Intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL) and DMF (2 mL) were combine and stirred at room temperature for 1 hour. The reaction mixture was purified by Preparative HPLC to give the title compound. LCMS (ES+) 422 (M+H)+, RT 2.45 min (Analytical method AcHSSC18). tH NMR (400 MHz, DMSO) $ 10.06 (s, 1H), 8.76 (d, J=1.1 Hz, 1H), 8.69 (s, 1H), 8.23 (s, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.11 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.83 - 3.69 (m, 2H), 3.56 - 3.48 (m, 1H), 3.39 (dd, J=6.9, 11.8 Hz, 1H), 2.89 - 2.89 (m, 1H), 2.56 (d, J=3.6 Hz, 4H), 2.20 - 2.19 (m, 1H), 2.01 - 1.97 (m, 1H), 1.73 (dd, J=5.0, 5.0 Hz, 4H). Example 93: (5)-5-([1,3"-bipyrrolidin]-1'-yl)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)pyrazine-2- carboxamide | °N NCO N 0 ( : on Anan LL . N —N ry , Fa No W / Lithium (8)-5-([1,3"-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate (95 mg, 0.36 mmol), Intermediate 3 (69 mg, 0.36 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL) and DMF (2.5 mL) were combined and stirred at room temperature overnight. The reaction mixture was purified by Preparative HPLC to give the title compound. LCMS (ES+) 436.5 (M+H)+, RT 2.6 min (Analytical method AcHSSCI8). 'H NMR (400 MHz, DMSO) 610.14 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.09 (s, 1H), 4.22 (q, J=6.9 Hz, 2H), 4.09 (s, 3H), 3.83 - 3.69 (m, 1H), 3.55 - 3.48 (m, 1H), 3.20 (s, 1H), 2.90 - 2.82 (m, 2H), 2.19 - 2.13 (m, 2H), 1.96 (dd, J=3.6, 8.2 Hz, 2H), 1.75 - 1.69 (m, 4H), 1.51 - 1.46 (m, 3H). Example 94: 5-((35*,4R*)-3-Fluoro-4-(methylamino)pyrrolidin- 1-y1)-N-(6-methoxy-2-methyl-2H- indazol-5-yl)pyrazine-2-carboxamide N o [nN o 7 N N 2N i I H ~ . - N BocN, \ BocN. \ Ow N o = yr RN HN, \ Lithium 5-((3R*,45*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine- 2-carboxylate (187 mg, 0.54 mmol), Intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL) and DMF (3 mL) were combined and stirred at room temperature for 3 hours. The reaction mixture was then purified by preparative HPLC to give terr-butyl ((3R*,45*)-4-fluoro-1-(5-((6- methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, which was used without further purification. tert-butyl ((3R*,45%)-4-fluoro-1-(5-((6-methoxy-2-methyl-2 H-indazol-5-yl )carbamoyl)pyrazin- 2-yl)pyrrolidin-3-yl)(methyl)carbamate was deprotected using general method C (HCI Boc deprotection) to give the title compound. LCMS (ES+) 400 (M+H)+, RT 2.3 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 610.07 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.12 (s, 1H), 5.39 (d, J=55.2 Hz, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 4.04 - 3.70 (m, 4H), 3.20 (dd, J=10.2, 10.2 Hz, 1H), 2.42 (s, 3H). Example 95: (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-5-(pyrrolidin-3-yloxy)pyrazine-2- carboxamide NM ony, yp Aen A A tert-butyl (S)-3-hydroxypyrrolidine- 1-carboxylate (100 mg, 0.53 mmol) in DMF (2 mL) was added to a suspension of NaH (32 mg, 0.801 mmol) in DMF (1 mL) and the reaction was stirred at room temperature for 30 minutes. Intermediate 1 (163 mg, 0.534 mmol) was added and the reaction was heated to 90 °C for 5.5 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (x2) and the combined organic solution dried with MgSO, and evaporated to dryness. The crude mixture was purified by flash chromatography to give rerr-butyl (8§)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)carbamoyl)pyrazin-2-yl)oxy)pyrrolidine- 1 -carboxylate. MS (ES+) 457 (M+H). tert-butyl (8)-3-((5-((8-fluoro-2-methylimidazo[1,2-alpyridin-6-yl)carbamoyl)pyrazin-2- yl)oxy)pyrrolidine- 1-carboxylate (63 mg, 0.14 mmol), methanol (1 mL) and 4N HCl in dioxane (0.35 mL, 1.38 mmol) were combined and stirred at room temperature for 17 hours. The reaction mixture was evaporated to dryness and the crude material was purified by Preparative HPLC to give the ritle compound. LCMS (ES+) 357 (M+H)+, RT 1.62 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 8 10.74 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 8.90 (s, 1H), 8.38 (s, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.5, 13.0 Hz, 1H), 5.50 (dd, J=5.8, 5.8 Hz, 1H), 3.68 - 3.52 (m, 1H), 3.15 (dd, J=5.2, 12.5 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.88 - 2.81 (m, 1H), 2.35 (s, 3H), 2.19 - 2.05 (m, 1H), 1.91 - 1.87 (m, 1H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCI in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by Preparative HPLC. | Ex. | Structure | Amine | Analytical data oh | ol oh 1A LCMS (ES+) 357 (M+H)+, RT 1.66 min (Analytical method AcHSSC18 'H NMR (400 MHz, DMSO) 810.74 (s, 1H), 9.22 (d, J=1.6 Hz, 1H), 8.90 (d, J=1.3 Hz, tert-butyl (R)-3- 1H), 8.38 (d, J=1.3 Hz, 1H), hydroxypyrrolidine- 7.92 (d, J=2.8 Hz, 1H), 7.57 1-carboxylate (dd, J=1.6, 13.0 Hz, 1H), 5.53 - 547 (m, 1H), 3.14 (dd, J=54, 12.5 Hz, 1H), 3.00 - | 2.90 (m, 2H), 2.88 - 2.80 (m, 1H), 2.35 (s, 3H), 2.15 - 2.05 (m, 1H), 1.92 - 1.84 (m, 1H). | Example 97 N-(8-fluoro-2-methylimidazo[ 1,2-alpyridin-6-yl)-5-((3R,4R)-3-methyl-4- (methylamino)pyrrolidin- 1-yl)pyrazine-2-carboxamide BocHN o SP GAN o oo a BocHN o yon Boch, = = x AX AX Sy Ae _ WS A; Boot, HN \ \ tert-Butyl ((3R,4R)-4-methylpyrrolidin-3-yl)carbamate (251 mg, 1.25 mmol) and methyl 5- chloropyrazine-2-carboxylate (216 mg, 1.25 mmol) were dissolved in DMF (4 mL) and the reaction was heated to 100°C for 18 h. The reaction was cooled to r.t., diluted with EtOAc and filtered through Celite. The solvent was removed in vacuo to give crude product. The crude was purified using silica chromatography, elution gradient 0-100% EtOAc / cyclohexane to give methyl 5-((3R,4R)-3-((zert- butoxycarbonyl)amino)-4-methylpyrrolidin- 1-yl)pyrazine-2-carboxylate. MS (ES+) 337 (M+H). Methyl 5-((3R,4R)-3-((terr-butoxycarbonyl)amino)-4-methylpyrrolidin-1-yl)pyrazine-2- carboxylate (344 mg, 1.02 mmol) was dissolved in DMF (2 mL) and cooled in an ice bath. Sodium hydride / 60% in mineral oil (45 mg, 1.12 mmol) was added and the reaction stirred for 15 minutes. Methyl iodide (145 mg, 1.02 mmol) was added and the reaction allowed to warm to r.t. over 3 h. LCMS indicated starting material. Further sodium hydride / 60% in mineral oil (45 mg, 1.12 mmol) was added followed by methyl iodide (145 mg, 1.02 mmol) and the reaction stirred for a further 18 h. Water (1 mL) was added followed by sodium hydroxide (82 mg, 1.04 mmol) and the reaction stirred for 18 h. The reaction was acidified with 1M HCI to pH=5 and the aqueous layer extracted with EtOAc x3. The organic layer was dried (MgSO) and the solvent removed in vacuo to give 5-((3R,4R)-3-((tert- butoxycarbonyl)(methyl)amino)-4-methylpyrrolidin- 1-yl)pyrazine-2-carboxylic acid. MS (ES+) 337 (M+H). 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidin- 1-yl)pyrazine-2- carboxylic acid (343 mg, 1.02 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (168 mg, 1.02 mmol) were dissolved in DMF (2 mL). HBTU (426 mg, 1.12 mmol) and trimethylamine (0.5 mL) were added and the reaction stirred overnight at r.t.. The solvent was removed in vacuo to give crude product. Purification using silica chromatography elution gradient 0-100% EtOAc / cyclohexane gave tert- butyl ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-alpyridin-6-yl }carbamoyl)pyrazin-2-yl)-4- methylpyrrolidin-3-yl)(methyl)carbamate. MS (ES+) 484 (M+H). tert-Butyl ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yl)-4-methylpyrrolidin-3-yl)(methyl)carbamate (610 mg, 1.02 mmol) was dissolved in methanol (2 mL) and 4M HCl in dioxane (10 mL) was added. The reaction was stirred overnight at r.t.. The solvent was removed in vacuo to give crude product. The crude was purified by SCX 5 g SCX cartridge (pre- conditioned with MeOH), eluting with 1:1 MeOH / DCM (2 CV) then 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated in vacuo to give a residue. Further purification by reverse phase HPLC gave the title compound. LCMS (ES+) 384.2 (M+H)+, RT 1.72 min (Analytical method AcHSSCI8); tH NMR (400 MHz, DMSO) §10.45 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.57 (dd, J=1.6, 13.1 Hz, 1H), 3.70 - 3.63 (m, 2H), 3.26-3.08 (m, 3H), 2.32 (m, 6H), 1.02 (d, J=5.9 Hz, 3H) NH obscured under DMSO peak. The following examples were prepared using an analogous procedure starting from methyl 5- chloropyrazine-2-carboxylate and the stated amine. Final products were isolated by SCX and / or Preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. Ex. | Structure | Amine | Analytical data min (Analytical = (35,48)-N.4- dimethylpyrrolidin-3- amine ~~ —NH min (Analytical (3S,4R)-N4- dimethylpyrrolidin-3- amine —NH =~ NY Ae —NH min (Analytical (3R,45)-N4- dimethylpyrrolidin-3- amine ON 0 or -y HN, \ 1.96 (m, 1H), 1.08 (d, J=6.8 Hz, 3H). 1.87 min (Analytical ACHSSC18) = H NMR (400 MHz, D) a or tert-butyl ()- | D0) 88.94 (s, 1H), 8.58 or N (pyrrolidin-3- 7.87 (s, 1H), 7.83 (s, IF pe ” ylmethyljcarbamate | 3.53 (m, 2H), 3.41 - 3.37 oe 3.12 - 3.06 (m, 1H), 2.64 oo 1.69 min (Analytical ACHSSCI8) iH NMR (400 MHz, D} 5 D:0) 8.94 (d, J=1.3 Hz, 0 IX tert-butyl (5 | (d, J=12 Hz, 1H), 7.93 oy F (pymolidin-3- 7.78 (d, 1=2.3 Hz, 1H), o z yimethyDcarbamate | J=14, 12.5 Hz, 1H), 3.7 iy (m, 1H), 3.44 (dd, J=8.0 oo = [193 min (Analytical tert-butyl ( (pyrrolidin-3- ylmethyl)carbamate e” f A a HN 1h / (m, 1H), 3.12 - 3.07 (m, 1H), 2.64 (s, 3H), 2.45 - 2.41 (m, 1H), 2.34 (s, 3H), 2.25 (s, 3H), 2.11 - 2.11 (m, 1H), 1.68 - 1.62 (m, 1H). 104 LCMS (ES+) 384.2 (M+H)+, RT min (Analytical tert-butyl ( (pyrrolidin-3- ylmethyl)carbamate = 0 8 HN iN a 1.67 min (Analytical AcHSSCI18) H NMR (400 MHz, DI =~ 10.49 (s, 1H), 9.23 (d, J Q or 1H), 8.81 (d, J=1.3 Hz, | 105 | NA a | rert-butyl (3R*,45%)-4- (c THY 704 (Ad 1-772 = SP Ap PI ~) HN, N Cis Isomer, Enantiomer 1 + Enantiomer 2 Example 106: (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-5-(3-(1- (methylamino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxamide and Example 107: (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)pyrazine-2-carboxamide ah 3 xo NSPS 0 Xo ‘OMe oe} oF Or x or Boe, Boc, Boc, Boc, NS oe, 'sil NM ¥ wt R > o NS ove ~ or Bos, ¢ ND R (R= Hor Me) (R =H or Me) (R = Hor Me) (R=Me) = = Ke; J Bo, > wv = =~ (R=H) a = & oN ZN wT Methyl 5-chloropyrazine-2-carboxylate (191 mg, 1.1 mmol), rerr-butyl (R)-(1-(pyrrolidin-3- yl)cyclopropyl)carbamate (250 mg, 1.1 mmol), cesium carbonate (487 mg, 1.5 mmol) and DMF (4 mL) were combined in a sealed tube and hot block heated to 100 °C for 23 hours. The reaction mixture was then diluted with EtOAc, washed with water (3x), brine (1x) and evaporated to dryness to give methyl (R)-5-(3-(1-((rerr-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification. Methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2- carboxylate (341 mg, 0.91 mmol) and DMF (10 mL) were combined at room temperature under nitrogen atmosphere. NaH (60% in oil, 45 mg, 1.13 mmol) was added followed by Mel (0.07 mL, 1.13 mmol) and stirring continued for 10 days. The reaction mixture was then diluted with EtOAc, washed with water (3x), brine (1x), dried (MgSOs) and evaporated to dryness to give a mixture of methyl (R)-5-(3-(1-((rerr- butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and methyl (R)-5-(3- (1-((rerr-butoxycarbonyl)amino)cyclopropyl)pyrrolidin- 1-yl)pyrazine-2-carboxylate, which was used crude without further purification. The mixture of methyl (R)-5-(3-(1-((rert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin- 1-yl)pyrazine-2-carboxylate and methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin- 1-yl)pyrazine-2-carboxylate (169 mg), LiOH- H,O (19 mg, 0.45 mmol), methanol (15 mL) and water (2 mL) were combined and hot block heated to 45 °C for 18 hours. The reaction mixture was then evaporated to dryness to give a mixture of lithium (R)-5-(3-(1-((tert- butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and lithium (R)-5-(3- (1-((rerr-butoxycarbonyl)amino)cyclopropyl)pyrrolidin- 1-yl)pyrazine-2-carboxylate, which was used crude without further purification. The mixture of lithium (R)-5-(3-(1-((zerr-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin- 1-yl)pyrazine-2-carboxylate and lithium (R)-5-(3-(1-((tert- butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, 8-fluoro-2- methylimidazo[ 1,2-a]pyridin-6-amine (74 mg, 0.45 mmol), HBTU (171 mg, 0.45 mmol), triethylamine (0.5 mL) and DMF (2 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to give; tert-butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yl)pyrrolidin-3-yl)cyclopropyl)(methyl)carbamate, which was used without further purification. tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-alpyridin-6-yl)carbamoyl)pyrazin-2- yl)pyrrolidin-3-yl)cyclopropyl)carbamate, which was used without further purification. tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yDpyrrolidin-3-yl)cyclopropyl)(methyl)carbamate (65.1 mg), methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-N-(8-fluoro-2-methylimidazo[1,2- alpyridin-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 410 (M+H)+, RT 1.93 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) & 10.42 (s, 1H), 9.19 (4, J=1.5 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.7, 13.0 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.46 - 3.42 (m, 1H), 3.13 (dd, J=10.2, 10.2 Hz, 1H), 2.73 - 2.68 (m, 1H), 2.35 (s, 3H), 2.29 (s, 3H), 2.00 (s, 1H), 1.65 (s, 1H), 0.51 (s, 4H). tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yDpyrrolidin-3-yl)cyclopropyl)carbamate (41.9 mg), methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8- fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 396 (M+H)+, RT 1.9 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) & 10.42 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.7, 13.1 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.50 - 3.41 (m, 2H), 2.35 (s, 3H), 2.09 (d, J=8.3 Hz, 1H), 2.00 (s, 1H), 1.93 (d, J=9.8 Hz, 1H), 0.49 (d, J=6.4 Hz, 4H). Example 108: (R)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine- 2-carboxamide ig » ! N N Ny" ol 0 7 o / aN et? A i A = en A om AN Ho ome and ZB UJ -N Boc —NH —, Boc Intermediate 3 (0.32 mmol), lithium (R)-5-(3-((rert-butoxycarbonyl)(methyl)amino)pyrrolidin-1- yl)pyrazine-2-carboxylate (100 mg, 0.32 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL) and DMF (2.5 mL) were combined and stirred at room temperature for 18 hours. The reaction mixture was then purified by preparative HPLC to give rerr-butyl (R)-(1-(5-((6-ethoxy-2-methyl-2H-indazol-5- yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate as an off white solid which was used without further purification. tert-butyl (R)-(1-(5-((6-ethoxy-2-methyl-2 H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3- yl)(methyl)carbamate, methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness then taken up in MeOH and stirred over sodium carbonate for 5 mins, then filtered through an Isolute NH; resin cartridge. The filtrate was evaporated to dryness to give the title compound. LCMS (ES+) 396 (M+H)+, RT 2.5 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 8 10.18 (s, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.13 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 4.13 (s, 3H), 3.73 - 3.60 (m, 3H), 3.45 - 3.40 (m, 1H), 3.34 - 3.32 (m, 1H), 2.38 - 2.34 (m, 3H), 2.17 - 2.09 (m, 1H), 1.94 - 1.91 (m, 2H), 1.53 (dd, J=6.9, 6.9 Hz, 3H). Further analogues were prepared using Method H (TCFH coupling) starting from (R)-5-(3-((zerr- butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid and the stated amine. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Ex. | Structure | Amine | Analytical data = NN : 3 o i Nz 2 min (Analytical 2 AcHSSCI18); 109 | NY NN | methylimidazo[1,2- 11 on H 1H NMR 400 MH» T ¢ (5 Z ON j=] —NH LCMS (ES+) 353 (M+H)+, RT 1.76 2 min (Analytical method AcHSSC18); methylimidazo[1,2- 'H NMR (400 MHz, DMSO) 39.80 a]pyrazin-6-amine (s, 1H), 9.31 (d, J=1.3 Hz, 1H), 8.83 (s, 1H), 8.79 (d, J=1.0 Hz, 1H), 8.08 Example 110: (R)-5-(3-(ethylamino)pyrrolidin-1-yl)-N-(6-methoxy-2-methyl-2 H-indazol-5-yl)pyrazine- 2-carboxamide Me Me NCH N 0 ( f aA OMe 78 N 0 Cy raat OMe of HN, \ 5-Chloropyrazine-2-carboxylic acid (159 mg, 1 mmol) and dichloromethane (10 mL) were combined under nitrogen atmosphere. Oxaly] chloride (0.17 mL, 2 mmol) was added followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness. Intermediate 4 (1.08 mmol), dichloromethane (20 mL) and triethylamine (2 mL) were added and the reaction mixture was stirred for 1.5 hours. The reaction was then evaporated to dryness to give 5-chloro-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide, which was used crude without further purification. MS (ES+) 318 / 320 (M+H). 5-Chloro-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide (150 mg, 0.25 mmol), (R)-N-ethylpyrrolidin-3-amine (28 mg, 0.25 mmol), Cs;COs (325 mg, 1 mmol) and DMF (2 mL) were combined in a sealed tube and hot block heated to 100 °C for 1 hour. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration and the reaction mixture was purified by Preparative HPLC to give the title compound. LCMS (ES+) 396 (M+H)+, RT 2.36 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) 8 10.05 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.23 (s, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.11 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.71 - 3.52 (m, 3H), 3.42 - 3.37 (m, 2H), 2.63 - 2.58 (m, 2H), 2.17 - 2.09 (m, 1H), 1.86 - 1.81 (m, 2H), 1.04 (dd, J=7.1, 7.1 Hz, 3H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCI in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or Preparative HPLC. Amine | Amine | Ex. | Structure | Analytical data | 11 | Q [ 11 | ~ 4 | Hi, LCMS (ES+) 382 (M+H)+, RT 3.1 min (Analytical method BicarbBEHC18) 'H NMR (400 MHz, DMSO) & 10.06 (s, 1H), 8.75 (d, J=1.1 tert-butyl (R)- | Hz, 1H), 8.69 (s, 1H), 8.23 (s, methyl(pyrrolid lh 1H), 8.06 (d, J=1.3 Hz, 1H), in-3- 7.11 (s, 1H), 4.10 (s, 3H), 3.99 yl)carbamate (s, 3H), 3.70 - 3.55 (m, 3H), 3.46 - 3.39 (m, 2H), 2.34 (s, 3H), 2.17 - 2.09 (m, 1H), 1.92 - 1.92 (m, 1H). Example 112: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin- 6-yl)pyrazine-2-carboxamide =~ | or or BR or _ Jor Ae HN (R)-(+)-1-Boc-3-aminopyrrolidine (400 mg, 2.15 mmol) and (1- ethoxycyclopropoxy)trimethylsilane (0.48 mL, 2.37 mmol) were combined in MeOH (30 mL). NaBH;CN (162 mg, 2.58 mmol) was added followed by AcOH (0.2 mL). The reaction mixture was then heated to 55 °C for 16 hours. The reaction was then diluted with dichloromethane, washed with sat. aq. NaHCO; solution, dried (MgSO4) and evaporated to dryness to give tert-butyl (R)-3- (cyclopropylamino)pyrrolidine-1-carboxylate, which was used crude in next step. tert-Butyl (R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate (455 mg, 2 mmol), MeOH (15 mL) and 4N HCl in dioxane (15 mL) were combined and stirred at room temperature for 24 hours. The reaction mixture was then evaporated to dryness to give (R)-N-cyclopropylpyrrolidin-3-amine-2HCI, which was used crude in next step. (R)-N-cyclopropylpyrrolidin-3-amine.2HCI (500 mg), Intermediate 1 (400 mg, 1.3 mmol), cesium carbonate (1.63 g, 5 mmol) and DMF (7 mL) were combined and heated to 100 °C for 20 hours. The cesium salts were then filtered off and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 396 (M+H)+, RT 1.75 min (Analytical method AcHSSC18). :H NMR (400 MHz, DMSO) 6 10.44 (s, 1H), 9.23 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 13.0 Hz, 1H), 3.78 - 3.53 (m, 4H), 3.51 - 3.42 (m, 1H), 2.61 - 2.58 (m, 1H), 2.39 (s, 3H), 2.21 - 2.12 (m, 2H), 1.99 - 1.99 (m, 1H), 0.45 (d, J=6.6 Hz, 2H), 0.33 - 0.25 (m, 2H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. Final products were isolated by Preparative HPLC. Ex. | Structure | Amine | Analytical data = 113 | (8)-1-Boc-3- aminopyrrolidine ° = u3 | Re | a uN ¥ | HN, > LCMS (ES+) 396 (M+H)+, RT 1.75 min (Analytical method AcHSSC18) H NMR (400 MHz, DMSO) & 10.44 (s, 1H), 9.23 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 13.0 Hz, 1H), 3.78 - 3.53 (m, 4H), 3.51 - 3.42 (m, 1H), 2.61 - 2.58 (m, 1H), 2.39 (s, 3H), 2.21 - 2.12 (m, 2H), 1.99 - 1.99 (m, 1H), 0.45 (d, J=6.6 Hz, 2H), 0.33 - 0.25 (m, 2H). Example 114 5-[3-(cyclopropylamino)pyrrolidin-1-y1]-N-(5-fluoro-2-methyl-1,3-benzoxazol-6- yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2) 0 NA on SA YY ox 0 a x N F 1 HN, - o~ vy i bg! N I - ON i" > Following Method H from 5-(3-((terr-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1- yl)pyrazine-2-carboxylic acid (126 mg, 0.361 mmol, 1 equiv) and 5-fluoro-2-methylbenzo[d]oxazol-6- amine (60 mg, 0.361 mmol, 1 equiv) in DMF (2.0 mL). The reaction mixture was diluted with water and the solids filtered and washed with 1:1 MeCN / H,O. The solid was purified using silica chromatography, elution gradient 0-10% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert-butyl cyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazol- 6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate. LCMS (ES+) 497 (M+H)+. Following Method E TFA Boc deprotection from zerz-butyl cyclopropyl(1-(5-((5-fluoro-2- methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (26 mg, 0.0511 mmol). The reaction mixture was concentrated in vacuo and the residue applied to a 2 g SCX cartridge, eluting with 2 column volumes methanol, then 3 column volumes 2 M methanolic ammonia. The ammonia fraction was concentrated in vacuo to give 5-[3-(cyclopropylamino)pyrrolidin-1-yI]-N-(5-fluoro-2- methyl-1,3-benzoxazol-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 397 (M+H)+, RT 4.57 min (Analytical method BicarbBEHC18) H NMR (400 MHz, DMSO) 3 9.91 (d, J=2.4 Hz, 1H), 8.75 (s, 1H), 8.47 (d, J=6.5 Hz, 1H), 8.04 (s, 1H), 7.71 (d, J=10.9 Hz, 1H), 3.74 - 3.50 (m, 4H), 3.45 (s, 1H), 2.63 (s, 3H), 2.19 - 2.10 (m, 2H), 1.96 (s, 1H), 0.43 (d, J=6.7 Hz, 2H), 0.32 - 0.23 (m, 2H). Example 115 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2,6-dimethylindazol-5-yl)pyrazine-2- carboxamide (Enantiomer 1 + Enantiomer 2) x N Ch o ON I \ rt oid J Following Method H from 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1- yl)pyrazine-2-carboxylic acid (140 mg, 0.403 mmol, 1 equiv) and 2,6-dimethyl-2H-indazol-5-amine (65 mg, 0.403 mmol, 1 equiv) in DMF (2.0 mL). The reaction mixture was diluted with water and the solid filtered and washed with 1:1 MeCN / H:O to give crude rert-butyl cyclopropyl(1-(5-((2,6-dimethyl-2H- indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate which was taken forward without further purification. Following Method E TFA Boc deprotection from ferr-butyl cyclopropyl(1-(5-((2,6-dimethyl- 2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (36 mg, 0.0732 mmol). The reaction mixture was concentrated in vacuo and the residue applied to a 2 g SCX cartridge, eluting with 2 column volumes methanol, then 3 column volumes 2 M methanolic ammonia. The ammonia fraction was concentrated in vacuo and the residue purified by reverse phase HPLC to give 5-[3- (cyclopropylamino)pyrrolidin- 1-y1]-N-(2,6-dimethylindazol-5-yl)pyrazine-2-carboxamide. LCMS (ES+) 392 (M+H)+, RT 2.38 min (Analytical method AcHSSC18) H NMR (400 MHz, DMSO) 69.74 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 8.26 - 8.22 (m, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 4.18 (s, 3H), 3.77 - 3.55 (m, 4H), 3.51 - 3.45 (m, 1H), 2.43 (s, 3H), 2.21 - 2.15 (m, 2H), 2.01 - 1.99 (m, 1H), 0.48 (d, J=6.6 Hz, 2H), 0.36 - 0.28 (m, 2H). Example 116 5-[3-(cyclopropylamino)pyrrolidin-1-y1]-N-(2,7-dimethylimidazo[1,2-a]pyridin-6- yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2) 0 ~ oy Cy dc (Lnantiomer 1 + enantiomer 2) o Fig! 5 Fig! [ | oP ue or or > "> Following method H, lithium 5-(3-((terr-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1- yl)pyrazine-2-carboxylate (97 mg, 0.273 mmol) was reacted with 2,7-dimethylimidazo[1,2-a]pyridin-6- amine (44 mg, 0.273 mmol) in DMF (2.0 mL). The reaction mixture was diluted with water and the solid filtered and washed with 1:1 MeCN / H:O and purified by reverse phase HPLC to give rerr-butyl cyclopropyl(1-(5-((2,7-dimethylimidazo[ 1,2-alpyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate. LCMS (ES+) 492 (M+H)+. Following method E, rerz-butyl cyclopropyl(1-(5-((2,7-dimethylimidazo[ 1,2-a]pyridin-6- yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (9.4 mg, 0.020 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo and the residue applied to a 2 g SCX cartridge, eluting with 2 column volumes methanol, then 3 column volumes 2 M methanolic ammonia. The ammonia fraction was concentrated in vacuo to give the title compound. LCMS (ES+) 392 (M+H)+, RT 3.95 min (Analytical method BicarbBEHC18) 'H NMR (400 MHz, MeOD) 5 8.78 (s, 1H), 8.65 (d, J=1.3 Hz, 1H), 7.87 (d, J=1.3 Hz, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 3.76 - 3.45 (m, 4H), 3.42 - 3.37 (m, 1H), 2.31 (d, J=0.8 Hz, 3H), 2.29 (d, J=0.7 Hz, 3H), 2.26 - 2.12 (m, 2H), 2.01 - 1.91 (m, 1H), 0.47 - 0.44 (m, 2H), 0.35 - 0.31 (m, 2H). Example 117 (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-5-(3-((2,2,2- trifluoroethyl)amino)pyrrolidin- 1-yl)pyrazine-2-carboxamide ~n-Eee .Boc / N I INS ~n-Boe ) 5 —: yr IN ~ HoN HN, \—CF3 "cr 4 3 =~ / NH.HCI NE So hd 1 0H HN, \—CF; | Youd HN, \—CF3 tert-Butyl (R)-3-aminopyrrolidine-1-carboxylate (1.0 g, 5.37 mmol) and ethyl trifluoroacetate (2.29 g, 16.1 mmol) were stirred in ethanol (20 mL) at 60 °C for 17 h. The reaction mixture was concentrated to dryness and the crude rerr-butyl (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine-1- carboxylate used in the next step. LCMS (ES+) 283 (M+H)*. To a stirred solution of rerr-butyl (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine- 1-carboxylate (5.37 mmol) in THF (10 mL) was added borane- THF (21.5 mL, 1 M, 21.5 mmol) dropwise. After addition the mixture was refluxed for 17 h. The reaction mixture was cooled to r.t. and sat. ag. NHsC1 (20 mL) was added, before heating to 60 °C for 2 h. The mixture was concentrated and the resulting aqueous solution was extracted with EtOAc (2 x 30 mL). The organic layer was collected, dried (MgSO), filtered and concentrated. Purification by flash silica column chromatography (gradient, DCM to DCM / MeOH / 7 M NH; in MeOH [89:10:1]), gave rerr-butyl (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylate. LCMS (ES+) 213 (M+H)*. tert-Butyl (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylate (600 mg, 3.29 mmol) and HCl in dioxane (4 M, 4 mL, 16 mmol) were stirred in MeOH (10 mL) for 17 h. The mixture was concentrated to dryness and the crude (R)-N-(2,2,2-trifluoroethyl)pyrrolidin-3-amine-HC] was used in the next step. To a stirred solution of Intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL) was added (R)-N- (2,2,2-trifluoroethyl)pyrrolidin-3-amine- HCI (87 mg, 0.36 mmol) and Cs2COs (533 mg, 1.64 mmol). The mixture was stirred at 100 °C for 17 h and then cooled to r.t.. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organics were separated from the aqueous layer, which was extracted with further EtOAc (10 mL). The combined organic layers were washed with water (3 x 30 mL), dried (MgSOx), filtered and concentrated to dryness. Purification by preparative HPLC gave the title compound. LCMS (ES+) 438 (M+H)+, RT 2.64 min (Analytical method AcHSSC18); 'H NMR (400 MHz, DMSO) 6 10.42 (s, 1H), 9.19 (d, J=1.2 Hz, 1H), 8.75 (s, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.90 (t, J=8 Hz, 1H), 7.56 (dd, J=1.6, 13.2 Hz, 1H), 3.68 - 3.49 (m, 4H), 3.41 - 3.21 (m, 2H), 2.82 — 2.73 (m, 1H), 2.34 (s, 3H), 2.20 — 2.11 (m, 1H), 2.01 — 1.85 (m, 1H), 1 proton obscured by water peak. Example 118 N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-5-((3'S,4'R)-4'-fluoro-[1,3'- bipyrrolidin]-1'-yl)pyrazine-2-carboxamide and Example 119 N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'- bipyrrolidin]-1'-yl)pyrazine-2-carboxamide “I F. ‘ op-see -—— or N—Boc __ Fo a a Trans Isomers Cis Isomers Cis |lsomers HO. _ JOSS a Trans Isomers 0 2 IN A LL TET 1 0 : | ox op H - ml Cis Enantiomer 1 Lf Cis Enantiomer 2 N N OD Cis Enantiomer 1 O tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.25 g, 6.75 mmol), pyrrolidine (6.816 g, 95.84 mmol) and water (12 mL) were combined in a sealed tube and heated to 50 °C for 5 days. The reaction was quenched with sat. aq. NaHCO3 solution and extracted with dichloromethane (2x). The combined organic layers were dried (MgSQO.) and evaporated to dryness onto silica which was purified by flash chromatography eluting with 1% NH.OH / 10% MeOH / CH.Cl, to give tert-butyl (3R*4'R¥)- 4'-hydroxy-[1,3'-bipyrrolidine]-1'-carboxylate, which was used crude in the next step. tert-Butyl (3'R*,4'R*)-4'-hydroxy-[1,3"-bipyrrolidine]-1'-carboxylate (200 mg, 0.78 mmol), dichloromethane (10 mL) and Deoxy-fluor® (50% in THF) (0.32 mL, 0.86 mmol) were combined under a nitrogen atmosphere at room temperature and stirred for 2 days. The reaction was quenched with sat. aq. NaHCO; solution and extracted with dichloromethane (2x). The combined organic layers were dried (MgSO) and evaporated to dryness to give rerr-butyl (3'R* 4'S*)-4'-fluoro-[1,3"-bipyrrolidine]-1'- carboxylate, which was used crude in the next step. tert-Butyl (3'R*,4'S*)-4'-fluoro-[1,3'-bipyrrolidine]-1'-carboxylate, methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred for 16 hours. The reaction mixture was evaporated to dryness to give (3'R*4'S*)-4'-fluoro-1,3"-bipyrrolidine-2HCI, which was used crude in the next step without further purification. (3'R*,4'S*)-4"-Fluoro-1,3"-bipyrrolidine- 2HCI, Intermediate 1 (200 mg, 0.65 mmol), cesium carbonate (800 mg, 2.45 mmol) and DMF (4 mL) were combined in a sealed tube and heated to 100 °C for 6 hours. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration and the filtrate was purified by preparative HPLC followed by chiral prep HPLC to give Example 118, Cis Isomer, Enantiomer 1 N-(8-fluoro-2-methylimidazo[ 1,2-alpyridin-6-y1)-5-((3'S,4'R)-4'-fluoro-[1,3"-bipyrrolidin]-1'- yl)pyrazine-2-carboxamide. LCMS (ES+) 428 (M+H)+, RT 1.82 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) & 10.47 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.58 (dd, J=1.6, 13.0 Hz, 1H), 5.47 (td, J=1.9, 51.0 Hz, 1H), 3.97 - 3.78 (m, 4H), 3.20 - 3.15 (m, 1H), 2.66 - 2.59 (m, 4H), 2.35 (s, 3H), 1.71 (dd, J=4.5, 4.5 Hz, 4H). Example 119, Cis Isomer, Enantiomer 2 N-(8-fluoro-2-methylimidazo[ 1,2-a]pyridin-6-y1)-5-((3'R,4'S)-4'-fluoro-[1,3"-bipyrrolidin]-1'- yl)pyrazine-2-carboxamide. LCMS (ES+) 428 (M+H)+, RT 1.82 min (Analytical method AcHSSCI8). 1H NMR (400 MHz, DMSO) §10.47 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.58 (dd, J=1.6, 13.0 Hz, 1H), 5.47 (td, J=1.9, 51.0 Hz, 1H), 3.97 - 3.78 (m, 4H), 3.20-3.15 (m, 1H), 2.66 - 2.59 (m, 4H), 2.35 (s, 3H), 1.71 (dd, J=4.5, 4.5 Hz, 4H). Further analogues were prepared using the same chemistry and suitable amines. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. | Ex. | Structure | Amine | Analytical data | Ethylamine HN, _ Cis Isomer, Enantiomer 1 LCMS (ES+) 402 (M+H)+, RT 3.17 min (Analytical method BicarbBEHC18); 1H NMR (400 MHz, DMSO) 10.46 Gs, = 1H), 9.20 (d, J=1.6 Hz, 1H), 877 (d, ™ | 0 Ox J=14 Hz, 1H), 804 (s, 1H), 7.90 (d, Nu F | Eteytamine 2.4 Hz, 1H), 7.59 - 7.55 (m, 1H), 5.35 or (d, J=54.6 Hz, 1H), 4.06 - 3.90 (m, 2H), I" 3.89-3.71 (m, 1H), 3.63 - 3.46 (m, 1H), } 321 (t, J=10.4 Hz, 1H), 2.79 - 2.62 (m, Ths lnsies Ersationsss.) 2H), 235 (4, J=0.8 Hz, 3H), 1.08 (t, J=7.2 Hz, 3H). Example 121 (R)-N-(6-fluoro-2-methyl-2H-indazol-5-y)-5-(3-(methylamino)pyrrolidin- 1-yl)pyrazine-2- carboxamide cl N ° T Me o ove NEY I I 2 - a — PS A A BocN, Boe, \ \ N N 0 AN 0 AUN oe Gh VN a LL ASN La oo, HN A mixture of tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (400 mg, 2.0 mmol), methyl 5- chloropyrazine-2-carboxylate (350 mg, 2.0 mmol), Cs2COs (976 mg, 3.0 mmol) and DMF (6 mL) was heated in a sealed tube to 110 °C for 17 hours. The reaction was cooled to room temperature and diluted with EtOAc, washed with water and brine and the organics concentrated in vacuo to give methyl (R)-5- (3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate. A mixture of methyl (R)-5-(3-((rerr-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2- carboxylate (671 mg) and ammonia in methanol (4N, 20 mL) was heated to 90 °C for 19 hours. The reaction was cooled to room temperature and concentrated in vacuo to give tert-butyl (R)-(1-(5- carbamoylpyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate. Following Method F, rert-butyl (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3- yl)(methyl)carbamate (308 mg, 0.96 mmol) and 5-bromo-6-fluoro-2-methyl-2H-indazole (229 mg, 1.0 mmol) were coupled. The crude material was purified by preparative HPLC to give rerr-butyl (R)-(1-(5- ((6-fluoro-2-methyl-2 H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate. Following Method E, zer-butyl (R)- (1-(5-((6-fluoro-2-methyl-2H-indazol-5- yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (78 mg, 0.17 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo and the residue taken up in MeOH and stirred with Na;CO:s for 5 minutes, filtered and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 370 (M+H)+, RT 2.37 min (Analytical method AcHSSC18). 'H NMR (400 MHz, DMSO) § 9.82 (d, J=2.8 Hz, 1H), 8.75 (d, J=1.0 Hz, 1H), 8.49 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.51 (d, J=12.1 Hz, 1H), 4.16 (s, 3H), 3.69 - 3.56 (m, 4H), 2.32 (s, 3H), 2.17 - 2.04 (m, 1H), 1.99 - 1.80 (m, 2H). Example 122 (R)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidin-1- yl)pyrazine-2-carboxamide o rT : 1X Y B ) NN Qo oT BocN, HN, \ \ Following Method F, rerr-butyl (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3- yl)(methyl)carbamate (150 mg, 0.47 mmol) and Intermediate 17 (119 mg, 0.49 mmol) were coupled. The crude material was purified by preparative HPLC to give rert-butyl (R)-(1-(5-((8-methoxy-2- methylimidazo[ 1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate. Following Method E, tert-butyl (R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6- yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (24 mg, 0.050 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo and the residue taken up in MeOH and stirred with Na;CO:; for 5 minutes, filtered and the filtrate was purified by preparative HPLC to give the ritle compound. LCMS (ES+) 383 (M+H)+, RT 1.9 min (Analytical method AcHSSC18). *H NMR (400 MHz, DMSO) 8 9.47 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 4.07 (s, 3H), 3.65 - 3.54 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H), 2.10 (s, 1H), 1.94 - 1.94 (m, 2H). Further analogues were prepared using the same chemistry from commercially available or synthesized amines. In some instances, Boc protected amines were used, in which case the Boc group was removed at end of the synthetic sequence using 4N HCl in dioxane (general Method C) or TFA / DCM (general Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned. | Ex. | Structure | Amine | Analytical data =~ | 123 | (R)-1,3- bipyrrolidine; dihydrochloride orld x 3 3 LCMS (ES+) 423 (M+H)+, RT 1.98 min (Analytical method AcHSSCI18) *H NMR (400 MHz, MeOD) 8.77 (1H, 5), 8.66 (1H, d, J=1.3 Hz), 7.88 (1H, d, J=1.3 Hz), 7.61 (1H, d, J=0.8 Hz), 4.05 (3H, 5), e |3.84-3.68 (2H, m), 3.50 - 3.40 (1H, m), 3.36 - 329 (1H, m), 2.96 - 2.86 (1H, m), 2.65 - 2.53 (4H, m), 2.31 (3H, s), 2.28 - 2.18 (1H, m), 2.00 - 1.90 (1H, | m), 1.81 - 1.73 (4H, m). LCMS (ES+) 397 (M+H)+, RT 2.02 min (Analytical method AcHSSCI8) =~ 'H NMR (400 MHz, DMSO) § NN tert-butyl o x1 9.48 (s, 1H), 8.90 (s, 1H), 8.72 A (25,65)-2,6- | 124 NY NTN Yo (d, J=1.1 Hz, 1H), 8.38 (s, 1H), PNG dimethylpiperazi NN 7.95 (s, 1H), 6.64 - 6.63 (m, | [ ne-1-carboxylate Y 1H), 4.07 (s, 3H), 3.85 - 3.78 (m, 2H), 3.45 - 3.40 (m, 2H), 3.18 (m, 2H), 2.35 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H). Example 125: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-5-(piperidin-4-yl)pyrazine-2- carboxamide =~ POPS. ANN H ’ oO — ~E nd or o 2 — FY 8 A of N —- 2X NSP Ae 1] H HN. To a solution of Intermediate 1 (200 mg, 0.65 mmol) in dioxane (15 mL) and water (2 mL) was added sodium carbonate (500 mg, 4.71 mmol) and zerr-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (202 mg, 0.65 mmol). Bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) was added and the reaction tube was sealed and heated at 100 °C for 22 h. The reaction was cooled to r.t. and the solvent removed in vacuo to give a residue, which was purified by silica chromatography to give zerr-butyl 4-(5-((8-fluoro-2- methylimidazo[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3,6-dihydropyridine- 1(2H)-carboxylate. MS (ES+) 453 (M+H). A solution of rerr-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-alpyridin-6-yl)carbamoyl)pyrazin- 2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in ethyl acetate (15 mL) was hydrogenated using the H-cube and a 20% Pd(OH). / C cartridge, in recycling mode at 1 mL / min, 40 °C, 40 bars for 6 h, after which LCMS analysis showed near complete conversion. The solvent was removed in vacuo to give tert-butyl 4-(5-((8-fluoro-2-methylimidazol[ 1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2- yl)piperidine-1-carboxylate, which was used in the next step without further purification. Prepared using general Method E and the following quantities: zerr-butyl 4-(5-((8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperidine- 1-carboxylate, DCM (3 mL) and TFA (1 mL). The reaction mixture was evaporated to dryness, taken up in MeOH, treated with Na;COs, and then filtered. Purification by reverse phase HPLC followed by achiral SFC gave N-(8-fluoro-2- methylimidazo[1,2-a]pyridin-6-y1)-5-(piperidin-4-yl)pyrazine-2-carboxamide. LCMS (ES+) 355.2 (M+H)+, RT 1.61 min (Analytical method AcHSSC18) H NMR (400 MHz, DMSO) 610.92 - 10.90 (m, 1H), 9.23 (d, J=1.6 Hz, 2H), 8.76 (s, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.57 (dd, J=2.0, 12.9 Hz, 1H), 3.10 - 3.00 (m, 3H), 2.63 (dd, J=10.5, 12.0 Hz, 2H), 2.36 (s, 3H), 1.84 - 1.81 (m, 2H), 1.70 (dq, J=3.9, 12.2 Hz, 2H). Example 126: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-y1)-2-(piperazin-1-yl)pyrimidine-5- carboxamide 1 NN NN yo LL — XIX SL . %, oA or . OY . O07 NZ NTN 5 Zh a ee ! IN La ot HN J " 2-Chloropyrimidine-5-carboxylic acid (159 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2- alpyridin-6-amine.2HCI (238 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (0.5 mL) and DMF (4 mL) were combine and stirred at room temperature for 2 hours. The reaction mixture was then purified by Preparative HPLC to give 2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2- a]pyridin-6-yl)pyrimidine-5-carboxamide. MS (ES+) 405 (M+H). 2-((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6- yl)pyrimidine-5-carboxamide (113 mg, 0.28 mmol), N-Boc piperazine (52 mg, 0.28 mmol), Cs2COs (162 mg, 0.5 mmol) and DMF (4 mL) were combined in a sealed tube and hot block heated to 100 °C for 3 days. The reaction mixture was purified by preparative HPLC to give tert-butyl 4-(5-((8-fluoro-2- methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H). terr-Butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2- yl)piperazine-1-carboxylate (27.5 mg), dichloromethane (2 mL) and TFA (1 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness then taken up in MeOH. Na COs was added and stirred for 5 mins. The reaction was then filtered, the filtrate evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 356 (M+H)+, RT 1.61 min (Analytical method AcHSSC18). *H NMR (400 MHz, DMSO) § 10.22 - 10.21 (m, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.89 (s, 2H), 7.91 (d, J=2.8 Hz, 1H), 7.28 (dd, J=1.4, 12.7 Hz, 1H), 3.81 -3.77 (m, 4H), 2.76 (dd, J=5.0, 5.0 Hz, 4H), 2.45 (s, 1H), 2.35 (s, 3H). Example 127: (R)-N-(2,8-dimethylimidazo[ 1,2-a]pyrazin-6-yl)-2-(3-(methylamino)pyrrolidin-1- yl)pyrimidine-5-carboxamide NN COME A # CI” ON NT CO,Me ~~ _ =| NCO ~F =| Boc—N, : N S$ Boc—N, \ ° i? ° Ih rye robe SN 8 - So ’ j= p= B N HN, oc—N : Methyl 2-chloropyrimidine-5-carboxylate (345 mg, 2 mmol), tert-butyl (R)-methyl(pyrrolidin-3- yl)carbamate (400 mg, 2 mmol), Cs>COs (975 mg, 3 mmol) and DMF (10 mL) were combined in a sealed tube and hot block heated to 100 °C for 1 hour. The reaction mixture was diluted with EtOAc, washed with water (x4), brine (x1) and evaporated to dryness to give methyl (R)-2-(3-((rerr- butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-5-carboxylate. MS RT (ES+) 337 (M+H). Methyl (R)-2-(3-((rerr-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrim...

Claims

CLAIMS ‘What is claimed is’ L. A compound of Formula I: ND 0 2 3 2” " 0 ~ PR Yr vi R' oF w or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, wherein: X* are ox N; . , and X* are CR? or N, , Wi ‘he rein at Ie ea st two bi ut no my Or e tha n thr ee of X! . X2 LX , an d each R* is independently hydrogen, halo, hydroxy, C1.ealkyl, Ci.shaloalkyl, or Cy. salkoxy; Y!is CR%or N; R® is hydrogen, cyano, halo, hydroxy, Crealkyl, C.shaloalkyl, Cy.ealkylthio, Cy.ealkoxy, C1ehaloalkoxy, heterocyclyl, -NHz, -NHRY, or -N(R'7),, and optionally substituted on an available nitrogen atom with C,salkyl or C,shaloalkyl; Y2 is absent, CR® or N: R® is hydrogen, cyano, halo, hydroxy, Ci.alkyl, C1.¢haloalkyl, Cy.salkylthio, Cy.ealkoxy, Cishaloalkoxy, heterocyclyl, -NHz, -NHR', or -N(R'7),, and optionally substituted on an available nitrogen atom with C;salkyl or C;¢haloalkyl; and Y3isCR}or N; R? is hydrogen, cyano, halo, hydroxy, Ci.alkyl, C1.¢haloalkyl, C1.salkylthio, Cy.ealkoxy, C1ehaloalkoxy, heterocyclyl, -NHa, -NHRY, or -N(R!7),, and optionally substituted on an available nitrogen atom with C,salkyl or C,shaloalkyl; each R'is independently Calkyl, or two R” join, with any intervening atoms, to form a 3- to 6-membered heterocyclyl; each of Z! and Z2is C or N: Ring A and Ring B together form a 9- or 10-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms; Ring B contains 1 to 3 heteroatoms independently selected from N, O, and S, and is optionally substituted on available carbon atom(s) with 1 to 3 substituents independently selected from halo, hydroxy, Ciealkyl, Ciehaloalkyl, Cisalkoxy, and C,shaloalkoxy, and optionally substituted on an available nitrogen atom with C,salkyl or C; haloalkyl; R'is -LL-R'%, wherein L! is -O-, -S-, -S(O)-, -S(O)2-, -N(R'?)-, -C\.salkylene-, -O-C.aalkylene-, -N(R!?)-C1.3alkylene-, or absent, and R*! is Ca.salkynyl, Ca.iocycloalkyl, Ce.ioaryl, heteroaryl, or heterocyclyl, wherein R'! is optionally substituted with 1 to 4 R" groups; R!'?is hydrogen or Cy.ealkyl; each R" is independently selected from halo, cyano, hydroxy, Ci.ealkyl optionally substituted with R'6, Cy.¢haloalkyl, Cishydroxyalkyl, Cs.iccycloalkyl optionally substituted with RS, Ca.iecycloalkyl-C alkyl optionally substituted with R'6, Ce.i0aryl optionally substituted with R'¢, Ce.i0aryl-Ci.ealkyl optionally substituted with R'®, heteroaryl optionally substituted with R'®, heteroaryl-Cy alkyl optionally substituted with R', heterocyclyl optionally substituted with R'6, heterocyclyl-Cyealkyl optionally substituted with R'6, OR', -NHz, -NHR", -N(R'*)s, -C1. salkylene-NH,, -C.ealkylene-NHR', -C) salkylene-N(R'4),, -C(O)R", -C(O)ORY, -C(O)NHR"*, -C(O)N(Ci4alkylR", -S(0)2R", -S(O)R™*, -NHC(O)R, -N(Cialky)C(O)R", -NHS(O)R™, -N(C,.alkyl)S(O)R'S, -NHS(0);R, and -N(C)alkyl)S(O).R!%:; each R'* is independently selected from Ch.salkyl, Cs.iocycloalkyl, Ceoaryl, heteroaryl, and heterocyclyl; and each R'* is optionally substituted with one to six halo, Cy.salkyl, Ci. salkoxy, Cs.jocycloalkyl, or -NHSO»-aryl-N(CHs)z; each R'is independently hydrogen, -OH, Cisalkyl, Cy.chaloalkyl, Ca.jocycloalkyl, Cs.10aryl, heteroaryl, or heterocyclyl; each R'® is independently halo, cyano, hydroxy, -NH,, -NHR?, -N(R?),, C\.salkyl, C1. shaloalkyl, OR?!, or Ca.iecycloalkyl; each R?! is independently selected from C alkyl, Ca.iocycloalkyl, Ceoaryl, heteroaryl, and heterocyclyl, and each R2! is optionally substituted with one to six halo or Cisalkoxy; and R? is hydrogen or Cyealkyl.

2. The compound of claim 1, of Formula Ia: “a Ia \ = i 22. 0 yz A ALA, NT N Y! R® An R? R I: or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

3. The compound of claim 1, of Formula Ib: ND Ib 0 2 3 NT fa r Ja 2 N ZN i} J \ v7 Rr? ” It or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

4. The compound of claim 1, of Formula Ic: ND Ic i = o v7 2 72 ANAS ore R' Na Re " Ic or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof. 3S. The compound of claim 1, of Formula Ila: | ot i la 0 NA 7 PN IX Lr ~X3 A Rx Re I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

6. The compound of claim 1, of Formula IIb: R10 / 1b # N i \ o A A os Ao = RT x# I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof. 2 The compound of claim 1, of Formula IIIa: | ol ] Mla | AY LCL R ZN R2 " I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

8. The compound of claim 1, of Formula IIIb: Re = IIb IN AL NT AN N 1 AJ ! Y R® I or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

9. The compound of claim 1, of Formula IIIc: | mL : Tc | 0 LH [> R! 2 ! - “N Rr? " x or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof.

10. The compound of any one of claims 1-9 wherein R!! is heterocyclyl optionally substituted with 1 to 4 groups independently selected from halo, Cisalkyl, Cishaloalkyl, Cs.iocycloalkyl, heteroaryl, heterocyclyl, heterocyclyl-Ci.salkyl, -NHz, -NHR', -N(R™),, -C.¢alkylene-NHa, -Ci.salkylene-NHR 4, -Cialkylene-N(R'),, and -C(O)OR'%; wherein each R' is independently selected from Cj.salkyl, Cs. 1ocycloalkyl, and heterocyclyl, and each R' is optionally substituted with one to three halo; and wherein RY is Cyealkyl. “e) Nh 11. The compound of any one of claims 1-10 wherein R!! is N wherein Ring C is a 3- to 10-membered heterocyclyl containing 0, 1 or 2 additional ring nitrogen atoms optionally substituted with 1 to 4 R" groups.

12. The compound of claim 11, wherein Ring C is a 5- to 10-membered bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'? groups.

13. The compound of claim 11, wherein Ring C is a 5- to 10-membered spirobicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'? groups.

14. The compound of claim 11, wherein Ring C is a 5- to 10-membered fused bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted with 1 to 4 R'? groups. w= Cn 15. The compound of any one of claims 1-10 wherein R! is selected from — ™ Ov = J oad aN On o~ ) Hn XH HN Mus aA “ A nC 7 SN H SN H H A A ~~ AL H \ 5 RH 5 TO WF wT oH a N Fao XZ pA x 3 IAANLON mw 15 Sy / ~ rr" wo N HN N HN _~ \ 5 SN H AN WOH WOH Sw CB \ NAVE | 7 \ (OH “NH N NH 0" wp and A sn O~\ N NN 0X NP pr A , each of which is optionally substituted with 1 to 4 R'3 groups. A 3 HN , 16. The compound of any one of the preceding claims wherein R!! is optionally substituted with 1 to 4 groups independently selected from fluoro, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2- difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1- ylamino)methyl, cyclopropyl, 1-(cyclopropylamino)-1-cyclopropyl, 1-pyrrolyl, N-morpholinyl, N- pyrrolidinyl, N-pyrrolidinylmethyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperdinyl, 1- cyclopropyl-2-piperdinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1- cyclopropylamino)methyl, N-tert-butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N- cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylaminomethyl, N-isopropyl-N-aminomethyl, tert- ‘butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3- difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, (3-methoxy-1-azetidinyl)methyl, (3- methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1- pyrrolidinyl)methyl, 4-morpholinylmethyl, and tert-butoxycarbonyl.

17. The compound of any one of the preceding claims wherein R? is halo.

18. The compound of any one of the preceding claims wherein R? is fluoro.

19. The compound of any one of claims 1-16 wherein R3 is methyl.

20. The compound of any one of claims 1-16 wherein R? is methoxy.

21. The compound of any one of the preceding claims, wherein each R* is hydrogen.

22. The compound of any one of the preceding claims wherein R® is hydrogen.

23. The compound of any one of claims 1-21 wherein R? is Cy.salkoxy.

24. The compound of any one of claims 1-21 wherein R® is methoxy.

25. The compound of any one of the preceding claims, wherein R7 is hydrogen.

26. The compound of any one of the preceding claims wherein R® is methyl.

27. The compound of any one of the preceding claims wherein L! is absent.

28. The compound of any one of the preceding claims wherein Y' is CR.

29. The compound of any one of claims 1-27 wherein Y'is N.

30. The compound of any one of the preceding claims wherein Y? is CRS.

31. The compound of any one of the preceding claims wherein Y* is CR. R8 rR? R N= XY 32. The compound of any one of the preceding claims wherein Ring B is R10 13. The compound of any one of claims 1-31 wherein Ring B is 7 RI R® rN is i 34. A compound selected from those in Table 1, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof. 3s. A pharmaceutical composition comprising the compound of any one of the preceding claims, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

36. A method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-34 or the pharmaceutical composition of claim 35.

37. A method for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-34 or the pharmaceutical composition of claim 35 in combination with a second active agent.