N-(2H-indazol-5-yl)pyrazine-2-carboxamide derivatives and analogues as HTT modulators for the treatment of Huntington's disease

Abstract

The present invention refers to compounds of formula (I) as HTT modulators for treating Huntington's disease. Exemplary compounds are, for example, Example 1: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-yl)pyrazine-2-carboxamide. The present invention discloses the synthesis and characterization of exemplary compounds, as well as their pharmacological data. [Formula 1] TIFF2024540477000099.tif32144

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 280,551, filed November 17, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to modulators of HTT and methods of preventing and / or treating neurodegenerative diseases or conditions. [Background technology]

[0003] Huntington's disease (HD) is a genetic, progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric deficits, as well as neurodegeneration and brain atrophy that begins in the striatum and cortex and spreads to other subcortical brain regions. HD has a prevalence of 5-10 cases per 100,000 people worldwide, making it the most common inherited monogenic neurodegenerative disorder.

[0004] Neurodegenerative diseases and conditions, such as Huntington's disease, have a significant negative impact on the lives of those who suffer from them. Current treatments for Huntington's disease are palliative, aiming to reduce the severity of symptoms. There is no disease-modifying treatment available.

[0005] 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 a mutant huntingtin protein (mHTT) that contains an expanded polyglutamine region in the amino-terminal domain of the protein. Although HD is monogenic and autosomal dominant, the molecular pathway of pathogenesis is not fully understood. Therefore, reducing mHTT is an elegant therapeutic strategy that targets the gene product of the causative gene. Indeed, several therapeutic strategies aimed at reducing mHTT via antisense oligonucleotides (ASOs) or AAV-miR-mediated degradation of HTT RNA have progressed through clinical trials in HD, demonstrating reduced mHTT levels in the CSF of treated patients. Summary of the Invention

[0006] While these modalities show great promise, they are invasive (involving repeated intrathecal injections), do not reliably distribute throughout the brain to all affected regions, and do not address any peripheral dysfunction that may be due to widespread mHTT distribution. Therefore, a small molecule HTT reducer that can be delivered non-invasively to the whole body is an attractive HTT reduction therapy to pursue. Thus, there is a need for small molecule modulators of HTT protein. Such molecules can find use in treating Huntington's disease symptoms and / or slowing disease progression.

[0007] The present disclosure relates generally to small molecule modulators of HTT and their use as therapeutic agents, for example, in the treatment of diseases, such as Huntington's disease.

[0008] Thus, provided herein are compounds, or isotopically enriched analogs, pharma- ceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers of the compounds, that are useful for the treatment of Huntington's disease.

[0009] In certain embodiments, compounds are provided that modulate a protein or protein fragment involved in a neurodegenerative disease, such as the HTT protein.

[0010] In certain embodiments, a pharmaceutical composition is provided comprising a compound described herein, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharma- ceutically acceptable excipient.

[0011] The disclosure also provides compositions, including pharmaceutical compositions, kits including the compounds, and methods of using (or administering) and making the compounds. The disclosure further provides the compounds or compositions thereof for use in methods of treating a disease or condition mediated at least in part by a protein or protein fragment involved in a neurodegenerative disease. The disclosure further provides the use of the compounds or compositions thereof in the manufacture of a medicament for the treatment of a disease or condition mediated at least in part by a protein or protein fragment involved in a neurodegenerative disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The following description describes exemplary embodiments of the present technology, however, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0013] definition As used herein, the following words, phrases and abbreviations are generally intended to have the meanings set forth below, except to the extent that the context in which they are used dictates otherwise.

[0014] A compound described herein refers to a compound of any formula described herein, including a compound of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula IIa, Formula IIb, Formula IIIa, Formula IIIb, Formula IIIc, or anywhere described herein, including the examples, or a compound of Table 1, Table 2, or Table 2A, or an isotopically labeled analog, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers thereof.

[0015] A dash ("-") that is not between two letters or abbreviations is used in the case of a substituent to indicate a point of attachment to the parent structure. For example, -C(O)NH2 is attached to the parent structure through a carbon atom. Dashes before or after a chemical group are a matter of convenience, and a chemical group may be written with or without one or more dashes without losing its normal meaning. Wavy or dotted lines drawn through bonds in a structure indicate a particular point of attachment. No anisotropy or stereochemistry is indicated or implied by the order in which chemical groups are written or specified, unless chemically or structurally required.

[0016] "C u~v " indicates that the following group has u to v carbon atoms, excluding further substitutions. For example, "C 1~6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0017] Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter per se. In certain embodiments, the term "about" includes the specified amount ±10%. In other embodiments, the term "about" includes the specified amount ±5%. In certain other embodiments, the term "about" includes the specified amount ±1%. Again, the term "about X" includes a reference to "X." Again, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, 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 of skill in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 12 carbon atoms (i.e. C 1~12 alkyl), 1 to 9 carbon atoms (i.e. C 1~9 alkyl), 1 to 8 carbon atoms (i.e. C 1~8 alkyl), 1 to 6 carbon atoms (i.e. C 1~6 alkyl) or 1 to 4 carbon atoms (i.e. C 1~4Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons may be included, thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] Alternative chemical names known to those skilled in the art may be used in place of the terms provided herein. For example, divalent groups, such as divalent "alkyl" groups or divalent "aryl" groups, may be referred to as "alkylene" or "arylene" groups, respectively. Again, unless expressly indicated otherwise, when a combination of groups is referred to herein as a moiety, such as arylalkyl or aralkyl, the last-mentioned group contains the atom that connects the moiety to the rest of the molecule.

[0020] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e. C 2~8 alkenyl), 2 to 6 carbon atoms (i.e. C 2~6 alkenyl) or 2 to 4 carbon atoms (i.e. C 2~4 Alkenyl refers to an alkyl group having an aryl group such as 1,2-butadienyl, 2,3-butadienyl, or 3,4-butadienyl. Examples of alkenyl groups include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and isoprenyl.

[0021] "Alkynyl" refers to an alkynyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e. C 2~8 alkynyl), 2 to 6 carbon atoms (i.e. C 2~6 alkynyl) or 2 to 4 carbon atoms (i.e. C 2~4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0022] "Alkoxy" refers to the group "alkyl-O-". Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0023] "Alkylamino" refers to an "alkyl-NH-" group. Examples of alkylamino groups include, for example, methylamino, ethylamino, isopropylamino, tert-butylamino, and n-hexylamino. "Dialkylamino" refers to an "(alkyl)2N-" group. Examples of dialkylamino groups include, for example, dimethylamino, diethylamino, (isopropyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and di-n-hexylamino.

[0024] "Alkylthio" refers to the group "alkyl-S-". "Alkylsulfinyl" refers to the group "alkyl-S(O)-". "Alkylsulfonyl" refers to the group "alkyl-S(O)2-".

[0025] "Acyl" is -C(O)R y R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] "Amide" is -C(O)NR y R z The "C-amide" group refers to the group -NR y C(O)R z "N-amide" refers to both the "N-amino" and "N-aryl" groups, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0027] "Amino" is -NR y R z R y and R z is 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 an NH group.

[0028] "Amidino" is -C(NR y )(NR z 2) group, wherein R y and R zis independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0029] "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 refers to a group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl) or 6 to 10 carbon ring atoms (i.e. C 6~10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0030] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

[0031] "Carbamoyl" is -OC(O)NR y R z The "O-carbamoyl" group refers to the -NR y C(O)OR z "N-carbamoyl" refers to both the "N-carbamoyl" group and the "N-carbamoyl" group, y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0032] "Carboxyl ester" or "ester" refers to the -OC(O)R x and -C(O)OR x In the formula, R xis alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0033] "Cycloalkyl" refers to cyclic alkyl groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems, that may be saturated or partially unsaturated. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., C 3~20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e. C 3~12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e. C 3~10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e. C 3~8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e. C 3~6 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. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring system, which may include fused aryl rings, independent of the attachment to the rest of the molecule. Still further, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. Cycloalkyl as a substituent may include spirocycloalkyl when there are two positions for substitution on one carbon atom of the parent structure. Cycloalkyls may be substituted at the carbon atom of the bond to the parent structure.

[0034] "Cycloalkoxy" refers to the group "-O-cycloalkyl."

[0035] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

[0036] "Guanidino" is -NR y C(=NR z )(NR y R z ) in which each R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0037] "Imino" is -C(NR y )R z R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0038] "Imide" is -C(O)NR y C(O)R z R y and R z Each is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0039] "Halogen" or "halo" refers to a substituent atom in Group VIIA of the periodic table, e.g., fluoro, chloro, bromo, or iodo.

[0040] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more (e.g., 1-6 or 1-3) hydrogen atoms, up to and including all hydrogen atoms, are replaced by halogen. For example, if a residue is substituted by 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 by two ("di") or three ("tri") halo groups, which may, but need not, be the same halogen. Perhaloalkyl groups are haloalkyl groups in which all hydrogen substituents are replaced by halo. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0041] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms, up to and including all of the upper limit, are replaced by halogen.

[0042] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group.

[0043] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) of the alkyl chain are each independently replaced by the same or different heteroatom groups, provided that 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, one, two or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., in which R yis 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, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and aminoalkyls (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y 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.

[0044] "Heteroaryl" refers to an aromatic group having a single ring or multiple condensed rings, in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur, and one or more (e.g., 1 to 3) N-oxides (-O - As used herein, heteroaryl may include an aryl group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e. C 3~12 Heteroaryl) or 3 to 8 carbon ring atoms (i.e. C 3~8Heteroaryl) and 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain examples, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each having independently 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, 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, iso Examples include indolyl, 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 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 bonded through any ring of the fused system. Any aromatic ring system having a single or multiple fused rings containing at least one heteroatom is considered to be a heteroaryl, regardless of the bond to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0045] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0046] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur atom is optionally oxidized to form an N-oxide, sulfinyl (-S(O)-), or sulfoxide (-S(O)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 containing at least one oxo), and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro. Regardless of the enumerated substituents, unless otherwise stated, a heterocyclyl may include one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moiety. Heterocyclyl can be attached through a carbon atom or a heteroatom, where valence allows. Additionally, the term heterocyclyl encompasses any ring system, including a non-aromatic ring containing at least one heteroatom, independent of attachment to the remainder of the molecule, which ring may be fused to an aryl or heteroaryl ring. Heterocyclyl may have a charge resonance structure that is aromatic (e.g., pyridin-2(1H)-one-1-yl). As used herein, heterocyclyl refers to a ring having 3-14 ring atoms, 3-10 ring atoms, 3-6 ring atoms, or 5-6 ring atoms, and / or 2-12 ring carbon atoms (i.e., C) having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom. 2~12 heterocyclyl), 2 to 10 ring carbon atoms (i.e. C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e. C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e. C3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e. C 3~8 heterocyclyl) or 3 to 6 ring carbon atoms (i.e. C 3~6Examples of heterocyclyl groups include, for example, 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, octahydroisoinyl, and the like. Examples of heterocyclyl include aryl, 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 spiroheterocyclyl rings include, for example, 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. Heterocyclyl as a substituent may include spiroheterocyclyl when there are two positions for substitution on one carbon atom of the parent structure. Examples of 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 attached via either ring of the fused system.

[0047] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0048] "Heterocyclyloxy" refers to the group "heterocyclyl-O-".

[0049] "Oxime" is -CR y (=NOH) group, where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0050] "Sulfonyl" is -S(O)R y R y 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.

[0051] "Sulfinyl" is -S(O)R y R y 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.

[0052] "Sulfonamide" is -SO2NR y R z and -NR y SO2R z R y and R zEach is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which is optionally substituted as defined herein.

[0053] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which said event or circumstance occurs as well as instances in which it does not occur. Also, the term "optionally substituted" refers to a group that is unsubstituted or substituted.

[0054] As used herein, the term "substituted" refers to any one or more (e.g., 1-5 or 1-3) hydrogen atoms being replaced with a non-hydrogen group, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, arylalkyl, azide, 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(O)OH, sulfonamide, thiol, thioxo, N-oxide or -Si(R y )3(in the formula, each R y refers to a group that is replaced by (which is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0055] In certain embodiments, "substituted" means that one or more (e.g., 1-5 or 1-3) hydrogen atoms are independently selected from the group consisting of 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, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g S(=O) 1~2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -OS(=O) 1~2 R g , -S(=O) 1~2 OR g , -NR g S(=O) 1~2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1~2 NR g R h , -SF5, or -SCF3. In certain embodiments, "substituted" refers to a group in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g, -C(=O)NR g R h , -CH2SO2R g or -CH2SO2NR g R h In the above, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl; or R g and R h two of these, together with the atom to which they are attached, form a heterocyclyl ring optionally substituted by oxo, halo, or alkyl optionally substituted by oxo, halo, amino, hydroxyl, or alkoxy.

[0056] It is not intended that the above definitions result in polymers or similar amorphous structures that are reached by defining a substituent with an infinite number of additional substituents (e.g., a substituted alkyl that is itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise noted, in the compounds described herein, the maximum number of consecutive substitutions is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definitions are not intended to encompass compounds with substitution patterns that are chemically infeasible or inisolatable (e.g., a methyl substituted by five fluorines, or a heteroaryl group with three consecutive oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may also describe other chemical groups as defined herein.

[0057] In certain embodiments, the phrase "one or more" as used herein refers to 1 to 5. In certain embodiments, the phrase "one or more" as used herein refers to 1 to 3.

[0058] Any compound or structure given herein is intended to represent the unlabeled form of the compound and "isotopically enriched analogs". Isotopically enriched forms of the compound may also be referred to as "labeled". Isotopically enriched analogs have the structure described herein except that one or more atoms are enriched with 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, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. In general, isotopically enriched analogs include compounds having any isotopic enrichment above the natural abundance of the isotope (e.g., at the earth's surface). Various isotopically labeled compounds, such as radioisotopes, e.g., 3 H, 18 F, 11 C. 13 C and 14 Compounds incorporating C are included in the present disclosure. 18 F, 3 H or 11 Compounds labeled with C may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques including drug or substrate tissue distribution assays, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or in radiation treatment of patients.

[0059] The term "isotopically enriched analog" includes "deuterated analogs" of compounds described herein in which one or more hydrogens, e.g., hydrogens on carbon atoms, are replaced by deuterium. Such compounds may exhibit increased resistance to metabolism and 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 using starting materials in which one or more hydrogens have been replaced by deuterium.

[0060] The therapeutic compounds of the present disclosure that are labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetic) properties in terms of distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, reduced dose requirements and / or improved therapeutic index. The isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by carrying out the procedures disclosed in the schemes or by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in the examples and preparations described below. When a compound is described as a deuterated analog, the compound can be obtained with deuterium as a substituent.

[0061] The concentration of such heavy isotopes, specifically deuterium, can be defined by the 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 specifically designated as "H" or "hydrogen", the position is understood to have hydrogen and its isotopes at their natural abundance.

[0062] 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.

[0063] Also provided are isotopically enriched analogues, pharma- ceutically acceptable salts, prodrugs, tautomers, stereoisomers and mixtures of stereoisomers of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0064] The term "pharmaceutically acceptable salt" of a compound described herein refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" of a compound described herein includes, for example, an acid addition salt obtained by interacting a compound having a basic functional group with an acid, and a base addition salt obtained by interacting a compound having an acidic functional group with a base. If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if a compound is a free base (e.g., of an amine), an addition salt can be generated 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 non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts of the compounds described herein can be prepared from inorganic and organic acids. Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Suitable organic acids include, for example, 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. Similarly, 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 alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(alkenyl)), di(substituted alkyl)amines (i.e., HN(alkenyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), and the like. Examples of amines that may be used include arylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), cyclic amines (e.g., piperidine, piperazine, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0065] Some compounds described herein may exist as tautomers.For example, if a compound is depicted as containing amide, it may also exist as imidic acid tautomer, and if a compound is depicted as containing ketone, it may also exist as enol tautomer.It is understood by those skilled in the art that the compound includes both tautomers, regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers.Thus, for example, an amide-containing compound is understood to include its imidic acid tautomer, and an imidic acid-containing compound is understood to include its amide tautomer.

[0066] The compounds described herein may contain asymmetric centers and may therefore give rise to enantiomers, diastereomers and other stereoisomeric forms, which in the case of amino acids can be defined in terms of absolute stereochemistry as (R)- or (S)-, or as (D)- or (L)-. The compounds described herein are meant to include all such possible isomers, as well as racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives), using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both cis and trans or E- and Z-geometric isomers.

[0067] "Stereoisomer" refers to one of a set of compounds composed of the same atoms joined by the same bonds but with different three-dimensional structures. Various stereoisomers and mixtures thereof are contemplated, including "enantiomers," which refer to stereoisomeric compounds that are non-superimposable mirror images of one another.

[0068] A "diastereomer" is one of a pair of stereoisomers that have at least two asymmetric atoms and are not mirror images of each other.

[0069] A "prodrug" is any molecule that releases the putatively active parent drug in vivo according to the compounds described herein when the prodrug is administered to a mammalian subject. A prodrug can be a form of a compound described herein that has been modified such that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds described herein such that the modification can be cleaved to the parent compound, either by routine manipulation or in vivo. Prodrugs include compounds described herein in which the hydroxy, amino, carboxyl, or sulfhydryl groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate the respective free hydroxy, amino, or sulfhydryl groups. 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), and the like, of the hydroxy functional groups in the compounds described herein. The preparation, selection and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0070] As used herein, the terms "group," "moiety," "radical," "substituent," and "fragment" are synonymous and are intended to indicate a portion of a molecule that can be attached to another portion of the molecule, e.g., through a designated point of attachment or bond.

[0071] The term "active agent" is used to indicate a compound that has biological activity in the treatment, amelioration, or prevention of a disease or condition. In some embodiments, an "active agent" is a compound or its isotopically labeled analog, pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers that has pharmaceutical utility. For example, the active agent may be for anti-neurodegenerative therapy.

[0072] The term "effective amount" refers to an amount of a compound, e.g., as described herein, sufficient to produce a desired response in an individual or patient. The term "therapeutically effective amount" refers to an amount effective when administered to a human or non-human patient to provide a therapeutic benefit, e.g., amelioration of symptoms, slowing down disease progression, or prevention of disease; e.g., a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease described herein. The (therapeutically) effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, which can be determined by one of skill in the art.

[0073] The term "huntingtin protein" or "HTT protein" as used herein refers to the protein encoded by the human huntingtin gene (HTT gene), located at position 16.3 on the short (p) arm of chromosome 4. More precisely, the IT coding for the HTT protein 15 The gene is located on chromosome 4 from base pair 3,076,407 to base pair 3,245,686.

[0074] The term "protein aggregates" as used herein refers to aggregations of proteins, which may be insoluble fibrillar amyloid, including, for example, misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). A "protein involved in a neurodegenerative disease" may be a protein, in wild-type or mutant form, capable of forming such aggregates, or may be a protein involved in a pathological process related to a neurodegenerative disease.

[0075] In some embodiments, the term "neurodegenerative disease" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative diseases include those described herein.

[0076] "Treatment" or "treating" means a) inhibiting the disease (e.g., alleviating one or more symptoms resulting from the disease or condition and / or reducing the extent of the disease or condition); b) slowing or preventing the onset of clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) Eliminating the disease, i.e., reversing clinical symptoms (e.g., ameliorating the appearance of the disease, causing partial or complete remission of the disease or condition, enhancing the effect of another medication, slowing the progression of the disease, improving quality of life, and / or prolonging survival). By this is meant any treatment of an aspect of a disease in a patient, including

[0077] "Prevention" or "preventing" refers to any treatment of a disease or condition that does not result in the development of clinical symptoms of the disease or condition. The compounds may, in some embodiments, be administered to subjects (including humans) who are at risk (e.g., have a genetic or epigenetic marker associated with the disease or condition, are involved in an activity or are exposed to an environmental condition) or have a family history of the disease or condition.

[0078] "Subject" or "patient" refers to an animal, e.g., a mammal, that is or becomes the object of treatment, observation, or experiment. The methods described herein can be useful in both human treatment and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.

[0079] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, as in an animal or human. In this context, the methods described herein can be used for treatment in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can 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 can 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 optimal schedules and / or dosing of the disclosed compounds for a given efficacy, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or to set up protocols for in vivo treatment in the clinic. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to one of skill in the art. Selected compounds may be further characterized to test for safety or tolerable dosage in human or non-human subjects. Such properties may be tested using methods commonly known to those of skill in the art.

[0080] It is understood that certain features described herein that are described in the context of separate embodiments for clarity may be provided in combination in a single embodiment. Conversely, various features described herein that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination. All combinations of the embodiments relating to the chemical groups represented by the variables contained in formula I are specifically incorporated herein to the extent that such combinations result in stable compounds (i.e. compounds that can be isolated, characterized, and tested for biological activity), just as if every combination were explicitly listed individually. In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of the uses and medical indications described herein, are also specifically incorporated herein, just as if every subcombination of the chemical groups, as well as subcombinations of the uses and medical indications, were explicitly listed individually herein. In addition, some embodiments include all combinations of one or more additional agents disclosed herein, just as if every combination were explicitly listed individually herein.

[0081] compound Compounds for modulating HTT are provided herein. In certain embodiments, the compound of formula I

[0082] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. (In the formula, X 1 , X 2 , X 3 and X 4 is CR 4 or N, where X 1 , X 2 , X 3 and X4 At least two but not more than three of are N, Each R 4 are independently hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy; Y 1 is CR 5 or N, R 5 is hydrogen, heterocyclyloxy, or C 2~6 Alkynyl, Aryl, C 1~6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1~6 is an alkoxy; Y 2 does not exist or CR 6 , or N, R 6 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, C 1~6 Haloalkoxy, heterocyclyl, -NH2, -NHR 17 Or -N(R 17 )2 and C on available nitrogen atoms 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Y 3 is CR 3 or N, R 3 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, C 1~6 Haloalkoxy, heterocyclyl, -NH2, -NHR 17 Or -N(R 17 )2 and C on available nitrogen atoms 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Each R 17 is independently C 1~4 alkyl, or two R 17 are linked together with any intervening atoms to form a 3- to 6-membered heterocyclyl; Z 1 and Z 2 each is 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 an available carbon atom with halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 Optionally substituted with 1 to 3 substituents independently selected from haloalkoxy and C on an available nitrogen atom. 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; R 1 -L 1 -R 11 where L 1 -O-, -S-, -S(O)-, -S(O)2-, -N(R 12 )-, -C 1~3 Alkylene-, -OC 1~3 Alkylene-, -N(R 12 )-C 1~3 alkylene- or absent, R 11 is C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, or heterocyclyl, where R 11 is 1 to 4 R 13 is optionally substituted by a group; R 12 is hydrogen or C 1~6 is alkyl, Each R 13 are independently halo, cyano, hydroxy, R 16 C optionally replaced by 1~6 Alkyl, C1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 16 C optionally replaced by 3~10 Cycloalkyl, R 16 C optionally replaced by 3~10 Cycloalkyl-C 1~6 Alkyl, R 16 C optionally replaced by 6~10 Aryl, R 16 C optionally replaced by 6~10 Aryl-C 1~6 Alkyl, R 16 heteroaryl optionally substituted by R 16 Heteroaryl-C optionally substituted with 1~6 Alkyl, R 16 heterocyclyl optionally substituted by R 16 Heterocyclyl-C optionally substituted by 1~6 Alkyl, OR 14 , -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2, -C 1~6 Alkylene-NHR 14 , -C 1~6 Alkylene-N(R 14 )2, -C(O)R 15 , -C(O)OR 15 , -C(O)NHR 15 , -C(O)N(C 1~4 Alkyl)R 15 , -S(O)2R 15 , -S(O)R 15 , -NHC(O)R 15 , -N(C 1~4 Alkyl)C(O)R 15 , -NHS(O)R 15 , -N(C 1~4 Alkyl)S(O)R 15 , -NHS(O)2R 15 and -N(C 1~4 Alkyl)S(O)2R 15 is selected from Each R14 is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, and heterocyclyl; each R 14 1 to 6 halos, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~10 optionally substituted by cycloalkyl or -NHSO2-aryl-N(CH3)2; Each R 15 are independently hydrogen, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl or heterocyclyl; Each R 16 are independently halo, cyano, hydroxy, -NH2, -NHR 21 , -N(R 21 )2, C 1~6 Alkyl, C 1~6 Haloalkyl, OR 21 Or C 3~10 is cycloalkyl, Each R 21 is independent, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, heteroaryl, heterocyclyl, and -CH2C(O)NHR 22 Each R 21 1 to 6 halo or C 1~3 Optionally substituted with alkoxy, R 22 C is substituted by heterocyclyl and N3 1~6 is alkyl, R 2 is hydrogen or C 1~6 is alkyl, However, R 5 If is hydrogen, R 1 -OCH2C(O)NHR 22 Heterocyclyl-C substituted by 1~6 Heterocyclyl substituted by alkyl is provided.

[0083] In certain embodiments, the compound of formula Ia

[0084] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , Y 1 , Y 2 , Z 1 , and Z 2 is as defined herein.

[0085] In certain embodiments, the compound of formula Ib

[0086] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , Y 1 , Y 2 , Z 1 , and Z 2 is as defined herein.

[0087] In certain embodiments, the compound of formula Ic

[0088] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein Ring A, Ring B, R 1 , R 2 , R 3 , Y 1 , Y2 , Z 1 , and Z 2 is as defined herein.

[0089] In certain embodiments, the compound of formula IIa

[0090] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and Y 1 is as defined herein, and R 8 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0091] In certain embodiments, compounds of formula IIa are provided, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , and X 4 is as defined herein, and Y 1 is CR 5 and R 5 is as defined herein, and R 8 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0092] In certain embodiments, the compound of formula IIb

[0093] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , and Y 1 is as defined herein, and R 10 is hydrogen, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0094] In certain embodiments, compounds of formula IIb are provided, wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , and X 4 is as defined herein, and Y 1 is CR 5 and R 5 is heterocyclyloxy, or C 2~6 Alkynyl, Aryl, C 1~6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1~6 Alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0095] In certain embodiments, the compound of formula IIIa

[0096] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R2 , R 3 , and Y 1 is as defined herein, and R 8 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0097] In certain embodiments, the compound of formula IIIb

[0098] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , and Y 1 is as defined herein, and R 8 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6 It is haloalkoxy.

[0099] In certain embodiments, the compound of formula IIIc

[0100] [ka] or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , and Y 1 is as defined herein, and R 8 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy or C 1~6It is haloalkoxy.

[0101] In certain embodiments, R 11 is halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, heteroaryl, heterocyclyl, heterocyclyl-C 1~6 Alkyl, -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2, -C 1~6 Alkylene-NHR 14 , -C 1~6 Alkylene-N(R 14 )2, and -C(O)OR 15 and wherein each R 14 is independent, C 1~6 Alkyl, C 3~10 cycloalkyl, and heterocyclyl; each R 14 is optionally substituted with 1 to 3 halo; R 15 is C 1~6 It is an alkyl.

[0102] In certain embodiments, R 11 is C 1~6 Alkyl, R 16 Heterocyclyl-C optionally substituted by 1~6 Alkyl, and -NHR 14 and wherein each R 14 is independent, C 1~6 Alkyl and C 3~10 cycloalkyl.

[0103] In certain embodiments, R 11is optionally substituted with 1 to 4 groups independently selected from cyclopropylamino, methyl, (3-(2-((2-(3-(2-azidoethyl)-3H-diazirin-3-yl)ethyl)amino)-2-oxoethoxy)azetidin-1-yl)methyl, and methylamino.

[0104] In certain embodiments, R 11 teeth

[0105] [ka] and ring C is 1 to 4 R 13 is a 3- to 10-membered heterocyclyl containing 0, 1 or 2 additional ring nitrogen atoms optionally substituted by a group.

[0106] In certain embodiments, ring C is selected from 1 to 4 R 13 is a 5-10 membered bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted by a group.

[0107] In certain embodiments, ring C is selected from 1 to 4 R 13 is a 5-10 membered spiro bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted by a group.

[0108] In certain embodiments, ring C is selected from 1 to 4 R 13 is a 5-10 membered fused bicyclic heterocyclyl containing one additional ring nitrogen atom optionally substituted by a group.

[0109] In certain embodiments, R 11 teeth

[0110] [ka] TIFF2024540477000013.tif66158, each of which contains 1 to 4 R 13 is optionally substituted by a group.

[0111] In certain embodiments, R 11 teeth

[0112] [ka] each of which is selected from 1 to 4 R 13 is optionally substituted by a group.

[0113] In certain embodiments, R 3 is halo. In certain embodiments, R 3 is hydrogen.

[0114] In certain embodiments, each R 4 is hydrogen.

[0115] In certain embodiments, R 11 teeth

[0116] [ka] Each of these is 1 to 4 R 13 optionally substituted with R 5 is heterocyclyloxy, or C 2~6 Alkynyl, Aryl, C 1~6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1~6 It is an alkoxy.

[0117] In certain embodiments, R 5 is heterocyclyloxy, or C 2~6 Alkynyl, Aryl, C 1~6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1~6 It is an alkoxy.

[0118] In certain embodiments, R 5 is heterocyclyloxy.

[0119] In certain embodiments, R 5 is C 2~6 Alkynyl, Aryl, C 1~6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1~6 It is an alkoxy.

[0120] In certain embodiments, R 5 is hydrogen.

[0121] In certain embodiments, R 2 is hydrogen.

[0122] In certain embodiments, L 1 does not exist.

[0123] In certain embodiments, Y 1 is CR 5 In certain embodiments, Y 1 is N.

[0124] In certain embodiments, Y 2 is CR 6 It is.

[0125] In certain embodiments, Y 3 is CR 3 It is.

[0126] In certain embodiments, Ring B is a 5-membered heteroaryl containing 1-3 nitrogen atoms.

[0127] In certain embodiments, ring B is

[0128] [ka] and R 7 is hydrogen, and R 8 is C 1~6 In certain embodiments, ring B is alkyl.

[0129] [ka] and R 7 is hydrogen, and R 8 is C 1~3 It is an alkyl.

[0130] In certain embodiments, ring B is

[0131] [ka] and R 7 is hydrogen, and R 10 is C 1~6 In certain embodiments, ring B is alkyl.

[0132] [ka] and R 7 is hydrogen, and R 10 is C 1~3 It is an alkyl.

[0133] In certain embodiments, a pharmaceutical composition is provided comprising a compound described herein, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharma- ceutically acceptable excipient.

[0134] In certain embodiments, methods are provided for treating Huntington's disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0135] In certain embodiments, methods are provided for treating Huntington's disease in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein in combination with a second active agent.

[0136] Also provided is a compound selected from Table 1, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0137] [Table 1] TIFF2024540477000021.tif232145TIFF2024540477000022.tif174146

[0138] Also provided is a compound selected from Table 2, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0139] [Table 2] TIFF2024540477000024.tif223143TIFF2024540477000025.tif243143TIFF2024540477000026.tif213142 TIFF2024540477000027.tif234142TIFF2024540477000028.tif243142TIFF2024540477000029.tif135142

[0140] Also provided is a compound selected from Table 2A, or an isotopically enriched analog, pharma- ceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0141] [Table 3] TIFF2024540477000031.tif212164TIFF2024540477000032.tif239164TIFF2024540477000033.tif124164

[0142] Indications and treatment methods The compounds described herein may be useful for treating diseases or conditions that are at least partially mediated by proteins involved in neurodegenerative diseases. In some embodiments, the compounds described herein are useful for detecting diseases or conditions that are at least partially mediated by HTT proteins. In some embodiments, the treatment of diseases or conditions that are at least partially mediated by proteins involved in neurodegenerative diseases may include administering the compounds described herein. The treatment may include administering the compounds described herein and one or more other active agents and / or therapies at the same time.

[0143] In some embodiments, there is provided a method of treating or preventing a disease or condition mediated at least in part by a protein involved in a neurodegenerative disease in a patient in need of such treatment or prevention, comprising administering to the patient a therapeutically effective amount of a compound described herein.

[0144] Exemplary diseases or conditions are as follows:

[0145] 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 begins in the striatum and cortex and may extend to other subcortical brain regions. HD belongs to a family of neurodegenerative diseases in which expanded CAG repeat tracts result in long polyglutamine (polyQ) expansions in encoded proteins. This family also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar degeneration (SCA). In HD, selective neurodegeneration of gamma-aminobutyric acid releasing spinous neurons of the striatum has been observed, but neuronal 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.

[0146] The huntingtin protein (HTT protein) is a 348 kDa multidomain protein that contains a polymorphic glutamine / proline-rich domain at its amino terminus. 15 The number of CAG repeats in the gene varies from 6 to 35 in healthy individuals; 36 or more repeats define the HD allele. The length of the CAG expansion correlates inversely with the age of disease onset, with cases of early-onset characterized by an expansion 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, pp. 24-34, which is incorporated by reference in its entirety. It is believed that longer polyQ domains induce conformational changes in the HTT protein, leading to the formation of intracellular aggregates that appear as nuclear inclusions in many HTT proteins. 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 several organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0147] The diagnosis of Huntington's disease is based on a confirmed family history or positive genetic testing and the onset of motor disturbances 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 (>= 99% due to HD), with a score of 4 being defined as the onset of movement or "onset" of HD. However, subtle motor, cognitive and psychiatric deficits can be identified up to 10-15 years before the onset of disease manifestations, referred to as the presymptomatic stage of the disease.

[0148] Huntington's disease (HD) stages are described, for example, in Winder, JY et al., Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP, Mov Disord Clin Pract., September-October 2018; 5(5):527-533, which is incorporated by reference in its entirety. HD can be classified as early stage (stage 1 or 2 total function (TFC) score), intermediate 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), p. 1; Shoulson, I., Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs, Neurology, 1981, vol. 31(10), p. 1333-35. A new framework for staging HD (HD-ISS) based on biological, clinical, and functional assessments has recently been published (Tabrizi et al., Huntington's Disease Regulatory Science Consortium (HD-RSC), A biological classification of Huntington's disease: the Integrated Staging System. Lancet Neurol. 2022, vol. 21, p. 632-644). The part of the brain most affected by HD, and therefore most likely to contain abnormalities in the HTT protein, is a group of nerve cells at the base of the brain collectively known as the basal ganglia. The basal ganglia organize the body's muscle-driven movements, or "motor actions." The main components of the basal ganglia are the caudate nucleus and putamen (together known as the striatum) and the globus pallidus (external and internal regions).The substantia nigra and subthalamic nucleus are also often included as part of the basal ganglia.

[0149] The basal ganglia are a group of subcortical nuclei that are primarily involved in motor control, as well as other roles such as motor learning, executive function and behavior, and emotion. Disruption of the basal ganglia network is 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 motor facilitation or inhibition at any given moment. This is mediated by the complex organization of the striatum, where intermediate spiny neuronal excitability is controlled by several pre- and post-synaptic mechanisms as well as interneuron activity, and is anchored by several recurrent or internal basal ganglia circuits. The motor circuit of the basal ganglia has two entry points, the striatum and subthalamic nucleus, and an output, the internal pallidal segment, which connects to the cortex via the motor thalamus.

[0150] The compounds described herein can inhibit neuronal degeneration when administered to a subject. In some embodiments, inhibiting neuronal degeneration can include inhibiting axon or neuronal degeneration in a neuron. Such inhibition can be with respect to the entire neuron or a portion thereof, such as the neuronal cell body, axon and dendrite. This can be assessed, for example, by analyzing the function of the nervous system according to methods known in the art.

[0151] Administration of a compound described herein may result in relief, e.g., at least a 10% (e.g., at least a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 100%) reduction in one or more symptoms of a disease or condition described herein. The disease or condition may be nervous system damage secondary to a disease, condition, or therapy that has a primary effect outside of the nervous system; nervous system damage caused by physical, mechanical, or chemical trauma; autoimmune neurodegeneration; neurodegeneration secondary to an infection; and / or ocular neurodegeneration. Symptoms of neurodegeneration include, for example, tremors, slowness of movement, ataxia, loss of balance, depression, decreased cognitive function, short-term memory loss, long-term memory loss, confusion, personality changes, language problems, loss of sensory perception, contact sensitivity, numbness in the hands and feet, muscle weakness, muscle paralysis, muscle spasms, muscle cramps, significant changes in eating habits, excessive anxiety or worry, insomnia, delusions, hallucinations, fatigue, back pain, chest pain, digestive problems, headache, rapid heart rate, dizziness, blurred vision, shadows or areas of vision loss, metamorphopsia, impaired color vision, decreased recovery of visual function after exposure to bright light, and loss of visual contrast sensitivity.

[0152] Administration of a compound described herein can result in at least a 10% (e.g., at least a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) reduction in the number of neurons (or their neuronal bodies, axons, or dendrites) that degenerate in a neuronal population or subject compared to the number of neurons (or their neuronal bodies, axons, or dendrites) that degenerate in a neuronal population or subject to which one or more compounds described herein have not been administered.

[0153] Neurons can convey information from tissues and organs to the central nervous system (afferent or sensory neurons) and transmit signals from the central nervous system to effector cells (efferent or motor neurons). Other neurons, designated interneurons, connect neurons within the central nervous system (brain and spinal column). Certain specific examples of types of neurons that can be subject to treatment according to the present disclosure include cerebellar granule neurons, dorsal root ganglion neurons, PNS neurons (e.g., sensory neurons), and cortical neurons. Other examples of cell types that can be subject to treatment according to the present disclosure include astrocytes and microglia.

[0154] A neurodegenerative disease is a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases include, for example, Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spillmeyer-Voigt-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, Chlamydia trachomatis, and Chlamydia trachomatis. -Lew, dementia with Lewy bodies, Machado-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration, spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance, or tabes dorsalis.

[0155] In some embodiments, the disease or condition is selected from Huntington's disease (HD), dentatorubral-pallidoluysian atrophy, spinal and bulbar muscular atrophy, spinocerebellar degeneration, 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 lesions, liver fibrosis, lupus, post-transplant liver failure, encephalomyelitis, epilepsy, and glioblastoma.

[0156] Additionally, the compounds described herein can be used to prevent or treat memory loss. Types of memory that may be affected by loss and thus treatable by the present disclosure include episodic memory, semantic memory, short-term memory, and long-term memory.

[0157] 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 degeneration. In some embodiments, the neurodegenerative 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.

[0158] In some embodiments, the neurodegenerative disease is Huntington's disease.

[0159] Also provided is the use of a compound described herein for the manufacture of a medicament for use in the diagnosis, prevention, or treatment of a disease or condition described herein. For example, the disease or condition can be Huntington's disease.

[0160] Pharmaceutical Compositions and Their Administration The compounds provided herein can be administered in the form of a pharmaceutical composition. Thus, also provided herein are pharmaceutical compositions containing the compounds described herein and a pharma- ceutical acceptable excipient.

[0161] Suitable pharma- ceutically acceptable excipients can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants.Such compositions are prepared in a manner well known in the pharmaceutical field.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Edition (edited by GS Banker & CT Rhodes).

[0162] The pharmaceutical compositions may be formulated for administration by a variety of methods, including, for example, oral, rectal, buccal, nasal, and transdermal routes, hi certain embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0163] Pharmaceutical compositions may be formulated for administration by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions with sesame oil, corn oil, cottonseed oil, or peanut oil, or emulsions, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical excipients.

[0164] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally 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 solvents or suspending media. For this purpose, any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, may be useful in the preparation of injectables. Such solutions may be formulated as 0.01% to 10% isotonic solutions, pH 5 to 7, with appropriate salts.

[0165] The compounds described herein may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection or infusion techniques. Depending on the vehicle and concentration used, the compounds described herein can be suspended or dissolved in the vehicle. Advantageously, adjuvants, such as local anesthetics, preservatives and buffering agents, can be dissolved in the vehicle. In most 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 selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.

[0166] The pharmaceutical composition, e.g., a pharmaceutical composition for injection, may include a cyclodextrin. The cyclodextrin may be, for example, hydroxypropyl cyclodextrin or sulfobutylether cyclodextrin. The cyclodextrin may be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0167] The compounds described herein may also be administered via microspheres, liposomes, other microparticulate delivery systems, or sustained release formulations that are placed in certain tissues, including blood.Suitable examples of sustained release carriers include semipermeable polymer matrices in the form of co-medicinal products, such as suppositories or microcapsules.Examples can be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition, Gennaro, AR, Lippincott Williams & Wilkins; 20th Edition (December 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, NC et al., 7th Edition, ISBN 0-683305-72-7, the entire disclosures of which are incorporated herein by reference.

[0168] The pharmaceutical composition may be formulated for oral administration. The pharmaceutical composition may be in the form of, for example, a capsule or tablet. The oral formulation may include an enteric coating. When preparing the pharmaceutical composition, the compound described herein is usually diluted with an excipient and / or enclosed in a carrier, which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may 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 composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and packaged sterile powders.

[0169] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Pharmaceutical compositions can further include lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents.

[0170] The pharmaceutical composition may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by utilizing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein utilizes transdermal delivery devices ("patches"). Such transdermal patches can 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 can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

[0171] To prepare solid compositions, such as tablets, the compounds described herein can be mixed with pharmaceutical excipients to form solid preformulation compositions containing a homogenous mixture. These preformulation compositions are referred to as homogenous because the compound is evenly dispersed throughout the composition, thereby allowing the composition to be readily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0172] The tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach.For example, the tablets or pills can contain an inner and an outer component, the latter being in the form of an envelope over the former.The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to reach the intestine intact or to be delayed in release.Various materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0173] The compounds described herein can be incorporated into oral liquid preparations, such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. In addition, pharmaceutical compositions containing the compounds 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 non-aqueous vehicles that can include suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar, syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats), emulsifiers (e.g., lecithin, sorbitan monooleate, or acacia), 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).

[0174] Compositions for inhalation or insufflation may include solutions and suspensions in pharma- ceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic action. In other embodiments, compositions in pharma- ceutically acceptable solvents may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner.

[0175] The compounds described herein, or pharmaceutical compositions thereof, may be administered at appropriate doses, as determined by an informed physician. The compounds or pharmaceutical compositions may be administered in single or multiple doses, and may be administered in single or multiple dosage forms (e.g., two tablets or three capsules). For any particular subject, the appropriate dose will depend on a variety of factors, including the activity of the particular compound utilized, the subject's age, 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. For example, doses may be expressed as milligrams of the compounds described herein per kilogram (mg / kg) of the subject's body weight per day. Doses of about 0.1 to about 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 to about 100 mg / kg may be appropriate. In some embodiments, a dose of about 0.0001 to about 100 mg of compound per kg of body weight, about 0.001 to about 50 mg of compound per kg of body weight, or about 0.01 to about 10 mg of compound per kg of body weight per day may be appropriate. In some embodiments, the dose may be administered multiple times per day, for example, one dose per day, two doses per day, or three doses per day. In some embodiments, the dose may be administered every other day, every third day, every fourth day, or once a week. Normalizing according to the subject's body weight is particularly useful when adjusting doses between subjects of widely differing sizes, such as occurs when a drug is used in both children and adult humans, or when converting a dose effective in a non-human subject, such as a dog, to a dose suitable for a human subject.

[0176] kit Also provided herein is a kit comprising the compound described herein and suitable packaging.In certain embodiments, the kit further comprises instructions for use.In one aspect, the kit comprises the compound described herein and a label and / or instructions for use of the compound in treating a disease or condition described herein.

[0177] Also provided herein is an article of manufacture comprising a compound described herein in a suitable container, which may be a vial, bottle, ampoule, pre-filled syringe, and / or intravenous bag.

[0178] Combination therapy In some embodiments, the compounds described herein are administered in combination with one or more additional active agents.

[0179] The methods described herein include methods for detecting, treating or preventing a disease or condition described herein, such as 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, the compounds described herein can be administered before, concurrently with, or after administration of the additional active agents. Administration can be by the same route or by different routes.

[0180] Also provided are pharmaceutical compositions comprising a compound described herein and one or more additional 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, packaged pharmaceutical compositions containing a pharmaceutical composition comprising a compound described herein and another composition comprising one or more additional 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, are also provided. 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.

[0181] 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, either 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.

[0182] In some embodiments, the compounds described herein can be administered with active agents for treating Parkinson's disease, such as 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, the compounds described herein can be administered with active agents for treating Alzheimer's disease, such as acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and / or NMDA receptor antagonists (e.g., memantine).

[0183] Compound synthesis The compounds described herein can be prepared using the methods disclosed herein and certain variations thereof, which are clear in light of the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods can be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0184] The compounds described herein can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, it will be recognized that other process conditions can also be used, unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, although such conditions can be determined by one skilled in the art by routine optimization procedures.

[0185] Furthermore, 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 and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and references cited therein.

[0186] Additionally, the compounds described herein may contain one or more asymmetric ("chiral") centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using 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 can be utilized as conventionally used in the art or as described in the Examples.

[0187] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious variations thereof. For example, many of the starting materials are available from commercial sources, such as Sigma Aldrich, Alfa Aesar, etc. Others can be prepared by procedures or obvious variations 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 supplements (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).

[0188] The terms "solvent", "inert organic solvent" and "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described therein (e.g., including 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 a reaction to form the desired target compound through a reaction to form a carbon-carbon bond. 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.

[0189] The term "quantity (qs)" means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0190] It is also recognized that in each of the following schemes, the addition of any substituents may result in the production of several 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.

[0191] Isotopic labeling, e.g., incorporation of deuterium atoms into the compounds described herein, can be accomplished by reacting the appropriate starting material(s) with a reagent that contains a radioisotope. The methods generally follow the same principles as standard organic chemistry reactions and can be accomplished by any method known to those of skill in the art, including those provided in this disclosure.

[0192] Scheme 1 provides an exemplary synthetic route for the synthesis of compounds provided herein (e.g., compounds of formula I). ​​Compounds of formula I, or other formulas or compounds disclosed herein, are generally prepared by first preparing compounds of formulas Va and Vb, and then attaching the desired substituents using appropriate conditions (e.g., amide bond formation, nucleophilic aromatic substitution, or cross-coupling).

[0193] In some embodiments, the synthesis of a compound of formula I proceeds according to Scheme 1. The synthesis of a compound of formula I can proceed by coupling compound Va with compound Vb to form compound Vc, coupling compound Vc with compound Vd, and one or more subsequent steps to prepare a compound of formula I.

[0194] [ka]

[0195] In Scheme 1, R 1 , R2 , R 3 , X 1 , X 2 , X 3 , X 4 , Y 1 , and Y 2 is as defined herein. 1 , A 2 , and A 3 is defined as follows, and Z 3 -Z 4 -Z 5 is N-CR 7 =CR 8 or C=CR 7 -NR 10 It is.

[0196] In Scheme 1, compound Va is 1 and the amine of compound Vb by formation of an amide bond (as shown in Scheme 1). 1 may be a suitable leaving group, such as a halide, pseudohalide, carboxylic acid or carboxylate. Compound Va may be 1 In the above, the carboxyl group can be activated by an activating agent (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 1 In the above embodiment, the carboxylate may first be activated with 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 an embodiment, the activated form of compound Va (e.g., A 1 When is a halide, e.g., chloride, it is not necessary to isolate it and the reaction can be carried out in one pot.

[0197] In scheme 1, compounds of formula I can be prepared. Thus, compound Vc can be prepared by a coupling reaction, e.g., by addition of a nucleophile, e.g., A 2 In such an embodiment, A can be linked to compound Vd in a coupling reaction by nucleophilic aromatic substitution to compound Vc. 2 may be a suitable leaving group (e.g., a halide, such as chloride or fluoride, or a pseudohalide, such as sulfonyl), A 3 may be a hydrogen atom, or R 1 When present as an anion, it may also be a cation (e.g., sodium ion, potassium ion). Nucleophilic aromatic substitution may be carried out by heating (e.g., to a temperature of 50-200° 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 linked to compound Vd in a coupling reaction (e.g., a metal-catalyzed coupling reaction). In such an embodiment, for example, A 2 may be a leaving group (e.g., a halide, such as chloride or bromide, or a pseudohalide, such as sulfonyl), and R 1 may contain a suitable coupling functional group (e.g., a carbon-carbon double bond), and A 3 A 2 (e.g., a hydrogen atom or a tin- or boron-containing group). The reaction may be carried out using a catalyst (e.g., bis(triphenylphosphine)palladium(II) dichloride) and optionally in the presence of a base (e.g., sodium carbonate).

[0198] In some embodiments, A 2 is R 1 and compound Vc can also be converted directly to a compound of formula I (without reaction with compound Vd).

[0199] In compounds Va, Vb, Vc, and / or Vd, R 1 , R 2 , R3 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Z 4 , and Z 5 Any of the above 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, for example, tert-butoxycarbonyl group. In such embodiments, an additional step of deprotection may be required. For example, when the protecting group is a tert-butoxycarbonyl group, an acidic deprotection step (for example, using HCl in dioxane or TFA) may be required to prepare a compound of formula I.

[0200] Those skilled in the art will recognize that any of compounds Va, Vb, Vc, or Vd may be available from commercial sources for certain embodiments. Alternative syntheses of compounds Va, Vb, Vc, or Vd may be as described herein or known to those skilled in the art. EXAMPLES

[0201] The following examples are included to illustrate specific embodiments of the present disclosure. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure and therefore may be considered to constitute specific modes for its practice. However, those skilled in the art will appreciate in light of the present disclosure that many changes can be made in the specific embodiments disclosed and still obtain similar or similar results without departing from the spirit and scope of the present disclosure.

[0202] Analysis method Acidic QC method AcHSSC18 - Standard Acid UPLC-MS

[0203] [Table 4]

[0204] 10cm_Formic Acid_AQ - Standard Acid UPLC-MS

[0205] [Table 5]

[0206] Acidic 1 - Standard Acidic UPLC-MS

[0207] [Table 6]

[0208] Basic QC method BicarbBEHC18 - Standard Basic UPLC-MS

[0209] [Table 7]

[0210] 10cm_Bicarb_AQ - Standard basic UPLC-MS

[0211] [Table 8]

[0212] General Procedure Compounds were named using Chemdraw 18.1 structure naming tool. All reactions involving air or moisture sensitive reagents were performed under a nitrogen atmosphere using dry solvents and glassware.

[0213] Example 1: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-yl)pyrazine-2-carboxamide

[0214] [ka]

[0215] To a solution of 2-methyl-5-nitro-indazol-6-ol (500 mg, 2.59 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (1018 mg, 3.88 mmol) and oxazol-4-ylmethanol (256 mg, 2.59 mmol). The mixture was cooled to 0° C., diisopropyl azodicarboxylate (0.76 mL, 3.88 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h.

[0216] LCMS evidence showed the reaction was about 60% complete. Additional triphenylphosphine (339 mg, 1.29 mmol) was added at room temperature followed by diisopropyl azodicarboxylate (0.25 mL, 1.29 mmol) and the reaction was stirred at room temperature for an additional 3 hours.

[0217] LCMS evidence showed the reaction was complete. The reaction mixture was concentrated onto silica and purified by silica chromatography (40 g, eluting with EtOAc / cyclohexane 0-100%) to give 5-(((2-methyl-5-nitro-2H-indazol-6-yl)oxy)methyl)oxazole.

[0218] To a solution of 5-(((2-methyl-5-nitro-2H-indazol-6-yl)oxy)methyl)oxazole (300 mg, 1.09 mmol) in ethyl acetate (10 mL) and dichloromethane (10 mL) at room temperature was added tin(II) chloride dihydrate (987 mg, 4.38 mmol) and the reaction mixture was stirred at room temperature for 18 hours.

[0219] LCMS showed the mixture was mainly starting material. A large amount of insoluble material was observed. MeOH (3 mL) was added to aid in solubility. Additional tin(II) chloride dihydrate (987 mg, 4.38 mmol) was added and the reaction mixture was stirred at room temperature for 18 h.

[0220] LCMS showed the reaction was complete. The reaction was filtered through Celite and the Celite was washed with DCM / MeOH (3:1). The solvent was removed in vacuo to give the crude material which was purified by silica chromatography (25 g, eluting with EtOAc / MeOH 0-10%) to give 2-methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-amine, contaminated with Ph3PO and approximately 75% pure by LCMS. The crude material was used in the next step without further purification.

[0221] 2-Methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-amine (50 mg, 0.205 mmol) and 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (76 mg, 0.218 mmol) were dissolved in acetonitrile (2 mL). 1-Methylimidazole (0.049 mL, 0.614 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (86 mg, 0.307 mmol). The reaction was stirred at room temperature for 18 hours. The solid was collected by filtration to give tert-butyl (R)-cyclopropyl(1-(5-((2-methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate.

[0222] tert-Butyl (R)-cyclopropyl(1-(5-((2-methyl-6-(oxazol-5-ylmethoxy)-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (32 mg, 0.0557 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.0 mL, 13.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residual oil was dried overnight in a vacuum oven. The residue was free based by passing through an SCX column (1 g, eluted with MeOH, then 10% 7M NH3 / MeOH in MeOH). The ammonia fractions were combined and the solvent removed in vacuo to give the title compound. LCMS (ES+) 475.2 (M+H)+, RT 2.48 min (analytical method AcHSSC18); 1 H NMR (400 MHz, DMSO-d6) d 10.06 (s, 1H), 8.73 (d, J=1.3 Hz, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.94 (d, J=1.3 Hz, 1H), 7.31 (s, 1H), 5.25 (s, 2H), 4.09 (s, 3H), 3.73 - 3.60 (m, 2H), 3.59 - 3.48 (m, 2H), 3.44 - 3.39 (m, 1H), 2.18 - 2.11 (m, 2H), 1.98 - 1.90 (m, 1H), 0.42 (m, 2H), 0.29 - 0.23 (m, 2H).

[0223] Example 2: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-2H-indazol-5-yl)pyrazine-2-carboxamide

[0224] [ka]

[0225] To a solution of 2-methyl-5-nitro-indazol-6-ol (300 mg, 1.55 mmol) in tetrahydrofuran (20 mL) was added triphenylphosphine (611 mg, 2.33 mmol) and tetrahydro-4-pyranol (0.15 mL, 1.55 mmol) and the resulting mixture was stirred at 0° C. Diisopropyl azodicarboxylate (0.46 mL, 2.33 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by silica chromatography (25 g, eluting with EtOAc / cyclohexane 0-100%) to give 2-methyl-5-nitro-6-((tetrahydro-2H-pyran-4-yl)oxy)-2H-indazole.

[0226] 2-Methyl-5-nitro-6-tetrahydropyran-4-yloxy-indazole (192 mg, 0.692 mmol) and tin(II) chloride dihydrate (625 mg, 2.77 mmol) were suspended in ethyl acetate (10 mL), dichloromethane (10 mL) and acetic acid (1 mL). The mixture was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give a residue which was dissolved in MeOH and loaded onto an SCX column (10 g, eluted with MeOH, then 10% 7M NH3 in MeOH / MeOH). The ammonia fractions were combined and the solvent was removed in vacuo to give 2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-2H-indazol-5-amine.

[0227] 2-Methyl-6-tetrahydropyran-4-yloxy-indazol-5-amine (100 mg, 0.404 mmol) was dissolved in acetonitrile (5 mL) and 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (150 mg, 0.431 mmol) and 1-methylimidazole (0.097 mL, 1.21 mmol) were added. Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (170 mg, 0.607 mmol, 1.50 eq) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give tert-butyl (R)-cyclopropyl(1-(5-((2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate.

[0228] tert-Butyl (R)-cyclopropyl(1-(5-((2-methyl-6-((tetrahydro-2H-pyran-4-yl)oxy)-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (63 mg, 0.109 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.0 mL, 13.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo to give a residual oil which was dried in a vacuum oven overnight. The residue was free based by passing through an SCX column (1 g, eluted with MeOH, then 7M NH3 / MeOH in 10% MeOH). The ammonia fractions were combined and the solvent removed in vacuo to give the title compound. LCMS (ES+) 478.2 (M+H)+, RT 2.67 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO-d6) d 10.26 (s, 1H), 8.74 (d, J=1.3 Hz, 1H), 8.66 (s, 1H), 8.21 (s, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.21 (s, 1H), 4.90 - 4.83 (m, 1H), 4.08 (s, 3H), 3.96 - 3.88 (m, 2H), 3.71 - 3.49 (m, 6H), 3.44 - 3.41 (m, 1H), 2.13 - 2.04 (m, 4H), 1.96 - 1.90 (m, 1H), 1.75 (m, 2H), 0.41 (m, 2H), 0.27 - 0.21 (m, 2H) NH was not observed.

[0229] Example 3: (R)-N-(6-(but-2-yn-1-yloxy)-2-methyl-2H-indazol-5-yl)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0230] [ka]

[0231] 2-Methyl-5-nitro-indazol-6-ol (200 mg, 1.04 mmol) was dissolved in tetrahydrofuran (20 mL) and triphenylphosphine (543 mg, 2.07 mmol) and 2-butyn-1-ol (0.085 mL, 1.14 mmol) were added. The mixture was cooled to 0° C. and diisopropyl azodicarboxylate (0.41 mL, 2.07 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by silica chromatography (25 g, eluting with EtOAc / cyclohexane 0-100%) to give 6-(but-2-yn-1-yloxy)-2-methyl-5-nitro-2H-indazole. The material contained triphenylphosphine oxide impurity and was 60% pure by LCMS. It was used in the next step without further purification.

[0232] 6-(but-2-yn-1-yloxy)-2-methyl-5-nitro-2H-indazole (490 mg, 1.20 mmol) was dissolved in ethyl acetate (10 mL) and dichloromethane (10 mL) and tin(II) chloride dihydrate (1082 mg, 4.80 mmol) was added at room temperature. The reaction was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give a residue which was dissolved in MeOH and loaded onto an SCX column (10 g, eluted with MeOH, then 10% 7M NH3 in MeOH / MeOH). The ammonia fractions were combined and the solvent removed in vacuo to give 6-(but-2-yn-1-yloxy)-2-methyl-2H-indazol-5-amine.

[0233] 6-(but-2-yn-1-yloxy)-2-methyl-2H-indazol-5-amine (168 mg, 0.780 mmol) was dissolved in acetonitrile (5 mL) and 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (272 mg, 0.780 mmol) and 1-methylimidazole (0.19 mL, 2.34 mmol) were added. Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (328 mg, 1.17 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give a residue which was purified by preparative HPLC to give tert-butyl (R)-(1-(5-((6-(but-2-yn-1-yloxy)-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(cyclopropyl)carbamate.

[0234] tert-Butyl (R)-(1-(5-((6-(but-2-yn-1-yloxy)-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(cyclopropyl)carbamate (97 mg, 0.179 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo to give a residual oil which was dried overnight in a vacuum oven. The residue was free based by passing through an SCX column (1 g, eluted with MeOH, then 10% 7M NH3 / MeOH in MeOH). The ammonia fractions were combined and the solvent removed in vacuo to give the title compound. LCMS (ES+) 446.2 (M+H)+, RT 4.09 min (analytical method BicarbBEHC18); 1 H NMR (400 MHz, DMSO-d6) d 9.99 (s, 1H), 8.74 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.22 (s, 1H), 8.01 (d, J=1.5 Hz, 1H), 7.18 (s, 1H), 5.00 - 4.97 (m, 2H), 4.09 (s, 3H), 3.72 - 3.50 (m, 4H), 3.45 - 3.40 (m, 1H), 2.15 - 2.10 (m, 2H), 1.98 - 1.89 (m, 1H), 1.87 - 1.85 (m, 3H), 0.43 - 0.39 (m, 2H), 0.28 - 0.22 (m, 2H) NH was not observed.

[0235] Example 4: (R)-N-(2-methyl-6-(prop-2-yn-1-yloxy)-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0236] [ka]

[0237] 5-Nitro-2H-indazol-6-ol (500 mg, 2.79 mmol, 1.00 eq), triphenylphosphine (1098 mg, 4.19 mmol, 1.50 eq), propargyl alcohol (0.16 mL, 2.79 mmol, 1.00 eq) in tetrahydrofuran (20 mL) were stirred at 0° C. Diisopropyl azodicarboxylate (0.82 mL, 4.19 mmol, 1.50 eq) was added dropwise and the reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic phase was dried on a hydrophobic frit and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated under reduced pressure to give 5-nitro-6-prop-2-ynoxy-1H-indazole. LCMS: ES+ 218.3. 1 H NMR (400 MHz, DMSO-d6) 13.49 (1H, s), 8.51 (1H, s), 8.27 (1H, s), 7.39 (1H, s), 5.11 (2H, d, J=2.4 Hz), 3.76 (1H, t, J=2.4 Hz).

[0238] 5-Nitro-6-prop-2-ynoxy-1H-indazole (480 mg, 2.21 mmol, 1.00 eq) in ethyl acetate (10.00 mL) was stirred at 0° C. Trimethyloxonium tetrafluoroborate (327 mg, 2.21 mmol, 1.00 eq) was added in portions and the reaction mixture was allowed to warm to room temperature with stirring overnight. Water was added and the organic phase was separated. The organic phase was dried on a hydrophobic frit and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated under reduced pressure to give 2-methyl-5-nitro-6-prop-2-ynoxy-indazole, which was used crude in the next step.

[0239] 2-Methyl-5-nitro-6-prop-2-ynoxy-indazole (460 mg, 1.99 mmol, 1.00 eq), tin(II) chloride dihydrate (1796 mg, 7.96 mmol, 4.00 eq) in ethyl acetate (10 mL) and dichloromethane (10 mL) was stirred at room temperature overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 2-methyl-6-prop-2-ynoxy-indazol-5-amine. LCMS: ES+ 202.2. 1 H NMR (400 MHz, DMSO-d6) 7.86 (1H, s), 6.98 (1H, s), 6.71 (1H, s), 4.90 (2H, d, J=2.7 Hz), 4.63 (2H, s), 4.05 (3H, s), 3.65 (1H, t, J=2.7 Hz).

[0240] A mixture of 2-methyl-6-prop-2-ynoxy-indazol-5-amine (50 mg, 0.248 mmol, 1.00 eq), 5-[(3R)-3-[tert-butoxycarbonyl(methyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (80 mg, 0.248 mmol, 1.00 eq), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (105 mg, 0.373 mmol, 1.50 eq), 1-methylimidazole (0.059 mL, 0.745 mmol, 3.00 eq) in acetonitrile (2 mL) was stirred at room temperature overnight. Ethyl acetate and water were added and the organic phase separated, dried through a hydrophobic frit and concentrated under reduced pressure to give tert-butyl N-methyl-N-[(3R)-1-[5-[(2-methyl-6-prop-2-ynoxy-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate. LCMS: ES+ 506.5.

[0241] tert-Butyl N-methyl-N-[(3R)-1-[5-[(2-methyl-6-prop-2-ynoxy-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (80 mg, 0.158 mmol, 1.00 eq), trifluoroacetic acid (0.12 mL, 1.58 mmol, 10.0 eq) were combined in dichloromethane (2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC. This gave (R)-N-(2-methyl-6-(prop-2-yn-1-yloxy)-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 406.2 (M+H)+, RT 2.74 min (Analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 10.02 (1H, s), 8.76 (1H, d, J=1.4 Hz), 8.71 (1H, s), 8.26 (1H, s), 8.04 (1H, d, J=1.4 Hz), 7.23 (1H, s), 5.08 - 5.03 (2H, m), 4.12 - 4.10 (3H, m), 3.71 - 3.56 (5H, m), 3.48 - 3.40 (2H, m), 2.35 (3H, s), 2.19 - 2.10 (1H, m), 1.93 (1H, d, J=5.6 Hz).

[0242] Example 5: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-(prop-2-yn-1-yloxy)-2H-indazol-5-yl)pyrazine-2-carboxamide

[0243] [ka]

[0244] 2-Methyl-6-prop-2-ynoxy-indazol-5-amine (50 mg, 0.248 mmol, 1.00 eq) and 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (75 mg, 0.215 mmol, 0.866 eq) were dissolved in acetonitrile (2 mL) at room temperature. Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (108 mg, 0.385 mmol, 1.55 eq) and 1-methylimidazole (0.060 mL, 0.753 mmol, 3.03 eq) were added and the reaction mixture was stirred for 24 hours. The resulting precipitate was collected by filtration to give tert-butyl N-cyclopropyl-N-[(3R)-1-[5-[(2-methyl-6-prop-2-ynoxy-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate. LCMS (ES+) 532(M+H)+.

[0245] tert-Butyl N-cyclopropyl-N-[(3R)-1-[5-[(2-methyl-6-prop-2-ynoxy-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (132 mg, 0.249 mmol, 1.00 eq) was suspended in dichloromethane (5 mL). Trifluoroacetic acid (1.5 mL, 19.6 mmol, 78.8 eq) was added and the mixture was stirred at room temperature for 80 min. The reaction mixture was quenched with methanol and concentrated under reduced pressure. The residue was purified by preparative HPLC followed by achiral SFC to give the title compound. LCMS (ES+) 432.2 (M+H)+, RT 2.66 min (analytical method AcHSSC18) 1H NMR (400 MHz, DMSO-d6) d 10.03 (s, 1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.25 (s, 1H), 5.08 (d, J=2.4 Hz, 2H), 4.13 (s, 3H), 3.76 - 3.51 (m, 6H), 3.44 - 3.38 (m, 1H), 2.16 - 2.06 (m, 2H), 1.94 (s, 1H), 0.43 - 0.39 (m, 2H), 0.28 - 0.19 (m, 2H).

[0246] Example 6: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)-2H-indazol-5-yl)pyrazine-2-carboxamide

[0247] [ka]

[0248] 5-Nitro-1H-indazol-6-ol (2.00 g, 11.2 mmol, 1 eq), trimethyloxonium tetrafluoroborate (1.98 g, 13.4 mmol, 1.20 eq) and ethyl acetate (100 mL) were combined and stirred at room temperature for 4 days. The mixture was then diluted with EtOAc, washed with water, dried over magnesium sulfate and concentrated in vacuo to give 2-methyl-5-nitro-indazol-6-ol. 1 H NMR (400 MHz, DMSO-d6) 10.45 (1H, s), 8.54 (1H, s), 8.46 (1H, s), 7.02 (1H, s), 4.15 (3H, s).

[0249] 2-Methyl-5-nitro-indazol-6-ol (405 mg, 2.10 mmol, 1 eq), tert-butyldimethylsilyl chloride (348 mg, 2.31 mmol, 1.1 eq), sodium hydride (60%, 92 mg, 2.31 mmol, 1.1 eq) and tetrahydrofuran (10 mL) were combined and stirred at room temperature under nitrogen for 90 minutes. The mixture was then concentrated in vacuo onto silica and purified by flash chromatography to give tert-butyl-dimethyl-(2-methyl-5-nitro-indazol-6-yl)oxy-silane. 1 H NMR (400 MHz, CDCl3) 8.17 (1H, s), 8.01 (1H, s), 7.11 (1H, s), 4.21 (3H, s), 1.01 (9H, s), 0.29 (6H, s).

[0250] tert-Butyl-dimethyl-(2-methyl-5-nitro-indazol-6-yl)oxy-silane (510 mg, 1.66 mmol, 1 eq), ethyl acetate (50 mL) and 10% palladium on carbon were combined and stirred under a hydrogen atmosphere for 20 h. The catalyst was then removed by filtration through a plug of Celite and the mixture was concentrated in vacuo to give 6-[tert-butyl(dimethyl)silyl]oxy-2-methyl-indazol-5-amine. 1 H NMR (400 MHz, CDCl3) 7.55 (1H, s), 6.98 (1H, s), 6.76 (1H, s), 4.09 (3H, s), 3.83 - 3.74 (2H, m), 1.04 (9H, s), 0.31 (6H, s).

[0251] 6-[tert-Butyl(dimethyl)silyl]oxy-2-methyl-indazol-5-amine (200 mg, 0.721 mmol, 1 eq), 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (251 mg, 0.721 mmol, 1 eq), HBTU (273 mg, 0.721 mmol, 1 eq), N,N-dimethylformamide (4 mL) and triethylamine (0.50 mL, 3.59 mmol, 4.98 eq) were combined and stirred at room temperature for 90 minutes. The mixture was then concentrated in vacuo onto silica and purified by flash chromatography eluting with 0-100% EtOAc in cyclohexane then 10% MeOH in EtOAc to give tert-butyl N-cyclopropyl-N-[(3R)-1-[5-[(6-hydroxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate. 1 H NMR (400 MHz, DMSO-d6) 10.49 (1H, s), 10.13 (1H, s), 8.77 (1H, d, J=1.3 Hz), 8.64 (1H, s), 8.17 (1H, s), 8.09 (1H, s), 6.94 (1H, s), 4.40 (1H, dd, J=7.8, 7.8 Hz), 4.06 (3H, s), 3.87 - 3.80 (2H, m), 3.62 (1H, dd, J=8.3, 10.8 Hz), 3.54 - 3.46 (1H, m), 2.46 - 2.40 (2H, m), 2.29 - 2.23 (1H, m), 1.43 (9H, s), 0.79 - 0.74 (2H, m), 0.67 - 0.63 (2H, m).

[0252] tert-Butyl N-cyclopropyl-N-[(3R)-1-[5-[(6-hydroxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (120 mg, 0.243 mmol, 1 eq), potassium carbonate (40 mg, 0.292 mmol, 1.20 eq), acetone (20 mL) and 4-(bromomethyl)tetrahydropyran (44 mg, 0.243 mmol, 1 eq) were combined and heated in a hot block to 50° C. for 3 days. Potassium tert-butoxide (27 mg, 0.243 mmol, 1 eq) was then added and the mixture was stirred at 50° C. for a further 24 hours. The mixture was then cooled to room temperature, the potassium salts removed by filtration through a plug of Celite and the solution concentrated in vacuo. The residue was purified by preparative HPLC to give partially purified tert-butyl (R)-cyclopropyl(1-(5-((2-methyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate, which was used in the subsequent step without further purification.

[0253] tert-Butyl N-cyclopropyl-N-[(3R)-1-[5-[[2-methyl-6-(tetrahydropyran-4-ylmethoxy)indazol-5-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (27 mg, 0.0448 mmol, 1.00 eq), methyl alcohol (2 mL), and 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 179 eq) were combined and stirred at room temperature for 1 h. The mixture was then concentrated in vacuo and purified by preparative HPLC to give (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(2-methyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)-2H-indazol-5-yl)pyrazine-2-carboxamide as the formate salt. LCMS (ES+) 492.2 (M+H)+, RT 2.82 min (Analysis method AcHSSC18) 1H NMR (400 MHz, DMSO-d6) 10.29 (1H, s), 8.73 (1H, d, J=1.1 Hz), 8.60 (1H, s), 8.22 (1H, s), 8.20 (1H, s), 7.88 (1H, d, J=1.4 Hz), 7.08 (1H, s), 4.08 (3H, s), 4.06 - 3.95 (5H, m), 3.70 - 3.53 (6H, m), 2.16 - 2.09 (3H, m), 1.97 - 1.94 (1H, m), 1.82 - 1.78 (2H, m), 1.58 - 1.49 (2H, m), 0.42 - 0.39 (2H, m), 0.27 - 0.21 (2H, m).

[0254] Example 7: (R)-N-(6-(cyanomethoxy)-2-methyl-2H-indazol-5-yl)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0255] [ka]

[0256] tert-Butyl N-cyclopropyl-N-[(3R)-1-[5-[(6-hydroxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (100 mg, 0.203 mmol, 1 eq, synthesis described in Example 6), potassium carbonate (34 mg, 0.243 mmol, 1.20 eq), acetone (10 mL) and bromoacetonitrile (0.014 mL, 0.203 mmol, 1.00 eq) were combined in a sealed tube and heated to 50° C. in a hot block. The reaction mixture was cooled to room temperature. The potassium salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC and the intermediate was used directly in the next step.

[0257] tert-Butyl N-[(3R)-1-[5-[[6-(cyanomethoxy)-2-methyl-indazol-5-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-cyclopropyl-carbamate (23 mg, 0.0430 mmol, 1 eq), dichloromethane (2 mL) and trifluoroacetic acid (1 mL, 13.1 mmol, 304 eq) were combined and stirred at room temperature. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC followed by achiral SFC purification. LCMS (ES+) 433.2 (M+H)+, RT 3.66 min (analytical method BicarbBEHC18). 1 H NMR (400 MHz, DMSO-d6) 9.96 (1H, s), 8.80 (1H, d, J=1.3 Hz), 8.71 (1H, s), 8.31 (1H, s), 8.11 (1H, s), 7.37 (1H, s), 5.44 (2H, s), 4.13 (3H, s), 3.86 - 3.81 (2H, m), 3.76 - 3.60 (3H, m), 2.95 - 2.91 (1H, m), 2.36 - 2.17 (2H, m), 1.17 (2H, t, J=7.3 Hz), 0.67 - 0.59 (3H, m).

[0258] Example 8: (R)-N-(6-(benzyloxy)-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0259] [ka]

[0260] 5-Nitro-2H-indazol-6-ol (500 mg, 2.79 mmol, 1.00 eq), triphenylphosphine (1098 mg, 4.19 mmol, 1.50 eq) and benzyl alcohol (0.29 mL, 2.79 mmol, 1.00 eq) in tetrahydrofuran (20 mL) were stirred at 0° C. Diisopropyl azodicarboxylate (0.82 mL, 4.19 mmol, 1.50 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the product extracted into ethyl acetate. The organic phase was dried on a hydrophobic frit and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated under reduced pressure to give 6-benzyloxy-5-nitro-1H-indazole. LCMS: ES+ 268.1. 1 H NMR (400 MHz, CDCl3) 10.04 (1H, s), 8.33 (1H, s), 8.12 (0H, s), 7.52 - 7.34 (5H, m), 7.05 (1H, s), 5.28 (2H, s).

[0261] 6-Benzyloxy-5-nitro-1H-indazole (371 mg, 1.42 mmol, 1.00 eq) in ethyl acetate (10 mL) was stirred at 0° C. Trimethyloxonium tetrafluoroborate (209 mg, 1.42 mmol, 1.00 eq) was added in portions and the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. Water was added and the organic phase was separated. The organic phase was washed with brine, dried through a hydrophobic frit and concentrated under reduced pressure to give 6-benzyloxy-2-methyl-5-nitro-indazole. LCMS: ES+ 284.1. 1 H NMR (400 MHz, CDCl3) 8.22 (1H, s), 8.01 (1H, s), 7.51 - 7.47 (2H, m), 7.41 - 7.31 (3H, m), 7.15 (1H, s), 5.25 (2H, s), 4.20 (3H, s).

[0262] 6-Benzyloxy-2-methyl-5-nitro-indazole (390 mg, 1.38 mmol, 1.00 eq) and tin(II) chloride dihydrate (1243 mg, 5.51 mmol, 4.00 eq) in dichloromethane (10 mL) and ethyl acetate (10 mL) were stirred at room temperature overnight. The mixture was filtered through Celite and concentrated under reduced pressure to give 6-benzyloxy-2-methyl-indazol-5-amine, which was used crude in the next step.

[0263] 6-Benzyloxy-2-methyl-indazol-5-amine (50 mg, 0.197 mmol, 1.00 eq), 5-[(3R)-3-[tert-butoxycarbonyl(methyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylic acid (80 mg, 0.248 mmol, 1.00 eq), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (105 mg, 0.373 mmol, 1.50 eq), and 1-methylimidazole (0.059 mL, 0.745 mmol, 3.00 eq) in acetonitrile (2 mL) were stirred at room temperature overnight. Water and ethyl acetate were added and the organic phase was separated and dried on a hydrophobic frit. The organic phase was concentrated under reduced pressure to give tert-butyl N-[(3R)-1-[5-[(6-benzyloxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate, which was used crude in the next step.

[0264] tert-Butyl N-[(3R)-1-[5-[(6-benzyloxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (180 mg, 0.323 mmol, 1.00 eq) and trifluoroacetic acid (0.25 mL, 3.23 mmol, 10.0 eq) in dichloromethane (2 mL) were stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC followed by achiral SFC to give (R)-N-(6-(benzyloxy)-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 458.2 (M+H)+, RT 3.23 min (Analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 10.30 (1H, s), 8.76 (1H, d, J=1.4 Hz), 8.68 (1H, s), 8.24 (1H, s), 7.94 (1H, d, J=1.5 Hz), 7.63 - 7.61 (2H, m), 7.53 - 7.48 (2H, m), 7.41 - 7.37 (1H, m), 7.22 (1H, s), 5.36 (2H, s), 4.10 (3H, s), 3.71 - 3.57 (3H, m), 3.44 - 3.39 (1H, m), 3.31 - 3.28 (1H, m), 2.35 - 2.31 (3H, m), 2.16 - 2.10 (1H, m), 1.95 - 1.87 (2H, m).

[0265] Example 9: (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(6-(2-methoxyethoxy)-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0266] [ka]

[0267] 5-Nitro-2H-indazol-6-ol (500 mg, 2.79 mmol, 1.00 eq), 2-methoxyethanol (0.22 mL, 2.79 mmol, 1.00 eq), and ethylenebis(diphenylphosphine) (834 mg, 2.09 mmol, 0.750 eq) in tetrahydrofuran (20 mL) were stirred at 0° C. Diisopropyl azodicarboxylate (0.82 mL, 4.19 mmol, 1.50 eq) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic phase was dried on a hydrophobic frit and purified by flash chromatography on silica using a gradient of 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and concentrated under reduced pressure to give 6-(2-methoxyethoxy)-5-nitro-1H-indazole. 1 H NMR (400 MHz, DMSO-d6) 13.42 - 13.38 (1H, m), 8.46 (1H, s), 8.24 (1H, s), 7.29 (1H, s), 4.38 - 4.34 (2H, m), 3.78 - 3.75 (2H, m), 3.37 (3H, s).

[0268] 6-(2-Methoxyethoxy)-5-nitro-1H-indazole (380 mg, 1.44 mmol, 1.00 eq) in ethyl acetate (10.00 mL) was stirred at 0° C. Trimethyloxonium tetrafluoroborate (213 mg, 1.44 mmol, 1.00 eq) was added in portions and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic phase was dried on a hydrophobic frit and concentrated under reduced pressure to give 6-(2-methoxyethoxy)-2-methyl-5-nitro-indazole. 1 H NMR (400 MHz, DMSO-d6) 8.59 (1H, s), 8.45 - 8.44 (1H, m), 7.32 - 7.31 (1H, m), 4.32 - 4.29 (2H, m), 4.21 (3H, s), 3.76 - 3.73 (2H, m), 3.37 (3H, s).

[0269] 6-(2-Methoxyethoxy)-2-methyl-5-nitro-indazole (340 mg, 1.35 mmol, 1.00 eq) and tin(II) chloride dihydrate (1221 mg, 5.41 mmol, 4.00 eq) in ethyl acetate (5 mL) and dichloromethane (5 mL) were stirred at room temperature overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give 6-(2-methoxyethoxy)-2-methyl-indazol-5-amine. LCMS (ES+) 222 (M+H).

[0270] 6-(2-Methoxyethoxy)-2-methyl-indazol-5-amine (50 mg, 0.226 mmol, 1.00 eq), [5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carbonyl]oxylithium (80 mg, 0.226 mmol, 1.00 eq), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (95 mg, 0.339 mmol, 1.50 eq), and 1-methylimidazole (0.05 mL, 0.68 mmol, 3.0 eq) in acetonitrile (2 mL) were stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The organic phase was dried through a hydrophobic frit and concentrated under reduced pressure to give tert-butyl N-cyclopropyl-N-[(3R)-1-[5-[[6-(2-methoxyethoxy)-2-methyl-indazol-5-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate. LCMS (ES+) 552(M+H)+.

[0271] tert-Butyl N-cyclopropyl-N-[(3R)-1-[5-[[6-(2-methoxyethoxy)-2-methyl-indazol-5-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (95 mg, 0.17 mmol, 1.0 eq) in 1,4-dioxane (2 mL) and 4 M hydrogen chloride in 1,4-dioxane (0.43 mL, 1.72 mmol, 10.0 eq) were stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, dissolved in DMSO, and purified by preparative HPLC to give (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(6-(2-methoxyethoxy)-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide. LCMS (ES+) 452.5 (M+H)+, RT 2.51 min (Analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 10.15 (1H, s), 8.73 (1H, d, J=1.4 Hz), 8.67 - 8.66 (1H, m), 8.21 - 8.20 (1H, m), 7.96 (1H, d, J=1.3 Hz), 7.11 (1H, s), 4.31 - 4.27 (2H, m), 4.08 (3H, s), 3.83 - 3.79 (2H, m), 3.72 - 3.47 (4H, m), 3.40 - 3.39 (4H, m), 2.13 - 2.09 (2H, m), 1.96 - 1.89 (1H, m), 0.42 - 0.38 (2H, m), 0.27 - 0.20 (2H, m). One peak was not visible due to overlap with DMSO or H2O.

[0272] Example 10: N-(6-(benzyloxy)-2-methyl-2H-indazol-5-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide

[0273] [ka]

[0274] To a suspension of 6-methyl-2,6-diazaspiro[3.5]nonane; hydrochloride (500 mg, 2.83 mmol, 1.00 eq) and triethylamine (1.2 mL, 8.49 mmol, 3.00 eq) in 1,4-dioxane (10 mL) was added methyl 5-chloro-2-pyrazinecarboxylate (488 mg, 2.83 mmol, 1.00 eq). The reaction mixture was heated to 100° C. for 2 h. Sodium hydroxide (170 mg, 4.24 mmol, 1.50 eq) and water (10 mL) were added and the mixture was stirred at 50° C. for 4 h. The reaction was acidified with 1 M aqueous HCl and loaded onto an SCX cartridge. The cartridge was washed with methanol and the product was eluted with 7N ammonia in methanol. The solution was concentrated under reduced pressure to give 5-(8-methyl-2,8-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxylic acid. LCMS (ES-) 261(MH)-.

[0275] 6-Benzyloxy-2-methyl-indazol-5-amine (100 mg, 0.395 mmol, 1.00 eq), 5-(8-methyl-2,8-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxylic acid (104 mg, 0.395 mmol, 1.00 eq), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (166 mg, 0.592 mmol, 1.50 eq), and 1-methylimidazole (0.094 mL, 1.18 mmol, 3.00 eq) in acetonitrile (2 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated, dried on a hydrophobic frit and concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-(6-(benzyloxy)-2-methyl-2H-indazol-5-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide. LCMS (ES+) 498.2 (M+H)+, RT 3.18 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) 10.30 (1H, s), 8.73 (1H, d, J=1.3 Hz), 8.67 (1H, s), 8.25 - 8.24 (1H, m), 7.84 (1H, d, J=1.4 Hz), 7.63 - 7.60 (2H, m), 7.53 - 7.48 (2H, m), 7.41 - 7.37 (1H, m), 7.23 (1H, s), 5.36 (2H, s), 4.10 (3H, s), 3.93 - 3.85 (4H, m), 2.47 - 2.44 (2H, m), 2.22 - 2.20 (5H, m), 1.69 - 1.65 (2H, m), 1.57 - 1.51 (2H, m).

[0276] Example 11: N-(2-methyl-6-(prop-2-yn-1-yloxy)-2H-indazol-5-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide

[0277] [ka]

[0278] A solution of 2-methyl-6-prop-2-ynoxy-indazol-5-amine (100 mg, 0.497 mmol, 1 eq), 5-(8-methyl-2,8-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxylic acid (130 mg, 0.497 mmol, 1 eq), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (209 mg, 0.745 mmol, 1.5 eq) and 1-methylimidazole (0.12 mL, 1.49 mmol, 3 eq) in acetonitrile (2 mL) was stirred at room temperature overnight. Ethyl acetate and water were added. The organic phase was separated, dried on a hydrophobic frit and concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-(2-methyl-6-(prop-2-yn-1-yloxy)-2H-indazol-5-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide. LCMS (ES+) 446.2 (M+H)+, RT 2.7 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 10.00 (1H, s), 8.73 (1H, d, J=1.4 Hz), 8.70 (1H, s), 8.26 (1H, s), 7.92 (1H, d, J=1.4 Hz), 7.23 (1H, s), 5.06 (2H, d, J=2.4 Hz), 4.11 (3H, s), 3.91 - 3.83 (4H, m), 3.68 (1H, t, J=2.3 Hz), 2.50 - 2.39 (2H, m), 2.29 - 2.20 (5H, m), 1.65 - 1.65 (2H, m), 1.57 - 1.51 (2H, m).

[0279] Example 12: N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-5-(3-((isopropylamino)methyl)azetidin-1-yl)pyrazine-2-carboxamide

[0280] [ka]

[0281] tert-Butyl 3-formylazetidine-1-carboxylate (300 mg, 1.62 mmol) was dissolved in dichloromethane (15 mL) and isopropylamine (0.14 mL, 1.62 mmol) was added at room temperature. Sodium triacetoxyborohydride (755 mg, 3.56 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with saturated sodium bicarbonate and stirred for 20 minutes. The layers were separated using a phase separator and the aqueous layer was further extracted using DCM×3. The DCM was removed in vacuo to give tert-butyl 3-((isopropylamino)methyl)azetidine-1-carboxylate. The material was used in the next step without further purification.

[0282] tert-Butyl 3-((isopropylamino)methyl)azetidine-1-carboxylate (350 mg, 1.53 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.0 mL, 13.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 h and the solvent was removed in vacuo to give N-(azetidin-3-ylmethyl)propan-2-amine; bis-2,2,2-trifluoroacetic acid. The crude product was used in the next step without further purification.

[0283] Methyl 5-chloro-2-pyrazinecarboxylate (140 mg, 0.814 mmol) and N-(azetidin-3-ylmethyl)propan-2-amine;bis-2,2,2-trifluoroacetic acid (290 mg, 0.814 mmol) were dissolved in acetonitrile (10 mL) and triethylamine (0.45 mL, 3.26 mmol) was added. The reaction was heated to 45° C. for 18 h. The reaction was cooled to room temperature and the solvent was removed in vacuo to give a residue. The residue was dissolved in DCM and washed with saturated sodium bicarbonate. The DCM was separated using a phase separator and the DCM layer was concentrated in vacuo to give a residue. The residue was purified by silica chromatography (10 g, eluting with 0-100% EtOAc in cyclohexane) to give methyl 5-(3-((isopropylamino)methyl)azetidin-1-yl)pyrazine-2-carboxylate.

[0284] Methyl 5-[3-[(isopropylamino)methyl]azetidin-1-yl]pyrazine-2-carboxylate (215 mg, 0.814 mmol) was dissolved in dichloromethane (10 mL) and di-tert-butyl dicarbonate (0.21 mL, 0.895 mmol) and 4-(dimethylamino)pyridine (10 mg, 0.081 mmol) were added. The reaction was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was purified by silica chromatography (10 g, eluting with 0-100% EtOAc in cyclohexane) to give methyl 5-(3-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)azetidin-1-yl)pyrazine-2-carboxylate.

[0285] Methyl 5-[3-[[tert-butoxycarbonyl(isopropyl)amino]methyl]azetidin-1-yl]pyrazine-2-carboxylate (130 mg, 0.357 mmol) was dissolved in methyl alcohol (3 mL) and water (1.5 mL) and lithium hydroxide (9.4 mg, 0.392 mmol) was added at room temperature. The reaction was stirred at room temperature for 18 h. The solvent was removed in vacuo to give a residue. Water (1 mL) was added to the residue and the pH was adjusted to about 3 with 1 M HCl. The aqueous layer was extracted with 3× EtOAc and the organic layer was dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give 5-(3-(((tert-butoxycarbonyl)(isopropyl)amino)methyl)azetidin-1-yl)pyrazine-2-carboxylic acid. The crude material was used in the next step without further purification.

[0286] 5-[3-[[tert-butoxycarbonyl(isopropyl)amino]methyl]azetidin-1-yl]pyrazine-2-carboxylic acid (95 mg, 0.271 mmol) and 4-fluoro-2-methyl-1,3-benzoxazol-6-amine (45 mg, 0.271 mmol) were dissolved in acetonitrile (3 mL). 1-Methylimidazole (0.065 mL, 0.813 mmol) was added followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (84 mg, 0.298 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was filtered to collect the solid, which was washed with acetonitrile and water to give tert-butyl ((1-(5-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)azetidin-3-yl)methyl)(isopropyl)carbamate. The material was used in the next step without further purification.

[0287] tert-Butyl N-[[1-[5-[(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)carbamoyl]pyrazin-2-yl]azetidin-3-yl]methyl]-N-isopropyl-carbamate (82 mg, 0.164 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.0 mL, 13.1 mmol) was added. The reaction was stirred at room temperature for 1 h. The solvent was removed by blowing nitrogen through the sample and the sample was further dried in a vacuum oven overnight. The resulting residue was dissolved in DCM / MeOH 9:1 (2 mL) and MP-carbonate was added and the sample was left at room temperature for 18 h. The MP-carbonate was removed by filtration and the solvent removed in vacuo to give the title compound. LCMS (ES+) 399.2 (M+H)+, RT 2.91 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO-d6) d 10.57 (s, 1H), 8.72 (d, J=1.3 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 7.85 - 7.80 (m, 2H), 4.23 (dd, J=8.3, 8.3 Hz, 2H), 3.88 (dd, J=5.1, 9.1 Hz, 2H), 2.87 - 2.76 (m, 4H), 2.61 (s, 3H), 1.00 (d, J=6.3 Hz, 6H) NH not observed; ); 19 F NMR (400 MHz, DMSO-d6) d -126.11 (d, J= 12.5 Hz, 1F).

[0288] Example 13: 5-((3S,4R)-3-(cyclopropylamino)-4-methylpyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0289] [ka]

[0290] tert-Butyl N-[(3S,4R)-4-methylpyrrolidin-3-yl]carbamate (125 mg, 0.624 mmol) and 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (191 mg, 0.624 mmol) were dissolved in acetonitrile (5 mL) and triethylamine (0.26 mL, 1.87 mmol) was added. The reaction was heated at 45° C. for 18 hours. The reaction was cooled to room temperature and the solvent removed in vacuo to give a residue which was purified by silica chromatography (10 g, eluting with EtOAc / cyclohexane) to give tert-butyl ((3S,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidin-3-yl)carbamate.

[0291] tert-Butyl ((3S,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidin-3-yl)carbamate (220 mg, 0.469 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.0 mL) was added at room temperature, and the reaction was stirred for 1 h. The solvent was removed in vacuo to give a residue. The residue was purified by SCX chromatography (10 g, eluted with MeOH, then 10% 7M NH3 in MeOH / MeOH). The ammonia fraction was concentrated in vacuo to give 5-((3S,4R)-3-amino-4-methylpyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide.

[0292] 5-((3S,4R)-3-amino-4-methylpyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (173 mg, 0.468 mmol) was dissolved in methyl alcohol (10 mL) and acetic acid (0.029 mL, 0.515 mmol) was added at room temperature. (1-Ethoxycyclopropoxy)trimethylsilane (0.094 mL, 0.468 mmol) was added and the reaction was stirred at room temperature for 18 hours. Sodium cyanoborohydride (32 mg, 0.515 mmol) was added at room temperature and the reaction was stirred at room temperature for a further 18 hours. The reaction was quenched by the addition of saturated sodium bicarbonate and extracted with DCM x 3. The layers were separated using a phase separator and the solvent removed in vacuo to give a residue which was purified by preparative HPLC followed by achiral SFC to give the title compound: LCMS (ES+) 410.2 (M+H)+, RT 2.15 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H), 9.18 (d, J=1.5 Hz, 1H), 8.73 (d, J=1.3 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.88 (d, J=2.9 Hz, 1H), 7.55 (dd, J=1.6, 13.1 Hz, 1H), 3.93 - 3.77 (m, 2H), 3.38 - 3.30 (m, 1H), 3.19 - 3.12 (m, 1H), 3.04 - 3.02 (m, 1H), 2.53 (dd, J=2.4, 6.2 Hz, 1H), 2.33 (s, 3H), 2.19 - 2.15 (m, 2H), 1.07 (d, J=6.8 Hz, 3H), 0.44 - 0.40 (m, 2H), 0.28 - 0.20 (m, 2H); 19 F NMR (400 MHz, DMSO-d6) d -132.19 (dd, J= 3.5, 12.7 Hz, 1F).

[0293] Example 14: N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-5-(methyl(piperidin-4-yl)amino)pyrazine-2-carboxamide

[0294] [ka]

[0295] 4-Amino-1-Boc-piperidine (671 mg, 3.35 mmol), methyl 5-chloro-2-pyrazinecarboxylate (578 mg, 3.35 mmol), cesium carbonate (2194 mg, 6.73 mmol) and 1,4-dioxane (35 mL) were combined and heated at reflux for 18 hours. The reaction was cooled to room temperature and solids were removed by filtration through Celite. The solvent was removed in vacuo to give a residue which was purified by silica chromatography (25 g, eluting with EtOAc / cyclohexane 0-100%) to give methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)pyrazine-2-carboxylate.

[0296] Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)amino]pyrazine-2-carboxylate (534 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (15 mL) and sodium hydride (60%, 95 mg, 2.38 mmol) was added at room temperature and stirred for 1 h. Iodomethane (0.15 mL, 2.38 mmol) was added and the reaction was stirred at room temperature for an additional 18 h. The reaction was quenched with MeOH (used to avoid ester hydrolysis) and the solvent was removed in vacuo to give methyl 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyrazine-2-carboxylate. The material was used in the next step without further purification.

[0297] Methyl 5-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]pyrazine-2-carboxylate (556 mg, 1.59 mmol) was dissolved in methyl alcohol (12 mL) and water (6 mL). Lithium hydroxide (57 mg, 2.38 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give an aqueous solution. The pH was adjusted to about 3 with 1M HCl to give a solid. The solid was collected by filtration, washed with water, and dried overnight in a vacuum oven to give 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)(methyl)amino)pyrazine-2-carboxylic acid. The material was used in the next step without further purification.

[0298] 4-Fluoro-2-methyl-1,3-benzoxazol-6-amine (80 mg, 0.481 mmol), 5-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]pyrazine-2-carboxylic acid (100 mg, 0.297 mmol), and 1-methylimidazole (0.12 mL, 1.44 mmol) were suspended in acetonitrile (8 mL), and chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (149 mg, 0.530 mmol) was added and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was purified by silica chromatography (10 g, eluting with EtOAc / cyclohexane 0-100%) to give tert-butyl 4-((5-((4-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)(methyl)amino)piperidine-1-carboxylate.

[0299] tert-Butyl 4-[[5-[(4-fluoro-2-methyl-1,3-benzoxazol-6-yl)carbamoyl]pyrazin-2-yl]-methyl-amino]piperidine-1-carboxylate (82 mg, 0.169 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.0 mL, 13.1 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo to give a residue which was dried overnight in a vacuum oven. The resulting residue was dissolved in DCM / MeOH 9:1 (2 mL) and MP-carbonate was added and the sample was left at room temperature for 18 h. The MP-carbonate was removed by filtration and the solvent was removed in vacuo to give a residue which was purified by achiral SFC to give the title compound. LCMS (ES+) 385.2 (M+H)+, RT 2.69 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO-d6) d 10.54 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.18 (d, J=1.5 Hz, 1H), 8.15 (d, J=1.3 Hz, 1H), 7.82 (dd, J=1.7, 12.8 Hz, 1H), 4.63 - 4.55 (m, 1H), 3.06 - 2.99 (m, 5H), 2.63 - 2.55 (m, 5H), 2.34 - 2.18 (m, 1H), 1.71 - 1.54 (m, 4H); 19 F NMR (400 MHz, DMSO-d6) d -126.11 (d, J= 12.5 Hz, 1F).

[0300] Example A: N-(7-chloro-2-methylpyrazolo[1,5-a]pyridin-5-yl)-5-(3-((cyclopropylamino)methyl)azetidin-1-yl)pyrazine-2-carboxamide

[0301] [ka]

[0302] 4-Aminopyridine (3 g, 31.9 mmol) was dissolved in EtOAc and di-tert-butyl dicarbonate (7.3 mL, 31.9 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic phases were filtered through a hydrophobic frit. The solvent was concentrated in vacuo to give the desired product. LCMS (ES+) 195.3 (M+H)+, RT 1.06 min. 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=1.5, 4.8 Hz, 2H), 7.33 - 7.29 (m, 2H), 6.83 (s, 1H), 1.53 (s, 9H).

[0303] 4-(Boc-amino)pyridine (7.22 g, 37.1 mmol) was dissolved in N,N-dimethylformamide (50.00 mL) and O-(2,4-dinitrophenyl)hydroxylamine (8.14 g, 40.9 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 h and used directly in the next step. LCMS (ES+) 210 (M+H)+, RT 1.05 min (broad signal).

[0304] To tert-butyl N-(1-aminopyridin-1-ium-4-yl)carbamate 2,4-dinitrophenolate (14 g, 35.6 mmol) in N,N-dimethylformamide (50 mL) was added ethyl 2-butynoate (2.0 mL, 17.2 mmol) and potassium carbonate (7.38 g, 53.4 mmol) at room temperature. The reaction was stirred at room temperature for 48 h. The reaction mixture was filtered and the precipitate was washed with EtOAc. The filtrate was concentrated in vacuo to give a residue. The crude was purified by column chromatography on silica gel eluting with EtOAc / cyclohexane 0-100% to give the desired product. LCMS (ES+) 319 (M+H)+, RT 1.66 min.

[0305] Ethyl 5-(tert-butoxycarbonylamino)-2-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate (537 mg, 1.68 mmol) was stirred in dry THF (10 mL) at -80°C. To this was added n-butyllithium solution (1.4 mL, 3.53 mmol, 2.5 M) dropwise and the reaction was stirred at -80°C for 15 minutes. p-Toluenesulfonyl chloride (1.3 g, 6.73 mmol) in dry THF (1 mL) was added to the reaction at -80°C. The reaction was stirred for 5 minutes and the ice bath was removed. The reaction was stirred for an additional 20 minutes. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was passed through a hydrophobic frit and concentrated in vacuo to give the crude product. LCMS (ES+) 353 (M+H)+, RT 1.75 min.

[0306] Ethyl 5-(tert-butoxycarbonylamino)-7-chloro-2-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate (420 mg, 1.19 mmol) and hydrogen bromide (48%, 1.8 mL, 15.9 mmol) were refluxed together for 17 h. The reaction mixture was concentrated in vacuo and the residue was loaded onto a 5 g SCX cartridge (preconditioned with MeOH). The residue was eluted with MeOH, then NH3 in MeOH (7M). The ammonia fraction was concentrated in vacuo to give the desired product. LCMS (ES+) 181 (M+H)+, RT 1.14 min.

[0307] 7-Chloro-2-methyl-pyrazolo[1,5-a]pyridin-5-amine (150 mg, 0.826 mmol), 5-chloro-2-pyrazinecarboxylic acid (131 mg, 0.826 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (348 mg, 1.24 mmol), and 1-methylimidazole (0.20 mL, 2.48 mmol) in MeCN (8 mL) were stirred at room temperature for 1 h under nitrogen. The reaction mixture was concentrated in vacuo, diluted with DCM, and washed with aqueous sodium bicarbonate. The organic layer was concentrated onto silica and purified by column chromatography eluting with cyclohexane and EtOAc (0-35% gradient). The appropriate fractions were combined and concentrated in vacuo to give the desired product. LCMS (ES+) 322 (M+H)+, RT 1.52 min. 1 H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 9.28 (d, J=1.5 Hz, 1H), 8.60 (d, J=1.3 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 6.42 (s, 1H), 2.55 (s, 3H).

[0308] Triethylamine (0.035 mL, 0.251 mmol), 5-chloro-N-(7-chloro-2-methyl-pyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (27 mg, 0.0838 mmol), and N-(azetidin-3-ylmethyl)cyclopropanamine (11 mg, 0.0838 mmol) were combined in MeCN (6 mL) and stirred at 40° C. for 1 h. The reaction was stopped and the mixture was concentrated in vacuo. The resulting crude material was subjected to achiral SFC for purification. LCMS (ES+) 412 (M+H)+, RT 2.86 min (Analytical Method AcHSSC18. NMR: 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.71 (d, J=1.4 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.63 (d, J=2.1 Hz, 1H), 6.48 (s, 1H), 4.22 (dd, J=8.3, 8.3 Hz, 2H), 3.88 - 3.79 (m, 2H), 2.89 - 2.84 (m, 3H), 2.39 (s, 3H), 2.08 - 2.03 (m, 1H), 0.39 - 0.34 (m, 2H), 0.22 - 0.18 (m, 2H).

[0309] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry as described in Example A. Final products were isolated by preparative HPLC.

[0310] [Table 9]

[0311] Example B: 5-(3-((cyclopropylamino)methyl)azetidin-1-yl)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0312] [ka]

[0313] A suspension of 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide (50 mg, 0.151 mmol), N-(azetidin-3-ylmethyl)cyclopropanamine dihydrochloride (39 mg, 0.196 mmol) and cesium carbonate (196 mg, 0.603 mmol) in DMF (1.50 mL) was heated at 100 °C overnight. The reaction mixture was cooled to room temperature, filtered, and sent to achiral reverse phase HPLC for purification (Xbridge Phenyl 19x150mm, 10μm 40-100% MeOH / H2O (10mM NH4CO3), 20mL / min, RT) to give 5-[3-[(cyclopropylamino)methyl]azetidin-1-yl]-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide. LCMS (ES+) 422.4 [M+H]+, RT 2.70min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.70 (d, J=1.3 Hz, 1H), 8.65 (s, 1H), 8.20 (s, 1H), 7.88 (d, J=1.3 Hz, 1H), 7.07 (s, 1H), 4.25 - 4.17 (m, 4H), 4.08 (s, 3H), 3.84 (dd, J=4.8, 8.9 Hz, 2H), 2.89 - 2.84 (m, 3H), 2.37 - 2.32 (m, 1H), 2.09 - 2.03 (m, 1H), 1.46 (t, J= 6.9 Hz, 3H), 0.39 - 0.34 (m, 2H), 0.22 - 0.17 (m, 2H).

[0314] Additional analogs were prepared using 1-(azetidin-3-ylmethyl)-3-fluoro-azetidine dihydrochloride using the same chemistry as described in Example B. The final products were isolated by preparative HPLC.

[0315] [Table 10]

[0316] Additional analogs were prepared using (R)-N-cyclopropylpyrrolidin-3-amine.2HCl using the same chemistry as described in Example 14. The final products were isolated by preparative HPLC.

[0317] [Table 11]

[0318] Example 19: (R)-N-(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0319] [ka]

[0320] N,N-Dimethylacetamide dimethyl acetal (2.7 mL, 18.7 mmol) was added to a solution of 5-bromo-3-fluoro-pyridin-2-amine (1.02 g, 5.34 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was heated at 130 °C for 16 h. After cooling, the crude reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (15 mL) followed by the addition of pyridine (5 mL). The reaction mixture was cooled to 0 °C and hydroxylamine-O-sulfonic acid (966 mg, 8.54 mmol) was added, the ice bath was removed and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was concentrated onto silica and purified by column chromatography eluting with ethyl acetate (0-70%) in cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the desired product. LCMS (ES+) 230.0 (M+H)+, RT 1.31 min. 1H NMR (400 MHz, DMSO-d6) d 9.25 (d, J=0.8 Hz, 1H), 7.98 (dd, J=1.5, 10.1 Hz, 1H), 2.55 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) d -128.54 (d, J=10.1 Hz, 1F). Note: 30% of the starting material was confirmed by NMR characterization.

[0321] tert-Butyl N-[(3R)-1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl]-N-methyl-carbamate (190 mg, 0.591 mmol), 6-bromo-8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (177 mg, 0.769 mmol), copper(I) iodide (11 mg, 0.0591 mmol), potassium carbonate (123 mg, 0.887 mmol) and N,N'-dimethylethylenediamine (0.013 mL, 0.118 mmol) in toluene (3 mL) were combined and degassed with nitrogen for 10 min. The reaction mixture was stirred at 100° C. for 16 h. After cooling, the reaction mixture was passed through Celite, diluted with ethyl acetate and washed with brine. The combined organics were concentrated onto silica and the product was purified by column chromatography eluting with a gradient of cyclohexane / ethyl acetate (0-100%). The appropriate fractions were combined and concentrated in vacuo. LCMS (ES+) 471.4 (M+H)+, RT 1.58 min.

[0322] tert-Butyl N-[(3R)-1-[5-[(8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (125 mg, 0.266 mmol), trifluoroacetic acid (0.66 mL, 8.64 mmol) and DCM (5 mL) were stirred at room temperature for 3 h. The reaction mixture was passed through an SCX cartridge and eluted with NH3 in MeOH (7M) to collect the product. The appropriate fractions were concentrated in vacuo to give the crude product, which was purified by achiral reverse phase purification. LCMS (ES+) 371.2 (M+H)+, RT 2.18 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.73 (s, 1H), 9.45 (d, J=1.6 Hz, 1H), 8.77 (d, J=1.3 Hz, 1H), 8.11 (dd, J=1.8, 12.4 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 3.71 - 3.56 (m, 3H), 3.45 - 3.38 (m, 2H), 2.50 (s, 3H), 2.33 (s, 3H), 2.16 - 2.07 (m, 1H), 2.01 - 1.82 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) d -130.19 (d, J=12.5 Hz, 1F).

[0323] Example 20: (R)-5-(3-((4,5-dihydro-1H-imidazol-2-yl)amino)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0324] [ka]

[0325] (R)-3-(Boc-amino)pyrrolidine (96 mg, 0.517 mmol), triethylamine (0.22 mL, 1.55 mmol), and 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (158 mg, 0.517 mmol) were combined in MeCN (6 mL) and stirred at 65° C. for 1 h. The reaction was stopped, concentrated in vacuo, dissolved in DCM, and washed with brine. The organic layer was concentrated in vacuo to give the desired product. LCMS (ES+) 456.5 (M+H)+, RT 1.49 min.

[0326] tert-Butyl N-[(3R)-1-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]carbamate (280 mg, 0.615 mmol), TFA (1.5 mL, 20.0 mmol) and DCM (5 mL) were stirred at room temperature for 3 h. The reaction mixture was passed through an SCX cartridge and eluted with NH3 in MeOH (7M) to collect the product. The appropriate fractions were concentrated in vacuo to give the desired product. LCMS (ES+) 356 (M+H)+, RT 1.10 min.

[0327] 5-[(3R)-3-aminopyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (67 mg, 0.189 mmol), 4,5-dihydro-1H-imidazole-2-sulfonic acid (37 mg, 0.245 mmol) were combined in 1-butanol (5 mL). The reaction was stirred at room temperature for 2 h, the reaction mixture was concentrated in vacuo and subjected to achiral SFC to give the desired product. LCMS (ES+) 423 (M+H)+, RT 1.18 min.

[0328] 5-[(3R)-3-(4,5-dihydro-1H-imidazol-2-ylamino)pyrrolidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (18 mg, 0.0434 mmol) and HCl (0.011 mL, 0.0434 mmol, 4 M) in MeOH (1 mL) were stirred at room temperature for 3 h. The reaction was stopped and nitrogen was passed through the sample for 2 h. The compound was further dried in a high vacuum oven for 24 h to give the desired HCl salt product. LCMS (ES+) 424.2 (M+H)+, RT 1.82 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.20 (s, 1H), 8.81 - 8.77 (m, 2H), 8.05 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.60 (d, J=12.5 Hz, 1H), 4.32 - 4.26 (m, 1H), 3.85 (dd, J=5.6, 11.5 Hz, 1H), 3.70 (t, J=7.0 Hz, 2H), 3.64 (s, 3H), 3.60 (dd, J=3.8, 11.9 Hz, 1H), 2.36 - 2.29 (m, 3H), 2.12 - 2.06 (m, 1H). 19 F NMR (376 MHz, DMSO-d6) δ -132.11 (dd, J=3.0, 12.4 Hz, 1F).

[0329] Example 21: (R)-N-(8-fluoro-2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0330] [ka]

[0331] 3-Fluoro-4-methyl-pyridin-2-amine (348 mg, 2.76 mmol) and N-bromosuccinimide (491 mg, 2.76 mmol) in DCM (20 mL) were stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, ethyl acetate was added to the residue, and the precipitate was isolated from the filtrate to give the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 6.40 - 6.33 (m, 2H), 2.26 (d, J=2.5 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -138.44 (s, 1F).

[0332] 5-Bromo-3-fluoro-4-methyl-pyridin-2-amine (500 mg, 2.44 mmol), 1-bromo-2,2-dimethoxypropane (0.49 mL, 3.66 mmol), pyridinium p-toluenesulfonate (61 mg, 0.244 mmol), and 2-propanol (15 mL) were combined in a sealed tube and heated in a hot block to 85° C. The precipitate was collected by vacuum filtration to give the desired product. 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.98 (s, 1H), 2.49 (d, J=0.7 Hz, 3H), 2.46 (d, J=3.0 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -132.66 (s, 1F).

[0333] tert-Butyl N-[(3R)-1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl]-N-methyl-carbamate (111 mg, 0.345 mmol), 6-bromo-8-fluoro-2,7-dimethyl-imidazo[1,2-a]pyridine (109 mg, 0.449 mmol), copper(I) iodide (6.6 mg, 0.0345 mmol), potassium carbonate (72 mg, 0.518 mmol), N,N'-dimethylethylenediamine (0.0074 mL, 0.0691 mmol), and toluene (3 mL) were combined and the reaction mixture was degassed with nitrogen for 10 minutes and stirred for 24 hours at 100° C. The reaction mixture was diluted with water and washed with EtOAc (×3). The combined organics were concentrated onto silica and the product was purified by column chromatography eluting with a gradient of cyclohexane / ethyl acetate (0-90%). The appropriate fractions were combined and concentrated in vacuo to give the product. LCMS (ES+) 484.4 (M+H)+, RT 1.56 min.

[0334] tert-Butyl-N-[(3R)-1-[5-[(8-fluoro-2,7-dimethyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (86 mg, 0.178 mmol), DCM (5 mL), and TFA (34 mg, 0.534 mmol) were stirred at room temperature for 1 h. The reaction was quenched and passed through an SCX cartridge, eluting with NH3 in MeOH (7M). The appropriate fractions were concentrated in vacuo to give the crude product, which was purified by achiral purification to give the desired compound. LCMS (ES+) 384.2 (M+H)+, RT 1.91 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.72 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.78 (d, J=2.8 Hz, 1H), 3.70 - 3.57 (m, 3H), 3.40 (d, J=10.4 Hz, 1H), 2.35 (d, J=0.8 Hz, 3H), 2.32 (s, 3H), 2.22 (d, J=2.5 Hz, 3H), 2.14 - 2.07 (m, 1H), 1.96 - 1.86 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) δ -136.76 (s, 1F).

[0335] Example 22: (R)-N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0336] [ka]

[0337] Methyl 5-[(3R)-3-[tert-butoxycarbonyl(methyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylate (1.50 g, 4.46 mmol) was dissolved in methanol (5 mL) and treated with ammonia (7 M in methanol, 34 mL, 0.237 mol). The reaction mixture was sealed in a tube and stirred at 80° C. for 3 days. After cooling to room temperature, the reaction was concentrated in vacuo to give crude tert-butyl N-[(3R)-1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl]-N-methyl-carbamate, which was used without further purification.

[0338] tert-Butyl N-[(3R)-1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl]-N-methyl-carbamate (106 mg, 0.330 mmol), 6-bromo-4-methoxy-2-methyl-1,3-benzoxazole (107 mg, 0.442 mmol), copper(I) iodide (12 mg, 0.0604 mmol), potassium carbonate (66 mg, 0.478 mmol), and N,N'-dimethylethylenediamine (0.013 mL, 0.119 mmol) were suspended in toluene (3 mL) and sparged with N2 for 10 min. The mixture was sealed in a tube and stirred at 100 °C for 4 days. After cooling to room temperature, the mixture was diluted with 20 mL of water and extracted with 3 x 30 mL of EtOAc; the combined organics were washed with 20 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by SFC to give crude tert-butyl N-[(3R)-1-[5-[(4-methoxy-2-methyl-1,3-benzoxazol-6-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate, which was used without further purification.

[0339] tert-Butyl N-[(3R)-1-[5-[(4-methoxy-2-methyl-1,3-benzoxazol-6-yl)carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methyl-carbamate (22 mg, 0.0456 mmol) was dissolved in dichloromethane (1.5 mL) at room temperature. Trifluoroacetic acid (0.47 mL, 6.14 mmol) was added. After stirring at room temperature for 15 min, most of the TFA was removed by evaporation under reduced pressure and the residue was dissolved in 5 ml of MeOH.

[0340] 0.97 g MP-carbonate beads were added (3 mmol / g). The mixture was stirred at room temperature for 20 min, then filtered and concentrated. The residue was combined with another smaller (half scale) run and purified by SFC to give (R)-N-(4-methoxy-2-methylbenzo[d]oxazol-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 383.2 (M+H)+, RT 2.53 min (analytical method AcHSSC18); 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.74 (d, J=1.3 Hz, 1H), 7.97 - 7.95 (m, 2H), 7.49 (d, J=1.5 Hz, 1H), 3.94 (s, 3H), 3.68 - 3.57 (m, 3H), 3.40 - 3.35 (m, 1H), 2.55 (s, 3H), 2.31 (s, 3H), 2.14 - 2.05 (m, 1H), 1.94 - 1.82 (m, 2H). No NH was observed.

[0341] Example 23: 5-(6-(ethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0342] [ka]

[0343] Methyl 5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (375 mg, 1.12 mmol, 1.00 eq), sodium hydride (60%, 54 mg, 1.35 mmol, 1.20 eq), N,N-dimethylformamide (10 mL), and iodoethane (0.11 mL, 1.35 mmol, 1.20 eq) were combined under nitrogen atmosphere and stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water (3×), and concentrated in vacuo to give methyl 5-[6-[tert-butoxycarbonyl(ethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate, which was used directly in the next step. LCMS (ES+) 363(M+H)+.

[0344] Methyl 5-[6-[tert-butoxycarbonyl(ethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (crude from previous step, 1.12 mmol, 1.00 eq), lithium hydroxide monohydrate (56 mg, 1.35 mmol, 1.20 eq), methyl alcohol (30 mL) and water (3 mL) were combined and heated on a hot block to 50° C. overnight. The mixture was concentrated in vacuo to remove MeOH and partitioned between EtOAc and water / AcOH. The organics were dried (MgSO4), concentrated in vacuo and dried in a vacuum oven to give 5-[6-[tert-butoxycarbonyl(ethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylic acid, which was used directly in the next step. LCMS (ES+) 349 (M+H)+.

[0345] 5-[6-[tert-Butoxycarbonyl(ethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylic acid (95 mg, 0.273 mmol, 1.00 eq), 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (45 mg, 0.273 mmol, 1.00 eq), HBTU (103 mg, 0.273 mmol, 1.00 eq), N,N-dimethylformamide (2 mL), and triethylamine (0.50 mL, 3.59 mmol, 13.2 eq) were combined and stirred at room temperature for 3 h. The reaction mixture was then purified by preparative HPLC to give tert-butyl N-ethyl-N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate, which was used directly in the next step. LCMS (ES+) 496(M+H)+.

[0346] tert-Butyl N-ethyl-N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (81 mg, 0.163 mmol, 1.00 eq), methyl alcohol (2 mL), and 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 48.9 eq) were combined and stirred at room temperature for 2 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound. LCMS (ES+) 396.2 (M+H)+, RT 1.8 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) d 10.43 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.56 (dd, J=1.6, 13.1 Hz, 1H), 3.78 (d, J=11.2 Hz, 2H), 3.64 - 3.57 (m, 2H), 2.61 (q, J=7.2 Hz, 2H), 2.35 (s, 3H), 2.19 (s, 1H), 1.90 (dd, J=2.2, 2.2 Hz, 1H), 1.72 (s, 2H), 1.02 (dd, J=7.2, 7.2 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) d -132.17 (dd, J = 3.8 Hz, J = 13.5 Hz).

[0347] Example 24: 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0348] [ka]

[0349] 5-Chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (120 mg, 0.393 mmol, 1.00 eq), 6-(Boc-amino)-3-azabicyclo[3.1.0]hexane (198211-38-0) (78 mg, 0.393 mmol, 1.00 eq), cesium carbonate (192 mg, 0.589 mmol, 1.50 eq), and N,N-dimethylformamide (3 mL) were combined in a sealed tube and heated to 100° C. for 1 hour in a hot block. The reaction was cooled to room temperature and filtered to remove the cesium salts. The crude was purified by preparative HPLC to give tert-butyl N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate. LCMS (ES+) 468 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) d 10.43 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H), 7.98 (d, J=1.3 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.56 (dd, J=1.6, 13.1 Hz, 1H), 7.21 - 7.17 (m, 1H), 3.84 (d, J=11.2 Hz, 2H), 3.63 (d, J=11.0 Hz, 2H), 2.35 (s, 3H), 2.28 - 2.25 (m, 1H), 1.87 (s, 2H), 1.41 (s, 9H).

[0350] tert-Butyl N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (100 mg, 0.214 mmol, 1.00 eq), methyl alcohol (2 mL), and 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 37.4 eq) were combined and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 368.2 (M+H)+, RT 1.98 min (Analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.42 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.73 (d, J=1.1 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.56 (dd, J=1.7, 13.0 Hz, 1H), 3.75 (d, J=11.2 Hz, 2H), 3.63 - 3.56 (m, 2H), 2.35 (s, 3H), 2.02 (dd, J=2.1, 2.1 Hz, 1H), 1.98 (s, 1H), 1.66 (s, 2H).

[0351] The following compounds were synthesized in a similar manner from the appropriate starting materials:

[0352] [Table 12] TIFF2024540477000066.tif161152

[0353] Example 29: N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-[6-(methylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxamide

[0354] [ka]

[0355] Methyl 5-chloro-2-pyrazinecarboxylate (223 mg, 1.29 mmol, 1.00 eq), 6-(Boc-amino)-3-azabicyclo[3.1.0]hexane (256 mg, 1.29 mmol, 1.00 eq) (Cas no. 198211-38-0), cesium carbonate (631 mg, 1.94 mmol, 1.50 eq), and acetonitrile (15 mL) were combined in a sealed tube and heated to 80° C. on a hot block for 4 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo onto silica gel, and purified by flash chromatography to give methyl 5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate. LCMS (ES+) 335 (M+H)+.

[0356] Methyl 5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (119 mg, 0.356 mmol, 1.00 eq), sodium hydride (60%, 17 mg, 0.427 mmol, 1.20 eq), N,N-dimethylformamide (3 mL), and iodomethane (0.044 mL, 0.712 mmol, 2.00 eq) were combined under nitrogen atmosphere and stirred at room temperature over the weekend. The reaction mixture was diluted with EtOAc, washed with water, and concentrated in vacuo to give methyl 5-[6-[tert-butoxycarbonyl(methyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate, which was used directly in the next step. LCMS (ES+) 349(M+H)+.

[0357] Methyl 5-[6-[tert-butoxycarbonyl(methyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (124 mg, 0.355 mmol, 1.00 eq), lithium hydroxide monohydrate (18 mg, 0.426 mmol, 1.20 eq), methyl alcohol (10 mL), and water (1 mL) were combined and heated in a hot block to 50° C. for 2 days. The reaction mixture was concentrated in vacuo to give [5-[6-[tert-butoxycarbonyl(methyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carbonyl]oxylithium, which was used directly in the next step. LCMS (ES+) 335 (M+H)+ for the acid.

[0358] 5-[6-[tert-Butoxycarbonyl(methyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylic acid (45 mg, 0.135 mmol, 1.00 eq), 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (22 mg, 0.135 mmol, 1.00 eq), HBTU (51 mg, 0.135 mmol, 1.00 eq), N,N-dimethylformamide (1 mL), and triethylamine (0.25 mL, 1.79 mmol, 13.3 eq) were combined and stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC to give tert-butyl N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-carbamate. LCMS (ES+) 482(M+H)+.

[0359] tert-Butyl N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]-N-methyl-carbamate (49 mg, 0.102 mmol, 1.00 eq), methyl alcohol (1 mL), and 4M hydrogen chloride in dioxane (1.0 mL, 4.00 mmol, 39.3 eq) were combined and stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo and purified by preparative HPLC to give the title compound. LCMS (ES+) 382.2 (M+H)+, RT 1.74 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.43 (s, 1H), 9.19 (d, J=1.6 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, 1H), 7.56 (dd, J=1.9, 13.1 Hz, 1H), 3.77 (d, J=11.2 Hz, 2H), 3.64 - 3.57 (m, 2H), 2.35 (d, J=1.1 Hz, 3H), 2.32 (s, 3H), 2.21 (s, 1H), 1.85 (dd, J=2.1, 2.1 Hz, 1H), 1.72 (s, 2H). 19 F NMR (376 MHz, DMSO-d6) d -132.18 (dd, J = 3 Hz, J = 13.6 Hz).

[0360] Example 30: 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(6-methoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide

[0361] [ka]

[0362] Methyl 5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (223 mg, 0.667 mmol, 1.00 eq), lithium hydroxide monohydrate (34 mg, 0.800 mmol, 1.20 eq), methyl alcohol (20 mL), and water (2 mL) were combined and heated on a hot block at 55° C. overnight. The reaction mixture was concentrated in vacuo to give [5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carbonyl]oxylithium, which was used directly in the next step. LCMS (ES+) 321 (M+H)+ for the acid.

[0363] [5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carbonyl]oxylithium (104 mg, 0.319 mmol, 1.00 eq), 6-methoxy-2-methyl-indazol-5-amine (56 mg, 0.319 mmol, 1.00 eq), HBTU (121 mg, 0.319 mmol, 1.00 eq), N,N-dimethylformamide (2 mL), and triethylamine (0.50 mL, 3.59 mmol, 11.3 eq) were combined and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, triturated with water, filtered off, and dried in a vacuum oven to give tert-butyl N-[3-[5-[(6-methoxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate, which was used directly in the next step. LCMS (ES+) 480(M+H)+.

[0364] tert-Butyl N-[3-[5-[(6-methoxy-2-methyl-indazol-5-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (111 mg, 0.231 mmol, 1.00 eq), methyl alcohol (2 mL), and 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 34.6 eq) were combined and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. Water was added and the resulting precipitate was filtered, rinsed with water, and dried in a vacuum oven to give the title compound. LCMS (ES+) 380.2 (M+H)+, RT 2.43 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.05 (s, 1H), 8.74 (d, J=1.0 Hz, 1H), 8.68 (s, 1H), 8.23 ​​(s, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.11 (s, 1H), 4.10 (s, 3H), 3.98 (s, 3H), 3.74 (d, J=11.2 Hz, 2H), 3.59 (dd, J=2.3, 9.0 Hz, 2H), 2.09 - 2.08 (m, 2H), 2.01 (dd, J=2.2, 2.2 Hz, 1H), 1.66 (s, 2H).

[0365] Example 31: 5-[(3R)-3-[(cyclopropylamino)methyl]pyrrolidin-1-yl]-N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0366] [ka]

[0367] 5-Chloro-2-pyrazinecarboxylic acid (159 mg, 1.00 mmol, 1.00 eq), dichloromethane (5 mL), oxalyl chloride, GMP (0.17 mL, 2.00 mmol, 2.00 eq), and 1 drop of DMF were combined and stirred at room temperature under nitrogen overnight. The reaction mixture was then concentrated in vacuo to give 5-chloropyrazine-2-carbonyl chloride, which was used directly in the next step.

[0368] 5-Chloropyrazine-2-carbonyl chloride (177 mg, 1.00 mmol, 1.00 eq), 7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-amine (197 mg, 1.10 mmol, 1.10 eq), dichloromethane (10 mL), and triethylamine (0.50 mL, 3.59 mmol, 3.59 eq) were combined and stirred at room temperature for 30 min. The reaction mixture was then concentrated in vacuo to give 5-chloro-N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, which was used directly in the next step. LCMS (ES+) 320 / 322 (M+H)+.

[0369] 5-Chloro-N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (250 mg, 0.782 mmol, 1.00 eq), N-[[(3S)-pyrrolidin-3-yl]methyl]cyclopropanamine (195 mg, 1.39 mmol, 1.78 eq), cesium carbonate (510 mg, 1.56 mmol, 2.00 eq), and N,N-dimethylformamide (4 mL) were combined and heated in a hot block to 100° C. for 3 hours. The reaction was cooled to room temperature and filtered to remove the cesium salts. The crude material was purified by preparative HPLC followed by SFC to give 5-[(3R)-3-[(cyclopropylamino)methyl]pyrrolidin-1-yl]-N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 424.2 (M+H)+, RT 2.1 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) d 9.82 (s, 1H), 8.99 (d, J=7.0 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.74 (s, 1H), 3.78 - 3.66 (m, 2H), 3.58 - 3.40 (m, 1H), 3.29 (dd, J=7.2, 11.2 Hz, 1H), 2.75 - 2.62 (m, 2H), 2.56 - 2.48 (m, 1H), 2.42 (d, J=1.9 Hz, 3H), 2.35 (s, 3H), 2.16 - 2.08 (m, 2H), 1.76 - 1.74 (m, 1H), 0.40 (dd, J=1.6, 6.5 Hz, 2H), 0.27 - 0.23 (m, 2H).

[0370] Example 32: N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-5-(6-pyrrolidin-1-yl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxamide

[0371] [ka]

[0372] Methyl 5-[6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylate (457 mg, 1.37 mmol, 1.00 eq), methyl alcohol (5 mL), and 4M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 14.6 eq) were combined and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give methyl 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate; hydrochloride salt, which was used directly in the next step. LCMS (ES+) 235 (M+H)+.

[0373] Methyl 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate; hydrochloride (1.36 mmol, 1.00 eq), 1,4-dibromobutane (0.16 mL, 1.36 mmol, 1.00 eq), acetonitrile (30 mL), and triethylamine (2 mL) were combined and the reaction was heated on a hot block to 80° C. over the weekend. The reaction was cooled to room temperature, diluted with EtOAc, filtered to remove potassium salts, and concentrated in vacuo. The crude product was purified by preparative HPLC to give methyl 5-(6-pyrrolidin-1-yl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate, which was used directly in the next step. LCMS (ES+) 289 (M+H)+.

[0374] Methyl 5-(6-pyrrolidin-1-yl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carboxylate (49 mg, 0.170 mmol, 1.00 eq), lithium hydroxide monohydrate (7.8 mg, 0.187 mmol, 1.10 eq), methyl alcohol (5 mL), and water (0.5000 mL) were combined in a sealed tube and heated on a hot block to 50° C. over the weekend. The reaction was cooled to room temperature, concentrated in vacuo, and dried in a vacuum oven overnight to give [5-(6-pyrrolidin-1-yl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl]oxylithium, which was used directly in the next step. LCMS (ES+) 275 (M+H)+ as the acid.

[0375] [5-(6-pyrrolidin-1-yl-3-azabicyclo[3.1.0]hexan-3-yl)pyrazine-2-carbonyl]oxylithium (48 mg, 0.170 mmol, 1.00 eq), 8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-amine (28 mg, 0.170 mmol, 1.00 eq), HBTU (64 mg, 0.170 mmol, 1.00 eq), N,N-dimethylformamide (2 mL), and triethylamine (0.024 mL, 0.170 mmol, 1.00 eq) were combined and stirred at room temperature for 2 hours. The reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 422.2 (M+H)+, RT 1.86 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.43 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.5, 13.3 Hz, 1H), 3.80 (d, J=11.2 Hz, 2H), 3.60 (dd, J=2.2, 9.0 Hz, 2H), 2.60 (s, 5H), 2.35 (s, 3H), 1.84 (s, 2H), 1.68 (d, J=3.0 Hz, 4H). 19 F NMR (376 MHz, DMSO-d6) d -132.17 (dd, J = 3.9 Hz, J = 13.2 Hz).

[0376] Example 33: 5-(4-((cyclopropylamino)methyl)piperidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0377] [ka]

[0378] N-(4-piperidylmethyl)cyclopropanamine (50 mg, 0.327 mmol), 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (100 mg, 0.327 mmol), and cesium carbonate (213 mg, 0.654 mmol, 2.00 eq) in N,N-dimethylformamide (1 mL) were stirred at 100° C. for 18 hours. The reaction mixture was diluted with DMSO and purified by preparative HPLC. This gave 5-(4-((cyclopropylamino)methyl)piperidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 424.2 (M+H)+, RT 2.03 min (analytical method AcHSSC18); 1 H NMR (400 MHz, DMSO-d6) 10.41 (1H, s), 9.17 (1H, d, J=1.6 Hz), 8.71 (1H, d, J=1.3 Hz), 8.31 (1H, d, J=1.4 Hz), 7.88 (1H, dd, J=0.6, 3.1 Hz), 7.55 (1H, dd, J=1.6, 13.1 Hz), 4.55 - 4.47 (2H, m), 3.04 - 2.95 (2H, m), 2.48 - 2.46 (2H, m), 2.34 - 2.33 (4H, m), 2.08 - 2.01 (1H, m), 1.83 - 1.71 (3H, m), 1.18 - 1.07 (2H, m), 0.37 - 0.32 (2H, m), 0.21 - 0.16 (2H, m); 19 F NMR (376 MHz, DMSO-d6) d -132.19 (dd, J = 12.5, 2.6 Hz).

[0379] Example 34: 5-(6-(ethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide

[0380] [ka]

[0381] 5-[6-[tert-Butoxycarbonyl(ethyl)amino]-3-azabicyclo[3.1.0]hexan-3-yl]pyrazine-2-carboxylic acid (102 mg, 0.293 mmol, 1.00 eq), 8-methoxy-2-methyl-imidazo[1,2-a]pyrazin-6-amine (52 mg, 0.293 mmol, 1.00 eq), HBTU (111 mg, 0.293 mmol, 1.00 eq), N,N-dimethylformamide (2 mL), and triethylamine (0.54 mL, 3.85 mmol, 13.2 eq) were combined and stirred at room temperature for 3 h. The mixture was then cooled to room temperature and purified by preparative HPLC to give tert-butyl ethyl (3-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate. LCMS (ES+) 509.2 (M+H)+, RT 4.45 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 9.52 (1H, s), 8.91 (1H, s), 8.76 (1H, d, J=1.5 Hz), 8.06 (1H, d, J=1.3 Hz), 7.95 (1H, d, J=0.9 Hz), 4.07 (3H, s), 3.87 (2H, d, J=11.4 Hz), 3.70 - 3.66 (2H, m), 3.28 - 3.22 (2H, m), 2.36 (3H, s), 2.28 - 2.25 (1H, m), 2.09 (2H, bs), 1.45 (9H, s), 1.09 - 1.04 (3H, m).

[0382] tert-Butyl N-ethyl-N-[3-[5-[(8-methoxy-2-methyl-imidazo[1,2-a]pyrazin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (21 mg, 0.0422 mmol, 1.00 eq), methyl alcohol (2 mL), and 4 M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 190 eq) were combined and stirred at room temperature for 90 min. The mixture was concentrated in vacuo and purified by preparative HPLC followed by SFC to give 5-(6-(ethylamino)-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 409.2 (M+H)+, RT 2.06 min (Analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 9.51 (1H, s), 8.90 (1H, s), 8.74 (1H, d, J=1.4 Hz), 8.01 (1H, d, J=1.6 Hz), 7.95 (1H, d, J=0.8 Hz), 4.07 (3H, s), 3.77 (2H, d, J=11.7 Hz), 3.63 - 3.59 (2H, m), 2.63 - 2.60 (2H, m), 2.35 (3H, s), 2.19 (1H, bs), 1.91 - 1.88 (1H, m), 1.73 (2H, bs), 1.02 (3H, t, J=6.7 Hz).

[0383] Example 35 and Example 36: 5-((1S)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide and 5-((1R)-1-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0384] [ka]

[0385] Cesium carbonate (394 mg, 1.21 mmol, 1.50 eq), 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (247 mg, 0.807 mmol, 1.00 eq), tert-butyl N-(3-azabicyclo[3.1.0]hexan-1-yl)carbamate (160 mg, 0.807 mmol, 1.00 eq), and N,N-dimethylformamide (4 mL) were combined in a sealed tube and heated to 100 °C in a hot block for 90 min. The mixture was then cooled to room temperature, filtered to remove cesium salts, and the residue purified by preparative HPLC to give tert-butyl N-(3-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate. LCMS (ES+) 419.2 (M+H)+, RT 1.81 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) 10.47 (1H, s), 9.19 (1H, d, J=1.7 Hz), 8.75 (1H, d, J=1.3 Hz), 8.00 (1H, d, J=1.0 Hz), 7.90 (1H, dd, J=1.0, 3.0 Hz), 7.62 - 7.55 (2H, m), 3.98 (1H, d, J=10.8 Hz), 3.80 - 3.72 (2H, m), 3.58 - 3.55 (1H, m), 2.35 (3H, s), 1.42 (9H, s), 1.13 - 1.08 (1H, m), 0.90 - 0.88 (1H, m), 0.73 - 0.70 (1H, m).

[0386] tert-Butyl N-[3-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]-3-azabicyclo[3.1.0]hexan-1-yl]carbamate (199 mg, 0.426 mmol, 1.00 eq), methyl alcohol (2 mL), and 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol, 18.8 eq) were combined and stirred at room temperature for 24 h. The mixture was concentrated in vacuo and purified by preparative HPLC followed by SFC to give two compounds: enantiomer 2, LCMS (ES+) 368.2 (M+H)+, RT 2.92 min (analytical method AcHSSC18 BicarbBEHC18). 1 H NMR (400 MHz, DMSO-d6) d 10.45 (s, 1H), 9.19 (d, J=1.4 Hz, 1H), 8.76 (d, J=1.4 Hz, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.91 - 7.90 (m, 1H), 7.56 (dd, J=1.5, 13.6 Hz, 1H), 4.04 (d, J=11.5 Hz, 1H), 3.78 - 3.71 (m, 2H), 3.57 (d, J=10.1 Hz, 1H), 2.35 (s, 3H), 1.81 (bs, 1H), 1.18 - 1.14 (m, 1H), 0.68 - 0.65 (m, 1H), no NH2 observed; and enantiomer 1, LCMS (ES+) 368.2 (M+H)+, RT 2.93 min (analytical method AcHSSC18 BicarbBEHC18). 1H NMR (400 MHz, DMSO-d6) 10.45 (1H, s), 9.19 (1H, d, J=1.6 Hz), 8.75 (1H, d, J=1.6 Hz), 7.99 (1H, d, J=1.5 Hz), 7.91 - 7.89 (1H, m), 7.57 (1H, dd, J=1.8, 13.2 Hz), 4.02 (1H, d, J=10.6 Hz), 3.77 - 3.70 (2H, m), 3.55 (1H, d, J=10.6 Hz), 2.35 (3H, s), 1.74 (1H, s), 1.15 - 1.10 (1H, m), 0.64 - 0.61 (1H, m), NH2 was not observed.

[0387] Example 37: 5-[6-(cyclopropylamino)-3-azabicyclo[3.1.0]hexan-3-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0388] [ka]

[0389] 5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (220 mg, 0.600 mmol, 1.00 eq), (1-ethoxycyclopropoxy)trimethylsilane (0.097 mL, 0.480 mmol, 0.800 eq), sodium cyanoborohydride (57 mg, 0.900 mmol, 1.50 eq), methyl alcohol (15 mL), and acetic acid (0.2000 mL) were combined and heated overnight in a hot block at 50° C. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by preparative HPLC and SFC purification to give the title compound. LCMS (ES+) 408.2 (M+H)+, RT 1.87 min (Analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H), 9.18 (d, J=1.5 Hz, 1H), 8.72 (d, J=1.1 Hz, 1H), 7.94 (d, J=1.3 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.55 (dd, J=1.7, 13.1 Hz, 1H), 3.78 (d, J=11.2 Hz, 2H), 3.59 (dd, J=2.0, 9.0 Hz, 2H), 2.67 (dd, J=1.8, 3.6 Hz, 1H), 2.33 (s, 3H), 2.16 - 2.10 (m, 1H), 1.96 (dd, J=2.3, 2.3 Hz, 1H), 1.72 (s, 2H), 0.38 - 0.33 (m, 2H), 0.25 - 0.21 (m, 2H). 19 F NMR (376 MHz, DMSO-d6) d -132.17 (dd, J = 2.8 Hz, J = 13.5 Hz).

[0390] Method Q: Formaldehyde reductive amination The amine (1 eq), formaldehyde (37% solution, 50 eq), methanol (1 mL), and sodium triacetoxyborohydride (2 eq) were combined and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried, and evaporated. The crude material was purified by achiral SFC or preparative HPLC.

[0391] Example 38 and Example 39: (S*)-5-(3-(dimethylamino)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide and (R*)-5-(3-(dimethylamino)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0392] [ka]

[0393] Method Q (formaldehyde reductive amination) from previously reported 5-(3-amino-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (100 mg, 0.27 mmol) was followed by purification by chiral SFC to give enantiomer 2, LCMS (ES+) 398.2 (M+H)+, RT 1.72 min (analytical method AcHSSC18). RT 2.01 min (SFC1, LUX CELLULOSE-3 + 0.1% DEAISO 30% ACN / IPA SOL4). 1 H NMR (400 MHz, DMSO-d6) d 10.91 (s, 1H), 9.72 (d, J=1.5 Hz, 1H), 9.23 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.6, 13.0 Hz, 1H), 4.12 - 4.06 (m, 1H), 3.83 - 3.74 (m, 2H), 2.38 (d, J=11.7 Hz, 9H), 2.30 - 2.22 (m, 1H), 2.16 - 2.04 (m, 1H). 19 F NMR (400 MHz, DMSO-d6) d -131.85 (dd, J= 2.7, 12.3 Hz); and enantiomer 1, LCMS (ES+) 398.2 (M+H)+, RT 1.72 min (analytical method AcHSSC18). RT 4.69 min (SFC1, LUX CELLULOSE-3 + 0.1% DEAISO 30% ACN / IPA SOL4). 1H NMR (400 MHz, DMSO-d6) d 10.91 (s, 1H), 9.72 (d, J=1.5 Hz, 1H), 9.23 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.5 Hz, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.9, 13.0 Hz, 1H), 4.12 - 4.06 (m, 1H), 3.83 - 3.75 (m, 2H), 2.39 (s, 6H), 2.36 (d, J=0.7 Hz, 3H), 2.31 - 2.23 (m, 1H), 2.16 - 2.04 (m, 1H). 19 F NMR (400 MHz, DMSO-d6) d -131.85 (dd, J = 2.7, 12.3 Hz) was obtained.

[0394] Example 40 and Example 41: (R*)-5-(4-((cyclopropylamino)methyl)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide and (S*)-5-(4-((cyclopropylamino)methyl)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide.

[0395] [ka]

[0396] A mixture of 4-(bromomethyl)pyrrolidin-2-one (500 mg, 2.81 mmol, 1 eq), cyclopropylamine (0.29 mL, 4.21 mmol, 1.5 eq), potassium carbonate (776 mg, 5.62 mmol, 2 eq), and 4-(dimethylamino)pyridine (69 mg, 0.562 mmol, 0.2 eq) in acetonitrile (14.04 mL) was placed in an Ace pressure tube and heated to 100 °C. A blast shield was placed around the setup and the mixture was left stirring overnight. The reaction mixture was cooled to room temperature, the solvent was evaporated in vacuo, and the residue was purified by chromatography (silica gel, gradient elution ethyl acetate + 7N NH3 in MeOH 1:0 to 84:16). 1 H NMR (400 MHz, CDCl3) d , 5.87 - 5.86 (brs, 1H), 3.50 (dd, J=8.7, 8.7 Hz, 1H), 3.13 (dd, J=5.7, 9.7 Hz, 1H), 2.82 - 2.61 (m, 3H), 2.45 (dd, J=8.8, 16.9 Hz, 1H), 2.14 - 2.01 (m, 2H), 0.48 - 0.41 (m, 2H), 0.33 - 0.28 (m, 2H).

[0397] To a solution of 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (99 mg, 0.324 mmol, 1 eq) and 4-[(cyclopropylamino)methyl]pyrrolidin-2-one (50 mg, 0.324 mmol, 1 eq) in 1,4-dioxane (2.14 mL) was added cesium carbonate (158 mg, 0.486 mmol, 1.5 eq) and the mixture was degassed under N2 sparging for 20 min. Xantphos (19 mg, 0.0324 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium(0) (7.4 mg, 8.11 μmol, 0.025 eq) were added and the mixture was heated to 100 °C under inert atmosphere for 24 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by chromatography (silica gel, gradient elution slow gradient of ethyl acetate / isopropanol 1:0 to 80:20 over 15 column volumes, then isocratic) followed by chiral SFC separation to give enantiomer 1, LCMS (ES+) 424.2 (M+H)+, RT 1.83 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.89 (s, 1H), 9.69 (d, J=1.4 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 9.12 (d, J=1.5 Hz, 2H), 7.95 (d, J=2.8 Hz, 1H),7.60 (dd, J=1.8, 12.7 Hz, 1H), 4.14 (dd, J=7.7, 11.1 Hz, 1H), 3.78 (dd, J=5.6, 11.2 Hz, 1H), 2.84 - 2.63 (m, 4H), 2.38 (s, 3H), 2.13 - 2.07 (m, 1H), 0.42 - 0.38 (m, 2H), 0.26 - 0.21 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d -131.86 (dd, J =2.4, 12.2 Hz, 1F); and enantiomer 2, LCMS (ES+) 424.2 (M+H)+, RT 1.84 min (Analytical method AcHSSC18) 1H NMR (400 MHz, DMSO-d6) d 10.89 (s, 1H), 9.69 (d, J=1.4 Hz, 1H), 9.24 (d, J=1.5 Hz, 1H), 9.12 (d, J=1.5 Hz, 2H), 7.95 (d, J=2.8 Hz, 1H),7.60 (dd, J=1.8, 12.7 Hz, 1H), 4.14 (dd, J=7.7, 11.1 Hz, 1H), 3.78 (dd, J=5.6, 11.2 Hz, 1H), 2.84 - 2.63 (m, 4H), 2.38 (s, 3H), 2.13 - 2.07 (m, 1H), 0.42 - 0.38 (m, 2H), 0.26 - 0.21 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) d -131.86 (dd, J = 2.4, 12.2 Hz, 1F) was obtained.

[0398] Example 42: 5-(3-amino-3-methyl-pyrrolidin-1-yl)-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, racemic

[0399] [ka]

[0400] 3-Methylpyrrolidin-3-amine; dihydrochloride (121 mg, 0.699 mmol, 1.00 eq), 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (214 mg, 0.699 mmol, 1.00 eq), cesium carbonate (456 mg, 1.40 mmol, 2.00 eq), and N,N-dimethylformamide (5 mL) were combined in a sealed tube and heated to 80° C. overnight on a hot block. The reaction was cooled to room temperature, filtered to remove the cesium salts, and purified by preparative HPLC to give the racemic title compound. LCMS (ES+) 370.519 (M+H)+, RT 1.72 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) d 10.42 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 7.94 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.7, 13.1 Hz, 1H), 3.75 - 3.61 (m, 2H), 3.42 - 3.37 (m, 2H), 2.35 (s, 3H), 1.88 - 1.88 (m, 4H), 1.30 (s, 3H). 19 F NMR (400 MHz, DMSO-d6) d -132.18 (dd, J = 2.6 Hz, J = 13.5 Hz).

[0401] Example 43 and Example 44: (R)-5-(3-(cyclopropylamino)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide and (S)-5-(3-(cyclopropylamino)-2-oxopyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0402] [ka]

[0403] 3-Bromopyrrolidin-2-one (250 mg, 1.52 mmol, 1.00 eq), cyclopropylamine (0.13 mL, 1.83 mmol, 1.20 eq), triethylamine (0.64 mL, 4.57 mmol, 3.00 eq), and 4-(dimethylamino)pyridine (37 mg, 0.305 mmol, 0.200 eq) were combined in acetonitrile (7.62 mL), sealed, and heated to 100° C. for 18 h. The cooled reaction mixture was concentrated in vacuo, loaded in DCM, and eluted with 100% ethyl acetate to 2.5% ammonia in methanol (7N). The product was isolated (contaminated with 20% DMAP by HNMR) and used without further purification.

[0404] To a solution of 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (473 mg, 1.55 mmol, 1.00 eq) and tert-butyl 3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate (350 mg, 1.55 mmol, 1.00 eq) in 1,4-dioxane (5.16 mL) was added cesium carbonate (756 mg, 2.32 mmol, 1.50 eq) and the mixture was deoxygenated under N2 sparging for 20 min. Xantphos (90 mg, 0.155 mmol, 0.100 eq) and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.0387 mmol, 0.0250 eq) were added and the mixture was heated to 100° C. under an inert atmosphere for 24 h. The cooled reaction mixture was concentrated (combined with an identical reaction of 3-(cyclopropylamino)pyrrolidin-2-one on a 60 mg scale) then diluted with DCM / acetone and eluted through a 12 g silica gel column using ethyl acetate / isopropyl alcohol (0-5%). The racemic product was isolated and further purified by SFC YMC Amylose-C 10x250mm, 5um 55 / 45 ACN / IPA(0.1%DEA) / CO2, 15ml / min, 120bar, 40°C, DAD 270nm to give the product: Enantiomer 1, 97.3% Rt = 1.86, ee, 100%, Rt = 5.41. LCMS (ES+) 410.2 (M+H)+, RT 1.85min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO-d6) d 10.90 (s, 1H), 9.72 (d, J=1.4 Hz, 1H), 9.24 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 8.33 - 8.19 (m, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.6, 13.0 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.86 - 3.78 (m, 2H), 2.99 - 2.90 (m, 2H), 2.36 (s, 3H), 2.00 - 1.92 (m, 1H), 0.47 - 0.44 (m, 2H), 0.36 - 0.30 (m, 2H); and enantiomer 2, 95.23% Rt = 1.86, ee, 98.3%, Rt = 13.15. LCMS (ES+) 410.2 (M+H)+, RT 1.85 min (analytical method AcHSSC18). 1 H NMR (400 MHz, DMSO-d6) d 10.90 (s, 1H), 9.72 (d, J=1.4 Hz, 1H), 9.24 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 8.33 - 8.19 (m, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.6, 13.0 Hz, 1H), 4.14 - 4.09 (m, 1H), 3.86 - 3.78 (m, 2H), 2.99 - 2.90 (m, 2H), 2.36 (s, 3H), 2.00 - 1.92 (m, 1H), 0.47 - 0.44 (m, 2H), 0.36 - 0.30 (m, 2H).

[0405] Example 45: 5-(3-((3-(2-(dimethylamino)-2-oxoethoxy)azetidin-1-yl)methyl)azetidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0406] [ka]

[0407] Ethyl bromoacetate (1.9 mL, 17.3 mmol, 1 eq) and sodium hydride (60%, 0.83 g, 20.8 mmol, 1.2 eq) were combined in tetrahydrofuran (40 mL). After this, a solution of 1-Boc-3-hydroxyazetidine (3.00 g, 17.3 mmol, 1 eq) in tetrahydrofuran (10 mL) was added dropwise within 2 min under stirring. The resulting solution was stirred at room temperature for 2 h. The reaction was then quenched by the addition of water (20 mL). The resulting solution was diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (3×40 mL) and the organic layers were combined. The resulting mixture was washed with saturated aqueous sodium chloride solution (3×40 mL). The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. Purification by flash silica chromatography (80 g Interchim cartridge, 20% EtOAc to 100% EtOAc in c-hex) gave tert-butyl 3-(2-ethoxy-2-oxo-ethoxy)azetidine-1-carboxylate. 1 H NMR (400 MHz, CDCl3) d , 4.37 - 4.31 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.09 (dd, J=6.7, 10.2 Hz, 2H), 4.04 (s, 2H), 3.92 (dd, J=4.4, 10.1 Hz, 2H), 1.44 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).

[0408] tert-Butyl 3-(2-ethoxy-2-oxo-ethoxy)azetidine-1-carboxylate (500 mg, 1.93 mmol, 1 eq) and trifluoroacetic acid (0.74 mL, 9.64 mmol, 5 eq) were combined in dichloromethane (20 mL) and stirred at room temperature for 17 h. The reaction mixture was concentrated to dryness to give ethyl 2-(azetidin-3-yloxy)acetate. 1H NMR (400 MHz, CDCl3) d 8.80 (s, 1H), 8.33 (s, 1H), 4.58 - 4.50 (m, 1H), 4.41 - 4.31 (m, 2H), 4.29 - 4.19 (m, 4H), 4.14 (s, 2H), 1.30 - 1.26 (m, 3H).

[0409] tert-Butyl 3-formylazetidine-1-carboxylate (339 mg, 1.83 mmol, 1 eq), sodium triacetoxyborohydride (776 mg, 3.66 mmol, 2 eq), and ethyl 2-(azetidin-3-yloxy)acetate;2,2,2-trifluoroacetic acid (500 mg, 1.83 mmol, 1 eq) were combined in dichloromethane (20 mL) and stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3(aq) (50 mL) and the organics were separated and washed with water and brine. The organics were dried over magnesium sulfate, filtered, concentrated to dryness and then passed through an SCX cartridge (10 g) and eluted with DCM:MeOH:7M methanol in ammonia (10:10:1). The collected fractions were concentrated to dryness to give tert-butyl 3-[[3-(2-ethoxy-2-oxo-ethoxy)azetidin-1-yl]methyl]azetidine-1-carboxylate. 1 H NMR (400 MHz, CDCl3) d , 4.24 - 4.16 (m, 3H), 4.01 (s, 2H), 3.97 (t, J=8.1 Hz, 2H), 3.71 - 3.55 (m, 4H), 3.03 - 2.98 (m, 2H), 2.68 - 2.65 (m, 2H), 2.56 - 2.44 (m, 1H), 1.43 (s, 9H), 1.29 (t, J=6.4 Hz, 3H).

[0410] Trifluoroacetic acid (3 mL, 39 mmol, 39 eq) and tert-butyl 3-[[3-(2-ethoxy-2-oxo-ethoxy)azetidin-1-yl]methyl]azetidine-1-carboxylate (330 mg, 1 mmol, 1 eq) were combined in dichloromethane (20 mL) and stirred at room temperature for 72 h. The reaction mixture was concentrated to dryness and passed through an SCX cartridge (5 g) and eluted with DCM:MeOH:7M methanol in ammonia (9:9:1). The eluted fractions were concentrated to dryness to give ethyl 2-[1-(azetidin-3-ylmethyl)azetidin-3-yl]oxyacetate. 1 H NMR (400 MHz, CDCl3) d , 4.24 - 4.00 (m, 6H), 3.75 - 3.56 (m, 4H), 3.39 (t, J=7.3 Hz, 1H), 3.06 - 2.89 (m, 2H), 2.71 - 2.61 (m, 3H), 1.31 - 1.24 (m, 3H), no NH was observed.

[0411] Ethyl 2-[1-(azetidin-3-ylmethyl)azetidin-3-yl]oxyacetate (130 mg, 0.569 mmol, 1 eq), 5-chloro-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (174 mg, 0.569 mmol, 1 eq), and triethylamine (0.16 mL, 1.14 mmol, 2 eq) were combined in acetonitrile (1 mL) and stirred at 55° C. for 6 days. The reaction mixture was concentrated to dryness, partitioned between DCM and water, and the organics were collected by phase separator. The organics were concentrated to dryness and purified by flash silica chromatography (5% MeOH in DCM [+1% 7M methanol in ammonia]) to give ethyl 2-[1-[[1-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]azetidin-3-yl]methyl]azetidin-3-yl]oxyacetate. LCMS (ES+) 498.3 (M+H)+. 1H NMR (400 MHz, CDCl3) d 9.25 - 9.20 (m, 1H), 9.06 (t, J=1.8 Hz, 1H), 8.89 - 8.86 (m, 1H), 7.59 - 7.58 (m, 1H), 7.43 - 7.41 (m, 1H), 6.85 - 6.79 (m, 1H), 4.30 - 4.19 (m, 5H), 4.03 (s, 2H), 3.92 - 3.85 (m, 2H), 3.74 - 3.64 (m, 2H), 3.10 - 3.01 (m, 2H), 2.91 - 2.82 (m, 1H), 2.80 (d, J=7.3 Hz, 2H), 2.47 (s, 3H), 1.29 (t, J=8.2 Hz, 3H).

[0412] Ethyl 2-[1-[[1-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]azetidin-3-yl]methyl]azetidin-3-yl]oxyacetate (40 mg, 0.0804 mmol, 1 eq) and 2M aqueous sodium hydroxide (0.40 mL, 0.804 mmol, 10 eq) were combined in tetrahydrofuran (1 mL) and methyl alcohol (1 mL) and stirred at 50° C. for 17 hours. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give 2-[1-[[1-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]azetidin-3-yl]methyl]azetidin-3-yl]oxyacetic acid. LCMS(ES+) 470.3(M+H)+.

[0413] A solution of 2-[1-[[1-[5-[(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)carbamoyl]pyrazin-2-yl]azetidin-3-yl]methyl]azetidin-3-yl]oxyacetic acid (7.4 mg, 0.0158 mmol, 1 eq) in tetrahydrofuran (1 mL) was diluted with N-(3-dimethylaminopropyl)-N'-ethyl azetidin-3-yl in THF (1 mL) in the dark. Carbodiimide (0.0028 mL, 0.0158 mmol, 1 eq), 1-hydroxybenzotriazole (2.1 mg, 0.0158 mmol, 1 eq), N,N-diisopropylethylamine (0.0055 mL, 0.0315 mmol, 2 eq), and 2-[3-(2-azidoethyl)diazirin-3-yl]ethanamine (2.4 mg, 0.0158 mmol, 1 eq) were added. The mixture was stirred at room temperature for 5 days, after which additional 2-[3-(2-azidoethyl)diazirin-3-yl]ethanamine (2.4 mg, 0.0158 mmol, 1 eq) was added and stirred at room temperature for 2 days. The reaction stalled at 33%. The reaction mixture was concentrated to dryness and purified by preparative HPLC to give 5-[3-[[3-[2-[2-[3-(2-azidoethyl)diazirin-3-yl]ethylamino]-2-oxo-ethoxy]azetidin-1-yl]methyl]azetidin-1-yl]-N-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 606.2 (M+H)+, RT 2.38 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, CD3CN) d 9.46 (s, 1H), 9.07 (d, J=2.3 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.18 (dd, J=1.4, 12.5 Hz, 1H), 6.93 (s, 1H), 4.25 (t, J=8.8 Hz, 2H), 4.22 - 4.16 (m, 1H), 3.87 (dd, J=5.5, 9.6 Hz, 2H), 3.83 (s, 2H), 3.61 - 3.56 (m, 2H), 3.22 (t, J=6.5 Hz, 2H), 3.14 (dd, J=6.9, 13.2 Hz, 2H), 3.05 - 3.00 (m, 2H), 2.89 - 2.79 (m, 1H), 2.76 (d, J=6.8 Hz, 2H), 2.41 (s, 3H), 1.71 (t, J=6.7 Hz, 2H), 1.65 (t, J=6.9 Hz, 2H).

[0414] Example 46: 5-(4-((cyclopropylamino)methyl)-1H-pyrazol-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0415] [ka]

[0416] To a mixture of tert-butyl 4-formyl-1H-pyrazole-1-carboxylate (2.00 g, 10.2 mmol) and cyclopropanamine (1.75 g, 30.6 mmol) in dichloromethane (100 mL) at room temperature was added sodium triacetoxyborohydride (6.48 g, 30.6 mmol). The mixture was stirred at room temperature for 18 h. After this time, aqueous sodium bicarbonate (10% in water, 10 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel; ethyl acetate to methanol; gradient elution) to give impure tert-butyl 4-((cyclopropylamino)methyl)-1H-pyrazole-1-carboxylate, which was used in the next step without further purification.

[0417] To a mixture of tert-butyl 4-((cyclopropylamino)methyl)-1H-pyrazole-1-carboxylate (3.40 g, 14.3 mmol) and triethylamine (2.90 g, 28.7 mmol) in dichloromethane (100 mL) was added di-tert-butyl dicarbonate (3.75 g, 17.2 mmol) at room temperature. The mixture was stirred for 18 h. After this time, the solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel; hexane to ethyl acetate; gradient elution) to give impure tert-butyl 4-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)-1H-pyrazole-1-carboxylate, which was used in the next step without further purification.

[0418] To tert-butyl 4-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)-1H-pyrazole-1-carboxylate (4.82 g, 14.3 mmol) in methanol (100 mL) at room temperature was added potassium carbonate (5.92 g, 42.9 mmol) and the mixture was stirred at room temperature for 18 hours. After this time, the volatiles were removed under reduced pressure and the resulting residue was purified by chromatography (silica gel; ethyl acetate to methanol; gradient elution) to give tert-butyl ((1H-pyrazol-4-yl)methyl)-(cyclopropyl)carbamate. 1H NMR (500 MHz, DMSO-d6) δ 12.65 (br s, 1H), 7.80-7.10 (br m, 2H), 4.18 (s, 2H), 2.40-2.25 (m, 1H), 1.40 (s, 9H), 0.70-0.60 (m, 2H), 0.60-0.50 (m, 2H).

[0419] To a mixture of tert-butyl ((1H-pyrazol-4-yl)methyl)(cyclopropyl)carbamate (0.0466 g, 0.196 mmol) and 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (0.0400 g, 0.131 mmol) in acetonitrile (10 mL) at room temperature was added potassium carbonate (0.0362 g, 0.262 mmol). The mixture was heated at 82° C. for 48 hours. After this time, the volatiles were removed under reduced pressure and the resulting residue was purified by chromatography (silica gel; hexane to ethyl acetate; gradient elution) to give tert-butyl cyclo-propyl((1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)carbamate. 1 H NMR(500 MHz, CDCl3) δ 9.42(s, 1H), 9.26(d, J = 1.4 Hz, 1H), 9.22(d, J = 1.3 Hz, 1H), 9.08(d, J = 1.6 Hz, 1H), 8.49(d, J = 0.5 Hz, 1H), 7.82(s, 1H), 7.45(dd, J = 2.9, 0.6 Hz, 1H), 6.90(dd, J = 10.8, 1.7 Hz, 1H), 4.37(s, 2H), 2.55-2.40(m, 1H), 2.48(d, J = 0.6 Hz, 3H), 1.49(s, 9H), 0.83-0.75(m, 2H), 0.72-0.65(m, 2H); MS(ESI) m / z: [M + H] + C 25 H 28 Calculated for FN8O3 507.2; Found 507.5.

[0420] To a solution of tert-butyl cyclopropyl ((1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-carbamoyl)pyrazin-2-yl)-1H-pyrazol-4-yl)methyl)carbamate (0.070 g, 1.4 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 1 h. After this time, the volatiles were removed under reduced pressure and the resulting residue was treated with sodium bicarbonate (10%, 1 mL). The mixture was concentrated under reduced pressure and purified by chromatography (silica gel; ethyl acetate to methanol; gradient elution). The impure product was repurified by preparative HPLC on an XBridge Prep C18 OBD column (5 μm, 250×19 mm) and eluted according to Method 4. The isolated product was converted to the free base by eluting with methanol on an MP-Carbonate (5 g) column and then purified again by preparative HPLC on an XBridge Prep C18 OBD column (5 μm, 250 × 19 mm) and eluted according to Method 5 to give 5-(4-((cyclopropylamino)methyl)-1H-pyrazol-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-pyrazine-2-carboxamide, mp 194-196 °C; 1 H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.25 (s, 1H), 9.22 (s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.00-7.85 (m, 2H), 7.58 (d, J = 12.8 Hz, 1H), 3.71 (s, 2H), 2.34 (s, 3H), 2.15-2.00 (m, 1H), 0.42-0.32 (m, 2H), 0.32-0.20 (m, 2H); 19 F NMR (471 MHz, DMSO-d6) δ -131.79; MS (ESI) m / z: [M + H] + C 20 H 20Calculated for FN8O 407.2; Found 407.4; UHPLC: Method 2, t R = 2.22 min, >99% (AUC) at 254 and 215 nm; UHPLC-MS: Method 3, t R = 1.16 min, >99% (AUC), MS (ESI) m / z: [M + H] + C 20 H 20 Calculated for FN8O 407.2; Measured 407.5.

[0421] [Table 13]

[0422] [Table 14]

[0423] Other compounds described herein were prepared according to the methods described herein.

[0424] Biological Assay Examples Time-resolved FRET assay: detection of Q48-huntingtin and total huntingtin Detection of endogenous HTT protein in cell lysates was performed using a protocol adapted from Weiss et al. (2009). Single-step detection of mutant huntingtin in animal and human tissues: a bioassay for Huntington's disease. Anal. Biochem. 395(1):8-15.

[0425] The multiplex assay was performed on human embryonic stem cells (GEN020 hESCs carrying a mutant 48Q repeat allele) obtained by Genea Biocell from human blastocysts of HD donors. Bradley CK et al. (2011). Derivation of Huntington's disease-affected human embryonic stem cell lines, Stem Cells Dev. 2011 March;20(3):495-502. Cells were plated in 384-well collagen-coated plates (10,000 cells per well) and left to attach for 24 hours, then test compounds were added for 48 hours (37°C, 5% CO2), then cells were lysed and lysates were transferred to black 384-well assay plates.

[0426] The assay plate contained a combination of HTRF-labeled monoclonal antibodies added to recognize distinct regions of the HTT protein: the Tb "donor" antibody (2B7-Tb: 0.2 ng / well) recognizes a sequence at the N-terminus of the protein, the Alexa488 "receptor 1" antibody (MW1-Alexa488: 30 ng / well) recognizes a region within the polyQ region, while the d2 "receptor 2" antibody (MAB2166-d2: 6 ng / well) recognizes a sequence beyond the polyQ region. These detection reagents were incubated with the cell lysates for 4-6 hours at room temperature, and then their fluorescence was quantified at 615 nm (donor) and 535 and 665 nm (receptor 1 and 2, respectively). The donor / receptor ratio between these signals indicated the relative amounts of mHTT and tHTT.

[0427] Results for various compounds described herein are provided in the table below. tHTT activity in this assay is classified as follows: 10-20 μM (-); 1-10 μM (+); 0.5-1 μM (++); 0.1-0.5 μM (+++); <0.1 μM (++++).

[0428] [Table 15]

[0429] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0430] The disclosure illustratively described herein may suitably be practiced in the absence of any element or limitation not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," etc., shall be read broadly and without limitation. Furthermore, the terms and expressions used herein are used as terms of description, not of limitation, and in the use of such terms and expressions, it is not intended to exclude any equivalents of the features or portions thereof shown and described, and it is recognized that various modifications are possible within the scope of the present disclosure.

[0431] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety as if each was individually incorporated by reference. In case of conflict, the present specification, including definitions, will control.

Claims

1. Compounds of Formula I 【Chemistry 1】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof. (In the formula, X 1 , X 2 , X 3 and X 4 is CR 4 or N, where X 1 , X 2 , X 3 and X 4 At least two but not more than three of are N, Each R 4 are independently hydrogen, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl or C 1～6 is an alkoxy; Y 1 is CR 5 or N, R 5 is hydrogen, heterocyclyloxy, or C 2～6 Alkynyl, aryl, C 1～6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1～6 is an alkoxy; Y 2 does not exist or CR 6 or N, R 6 is hydrogen, cyano, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkylthio, C 1～6 Alkoxy, C 1～6 Haloalkoxy, heterocyclyl, -NH 2 , -NHR 17 or -N(R 17 ) 2 and C on available nitrogen atoms 1～6 Alkyl or C 1～6 optionally substituted with haloalkyl; Y 3 is CR 3 or N, R 3 is hydrogen, cyano, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkylthio, C 1～6 Alkoxy, C 1～6 Haloalkoxy, heterocyclyl, -NH 2 , -NHR 17 or -N(R 17 ) 2 and C on available nitrogen atoms 1～6 Alkyl or C 1～6 optionally substituted with haloalkyl; Each R 17 is independently C 1～4 alkyl, or two R 17 are joined together with any intervening atoms to form a 3- to 6-membered heterocyclyl; Z 1 and Z 2 each of which is 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 may contain halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy and C 1～6 optionally substituted with 1 to 3 substituents independently selected from haloalkoxy and C on an available nitrogen atom; 1～6 Alkyl or C 1～6 optionally substituted with haloalkyl; R 1 Ha-L 1 -R 11 where L 1 -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 12 )-, -C 1～3 Alkylene-, -OC 1～3 Alkylene-, -N(R 12 )-C 1～3 alkylene- or absent, R 11 is C 2～6 Alkynyl, C 3～10 Cycloalkyl, C 6～10 aryl, heteroaryl, or heterocyclyl, where R 11 is 1 to 4 R 13 optionally substituted by a group, R 12 is hydrogen or C 1～6 is alkyl, Each R 13 are independently halo, cyano, hydroxy, R 16 C optionally substituted by 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Hydroxyalkyl, R 16 C optionally substituted by 3～10 Cycloalkyl, R 16 C optionally substituted by 3～10 Cycloalkyl-C 1～6 Alkyl, R 16 C optionally substituted by 6～10 Aryl, R 16 C optionally substituted by 6～10 Aryl-C 1～6 Alkyl, R 16 heteroaryl optionally substituted by R 16 heteroaryl-C optionally substituted by 1～6 Alkyl, R 16 heterocyclyl optionally substituted by R 16 heterocyclyl-C optionally substituted by 1～6 Alkyl, OR 14 , -NH 2 , -NHR 14 , -N(R 14 ) 2 , -C 1～6 Alkylene-NH 2 , -C 1～6 Alkylene-NHR 14 , -C 1～6 Alkylene-N(R 14 ) 2 , -C(O)R 15 , -C(O)OR 15 , -C(O)NHR 15 , -C(O)N(C 1～4 alkyl)R 15 , -S(O) 2 R 15 , -S(O)R 15 , -NHC(O)R 15 , -N(C 1～4 alkyl)C(O)R 15 ,-NHS(O)R 15 , -N(C 1～4 alkyl)S(O)R 15 , -NHS(O) 2 R 15 and -N(C 1～4 alkyl)S(O) 2 R 15 is selected from Each R 14 is independently C 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 aryl, heteroaryl, and heterocyclyl; each R 14 1 to 6 halos, C 1～3 Alkyl, C 1～3 Alkoxy, C 3～10 Cycloalkyl or -NHSO 2 -aryl-N(CH 3 ) 2 and optionally replaced by Each R 15 are independently hydrogen, -OH, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～10 Cycloalkyl, C 6～10 aryl, heteroaryl or heterocyclyl; Each R 16 are independently halo, cyano, hydroxy, -NH 2 , -NHR 21 , -N(R 21 ) 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, OR 21 or C 3～10 is cycloalkyl, Each R 21 independently, C 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 Aryl, heteroaryl, heterocyclyl, and -CH 2 C(O)NHR 22 Each R 21 1 to 6 halos or C 1～3 optionally substituted with alkoxy, R 22 Heterocyclyl and N 3 C is replaced by 1～6 is alkyl, R 2 is hydrogen or C 1～6 is alkyl, However, R 5 is hydrogen, R 1 Ha-OCH 2 C(O)NHR 22 Heterocyclyl-C substituted by 1～6 and heterocyclyl substituted by alkyl.

2. The compound of claim 1 of formula Ia 【Chemistry 2】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or The compound of claim 1 of formula Ib 【Transformation 3】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or The compound of claim 1 of formula Ic 【Chemistry 4】 or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or R8 is hydrogen, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 The compound of claim 1 of formula IIa, which is haloalkoxy. 【Transformation 5】 or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or R 10 is hydrogen, C 1～6 Alkyl or C 1～6 The compound of claim 1 of formula IIb, which is haloalkyl 【Transformation 6】 or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or R8 is hydrogen, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 The compound of claim 1 of formula IIIa, which is haloalkoxy. 【Transformation 7】 or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or R8 is hydrogen, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 The compound of claim 1 of formula IIIb, which is haloalkoxy. 【Transformation 8】 or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof; or R8 is hydrogen, halo, hydroxy, C 1～6 Alkyl, C 1～6 Haloalkyl, C 1～6 Alkoxy or C 1～6 The compound of claim 1 of formula IIIc, which is haloalkoxy. 【Chemistry 9】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

3. R 11 Halo, C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～10 Cycloalkyl, heteroaryl, heterocyclyl, heterocyclyl-C 1～6 Alkyl, -NH 2 , -NHR 14 , -N(R 14 ) 2 , -C 1～6 Alkylene-NH 2 , -C 1～6 Alkylene-NHR 14 , -C 1～6 Alkylene-N(R 14 ) 2 and -C(O)OR 15 and wherein each R 14 independently C 1～6 Alkyl, C 3～10 cycloalkyl and heterocyclyl, and each R 14 is optionally substituted with 1 to 3 halo, where R 15 C 1～6 is alkyl; or R11 【Chemistry 10】 and ring C is a ring having 1 to 4 R 13 or ring C is a 3- to 10-membered heterocyclyl containing 0, 1, or 2 additional ring nitrogen atoms optionally substituted by 1 to 4 R 13 a 5- to 10-membered spiro bicyclic heterocyclyl containing one additional ring nitrogen atom, optionally substituted by a group; or R11 【Chemistry 11】 【change】 each of which is selected from 1 to 4 R 13 optionally substituted by a group; or R11 【Chemistry 12】 each of which is selected from 1 to 4 R 13 10. The compound of claim 1, optionally substituted with a group.

4. R 3 is a halo; or 2. The compound of claim 1, wherein R3 is hydrogen.

5. Each R 4 2. The compound of claim 1, wherein is hydrogen.

6. R 5 is heterocyclyloxy; or R 5 is C 2～6 Alkynyl, aryl, C 1～6 C substituted by alkoxy, heteroaryl, heterocyclyl, or cyano 1～6 2. The compound of claim 1, which is alkoxy.

7. R 5 2. The compound of claim 1, wherein is hydrogen.

8. R 2 2. The compound of claim 1, wherein is hydrogen.

9. L 1 2. The compound of claim 1, wherein:

10. Y 1 is CR 5 2. The compound of claim 1, wherein:

11. Y 2 is CR 6 2. The compound of claim 1, wherein:

12. Y 3 is CR 3 2. The compound of claim 1, wherein:

13. Ring B 【Chemistry 13】 and R 7 is hydrogen and R 8 C 1～6 is alkyl; or Ring B 【Chemistry 14】 and R 7 is hydrogen and R 10 C 1～6 2. The compound of claim 1, wherein the aryl group is alkyl.

14. A compound selected from those in Table 1, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

15. A compound selected from those in Table 2, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

16. 16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15, or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition for treating Huntington's disease in a patient, comprising a compound described in any one of claims 1 to 15, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

18. A pharmaceutical composition for treating Huntington's disease in a patient, comprising a compound described in any one of claims 1 to 15, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein the pharmaceutical composition is administered to the patient in combination with a second active agent.

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