HTT modulators for treating huntington's disease

Abstract

To provide compounds useful as HTT modulators, which are useful in the treatment of Huntington's disease.SOLUTION: Provided are compounds of Formula I, or isotopically enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers thereof, wherein X1 to X4, Y1 to Y3, Z1, Z2, R1, and R2 each represent a specific group, and ring A and ring B each represent a specific ring.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 024,052, filed May 13, 2020, which is hereby incorporated by reference in its entirety.

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

[0003] Huntington's disease (HD) is a genetically inherited, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric deficits, as well as neurodegeneration and brain atrophy that begin in the striatum and cortex and spread to other subcortical brain regions. HD has a worldwide prevalence of 5-10 cases per 100,000 people, 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 are no available treatments that alleviate the disease.

[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) containing an expanded polyglutamine tract 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 obvious therapeutic strategy that targets the gene product of the causative gene. Indeed, several therapeutic strategies aimed at reducing mHTT via antisense oligonucleotide (ASO)- 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 [Problem to be solved by 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 areas, and do not address any peripheral dysfunction that may be caused by widespread mHTT distribution. Therefore, small molecule HTT-reducing agents that can be delivered non-invasively throughout the body are attractive HTT-reducing therapies to pursue. Therefore, there is a need for small molecule modulators of the HTT protein. Such molecules could find use in treating the symptoms of Huntington's disease and / or slowing disease progression. [Means for solving the problem]

[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, pharmaceutically 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 proteins or protein fragments involved in neurodegenerative diseases, such as HTT protein.

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

[0011] The present disclosure also provides compositions, including pharmaceutical compositions, kits, including the compounds, and methods of using (or administering) and making the compounds. The present 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 present 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 INVENTION

[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] Compounds described herein refer to compounds of Formula I, Formula Ia, Formula Ib, Formula Ic, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, Formula IIIf, or compounds described anywhere herein, including the examples, or compounds of any formula described herein, including the compounds of Table 1 or Table 1A, or an isotopically labeled analog, pharmaceutically 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 the 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; a chemical group may be written with or without one or more dashes without losing its normal meaning. A wavy or dotted line drawn through a bond in a structure indicates a particular point of attachment. No anisotropy or stereochemistry is directed or implied by the order in which chemical groups are written or designated, unless chemically or structurally required.

[0016] "C u~v " prefix indicates that the following group has u to v carbon atoms, excluding further substitution. 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 itself. 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 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 specific 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 also be referred to as "alkylene" or "arylene" groups, respectively. Again, unless explicitly stated otherwise, when combinations of groups are referred to herein as a single 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 Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl), and isoprenyl.

[0021] "Alkynyl" refers to an alkyl 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-". Examples of 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 a "(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 refers to a group, wherein R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] "Amide" is -C(O)NR y R z The group refers to the "C-amido" group and the -NR y C(O)R z "N-amido" refers to both the group and the "N-amido" group, where 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, or R y and R z together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0027] "Amino" is -NR y R z refers to a group, wherein 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 may be 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 in no way encompasses or overlaps 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 group refers to the "O-carbamoyl" group and the -NR y C(O)OR z "N-carbamoyl" refers to both the "N-carbamoyl" group and the "N-carbamoyl" group, where 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.

[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 that are saturated or partially unsaturated, having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups that have at least one double bond) and cyclic groups that have 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 contain fused aryl rings, independent of attachment to the rest of the molecule. Furthermore, 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 a single carbon atom of the parent structure. A cycloalkyl 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 ) where each 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.

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

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

[0039] "Halogen" or "halo" refers to a substituent element from Group VIIA of the periodic table, for example, 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 to 6 or 1 to 3) hydrogen atoms, up to and including all hydrogen atoms, are replaced by halogen. For example, if a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may, 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 hydrogen atoms, 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 hydroxy groups.

[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 with 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 with the same or different heteroatom groups. Heteroatom groups include, but are not limited to, NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where 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 fused 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 refers to a heteroaryl 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 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain examples, heteroaryl includes 5-10, 5-7, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, 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, and 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 single or multiple fused rings containing at least one heteroatom is considered 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, and wherein 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., heterocyclyl groups having at least one endocyclic or exocyclic double bond), bridged heterocyclyl groups, fused heterocyclyl groups, oxo-heterocyclyl (i.e., 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 contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O - ) moiety. A heterocyclyl can be attached through a carbon atom or a heteroatom, where valency allows. Furthermore, the term heterocyclyl encompasses any ring system, independent of attachment to the rest of the molecule, including a non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring. A heterocyclyl may have a charge resonance structure that is aromatic (e.g., pyridin-2(1H)-one-1-yl). As used herein, a heterocyclyl refers to a ring system having 3 to 14 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms, or 5 to 6 ring atoms, and / or 2 to 12 ring carbon atoms (i.e., C), with 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 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, and octahydroisoindolyl. Examples include hydroxyl, 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 and 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] "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.

[0049] "Sulfonyl" is -S(O)R y refers to a group, wherein 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.

[0050] "Sulfinyl" is -S(O)R y refers to a group, wherein 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.

[0051] "Sulfonamide" is -SO2NR y R z and -NR y SO2R z refers to a group, wherein R y and R zare each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0052] The term "optionally" 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.

[0053] As used herein, the term "substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms have been 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 replaced by (which is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0054] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, hydroxyl, imino, nitro, azido, oxo, thioxo, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkyl, haloalkoxy, cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -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 have been 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 and R i two of these, together with the atoms 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.

[0055] It is not intended that the above definitions result in polymers or similar amorphous structures, which are arrived at by defining a substituent with an infinite number of additional substituents (e.g., a substituted aryl having a substituted alkyl which 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 impractical or cannot be isolated (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.

[0056] 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.

[0057] Any compound or structure provided herein is intended to represent unlabeled forms of the compound and "isotopically enriched analogs." Isotopically enriched forms of compounds may also be referred to as "labeled." Isotopically enriched analogs have the structures 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. Generally, 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 enriched compounds, for example, radioactive isotopes, 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.

[0058] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogen atoms, e.g., hydrogen atoms on a carbon atom, are replaced by deuterium. Such compounds may exhibit increased resistance to metabolism and may therefore 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 hydrogen atoms have been replaced by deuterium.

[0059] 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 confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by following the procedures disclosed in the schemes or by substituting readily available isotopically enriched reagents for non-isotopically labeled reagents in the examples and preparations described below. Where a compound is described as a deuterated analog, the compound can be obtained using deuterium as a substituent.

[0060] The concentration of such a heavy isotope, specifically deuterium, can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any element not specifically designated as a particular isotope is meant to represent any stable isotope of that element. 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.

[0061] 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.

[0062] Also provided are isotopically enriched analogs, pharmaceutically 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.

[0063] 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 salts" or "physiologically acceptable salts" of the compounds described herein include, for example, acid addition salts obtained by interacting a compound having a basic functional group with an acid, and base addition salts 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 the 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-toluenesulfonic 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(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., Examples of suitable amines include N(substituted alkenyl), mono-, di-, or tri-cycloalkylamines (i.e., NH(cycloalkyl), HN(cycloalkyl), N(cycloalkyl), mono-, di-, or tri-arylamines (i.e., NH(aryl), HN(aryl), N(aryl), 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.

[0064] Some compounds described herein may exist as tautomers. For example, if a compound is depicted as containing an amide, it may also exist as an imidic acid tautomer, and if a compound is depicted as containing a ketone, it may also exist as an enol tautomer. Regardless of which tautomer is depicted and regardless of the nature of the equilibrium between tautomers, it is understood by those skilled in the art that the compound includes both 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.

[0065] 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 configuration 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 racemate (or racemate of a salt or derivative), using, for example, chiral high-performance liquid chromatography (HPLC). When 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.

[0066] "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 each other.

[0067] A "diastereomer" is one of a pair of stereoisomers that have at least two asymmetric elements and are not mirror images of each other.

[0068] A "prodrug" is any molecule that releases a 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 a hydroxy, amino, carboxyl, or sulfhydryl group in the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the respective free hydroxy, amino, or sulfhydryl group. 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 group 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," ACS Symposium Series, Vol. 14, "Design of Prodrugs," H. Bundgaard (ed.), Elsevier, 1985, and Bioreversible Carriers in Drug Design, Edward B. Roche (ed.), American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0069] As used herein, the terms "group," "moiety," "radical," "substituent," and "fragment" are synonymous and are intended to refer to 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.

[0070] The term "active agent" is used to refer to 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, pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or mixture of stereoisomers that has pharmaceutical utility. For example, the active agent may be for anti-neurodegenerative therapy.

[0071] The term "effective amount" refers to an amount of a compound, e.g., as described herein, sufficient to bring about 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 of disease progression, or prevention of disease; for example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease described herein. The (therapeutically) effective amount can vary depending on the subject and 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 skilled in the art.

[0072] 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.

[0073] 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 its wild-type or mutant form, that is capable of forming such aggregates, or may be a protein that is involved in a pathological process related to a neurodegenerative disease.

[0074] In some embodiments, the term "neurodegenerative disease" refers to a disease or condition that impairs the function of a subject's nervous system. Examples of neurodegenerative diseases include those described herein.

[0075] "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 "treatment" is meant any treatment of a disease state in a patient, including

[0076] "Prevention" or "preventing" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may 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.

[0077] "Subject" or "patient" refers to an animal, e.g., a mammal, that is or will be the object of treatment, observation, or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is human.

[0078] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as within 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 the optimal schedule 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 design 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 become apparent to those skilled in the art. Selected compounds may be further characterized to test for safety or tolerability in human or non-human subjects. Such properties may be tested using methods commonly known to those skilled in the art.

[0079] It is understood that certain features described herein, which are described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various features described herein, which are described in the context of a single embodiment for brevity, may also be provided separately or in any suitable subcombination. All combinations of embodiments involving chemical groups represented by variables contained in Formula I, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically incorporated herein, just as if every combination were individually and explicitly recited. In addition, all subcombinations of chemical groups listed in embodiments describing such variables, and all subcombinations of uses and pharmaceutical indications described herein, are also specifically incorporated herein, just as if every subcombination of chemical groups and subcombinations of uses and pharmaceutical indications were individually and explicitly recited. In addition, some embodiments include all combinations of one or more additional agents disclosed herein, just as if every combination were individually and explicitly recited.

[0080] [Table 1] TIFF2025160356000002.tif251158TIFF2025160356000003.tif28158

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

[0082] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: X1 , 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, 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 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 on an available nitrogen atom, C 1~6 Alkyl or C 1~6 optionally substituted with haloalkyl; Y 3 is CR 3 or N, R 3is 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 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 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 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 3~10Cycloalkyl, 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 , -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)2R15 , -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 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 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 independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, and heterocyclyl; each R 21 1 to 6 halo or C 1~3 optionally substituted with alkoxy; R 2 is hydrogen or C1~6 alkyl) is provided.

[0083] In certain embodiments, compounds of formula I

[0084] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: 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, Y 1 is CR 5 or N, Y 2 is CR 6 or N, Y 3 is CR 3 or N, 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 1-3 nitrogen atoms and is substituted on an available carbon atom with halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 Optionally substituted by alkoxy and C on available nitrogen atoms 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 )- or absent, R 11 is 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 , -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)OR15 , -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 R 14 independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, and heterocyclyl; each R 14 is optionally substituted with 1 to 3 halo; 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, amino, alkylamino, dialkylamino or C 1~6 is alkyl, R 2 is hydrogen or C 1~6 is alkyl, R 3 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, heterocyclyl, -NH2, -NHR 17 or -N(R 17 )2, Here, each R 17 is independently C 1~4 alkyl, or two R17 are linked together with any intervening atoms to form a 3- to 6-membered heterocyclyl; Each R 4 are independently hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy; R 5 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, heterocyclyl, -NH2, -NHR 17 , -N(R 17 )2, R 6 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 alkoxy) is provided.

[0085] In certain embodiments, Ring B is a 5-membered heteroaryl containing 1-3 nitrogen atoms.

[0086] In certain embodiments, Ring B is a 6-membered heteroaryl containing 1-3 nitrogen atoms.

[0087] In certain embodiments, ring B is

[0088] [ka] (In the formula, R 7 , R 8 and R 9 each independently represents hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is alkoxy, and R 10 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl).

[0089] In certain embodiments, ring B is

[0090] [ka] (In the formula, R 7 , R 8 and R 9 each independently represents hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is alkoxy, and R 10 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl).

[0091] In certain embodiments, ring B is

[0092] [ka] (In the formula, R 7 , R 8 and R 9 Each of these is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl) is selected from.

[0093] In certain embodiments, ring B is

[0094] [ka] (In the formula, R 7 and R 8 Each of these is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy, R 10 is hydrogen, C 1~6Alkyl or C 1~6 haloalkyl) is selected from.

[0095] In certain embodiments, ring B is

[0096] [ka] (In the formula, R 7 , R 8 and R 9 Each of these is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 alkoxy) is selected from.

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

[0098] [ka] or an isotopically enriched analog, pharmaceutically 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.

[0099] In certain embodiments, a compound of formula Ib

[0100] [ka] or an isotopically enriched analog, pharmaceutically 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 , Z1 and Z 2 is as defined herein.

[0101] In certain embodiments, a compound of formula Ic

[0102] [ka] or an isotopically enriched analog, pharmaceutically 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.

[0103] In certain embodiments, the compound of formula IIa

[0104] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 7 , R 8 , X 1 , X 2 , X 3 , X 4 and Y 1 is as defined herein.

[0105] In certain embodiments, a compound of formula IIb

[0106] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 7 , R 10 , X 1 , X 2 , X 3 , X 4 and Y 1 is as defined herein.

[0107] In certain embodiments, a compound of formula IIc

[0108] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , X 1 , X 2 , X 3 , X 4 and Y 1 is as defined herein.

[0109] In certain embodiments, a compound of formula IId

[0110] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , X 1 , X 2 , X 3 , X4 and Y 1 is as defined herein.

[0111] In certain embodiments, the compound of formula IIIa

[0112] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 8 and Y 1 is as defined herein.

[0113] In certain embodiments, a compound of formula IIIb

[0114] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 8 and Y 1 is as defined herein.

[0115] In certain embodiments, a compound of formula IIIc

[0116] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 8 and Y 1 is as defined herein.

[0117] In certain embodiments, a compound of formula IIId

[0118] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 5 and R 10 is as defined herein.

[0119] In certain embodiments, a compound of formula IIIe

[0120] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 5 and R 10 is as defined herein.

[0121] In certain embodiments, a compound of formula IIIf

[0122] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein R 1 , R 2 , R 3 , R 5 and R 10 is as defined herein.

[0123] In certain embodiments, L1 does not exist or -N(R 12 In certain embodiments, L 1 does not exist.

[0124] 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 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 is C 1~6 It is alkyl.

[0125] In certain embodiments, R 11 is unsubstituted heterocyclyl. In certain embodiments, R 11 is heterocyclyl substituted by methyl.

[0126] In certain embodiments, R 11 teeth

[0127] [ka] and ring C is one to four R 13In certain embodiments, ring C is a 3-10 membered heterocyclyl containing 0, 1, or 2 additional ring nitrogen atoms, optionally substituted by 1 to 4 R groups. 13 substituted by a group

[0128] [ka] In certain embodiments, ring C is selected from 1 to 4 R 13 substituted by a group

[0129] [ka] In certain embodiments, ring C is selected from 1 to 4 R 13 substituted by a group

[0130] [ka] is.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] In certain embodiments, R 11 teeth

[0135] [ka] each of which is selected from 1 to 4 R 13 Optionally substituted by groups.

[0136] In certain embodiments, R 11 teeth

[0137] [ka] each of which is selected from 1 to 4 R 13 Optionally substituted by groups.

[0138] In certain embodiments, R 11 is optionally substituted with 1 to 4 groups independently selected from fluoro, methyl, ethyl, trifluoromethyl, cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, cyclopropylamino, amino, aminomethyl, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, and tert-butoxycarbonyl.

[0139] In certain embodiments, R 11are independently fluoro, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1-ylamino)methyl, cyclopropyl, 1-(cyclopropylamino)-1-cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperdinyl, 1-cyclopropyl-2-piperdinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert-butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxy and optionally substituted by 1 to 4 groups selected from diethyl-N-cyclopropylaminomethyl, N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylaminomethyl, N-isopropyl-N-aminomethyl, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, (3-methoxy-1-azetidinyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, 4-morpholinylmethyl, and tert-butoxycarbonyl.

[0140] In certain embodiments, R 11are independently 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1-ylamino)methyl, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert-butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl and optionally substituted with 1 to 4 groups selected from propyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, isopropylaminomethyl, N-isopropyl-N-aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, (3-methoxy-1-azetidinyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, and 4-morpholinylmethyl.

[0141] In certain embodiments, R 11 is optionally substituted with 1 to 4 groups independently selected from amino, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, and oxetanylamino.

[0142] In certain embodiments, X 1 , X 2 , X 3 and X 4 are N. In certain embodiments, X 1 , X 2 , X 3 and X 4 One of them is N.

[0143] In certain embodiments, Y 2 does not exist or CR 6 Or N.

[0144] In certain embodiments, 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 groups.

[0145] In some embodiments, 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, -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 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 optionally substituted by cycloalkyl or -NHSO-aryl-N(CH), and 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, and 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 3~10cycloalkyl, and each R 21 is independently C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, and heterocyclyl; each R 21 1 to 6 halo or C 1~3 Optionally substituted with alkoxy.

[0146] In certain embodiments, R 2 is hydrogen.

[0147] In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is C 1~6 In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is C 1~6 In certain embodiments, R 3 is methoxy.

[0148] In certain embodiments, each R 4 is hydrogen. In certain embodiments, one R 4 are halo and the rest are hydrogen.

[0149] In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1~6 In certain embodiments, R 5 is methoxy.

[0150] In certain embodiments, R 6 is hydrogen.

[0151] In certain embodiments, R 7 is hydrogen.

[0152] In certain embodiments, R 8 is C 1~6 In certain embodiments, R 8 is methyl.

[0153] In certain embodiments, R 9 is C 1~6 In certain embodiments, R 9 is methyl.

[0154] In certain embodiments, R 10 is C 1~6 In certain embodiments, R 10 is methyl.

[0155] In certain embodiments, L 1 does not exist.

[0156] In certain embodiments, Y 1 is CR 5 In certain embodiments, Y 1 is N. In certain embodiments, Y 1 is CH.

[0157] In certain embodiments, Y 2 is CR 6 In certain embodiments, Y 2 is N. In certain embodiments, Y 2 is CH.

[0158] In certain embodiments, Y 3 is CR 3 In certain embodiments, Y 3 is CH.

[0159] In certain embodiments, Ring B contains 1-3 heteroatoms independently selected from N, O, and S, and is optionally substituted on available carbon atoms with halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C1~6 optionally substituted on an available nitrogen atom with 1 to 3 substituents independently selected from haloalkoxy; 1~6 Alkyl or C 1~6 Optionally substituted with haloalkyl.

[0160] In certain embodiments, ring B is

[0161] [ka] is.

[0162] In certain embodiments, ring B is

[0163] [ka] is.

[0164] In certain embodiments, ring B is

[0165] [ka] is.

[0166] In certain embodiments, each R 13 is halo, C 1~6 Alkyl, R 16 C optionally substituted by 3~10 Cycloalkyl, R 16 heterocyclyl optionally substituted by -NH, -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, independently selected from 16 and R 14 is as defined herein. In certain embodiments, each R 13-NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2, -C 1~6 Alkylene-NHR 14 and -C 1~6 Alkylene-N(R 14 )2, independently selected from 14 is as defined herein. In certain embodiments, each R 13 is halo, C 1~6 Alkyl, -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2, -C 1~6 Alkylene-NHR 14 and -C 1~6 Alkylene-N(R 14 )2, independently selected from 14 is as defined herein. In certain embodiments, R 13 The heterocyclyl of R contains one ring nitrogen atom. 13 is R 16 wherein the heterocyclyl contains one ring nitrogen atom.

[0167] In certain embodiments, R 13 -NH2, -NHR 14 or -C 1~6 Alkylene-NHR 14 and R 14 is as defined herein. In certain embodiments, R 13 Ha-NHR 14 or -C 1~6 Alkylene-NHR 14 and R 14 is as defined herein. In certain embodiments, R 13 Ha-NHR 14 or -C 1~6 Alkylene-NHR 14 and R 14 is C 3~10In certain embodiments, R 13 is -NH-cyclopropyl. In certain embodiments, R 13 is -NH-methyl. In certain embodiments, R 13 is —CH—NH-cyclopropyl. In certain embodiments, R 13 is —CH—NH-methyl. In certain embodiments, R 13 is R 16 -CH2-heterocyclyl optionally substituted by, where R 16 is as defined herein.

[0168] In certain embodiments, R 14 is C 1~6 In certain embodiments, R 14 C is substituted with 1 to 6 fluoro 1~6 In certain embodiments, R 14 is methyl. In certain embodiments, R 14 is C 3~10 In certain embodiments, R 14 is cyclopropyl.

[0169] In certain embodiments, R 15 is hydrogen or C 1~6 It is alkyl.

[0170] In certain embodiments, R 16 is amino, alkylamino, or dialkylamino. In certain embodiments, each R 16 are independently -NH2 and -NHR 21 or -N(R 21 )2, and each R 21 is C 1~6 Alkyl, C 1~6 Haloalkyl or C 3~10 In certain embodiments, each R 16 is independently halo, C 1~6 Alkyl or R 21 and R21 is as defined herein.

[0171] In certain embodiments, compounds of formula I

[0172] [ka] or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: 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, Y 1 is CR 5 or N, Y 2 is CR 6 or N, Y 3 is CR 3 or N, Z 1 and Z 2 each of which is C or N; Ring A and Ring B together form a 9-membered bicyclic heteroaryl containing 1 to 3 ring nitrogen atoms; Ring B is

[0173] [ka] is selected from R 1 Ha-L 1 -R 11 where L 1 -O-, -S-, -S(O)-, -S(O)2-, -N(R 12 )- or absent, R 11 is C 3~10 Cycloalkyl, C 6~10aryl, 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 , -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)R15 , -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 R 14 independently, C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 aryl, heteroaryl, and heterocyclyl; each R 14 is optionally substituted with 1 to 3 halo; 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, amino, alkylamino, dialkylamino or C 1~6 is alkyl, R 2 is hydrogen or C 1~6 is alkyl, R 3 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, heterocyclyl, -NH2, -NHR 17 or -N(R 17 )2, Here, 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; Each R 4 are independently hydrogen, halo, hydroxy, C1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy, R 5 is hydrogen, cyano, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkoxy, heterocyclyl, -NH2, -NHR 17 , -N(R 17 )2, R 6 is hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy, R 7 , R 8 and R 9 each independently represents hydrogen, halo, hydroxy, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 is an alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 haloalkyl) is provided.

[0174] In certain embodiments, a pharmaceutical composition is provided comprising a compound described herein, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

[0175] In certain embodiments, provided are methods of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0176] In certain embodiments, provided are methods of treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein in combination with a second active agent.

[0177] Also provided is a compound selected from Table 1, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0178] [Table 2] TIFF2025160356000036.tif202170TIFF2025160356000037.tif244170TIFF2025160356000038.tif249170TIFF2025160356000039.tif245170TIFF2025160356000040.tif231170TIFF2025160356000041.tif250170TIFF2025160356000042.tif218170TIFF2025160356000043.tif226170TIFF2025160356000044.tif246170TIFF2025160356000045.tif223170TIFF2025160356000046.tif250170TIFF2025160356000047.tif248170TIFF2025160356000048.tif221170TIFF2025160356000049.tif250170TIFF2025160356000050.tif244170TIFF2025160356000051.tif234170TIFF2025160356000052.tif218170TIFF2025160356000053.tif233170TIFF2025160356000054.tif236170TIFF2025160356000055.tif237170TIFF2025160356000056.tif229170TIFF2025160356000057.tif241170TIFF2025160356000058.tif252170TIFF2025160356000059.tif252170TIFF2025160356000060.tif225170TIFF2025160356000061.tif245170TIFF2025160356000062.tif240170TIFF2025160356000063.tif238170TIFF2025160356000064.tif239170TIFF2025160356000065.tif243170TIFF2025160356000066.tif252170TIFF2025160356000067.tif244170TIFF2025160356000068.tif234170TIFF2025160356000069.tif44156.

[0179] Also provided is a compound selected from Table 1A, or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof:

[0180] [Table 3] TIFF2025160356000071.tif236163TIFF2025160356000072.tif245163TIFF2025160356000073.tif254163TIFF202 5160356000074.tif249164TIFF2025160356000075.tif250162TIFF2025160356000076.tif228162TIFF20251603560 00077.tif255162TIFF2025160356000078.tif255161TIFF2025160356000079.tif254164TIFF2025160356000080.t if255162TIFF2025160356000081.tif234163TIFF2025160356000082.tif252164TIFF2025160356000083.tif255162 TIFF2025160356000084.tif254163TIFF2025160356000085.tif239164TIFF2025160356000086.tif253164TIFF202 5160356000087.tif244164TIFF2025160356000088.tif224165TIFF2025160356000089.tif255164TIFF20251603560 00090.tif239164TIFF2025160356000091.tif249163TIFF2025160356000092.tif255163TIFF2025160356000093.t if255164TIFF2025160356000094.tif255164TIFF2025160356000095.tif248165TIFF2025160356000096.tif201164

[0181] Symptoms and Treatment Methods The compounds described herein may be useful for treating diseases or conditions mediated, at least in part, by proteins involved in neurodegenerative diseases. In some embodiments, the compounds described herein are useful for detecting diseases or conditions mediated, at least in part, by HTT protein. In some embodiments, treating diseases or conditions mediated, at least in part, by proteins involved in neurodegenerative diseases may include administering a compound described herein. Treatment may include simultaneously administering a compound described herein and one or more other active agents and / or therapies.

[0182] In some embodiments, provided are methods of treating or preventing a disease or condition mediated, at least in part, by a protein involved in neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein.

[0183] Exemplary diseases or conditions are as follows:

[0184] Huntington's disease (HD) Huntington's disease (HD) is a hereditary, progressive neurodegenerative condition characterized by motor, cognitive, and mental deficits, as well as neurodegeneration and brain atrophy. Atrophy begins in the striatum and cortex and can extend to other subcortical brain regions. HD belongs to a family of neurodegenerative disorders 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 γ-aminobutyric acid-releasing spinous neurons in 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, and memory and / or cognitive impairment.

[0185] Huntingtin protein (HTT protein) is a 348 kDa multidomain protein containing 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; repeats of 36 or more represent the HD allele. The length of the CAG expansion is inversely correlated with the age of disease onset, with cases with 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, incorporated herein by reference in its entirety. Longer polyQ domains are thought to induce conformational changes in the HTT protein, leading to the formation of intracellular aggregates that manifest 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.

[0186] The diagnosis of Huntington's disease is based on a confirmed family history or positive genetic test 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% HD is the cause), with a score of 4 being defined as the onset of motor impairment or "onset" of HD. However, subtle motor, cognitive, and mental deficits can be identified up to 10–15 minutes before the onset of disease symptoms, referred to as the presymptomatic phase of the disease.

[0187] 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., 2018, September-October; 5(5):527-533, which are incorporated herein by reference in their entireties. HD is classified as early stage (stage 1 or 2 TFC score), intermediate stage (stage 3 TFC score), or late stage (stage 4 or 5 TFC score). See, for example, Shoulson, I. et al., Huntington disease: Clinical care and evaluation, Neurology, 1979, 29(1):1; Shoulson, I., Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs, Neurology, 1981, 31(10):1333-35. The parts of the brain most affected by HD, and therefore most likely to contain abnormalities in the HTT protein, are groups 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.

[0188] The basal ganglia are a group of subcortical nuclei 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 thought 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 medium spiny neuron excitability is controlled by several pre- and post-synaptic mechanisms and interneuron activity, and is anchored by several recurrent or internal basal ganglia circuits. The basal ganglia motor circuit 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.

[0189] The compounds described herein, when administered to a subject, can inhibit neuronal degeneration. In some embodiments, inhibiting neuronal degeneration can include inhibiting axon or neuronal degeneration in a neuron. Such inhibition can involve inhibiting the entire neuron or portions thereof, such as the neuronal cell body, axon, and dendrites. This can be assessed, for example, by analyzing nervous system function according to methods known in the art.

[0190] Administration of a compound described herein may result in relief, e.g., at least a 10% (e.g., at least 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 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, touch sensitivity, numbness in the hands and feet, muscle weakness, muscle paralysis, muscle spasms, muscle cramps, muscle spasms, 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.

[0191] Administration of a compound described herein can result in at least a 10% (e.g., at least 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.

[0192] 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 treated 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 treated according to the present disclosure include astrocytes and microglia.

[0193] Neurodegenerative diseases are diseases or conditions that impair the function of a subject's nervous system. Examples of neurodegenerative diseases include, for example, Alexander 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 disease, Krabbe disease, and Chlamydia trachomatis. Examples of conditions that may be present include 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 diseases, 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, and tabes dorsalis.

[0194] 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.

[0195] 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 can be treated by the present disclosure include episodic memory, semantic memory, short-term memory, and long-term memory.

[0196] 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 diseases, 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.

[0197] In some embodiments, the neurodegenerative disease is Huntington's disease.

[0198] 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.

[0199] Pharmaceutical Compositions and Their Administration The compounds provided herein can be administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions containing a compound described herein and a pharmaceutically acceptable excipient are also provided herein.

[0200] Suitable pharmaceutically 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 G.S. Banker & C.T. Rhodes).

[0201] 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, pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0202] Pharmaceutical compositions may be formulated for administration by injection. Examples of forms into 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, glucose, or sterile aqueous solutions, and similar pharmaceutical excipients.

[0203] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable vehicles, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic monoglycerides or diglycerides. Additionally, 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, and with appropriate salts.

[0204] 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 many pharmaceutical compositions for parenteral administration, the carrier constitutes 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.

[0205] Pharmaceutical compositions, e.g., pharmaceutical compositions for injection, may contain cyclodextrin. The cyclodextrin may be, for example, hydroxypropyl cyclodextrin or sulfobutyl ether cyclodextrin. The cyclodextrin may be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0206] The compounds described herein may also be administered via microspheres, liposomes, other microparticle 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-medical 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.

[0207] Pharmaceutical compositions may be formulated for oral administration. Pharmaceutical compositions may be in the form of, for example, capsules or tablets. Oral formulations may include enteric coatings. When prepared, pharmaceutical compositions of the compounds described herein are typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid vehicles), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and packaged sterile powders.

[0208] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Pharmaceutical compositions may 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.

[0209] Pharmaceutical compositions 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 drug delivery is well known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of drugs.

[0210] To prepare solid compositions, e.g., tablets, the compounds described herein can be mixed with pharmaceutical excipients to form solid preformulation compositions containing a homogeneous mixture. These preformulation compositions are referred to as homogeneous because the compound is evenly dispersed throughout the composition, thereby permitting the composition to be readily divided into equally effective unit dosage forms, e.g., tablets, pills, and capsules.

[0211] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, a tablet or pill can contain an inner and outer component, the latter in the form of an outer coating 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 released later. 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.

[0212] The compounds described herein can be incorporated into oral liquid preparations, such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Additionally, pharmaceutical compositions containing the compounds described herein can be presented as a dry product for constitution with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as a non-aqueous vehicle 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).

[0213] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of 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.

[0214] The compounds described herein, or pharmaceutical compositions thereof, may be administered at an appropriate dosage, as determined by an informed physician. The compounds or pharmaceutical compositions may be administered in a single dose or multiple doses, and in a single or multiple dosage form (e.g., two tablets or three capsules). For any particular subject, the appropriate dosage will depend on a variety of factors, including the activity of the specific compound employed, the subject's age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, active agents used in combination, and the severity of the particular disease or condition. For example, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg) 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 daily 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 may be appropriate. In some embodiments, the dose may be administered multiple times per day, e.g., once per day, twice per day, or three times per day. In some embodiments, the dose may be administered every other day, every third day, every fourth day, or once per week. Normalizing according to subject 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 appropriate for a human subject.

[0215] kit Also provided herein is a kit comprising a compound described herein and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound described herein and a label and / or instructions for using the compound in the treatment of a disease or condition described herein.

[0216] 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.

[0217] Combination therapy In some embodiments, the compounds described herein are administered in combination with one or more additional active agents.

[0218] The methods described herein include methods for detecting, treating, or preventing a disease or condition described herein, e.g., 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 compound described herein can be administered before, concurrently with, or after the administration of the additional active agents. Administration can be by one route or by different routes.

[0219] 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. Also provided are 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. 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.

[0220] Also provided are methods for treating or preventing Alzheimer's disease, including treating memory and / or cognitive impairment associated with Alzheimer's disease, comprising administering to a subject, simultaneously or sequentially, a compound described herein and one or more additional agents. In some embodiments, the active agents are Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin™, Eldepryl®, estrogen, or clioquinol.

[0221] 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).

[0222] Compound synthesis The compounds described herein can be prepared using the methods disclosed herein and certain variations thereof, which will be apparent in light of the disclosure herein and methods known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of exemplary 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.

[0223] The compounds described herein can be prepared from readily available starting materials using, for example, 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.

[0224] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, 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.

[0225] Additionally, the compounds described herein may contain one or more asymmetric ("chiral") centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., 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 using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, and the like. When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials can be utilized as routinely used in the art or as described in the Examples.

[0226] 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 commercially 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 ed., 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0227] The terms "solvent," "inert organic solvent," and "inert solvent" refer to a solvent that is inert under the conditions of the reaction being described therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, and the like). Generally, the term inert, as used herein with respect to a solvent, refers to a material that does not undergo 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 conducted under an inert gas, preferably nitrogen or argon.

[0228] The term "quantity" means adding a quantity sufficient to accomplish a stated function, for example, to bring a solution to the desired volume (ie, 100%).

[0229] It will also be 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.

[0230] Incorporation of an isotopic label, e.g., a deuterium atom, into the compounds described herein can be accomplished by reacting the appropriate starting material(s) with a reagent containing a radioisotope. The method generally follows the same principles as standard organic chemistry reactions and can be accomplished by any method known to those skilled in the art, including those provided in this disclosure.

[0231] 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).

[0232] 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 the compound of Formula I.

[0233] [ka]

[0234] In Scheme 1, R 1 , R 2, R 3 , X 1 , X 2 , X 3 , X 4 , Y 1 , and Y 2 is as defined herein. A 1 , A 2 , and A 3 is defined below, and Z 3 -Z 4 -Z 5 is N-CR 7 =CR 8 or C=CR 7 -NR 10 is.

[0235] In Scheme 1, compound Va is 1 can be linked to compound Vb by forming an amide bond via the leaving group in and the amine of compound Vb (as shown in Scheme 1). 1 may be a suitable leaving group, such as a halide, pseudohalogen, carboxylic acid, or carboylate. Compound Va may be prepared by reacting A 1 In the above, the carboxyl group can be activated with 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, e.g., acetonitrile, DMF, or dichloromethane). Alternatively, A 1 In this 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 this embodiment, an 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.

[0236] In Scheme 1, compounds of formula I can be prepared. Thus, compounds Vc can be prepared by a coupling reaction, for example, by addition of a nucleophile, e.g., A 2 In this embodiment, compound Vc can be linked to compound Vd in a coupling reaction by nucleophilic aromatic substitution. 2 may be a suitable leaving group (e.g., a halide, e.g., chloride or fluoride, or a pseudohalogen, e.g., sulfonyl), and A 3 may be a hydrogen atom, or R 1 When A exists 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, e.g., chloride or bromide, or a pseudohalogen, e.g., sulfonyl), and R 1 may contain a suitable coupling functionality (e.g., a carbon-carbon double bond), and A 3 is A 2 (e.g., a hydrogen atom or a tin- or boron-containing group) to the aryl 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).

[0237] In some embodiments, A 2 is R 1 and compound Vc can also be converted directly to compounds of formula I (without reaction with compound Vd).

[0238] 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 Either of the protecting groups may be present in a protected form, for example, an amine or a hydroxyl group. Amine protecting groups include those known in the art and those described herein, such as a tert-butoxycarbonyl group. In such embodiments, an additional deprotection step may be required. For example, if the protecting group is a tert-butoxycarbonyl group, an acidic deprotection step (e.g., using HCl in dioxane or TFA) may be required to prepare a compound of Formula I.

[0239] 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.

[0240] [Example] The following examples are included to demonstrate specific embodiments of the present disclosure. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent well-functioning techniques in the practice of the present disclosure and, therefore, can be considered to constitute specific modes for its practice. However, those skilled in the art will, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments disclosed and still obtain like or similar results without departing from the spirit and scope of the present disclosure.

[0241] Analysis method Acidic QC method AcHSSC18 - Standard Acid UPLC-MS

[0242] [Table 4]

[0243] 10cm_Formic Acid_AQ - Standard Acidic UPLC-MS

[0244] [Table 5]

[0245] Acidic 1 - Standard Acidic UPLC-MS

[0246] [Table 6]

[0247] Basic QC method BicarbBEHC18 - Standard basic UPLC-MS

[0248] [Table 7]

[0249] 10cm_Bicarb_AQ - Standard Basic UPLC-MS

[0250] [Table 8]

[0251] 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.

[0252] Examples 1 to 140 Examples 1-140 were carried out according to the following method: Method A: Ester Hydrolysis The ester, methanol (11 mL / mmol), water (1.08 mL / mmol), and LiOH·HO (1 equiv.) were combined and stirred at room temperature for 17 h and then at 50 °C for 3 days. The reaction mixture was evaporated to dryness to give the corresponding lithium carboxylate salt. Method B HBTU Coupling The lithium carboxylic acid salt, amine (1.0 equiv.), HBTU (1.0 equiv.), triethylamine (12 equiv.), and DMF (7 mL / mmol) were combined and stirred at room temperature for 19 hours. The reaction mixture was filtered and purified by preparative HPLC. Method C HCl Boc Deprotection The Boc-protected amine, methanol (20 mL / mmol), and 4N HCl in dioxane (20 mL / mmol) were combined and stirred at room temperature for 2-17 hours. The reaction mixture was evaporated to dryness and purified by preparative HPLC. method ds N Ar replacement The substituted aryl halide, amine (1 equiv.), cesium carbonate (1.1 equiv.), and DMF (5 mL / mmol) were combined in a sealed tube and heated to 100 °C for 1-5 days. The reaction mixture was cooled to room temperature. The cesium salts were removed by filtration, and the filtrate was evaporated to dryness to give the crude product, which was used directly in the next step. Method D2 S N Ar replacement The substituted aryl halide, amine (1 equiv.), triethylamine (1.1 equiv.), and MeCN (5 mL / mmol) were combined in a sealed tube and heated to 60° C. for 1-5 days. The reaction mixture was evaporated to dryness to give the crude product, which could be purified or used directly in the next step. Method E: TFA Boc Deprotection The Boc-protected amine, dichloromethane (4 mL / mmol) and TFA (23 equiv.) were combined and stirred for 1 day. The reaction mixture was evaporated to dryness and purified by preparative HPLC. Method F CuI coupling conditions A solution of benzamide, aryl halide (1.05 equiv.), copper(I) iodide (0.10 equiv.), potassium carbonate (1.5-2.5 equiv.), and DMEDA (0.20 equiv.) in toluene (2 mL / mmol) was degassed, sealed, and heated at 100° C. for 20-114 h. After this time, the reaction mixture was filtered through Celite and concentrated under reduced pressure. Method G t-BuBrettPhos Conditions The benzamide, aryl halide (1.05 equiv.), tert-BuBrettPhos-Pd-G3 (0.10 equiv.), and K3PO4 (1.4-2.4 equiv.) were placed in a stem block tube. Toluene (3 mL / mmol) was added, and the reaction was degassed. The reaction mixture was heated at 110 °C for 18-114 h. After this time, the reaction mixture was filtered through Celite and concentrated under reduced pressure. Method H TCFH Coupling TCFH (1.20 equiv.) was added to the acid (1.0 equiv.), amine (1.30 equiv.) and 1-methylimidazole (2.5-3.5 equiv.) in MeCN (3 mL / mmol) at room temperature with stirring for 16 hours. Method I: Tri-tert-butylphosphine Buchwald conditions The aryl bromide, amine (2 equiv.), Pd(PtBu3)2 (0.2 equiv.), and Cs2CO3 (3 equiv.) were suspended in dioxane (3 mL / mmol), and the mixture was purged with N2 for 10 min. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washed with DCM, and the filtrate was concentrated to dryness. Method J Pd2(dba)3Buchwald Condition The aryl bromide, amine (1 equiv.), Pd(dba) (0.1 equiv.), rac-BINAP (0.2 equiv.), and CsCO (4 equiv.) were suspended in DMF (3 mL / mmol), and the mixture was purged with N for 10 min. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated to dryness. Method K RuPhos Pd G2 Buchwald Condition Aryl bromide, amine (2 equivalents), RuPhos Pd G2 (0.1 equivalents), and Cs2CO3 (3 equivalents) were added. t BuOH (20 mL / mmol), and the mixture was purged with N for 10 min. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated to dryness. Method L Boc Protection The arylamine (1 equiv.), di-tert-butyl dicarbonate (1.3 equiv.), and EtOAc (0.298 M) were combined and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was washed with EtOAc (×2), and the combined organic layers were washed with brine, dried (phase separation filter paper), and concentrated in vacuo. Method M Aminopyridinium Salt Formation The substituted pyridine (1 equiv.) was dissolved in DMF (0.13 M) and O-(2,4-dinitrophenyl)hydroxylamine (1.1 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. Method N 1,3 Dipolar Addition The aminopyridinium salt (1 equiv.), ethyl 2-butynoate (1.1 equiv.), K2CO3 (1.5 equiv.) were dissolved in DMF (0.088 M) and the reaction mixture was stirred at room temperature overnight. Method O. HBr Decarboxylation The ester (1 equiv.) was dissolved in 48 wt % hydrobromic acid in H2O (0.2 M) and the reaction mixture was stirred at 100°C for 4 h. Method P Pd-catalyzed amidation The lactam (1 equiv.), heteroaryl chloride (1 equiv.), and CsCO (1.5 equiv.) were suspended in dioxane (0.2 M), and the mixture was purged with N for 10 min. Pd(dba) (0.2 equiv.) and Xantphos (0.2 equiv.) were then added, and the tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was evaporated to dryness, loaded onto silica gel in DCM / MeOH, and purified by silica gel chromatography. Method Q Formaldehyde Reductive Amination The amine (1 equiv.), formaldehyde (37% solution, 50 equiv.), methanol (1 mL), and sodium triacetoxyborohydride (2 equiv.) (1.5 equiv.) 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.

[0253] Intermediate 1: 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0254] [ka] 5-Chloro-2-pyrazinecarboxylic acid (960 mg, 6.05 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (1000 mg, 6.05 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (2038 mg, 7.25 mmol), 1-methylimidazole (1.49 mL, 18.16 mmol), and acetonitrile (25 mL) were combined and stirred at room temperature for 18 hours. Water (50 mL) was added, the reaction mixture was filtered, and the solid was dried in vacuo to give 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step. MS (ES+) 306 (M+H), 1 H NMR (400 MHz, CDCl3) 9.37 (1H, s), 9.26 (1H, d, J=1.4 Hz), 9.08 (1H, d, J=1.8 Hz), 8.60 (1H, d, J=1.4 Hz), 7.46 (1H, d, J=2.8 Hz), 6.87 (1H, dd, J=1.8, 10.8 Hz), 2.49 (3H, s).

[0255] Intermediate 2: 5-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide

[0256] [ka] 5-Chloro-2-pyrazinecarboxylic acid (1466 mg, 9.25 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (1500 mg, 9.25 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (3114 mg, 11.10 mmol), 1-methylimidazole (2.20 mL, 27.74 mmol), and acetonitrile (25 mL) were combined and stirred at room temperature for 2 hours. Water (50 mL) was added and stirring was continued for 16 hours. After that, the reaction mixture was filtered and the solid was dried in vacuo to give 5-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step. MS (ES+) 302 (M+H), 1 H NMR (400 MHz, CDCl3) 9.82 (s, 1H), 9.25 (d, J=1.4 Hz, 1H), 9.14 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 7.50 (s, 1H), 2.85 (s, 3H), 2.52 (s, 3H).

[0257] Intermediate 3: 6-ethoxy-2-methyl-2H-indazol-5-amine

[0258] [ka] 6-Ethoxy-5-nitro-1H-indazole (3.12 g, 15.07 mmol), DMF (30 mL), potassium carbonate (2.29 g, 16.58 mmol), and MeI (1.03 mL, 16.58 mmol) were combined and stirred at room temperature for 20 h. The reaction was then diluted with EtOAc, washed with water (3×), brine (1×), evaporated to dryness onto silica, and purified by flash chromatography, revealing that the minor of the two major peaks was 6-ethoxy-2-methyl-5-nitro-2H-indazole, which was used directly in the next step.

[0259] 6-Ethoxy-2-methyl-5-nitro-2H-indazole (117 mg, 0.53 mmol), EtOAc (15 mL), and methanol (15 mL) were combined and pumped through an H-cube equipped with a 10% Pd / C cartridge at a flow rate of 1 mL per minute at 40° C. and 40 bar pressure. The reaction mixture was evaporated to dryness to give 6-ethoxy-2-methyl-2H-indazol-5-amine, which was used crude in the next step.

[0260] Intermediate 4: 6-Methoxy-2-methyl-2H-indazol-5-amine

[0261] [ka] 6-Methoxy-5-nitro-1H-indazole (1 g, 5.18 mmol), potassium carbonate (0.79 g, 5.7 mmol), DMF (10 mL), and MeI (0.35 mL, 5.7 mmol) were combined at room temperature under a nitrogen atmosphere and stirred for 3 days. The reaction mixture was then diluted with EtOAc, washed with water (×3), brine (×1), evaporated to dryness onto silica, and purified by flash chromatography to give two regioisomeric products. The minor regioisomer corresponds to 6-methoxy-2-methyl-5-nitro-2H-indazole. MS (ES+) 208 (M+H). 1 H NMR (400 MHz, DMSO) δ 8.56 (s, 1H), 8.42 (s, 1H), 7.25 (s, 1H), 4.18 (s, 3H), 3.92 (s, 3H).

[0262] 6-Methoxy-2-methyl-5-nitro-2H-indazole (224 mg, 1.08 mmol), EtOAc (15 mL), and MeOH (15 mL) were combined and then pumped at 1 mL per minute through an H-Cube equipped with a 10% Pd / C cartridge at 50 bar of hydrogen and 40° C. The reaction mixture was evaporated to dryness to give 6-methoxy-2-methyl-2H-indazol-5-amine, which was used crude in the next reaction. MS (ES+) 178 (M+H).

[0263] Intermediate 5: N-Isopropylpyrrolidin-3-amine·2HCl

[0264] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1.31 g, 7.07 mmol), isopropylamine (0.67 mL, 7.78 mmol), dichloromethane (10 mL), and sodium triacetoxyborohydride (3.15 g, 14.85 mmol) were combined and stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous NaHCO, extracted with dichloromethane, dried (MgSO), and evaporated to dryness to give tert-butyl 3-(isopropylamino)pyrrolidine-1-carboxylate, which was used crude in the next step.

[0265] tert-Butyl 3-(isopropylamino)pyrrolidine-1-carboxylate (1.53 g, 6.7 mmol), MeOH (5 mL), and 4 N HCl in dioxane (20 mL) were combined and stirred at room temperature for 16 h. The reaction mixture was then evaporated to dryness to give the title compound, which was used crude in the next step.

[0266] Intermediate 6: N-(3,3-Difluorocyclobutyl)pyrrolidin-3-amine·2HCl

[0267] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1310 mg, 7.07 mmol, 1 equiv.) was dissolved in DCM (80 mL) and 3,3-difluorocyclobutan-1-amine (1120 mg, 7.78 mmol, 1.10 equiv.), and sodium triacetoxyborohydride (4650 mg, 21.9 mmol, 3.10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO (aq.) and extracted three times with DCM. The combined organic layers were dried (MgSO) and concentrated in vacuo to give crude tert-butyl 3-((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate, which was used without further purification.

[0268] Crude tert-butyl 3-((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate (1910 mg, 6.92 mmol, 1 equiv.) was dissolved in methanol (5 mL), 4 M HCl in dioxane (20 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to give the crude title compound, which was used without further purification.

[0269] Intermediate 7: N-(oxetan-3-yl)pyrrolidin-3-amine·2TFA

[0270] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1310 mg, 7.70 mmol, 1 equiv.) was dissolved in DCM (10 mL) and oxetan-3-amine (568 mg, 7.78 mmol, 1.10 equiv.), and sodium triacetoxyborohydride (3140 mg, 14.84 mmol, 2.10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO (aq.) and washed three times with DCM. The combined organic layers were washed with saturated brine solution, dried (phase separation filter paper), and concentrated in vacuo to give crude tert-butyl 3-(oxetan-3-ylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0271] Crude tert-butyl 3-(oxetan-3-ylamino)pyrrolidine-1-carboxylate (1.69 g, 7 mmol, 1 equiv.) was dissolved in dichloromethane (5 mL), TFA (4 mL) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to give the crude title compound, which was used without further purification.

[0272] Intermediate 8: (3R * ,4S * )-N-Cyclopropyl-4-fluoro-N-methylpyrrolidin-3-amine·2HCl

[0273] [ka] tert-Butyl (1R * ,5S * )-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (896 mg, 4.69 mmol), N-methylcyclopropanamine (1 g, 14.08 mmol), and water (1 mL) were combined in a sealed tube and heated to 50 °C for 2 days. The reaction was cooled to room temperature, quenched with saturated aqueous NaHCO, extracted with dichloromethane (2x), dried (MgSO), and evaporated to dryness to give tert-butyl (3R * ,4R * )-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate, which was used crude in the next step.

[0274] tert-Butyl (3R * ,4R *)-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate (200 mg, 0.78 mmol) and dichloromethane (10 mL) were combined. Deoxo-Fluor® 50% in THF (0.32 mL, 0.86 mmol) was added dropwise at room temperature and the reaction was stirred overnight. The reaction was quenched by the addition of saturated sodium bicarbonate and extracted with DCM (×2). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give tert-butyl (3R * ,4S * )-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine-1-carboxylate, which was used crude in the next step.

[0275] tert-Butyl (3R * ,4S * )-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine-1-carboxylate, MeOH (3 mL), and 4 N HCl in dioxane (3 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a brown oil, which was used crude in the next step.

[0276] Intermediate 9:(3aR * ,6aS * )-3-Cyclopropylhexahydro-2H-pyrrolo[3,4-d]oxazol-2-one hydrochloride

[0277] [ka] tert-Butyl (1R * ,5S *)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.25 g, 6.75 mmol), cyclopropylamine (8.0 mL, 95.84 mmol), and water (12 mL) were added to the reaction tube. The reaction tube was sealed and heated to 50° C. for 48 hours. The reaction was cooled to room temperature and quenched by the addition of saturated sodium bicarbonate. The aqueous layer was extracted with DCM (×2), and the organic layer was dried (MgSO4). The solvent was removed in vacuo to afford the crude tert-butyl (3R * ,4R * )-3-(cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylate, which was used in the next step without further purification.

[0278] The crude material from the previous step, tert-butyl (3R * ,4R * )-3-(cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylate was dissolved in DCM (40 mL) and di-tert-butyl dicarbonate (1.62 g, 7.43 mmol) was added, followed by triethylamine (2 mL, 14.35 mmol). The reaction was stirred overnight at room temperature. The solvent was removed in vacuo to give the crude tert-butyl (3R * ,4R * )-3-((tert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine-1-carboxylate, which was used in the next step without further purification.

[0279] Crude tert-butyl (3R * ,4R * )-3-((tert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine-1-carboxylate (342 mg, 1.00 mmol) was dissolved in DCM (10 mL). Deoxo-Fluor® 50% in THF (487 mg, 1.10 mmol) was added dropwise at room temperature and the reaction was stirred overnight. The reaction was quenched by the addition of saturated sodium bicarbonate and extracted with DCM (×2). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give tert-butyl (3aR* ,6aS * )-3-Cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate, which was used without further purification.

[0280] Crude tert-butyl (3aR * ,6aS * )-3-Cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate (239 mg, 0.69 mmol) was dissolved in methanol (3 mL) and 4N HCl in dioxane (3 mL) was added dropwise. The reaction was stirred at room temperature overnight and the solvent was removed in vacuo to give the title compound. The material was used in the next step without further purification.

[0281] Intermediate 10: 8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-amine·2HCl

[0282] [ka] 1-Bromo-2,2-dimethoxypropane (4.2 mL, 31.0 mmol) was added to 2-amino-5-bromo-3-methoxypyrazine (3.96 g, 19.4 mmol) and pyridinium p-toluenesulfonate (0.51 g, 1.94 mmol) in isopropanol (60 mL). The reaction mixture was heated at 65° C. for 66 hours. The reaction mixture was cooled to room temperature and diluted with DCM and saturated sodium bicarbonate solution. The layers were separated and the DCM layer was dried (phase separator). The solvent was removed under reduced pressure and the crude material was purified by silica gel column chromatography (gradient elution, 0-100% ethyl acetate in cyclohexane) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J=1.6 Hz, 1H), 6.49 (d, J=1.5 Hz, 1H), 3.99 (s, 3H), 2.43 (s, 3H). LCMS (ES+) 244 (M+H)+, RT 3.07 min (Analysis method AcHSSC18).

[0283] 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine (1 g, 4.13 mmol), acetamide (240 mg, 4.13 mmol), CuI (79 mg, 0.413 mmol), KCO (1.71 g, 12.39 mmol), N,N'-dimethylethylenediamine (73 mg, 0.826 mmol), and toluene (11 mL) were placed in a sealed tube, degassed by bubbling nitrogen through for 5 minutes, and then heated to 100 °C in a hot block for 42 hours. After cooling to room temperature, LCMS analysis indicated partial conversion. The reaction mixture was evaporated to dryness onto silica and purified by flash chromatography eluting with 1–9% MeOH in EtOAc to give N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)acetamide. MS (ES+) 221 (M+H). 1 H NMR (400 MHz, d6-DMSO) δ 10.20 (s, 1H), 8.79 (s, 1H), 7.88 (s, 1H), 4.04 (s, 3H), 2.32 (s, 3H), 2.10 (s, 3H). HCl (4 M in dioxane, 4.3 mL, 17.25 mmol) was added to N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)acetamide (380 mg, 1.73 mmol) in methanol (11 mL) at room temperature with stirring. After 18 hours, the reaction mixture was concentrated under reduced pressure to give the title compound.

[0284] Intermediate 11: N-(tert-butyl)pyrrolidin-3-amine·2HCl

[0285] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv.) was dissolved in DCM (10 mL) and tert-butylamine (0.62 mL, 5.94 mmol, 1.10 equiv.), and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO (aq.) and washed three times with DCM. The combined organic layers were washed with saturated brine solution, dried (phase separation filter paper), and concentrated in vacuo to give crude tert-butyl 3-(tert-butylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0286] Crude tert-butyl 3-(tert-butylamino)pyrrolidine-1-carboxylate (1310 mg, 5.41 mmol, 1 equiv.) was dissolved in methanol (10 mL), 4 M HCl in dioxane (13.5 mL, 54.05 mmol, 10 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude N-(tert-butyl)pyrrolidin-3-amine 2HCl, which was used without further purification.

[0287] Intermediate 12: N-Cyclopropylpyrrolidin-3-amine·2HCl

[0288] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv.) was dissolved in DCM (10 mL) and cyclopropylamine (0.41 mL, 5.94 mmol, 1.10 equiv.), and sodium triacetoxyborohydride (2400 g, 11.34 mmol, 2.10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO (aq.) and washed three times with DCM. The combined organic layers were washed with saturated brine solution, dried (phase separation filter paper), and concentrated in vacuo to give crude tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0289] Crude tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate (1220 mg, 5.39 mmol, 1 equiv.) was dissolved in methanol (10 mL), 4 M HCl in dioxane (13.5 mL, 53.91 mmol, 10 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo to give crude N-cyclopropylpyrrolidin-3-amine 2HCl, which was used without further purification.

[0290] Intermediate 13: N-(cyclopropylmethyl)pyrrolidin-3-amine

[0291] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1000 mg, 5.40 mmol, 1 equiv.) was dissolved in DCM (10 mL) and cyclopropanemethylamine (0.42 mL, 5.94 mmol, 1.10 equiv.), and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO (aq.) and extracted three times with DCM. The combined organic layers were washed with saturated brine solution, dried (phase separation filter paper), and concentrated in vacuo to give crude tert-butyl 3-((cyclopropylmethyl)amino)pyrrolidine-1-carboxylate, which was used without further purification.

[0292] Crude tert-butyl 3-((cyclopropylmethyl)amino)pyrrolidine-1-carboxylate (1340 mg, 5.58 mmol, 1 equiv.) was dissolved in methanol (10 mL), 4 M HCl in dioxane (13.9 mL, 55.75 mmol, 10 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo, and the residue in MeOH was loaded onto a 10 g SCX cartridge (pre-conditioned with MeOH) and eluted with MeOH (2 CV) followed by 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated in vacuo to give crude N-(cyclopropylmethyl)pyrrolidin-3-amine, which was used without further purification.

[0293] Intermediate 14: 4-(pyrrolidin-3-yl)morpholine

[0294] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.4 mmol) and morpholine (0.52 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at room temperature, and the reaction was stirred for 18 hours. The reaction was diluted with DCM, washed with water and brine, and the layers were separated using a phase separator. The solvent was removed in vacuo to give crude tert-butyl 3-morpholinopyrrolidine-1-carboxylate, which was used without further purification.

[0295] tert-Butyl 3-morpholinopyrrolidine-1-carboxylate (1.38 g, 5.40 mmol) was dissolved in methanol (10 mL) and 4 M HCl in dioxane (13.5 mL, 53.99 mL) was added at room temperature. The reaction was stirred for 18 hours, and the solvent was removed in vacuo to give the crude product, which was purified on an SCX 10 g cartridge (pre-conditioned with MeOH) eluting with MeOH (2 CV) followed by 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated in vacuo to give crude 4-(pyrrolidin-3-yl)morpholine, which was used without further purification.

[0296] Intermediate 15: N-Butylpyrrolidin-3-amine·2HCl

[0297] [ka] tert-Butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.4 mmol) and butylamine (0.59 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at room temperature, and the reaction was stirred for 18 hours. The reaction was diluted with DCM, washed with water and brine, and the layers were separated using a phase separator. The solvent was removed in vacuo to give crude tert-butyl 3-(butylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0298] tert-Butyl 3-(butylamino)pyrrolidine-1-carboxylate (1.31 g, 5.41 mmol) was dissolved in methanol (10 mL) and 4 M HCl in dioxane (13.5 mL, 13.5 mL) was added at room temperature. The reaction was stirred for 18 hours and the solvent was removed in vacuo to give crude N-butylpyrrolidin-3-amine, which was used without further purification.

[0299] Intermediate 16: N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine·2HCl

[0300] [ka] Tert-butyl 3-oxopyrrolidine-1-carboxylate (1.31 g, 7.07 mmol) and tetrahydro-2H-pyran-4-amine (787 mg, 7.78 mmol) were dissolved in DCM (50 mL). Sodium triacetoxyborohydride (3.14 g, 14.84 mmol) was added at room temperature, and the reaction was stirred for 18 hours. The reaction was diluted with DCM, washed with water and brine, and the layers were separated using a phase separator. The solvent was removed in vacuo to give crude tert-butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine-1-carboxylate, which was used without further purification.

[0301] tert-Butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine-1-carboxylate (1.82 g, 4.74 mmol) was dissolved in methanol (5 mL) and 4 M HCl in dioxane (20.0 mL, 80 mmol) was added at room temperature. The reaction was stirred for 18 h, and the solvent was removed in vacuo to give crude N-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-amine 2HCl, which was used without further purification.

[0302] Intermediate 17: 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0303] [ka] Sodium hydride (60% dispersion in mineral oil, 256 mg, 6.4 mmol) was added portionwise to a mixture of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine (1.69 g, 5.8 mmol) in methanol (30 mL), and the reaction was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water and brine. The organic layer was concentrated in vacuo to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine, which was used without further purification.

[0304] Intermediate 18: N-(pyrrolidin-3-ylmethyl)cyclopropanamine.2HCl

[0305] [ka] tert-Butyl 3-formylpyrrolidine-1-carboxylate (2 g, 10 mmol), cyclopropylamine (630 mg, 11 mmol), dichloromethane (60 mL), and sodium triacetoxyborohydride (4.45 g, 21 mmol) were combined and stirred at room temperature for 18 h. The reaction mixture was then quenched with saturated aqueous NaHCO, extracted with dichloromethane, dried (MgSO), and evaporated to dryness to give tert-butyl 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylate (2.29 g) as a clear oil, which was used crude in the next step.

[0306] tert-Butyl 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylate (2.29 g, 9.54 mmol), MeOH (20 mL), and 4 N HCl in dioxane (10 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a clear oil, which was used crude in the next step.

[0307] Intermediate 19: N-methyl-N-(pyrrolidin-3-ylmethyl)propan-2-amine.2HCl

[0308] [ka] tert-Butyl 3-((isopropylamino)methyl)pyrrolidine-1-carboxylate (200 mg, 0.83 mmol) was dissolved in DMF (3 mL), and then sodium hydride (60%, 50 mg, 1.24 mmol) and iodomethane (51 μL, 0.83 mmol) were added at room temperature and stirred for 65 h. The reaction mixture was then quenched with aqueous LiCl (4%), extracted with ethyl acetate (×2), dried through phase separator paper, and evaporated to dryness to give tert-butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate (190 mg) as a clear oil, which was used crude in the next step.

[0309] tert-Butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate (190 mg, 0.74 mmol), MeOH (3 mL), and 4 N HCl in dioxane (1.9 mL) were combined and stirred at room temperature for 19 hours. The reaction mixture was then evaporated to dryness to give the title compound as an oil, which was used crude in the next step.

[0310] Intermediate 20: N-(pyrrolidin-3-ylmethyl)propan-2-amine.2HCl

[0311] [ka] tert-Butyl 3-((isopropylamino)methyl)pyrrolidine-1-carboxylate (300 mg, 1.24 mmol), MeOH (5 mL), and 4 N HCl in dioxane (4 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a white solid, which was used crude in the next step.

[0312] Intermediate 21: 6-Methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr

[0313] [ka] From 3-methoxypyridin-4-amine (370 mg, 2.98 mmol, 1 equiv.) following Method L Boc protection. The crude material was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert-butyl (3-methoxypyridin-4-yl)carbamate (590 mg, 88%) as a white solid. LCMS (ES+) 225 (M+H)+

[0314] From tert-butyl (3-methoxypyridin-4-yl)carbamate (590 mg, 2.63 mmol, 1 equiv.) according to Method M. Aminopyridinium salt formation. LCMS showed consumption of the starting material and a new peak with the correct target mass ion (240). The reaction mixture was carried on to the next step without workup (assuming 100% yield).

[0315] From 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridin-1-ium 2,4-dinitrophenolate (1114 mg, 2.63 mmol, 1 equiv.) according to Method N 1,3 dipolar addition. The reaction mixture was concentrated in vacuo onto silica and the crude material purified by silica chromatography, elution gradient 0-75% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (169 mg, 18%) as an off-white solid. LCMS (ES+) 350 (M+H)+ 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.93 (s, 1H), 7.20 (s, 1H), 4.37 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 2.62 (s, 3H), 1.55 (s, 9H), 1.44 (t, J=7.1 Hz, 3H).

[0316] From ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (169 mg, 0.484 mmol, 1 equiv.) according to Method O HBr decarboxylation. The reaction mixture was concentrated in vacuo to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr as a brown oil. Carried on to the next step without further purification.

[0317] Intermediate 22: Ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate and Intermediate 23: Ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate

[0318] [ka] From 3-fluoropyridin-4-amine (925 mg, 8.25 mmol, 1 equiv.) following Method L Boc protection. The crude material was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert-butyl (3-fluoropyridin-4-yl)carbamate (1453 mg, 83%) as a white solid. LCMS (ES+) 213 (M+H)+

[0319] From tert-butyl (3-fluoropyridin-4-yl)carbamate (503 mg, 2.37 mmol, 1 equiv.) according to Method M. Aminopyridinium salt formation. LCMS showed consumption of starting material and a new peak containing the correct target mass ion (228). The reaction mixture was carried on to the next step without workup (assuming 100% yield).

[0320] From 1-amino-4-((tert-butoxycarbonyl)amino)-3-fluoropyridin-1-ium 2,4-dinitrophenolate (1278 mg, 3.11 mmol, 1 equiv.) according to Method N 1,3 dipolar addition. The reaction mixture was concentrated in vacuo onto silica, and the crude material was purified by silica chromatography using an elution gradient of 0 to 20% EtOAc in cyclohexane. Fractions containing the target mass were combined, and the solvent removed in vacuo to give a mixture of ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate and ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate. The crude material was repurified using silica chromatography using an elution gradient of 0 to 18% EtOAc in cyclohexane to give the title compound.

[0321] Ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (product 1) as a yellow solid (127 mg, 12%) LCMS (ES+) 338 (M+H)+

[0322] Ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (product 2) as a yellow solid (265 mg, 25%) LCMS (ES+) 338 (M+H)+ 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.18 (m, 1H), 7.90 (dd, J=7.0, 7.0 Hz, 1H), 6.90 (d, J=1.9 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.55 (s, 9H), 1.40 (t, J=7.3 Hz, 3H).

[0323] Intermediate 24: 6-Fluoro-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr

[0324] [ka] From ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (127 mg, 0.376 mmol, 1 equiv.) according to Method O HBr decarboxylation. The reaction mixture was concentrated in vacuo to give crude 6-fluoro-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr as a brown solid, which was carried on to the next step without further purification.

[0325] Intermediate 25: Ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate and Intermediate 26: Ethyl 5-((tert-butoxycarbonyl)amino)-2,4-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate

[0326] [ka] From 3-methylpyridin-4-amine (600 mg, 5.55 mmol, 1 equiv.) following Method L Boc protection. The crude material was purified using silica chromatography, elution gradient 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give tert-butyl (3-methylpyridin-4-yl)carbamate (939 mg, 81%) as a white solid. LCMS (ES+) 209 (M+H)+

[0327] From tert-butyl (3-fluoropyridin-4-yl)carbamate (939 mg, 4.51 mmol, 1 equiv.) according to Method M. Aminopyridinium salt formation. LCMS showed consumption of starting material and a new peak containing the correct target mass ion (224). The reaction mixture was carried on to the next step without workup (assuming 100% yield).

[0328] From 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium 2,4-dinitrophenolate (1835 mjg, 4.51 mmol, 1 equiv.) according to Method N 1,3 dipolar addition. The reaction mixture was concentrated in vacuo onto silica and the crude material purified by silica chromatography, elution gradient 0 to 50% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give the title compound.

[0329] Ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (product 1) as a yellow oil (516 mg, 34%) LCMS (ES+) 334 (M+H)+ 1 H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 6.45 (s, 1H), 4.37 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 2.26 (s, 3H), 1.56 (s, 9H), 1.44 (dd, J=7.2, 7.2 Hz, 3H).

[0330] Ethyl 5-((tert-butoxycarbonyl)amino)-2,4-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (product 2) as a yellow solid (253 mg, 18%) LCMS (ES+) 334 (M+H)+ 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(d, J=7.4 Hz, 1H), 7.67 (d, J=7.3 Hz, 1H), 6.54 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 2.57 (s, 3H), 1.54 (s, 9H), 1.40 (t, J=7.1 Hz, 3H).

[0331] Intermediate 27: 2,6-Dimethylpyrazolo[1,5-a]pyridin-5-amine.2HBr

[0332] [ka] From ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (250 mg, 0.750 mmol, 1 equiv.) according to Method O HBr decarboxylation. The reaction mixture was concentrated in vacuo to give crude 2,6-dimethylpyrazolo[1,5-a]pyridin-5-amine 2HBr as a brown oil, which was carried on to the next step without further purification.

[0333] Intermediate 28: 6-Ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine

[0334] [ka] From 3-ethoxypyridin-4-amine (2200 mg, 15.9 mmol, 1 equiv.) following Method L Boc protection. tert-Butyl (3-ethoxypyridin-4-yl)carbamate as a yellow solid. Carried on to the next step without further purification.

[0335] From tert-butyl (3-ethoxypyridin-4-yl)carbamate (4200 mg, 17.6 mmol, 1 equiv.) according to Method M. Aminopyridinium salt formation. LCMS showed consumption of starting material and a new peak containing the correct target mass ion (254). The reaction mixture was carried on to the next step without workup (assuming 100% yield).

[0336] From 1-amino-4-((tert-butoxycarbonyl)amino)-3-ethoxypyridin-1-ium 2,4-dinitrophenolate (7702 mg, 17.626 mmol, 1 equiv.) according to Method N 1,3 dipolar addition. The reaction mixture was concentrated in vacuo onto silica and the crude material purified by silica chromatography, elution gradient 0-60% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 5%) as a yellow solid. LCMS (ES+) 364 (M+H)+ 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 4.16 (dt, J=7.5, 14.6 Hz, 2H), 1.52 (s, 9H), 1.50 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.37 - 1.33 (m, 3H).

[0337] From ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 0.941 mmol, 1 equiv.) according to Method O HBr decarboxylation. The reaction mixture was concentrated in vacuo to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr as a brown oil. The crude material was loaded onto a 5 g SCX cartridge (preconditioned with MeOH). The residue was eluted with MeOH and then with 7 M NH3 in MeOH. The ammonia fractions were concentrated in vacuo to give 6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine as a light brown oil. This was carried on to the next step without further purification.

[0338] Intermediate 29: 6-(difluoromethoxy)-2-methyl-2H-indazol-5-amine

[0339] [ka] 5-Bromo-1H-indazol-6-ol (900 mg, 4.22 mmol, 1 equiv.), sodium chlorodifluoroacetate (1288 mg, 8.45 mmol, 2 equiv.), and CsCO (2065 mg, 6.34 mmol, 1.5 equiv.) were dissolved in DMF (10 mL), and the reaction mixture was stirred at 100 °C in a sealed tube for 18 h. EtOAc and HO were added, and the layers were separated. The aqueous layer was washed with EtOAc (×2), and the combined organic layers were washed with brine, dried (phase separator filter paper), and concentrated in vacuo. The crude material was purified by silica chromatography using an elution gradient of 5 to 100% EtOAc in cyclohexane. Fractions containing the desired material were combined, and the solvent was removed in vacuo to give 5-bromo-6-(difluoromethoxy)-1H-indazole (490 mg, 44%) as a yellow solid. LCMS (ES+) 253, 265 (M+H)+ (Br)

[0340] 5-Bromo-6-(difluoromethoxy)-1H-indazole (490 mg, 1.86 mmol, 1 equiv.) was dissolved in EtOAc (50 mL), trimethyloxonium tetrafluoroborate (413 mg, 2.79 mmol, 1.5 equiv.) was added, and the RM was stirred at room temperature for 16 h. EtOAc and HO were added, and the layers were separated. The aqueous layer was washed with EtOAc (×2), and the combined organic layers were washed with brine, dried (phase separation filter paper), and concentrated in vacuo to give 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 77%). LCMS (ES+) 277, 279 (M+H)+ (Br) 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.50 (s, 1H), 7.34 (t, J=74.6 Hz, 1H), 4.18 (s, 3H).

[0341] 5-Bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 1.44 mmol, 1 equiv.), diphenylmethanimine (0.24 mL, 1.44 mmol, 1 equiv.), CsCO (706 mg, 2.16 mmol, 1.5 equiv.), Pd(OAc) (32 mg, 0.14 mmol, 0.1 equiv.), and rac-BINAP (90 mg, 0.14 mmol, 0.1 equiv.) were combined in THF (5 mL), and the mixture was purged with N for 15 min. The reaction mixture was stirred at 80 °C for 18 h in a sealed tube. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous phase was extracted with EtOAc (x3). The combined organic phases were washed with brine, dried (phase separation filter paper), and the solvent was removed in vacuo. The crude material was purified using silica chromatography, elution gradient 0 to 75% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent removed in vacuo to give N-(6-(difluoromethoxy)-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine. Impurities were still present, but it was carried on to the next step without further purification.

[0342] N-(6-(difluoromethoxy)-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine (220 mg, 0.48 mmol, 1 equiv) was dissolved in MeOH (10 mL) and 4 M HCl in dioxane (0.48 mL, 1.91 mmol, 4 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give 6-(difluoromethoxy)-2-methyl-2H-indazol-5-amine.2HCl as a red solid, which was carried on to the next step without further purification.

[0343] Intermediate 30: 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide

[0344] [ka] Method H: From 5-chloropyrazine-2-carboxylic acid (321 mg, 2.02 mmol, 1 equiv.) and 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine.2HBr (858 mg, 2.02 mmol, 1 equiv.) according to TCFH coupling. The reaction mixture was diluted with HO and the solid was filtered. The solid was washed with MeCN:HO (1:2) (×3) to give 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (327 mg, 80% purity, 40%) as a yellow solid. LCMS (ES+) 318 (M+H)+

[0345] Intermediate 31: (6-bromo-8-fluoroimidazo[1,2-a]pyridin-2-yl)methanol

[0346] [ka] 5-Bromo-3-fluoropyridin-2-amine (2 g, 10.47 mmol) and ethyl bromopyruvate (1.4 mL, 11.52 mmol) were dissolved in ethanol (50 mL) and heated at reflux for 18 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo to give a residue. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The EtOAc layer was dried (MgSO4) and the solvent was removed in vacuo to give a residue that was purified using silica chromatography, elution gradient 0-50% EtOAc / cyclohexane to give the title compound as an off-white solid (1.76 g, 59%).

[0347] Methyl 6-bromo-8-fluoroimidazo[1,2-a]pyridine-2-carboxylate (1.76 g, 6.13 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. 1 M DIBAL in toluene (12.88 mL, 12.88 mmol) was added dropwise, and the reaction was allowed to warm to room temperature over 18 hours. The reaction was cooled to 0 °C in an ice bath and quenched by the addition of water. The aqueous layer was extracted with 3 portions of EtOAc, and the organic layer was dried (MgSO). The solvent was removed in vacuo to give a residue that was purified using silica chromatography, eluting with a gradient of 0-100% EtOAc / cyclohexane, to give the title compound as a clear oil (1.1 g, 73%).

[0348] Intermediate 32: (S)-5-(3-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)pyrrolidin-1-yl)pyrazine-2-carboxylate lithium

[0349] [ka] (R)-3-(aminomethyl)-1-Boc-pyrrolidine (1000 mg, 4.99 mmol, 1.00 equiv.), (1-ethoxycyclopropoxy)trimethylsilane (1.0 mL, 4.99 mmol, 1.00 equiv.), and methyl alcohol (50.00 mL) were combined. Sodium cyanoborohydride (345 mg, 5.49 mmol, 1.10 equiv.) was added, followed by acetic acid (0.20 mL). The reaction was then heated to 55° C. in a hot block for 2 days. The reaction was allowed to cool to room temperature. Dilution with dichloromethane, washing with 10% NaOH solution, drying (MgSO4), and concentration in vacuo gave a mixture of tert-butyl (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1-carboxylate and tert-butyl (R)-3-((dicyclopropylamino)methyl)pyrrolidine-1-carboxylate as a clear oil (1.29 g) which was used crude in the next step.

[0350] A mixture of tert-butyl (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1-carboxylate and tert-butyl (R)-3-((dicyclopropylamino)methyl)pyrrolidine-1-carboxylate (1.20 g, 4.99 mmol, 1.00 equiv.), methyl alcohol (10 mL), and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.01 equiv.) was combined and stirred at room temperature for 23 hours. The reaction was then concentrated in vacuo and partitioned between dichloromethane and 15% aqueous NaOH. The organic layer was concentrated in vacuo to give a mixture of N-[[(3S)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride and (S)-N-cyclopropyl-N-(pyrrolidin-3-ylmethyl)cyclopropanamine dihydrochloride as a clear gum (718 mg), which was used directly in the next step.

[0351] A mixture of N-[[(3S)-pyrrolidin-3-yl]methyl]cyclopropanamine and (S)-N-cyclopropyl-N-(pyrrolidin-3-ylmethyl)cyclopropanamine dihydrochloride (700 mg, 4.99 mmol, 1.00 equiv), methyl 5-chloro-2-pyrazinecarboxylate (861 mg, 4.99 mmol, 1.00 equiv), N,N-diisopropylethylamine (2.0 mL, 11.5 mmol, 2.30 equiv), and 1,4-dioxane (100.00 mL) was combined and heated to 100° C. in a hot block for 16 hours. The reaction was cooled to room temperature, and the reaction mixture was used directly in the next step.

[0352] Di-tert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.00 equiv) was added to the reaction mixture from the previous step and stirred at room temperature for 2 hours. The crude reaction was concentrated in vacuo onto silica and purified by flash chromatography to afford methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidin-1-yl]pyrazine-2-carboxylate as a clear gum (682 mg). Used directly in the next step. LCMS (ES+) 377 (M+H)+

[0353] Methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidin-1-yl]pyrazine-2-carboxylate (682 mg, 1.81 mmol, 1.00 equiv.), lithium hydroxide monohydrate (76 mg, 1.81 mmol, 1.00 equiv.), methyl alcohol (30.00 mL), and water (3.00 mL) were combined and heated to 50° C. in a hot block for 16 hours. Concentration in vacuo afforded [5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidin-1-yl]pyrazine-2-carbonyl]oxylithium as a white solid (672 mg). LCMS (ES+) 363 (M+H)+ as the acid.

[0354] Intermediate 33: N-[[(3R)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride

[0355] [ka] N-[[(3R)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride was made using the same chemistry as its enantiomer N-[[(3S)-pyrrolidin-3-yl]methyl]cyclopropanamine dihydrochloride and used directly in the next step.

[0356] Intermediate 34: (R)-5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate lithium

[0357] [ka] (R)-(+)-1-Boc-3-aminopyrrolidine (1000 mg, 5.37 mmol, 1.00 equiv.), (1-ethoxycyclopropoxy)trimethylsilane (1.1 mL, 5.37 mmol, 1.00 equiv.), and methyl alcohol (50.00 mL) were combined. Sodium cyanoborohydride (371 mg, 5.91 mmol, 1.10 equiv.) was added, followed by acetic acid (0.20 mL). The reaction was then heated to 55°C in a hot block for 20 hours. The reaction was cooled to room temperature, diluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO), and concentrated in vacuo to afford tert-butyl (3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate as a clear oil (1.11 g), which was used directly in the next step.

[0358] tert-Butyl (3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate (1.11 g, 4.91 mmol, 1.00 equiv.), methyl alcohol (10.00 mL), and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.07 equiv.) were combined and stirred at room temperature for 20 hours. The reaction was concentrated in vacuo to afford (3R)-N-cyclopropylpyrrolidin-3-amine dihydrochloride as a white semi-solid (985 mg), which was used directly in the next step.

[0359] (3R)-N-Cyclopropylpyrrolidin-3-amine dihydrochloride (985 mg, 4.95 mmol, 1.00 equiv), methyl 5-chloro-2-pyrazinecarboxylate (854 mg, 4.95 mmol, 1.00 equiv), 1,4-dioxane (100.00 mL), and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol, 2.32 equiv) were combined and heated in a hot block at 100° C. for 3 days. The reaction was cooled to room temperature and used crude in the next step.

[0360] Di-tert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.01 equiv) was added to the reaction mixture from the previous step and stirred for 3 days. The reaction was concentrated in vacuo onto silica and purified by flash chromatography to afford methyl 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylate as a pale yellow gum (436 mg), which was used directly in the next step. LCMS (ES+) 363 (M+H)+

[0361] Methyl 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carboxylate (436 mg, 1.20 mmol, 1.00 equiv), lithium hydroxide monohydrate (50 mg, 1.20 mmol, 1.00 equiv), methyl alcohol (30.00 mL), and water (3.00 mL) were combined and heated to 55° C. in a hot block for 20 hours. The reaction was concentrated in vacuo to afford [5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidin-1-yl]pyrazine-2-carbonyl]oxylithium as a light brown glass (349 mg). LCMS (ES+) 349 (M+H)+ as the acid.

[0362] Intermediate 35: N-(azetidin-3-ylmethyl)cyclopropanamine

[0363] [ka] Cyclopropylamine (2.1 mL, 29.7 mmol), tert-butyl 3-formylazetidine-1-carboxylate (5.00 g, 27.0 mmol), and sodium triacetoxyborohydride (12.59 g, 59.4 mmol) were combined in dichloromethane (50.00 mL) and stirred at room temperature for 17 hours. Saturated aqueous sodium bicarbonate (200 mL) was added to the reaction mixture and stirred vigorously for 10 minutes. The organic layer was collected, washed with water and brine, then passed through a phase separator and concentrated to dryness to give the title compound as a clear oil (5.1 g, 83%), which was carried on directly to the next step.

[0364] tert-Butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate (3.00 g, 13.3 mmol, 1.00 equiv.) and trifluoroacetic acid (5.1 mL, 66.3 mmol, 5.00 equiv.) were combined in dichloromethane (30 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated in vacuo, loaded onto an SCX cartridge, and washed with DCM / MeOH (1:1). The compound was released using DCM / MeOH / 7 M ammonia in MeOH (5:5:1) and concentrated to dryness to give N-(azetidin-3-ylmethyl)cyclopropanamine as a colorless oil (1.19 g, 71%). Note: Multiple elutions were required to release the product from the SCX cartridge. 1 H NMR (400 MHz, CDCl3) δ , 3.74 (dd, J=7.8, 7.8 Hz, 2H), 3.44 - 3.35 (m, 2H), 2.94 - 2.91 (m, 2H), 2.91 - 2.83 (m, 1H), 2.13 - 2.05 (m, 1H), 0.46 - 0.40 (m, 2H), 0.33 - 0.28 (m, 2H).

[0365] Intermediate 36: 3-(Azetidin-3-yl)-1-methylpiperidine hydrochloride

[0366] [ka] A mixture of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (250 mg, 1.04 mmol), formaldehyde (37% solution, 3.9 mL, 52.0 mmol), and sodium triacetoxyborohydride (441 mg, 2.08 mmol) in methanol (1 mL) was stirred for 20 hours. Water was added, and the organic layer was extracted with DCM. The combined organic layers were passed through a phase separator and concentrated under reduced pressure to give the crude material as an off-white gum, which was used without further purification (tert-butyl 3-(1-methylpiperidin-3-yl)azetidine-1-carboxylate, 330 mg).

[0367] A solution of tert-butyl 3-(1-methylpiperidin-3-yl)azetidine-1-carboxylate (265 mg, 1.04 mmol) in 4 M HCl in dioxane (8.7 mL, 34.7 mmol) and methanol (8.7 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give the crude material as a colorless oil, which was used without further purification (3-(azetidin-3-yl)-1-methylpiperidine hydrochloride, 310 mg). MS (ES+) 155.1 [M-HCl+H] + .

[0368] Intermediate 37: 3-(Azetidin-3-yl)-1-cyclopropylpiperidine hydrochloride

[0369] [ka] A mixture of tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (250 mg, 1.04 mmol), 1-(ethoxycycloproxy)trimethylsilane (0.23 mL, 1.14 mmol), and sodium cyanoborohydride in methanol (10 mL) and acetic acid (0.1 mL) was heated to 50° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give the crude material as an orange gum, which was carried on without further purification (tert-butyl 3-(1-cyclopropylpiperidin-3-yl)azetidine-1-carboxylate, 224 mg). MS (ES+) 281.2 [M+H] + .

[0370] A solution of tert-butyl 3-(1-cyclopropylpiperidin-3-yl)azetidine-1-carboxylate (224 mg, 0.799 mmol) in 4 M HCl in dioxane (6.7 mL, 26.6 mmol) and methanol (6.7 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give the crude material as a colorless oil, which was used without further purification (3-(azetidin-3-yl)-1-cyclopropylpiperidine hydrochloride, 144 mg). MS (ES+) 181.1 [M-HCl+H] + .

[0371] Intermediate 38: 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide

[0372] [ka] To a suspension of 6-ethoxy-5-nitro-1H-indazole (2.30 g, 11.1 mmol) and potassium carbonate (1.69 g, 12.2 mmol) in N,N-dimethylformamide (20 mL) was added iodomethane (0.76 mL, 12.2 mmol) dropwise, and the reaction was stirred overnight. The reaction mixture was diluted with EtOAc and water, and the organic layer was separated and further extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, decanted, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (0-100% EtOAc in cyclohexane, 80 g column). Product-containing fractions were concentrated under reduced pressure to afford the title compound as a light brown solid (586 mg, 23% yield). MS (ES+) 222.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 4.21 - 4.15 (m, 5H), 1.49 (t, J=7.0 Hz, 3H).

[0373] To a well-degassed suspension of 6-ethoxy-2-methyl-5-nitro-indazole (580 mg, 2.62 mmol) and 1-methyl-1,4-cyclohexadiene (2.9 mL, 26.2 mmol) in ethanol (25 mL) was added 10% palladium on carbon (279 mg, 2.62 mmol), and the reaction was heated to 70 °C overnight. After 24 h, the reaction was cooled to room temperature, filtered through a pad of Celite, and washed with MeOH. The filtrate was concentrated under reduced pressure to give a brown gum, and the crude material was used directly in the next step without further purification (460 mg, 92% yield). MS (ES+) 192.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 4.09 (s, 3H), 3.72 (q, J=7.0 Hz, 2H), 1.49 (t, J=7.0 Hz, 3H).

[0374] A suspension of 6-ethoxy-2-methyl-indazol-5-amine (460 mg, 2.41 mmol), 5-chloro-2-pyrazinecarboxylic acid (381 mg, 2.41 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (810 mg, 2.89 mmol), and 1-methylimidazole (0.58 mL, 7.22 mmol) in acetonitrile (12 mL) was stirred under nitrogen over the weekend. The reaction mixture was diluted with water and stirred for 15 minutes. The reaction mixture was filtered, and the filter cake was collected and dried under reduced pressure to give 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide as a yellow powder (410 mg, 51% yield). MS (ES+) 332.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 9.27 (d, J=1.4 Hz, 1H), 8.81 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 7.82 (s, 1H), 7.02 (s, 1H), 4.22 (q, J=7.0 Hz, 2H), 4.16 (s, 3H), 1.57 (t, J=7.0 Hz, 3H).

[0375] Intermediate 39: N-(azetidin-3-ylmethyl)cyclopropanamine dihydrochloride

[0376] [ka] A suspension of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.44 mmol) and Dess-Martin periodinane (1.24 g, 2.92 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with aqueous sodium thiosulfate (10% w / v) and saturated aqueous sodium bicarbonate and stirred for 20 minutes. The mixture was passed through a phase separator, and the organic layer was concentrated under reduced pressure to give a colorless oil (480 mg, 97% yield), which was used without further purification.

[0377] A mixture of tert-butyl 3-fluoro-3-formyl-azetidine-1-carboxylate (240 mg, 1.18 mmol), sodium triacetoxyborohydride (526 mg, 2.48 mmol), and cyclopropylamine (0.090 mL, 1.30 mmol) in dichloromethane (10 mL) was stirred under nitrogen at room temperature overnight. The reaction mixture was diluted with water and stirred for 10 minutes. The mixture was passed through a phase separator, and the organic layer was concentrated under reduced pressure to give the crude material as a pale yellow gum (250 mg, 87% yield).

[0378] A solution of tert-butyl 3-[(cyclopropylamino)methyl]-3-fluoroazetidine-1-carboxylate (250 mg, 1.02 mmol) in 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) and methanol (5 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to give the crude material as a light brown solid, which was used without further purification (210 mg, 95% yield).

[0379] Intermediate 40: 1-(azetidin-3-ylmethyl)-3-methoxy-azetidine

[0380] [ka] tert-Butyl 3-formylazetidine-1-carboxylate (0.50 g, 2.70 mmol), sodium triacetoxyborohydride (1.26 g, 5.94 mmol), and 3-methoxyazetidine hydrochloride (334 mg, 2.70 mmol) were combined in dichloromethane (50 mL) and stirred at room temperature for 17 hours. Saturated aqueous sodium bicarbonate (15 mL) was added to the reaction mixture, which was stirred vigorously for 10 minutes. The organic layer was collected, washed with water and brine, then passed through a phase separator and concentrated to dryness to give tert-butyl 3-[(3-methoxyazetidin-1-yl)methyl]azetidine-1-carboxylate as a clear oil (700 mg), which was used without further purification.

[0381] tert-Butyl 3-[(3-methoxyazetidin-1-yl)methyl]azetidine-1-carboxylate (700 mg, 2.73 mmol) and trifluoroacetic acid (1.0 mL, 13.7 mmol) were combined in dichloromethane (30 mL) and stirred at room temperature for 21 hours. The reaction mixture was concentrated in vacuo and then dissolved in DCM:MeOH (1:1, 20 mL) and passed through an SCX cartridge. The column was eluted with DCM:MeOH (1:1) to remove TFA, and the product was released using DCM:MeOH:7M NH3 in MeOH (5:5:1). The product-containing fractions were concentrated to dryness to give 1-(azetidin-3-ylmethyl)-3-methoxyazetidine as a colorless oil (400 mg).

[0382] Intermediate 41: 1-Cyclopropyl-3,3'-biazetidine

[0383] [ka] tert-Butyl [3,3'-biazetidine]-1-carboxylate (80 mg, 0.38 mmol), (1-ethoxycyclopropoxy)trimethylsilane (0.15 mL, 0.75 mmol), methanol (2.5 mL), acetic acid (0.01 mL), and sodium cyanoborohydride (47 mg, 0.75 mmol) were combined and stirred for 18 hours at 50° C. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried, and evaporated to give tert-butyl 1'-cyclopropyl-[3,3'-biazetidine]-1-carboxylate (103 mg) as a colorless oil, which was used crude in the next step.

[0384] tert-Butyl 1'-cyclopropyl-[3,3'-biazetidine]-1-carboxylate (100 mg, 0.38 mmol), DCM (1 mL), and TFA (1 mL) were combined and stirred at room temperature for 65 h. The reaction mixture was purified by SCX to give 1-cyclopropyl-3,3'-biazetidine as a crude yellow oil (56 mg), which was used directly in the next step.

[0385] Intermediate 41a: 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine

[0386] [ka] A mixture of 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (prepared according to WO 2015 / 197503, 991 mg, 4.38 mmol) and CuSO (401 mg, 2.51 mmol) in 35% aqueous ammonia (8 mL) was heated to 90 °C under microwave irradiation for 3 h. After cooling to room temperature, the material was filtered through Celite and washed with water and methanol. The filtrate was acidified to pH 4 with 2 M HCl and then concentrated. The residue was applied to a 70 g SCX cartridge and eluted with 100 mL of MeOH followed by 150 mL of 2.3 M NH / MeOH. The ammoniacal fraction was concentrated, and the residue was purified by silica gel column chromatography (gradient elution, 0-20% MeOH / DCM) to give 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine as a brown powder (450 mg, 2.77 mmol, 63%).

[0387] Intermediate H1: 5-chloro-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0388] [ka] 3-Chloro-5-nitro-pyridin-2-amine (0.0010 g, 5.76 μmol), 1-bromo-2,2-dimethoxypropane (0.0012 mL, 9.22 μmol), pyridinium p-toluenesulfonate (0.00014 g, 0.576 μmol), and IPA (10.00 mL) were combined and the RM was stirred at 95° C. for 4.5 hours. The reaction mixture was filtered and washed with IPA to give the desired product (91% purity, 1.5 g, quantitative). LCMS (ES) + ) 212 (M+H) + , RT 1.35 minutes.

[0389] 8-Chloro-2-methyl-6-nitro-imidazo[1,2-a]pyridine (300 mg, 1.42 mmol) and iron (396 mg, 7.09 mmol) in acetic acid (1 mL) were stirred at 60° C. for 1 h. The reaction mixture was loaded onto an SCX cartridge and passed through using NH3 in MeOH (7 M). The filtrate was concentrated, diluted with DCM, and washed with 15 mol% aqueous NaOH. The organic layer was concentrated in vacuo to give the desired product (211 mg, 82%). LCMS (ES + ) 181 (M+H) + , RT 1.05 minutes.

[0390] 8-Chloro-2-methyl-imidazo[1,2-a]pyridin-6-amine (211 mg, 1.16 mmol), 5-chloro-2-pyrazinecarboxylic acid (184 mg, 1.16 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (489 mg, 1.74 mmol), and 1-methylimidazole (0.28 mL, 3.49 mmol) in acetonitrile (8.00 mL) were stirred under nitrogen for 16 hours at room temperature. The reaction mixture was concentrated, diluted with DCM, and washed with aqueous sodium bicarbonate. The organic layer was concentrated onto silica and purified by column chromatography eluting with cyclohexane / EtOAc (0-100% gradient). The appropriate fractions were combined and concentrated in vacuo to give the desired product (211 mg, 75%). LCMS (ES) + ) 322 (M+H) + , RT 1.23 minutes. 1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 9.26 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 7.47 (s, 1H), 7.19 (d, J=1.6 Hz, 1H), 2.51 (s, 3H).

[0391] Intermediate H2 (5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide)

[0392] [ka] 5-Bromo-3-methoxy-pyridin-2-amine (3.57 g, 17.6 mmol), 1-bromo-2,2-dimethoxypropane (3.8 mL, 28.1 mmol), pyridinium p-toluenesulfonate (0.44 g, 1.76 mmol), and IPA (10.00 mL) were combined. The RM was stirred at 95 °C for 5 h. The reaction mixture was diluted with 3:1 DCM / IPA and washed with brine. The organic layer was concentrated in vacuo to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (4.2 g, 96%). LCMS (ES) + ) 242 (M+H) + , RT 1.02 minutes. 1 H NMR (400 MHz, DMSO) δ 8.44 (1H, d, J=1.6 Hz), 7.66 (1H, s), 6.81 (1H, d, J=1.5 Hz), 3.95 (3H, s), 2.32 (3H, s).

[0393] 6-Bromo-8-methoxy-2-methyl-imidazo[1,2-a]pyridine (1.01 g, 4.19 mmol), copper(I) iodide (0.16 g, 0.838 mmol), potassium carbonate (0.87 g, 6.28 mmol), ammonium hydroxide solution (0.26 mL, 6.28 mmol), L-proline (0.19 g, 1.68 mmol), and DMSO (10.00 mL) were added to a reaction flask. The reaction vessel was sealed and heated at 90° C. for 16 hours. The reaction mixture was passed through an SCX cartridge using MeOH and NH3 in MeOH (7 M), and the appropriate fractions were concentrated in vacuo to give the desired product (1.19 g, 99%). LCMS (ES) + ) 179 (M+H) + .

[0394] A mixture of 8-methoxy-2-methyl-imidazo[1,2-a]pyridin-6-amine (326 mg, 1.84 mmol), 5-chloro-2-pyrazinecarboxylic acid (292 mg, 1.84 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (774 mg, 2.76 mmol), and 1-methylimidazole (0.44 mL, 5.52 mmol) in acetonitrile (8.00 mL) was stirred at room temperature under nitrogen for 16 h. The reaction mixture was concentrated, diluted with 3:1 DCM:IPA, and washed with brine. The crude product was purified by column chromatography eluting with cyclohexane / EtOAc (0-100% gradient) to give 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (909 mg, 87%). LCMS (ES + ) 317 (M+H) + .

[0395] Intermediate H3: 5-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0396] [ka] HBTU (1.88 g, 4.96 mmol, 1.00 equiv.), triethylamine (3.5 mL, 24.8 mmol, 5.00 equiv.), 5-chloro-2-pyrazinecarboxylic acid (0.79 g, 4.96 mmol, 1.00 equiv.), N,N-dimethylformamide (10.00 mL), and 7-fluoro-2-methyl-indazol-5-amine hydrochloride (1.00 g, 4.96 mmol, 1.00 equiv.) were combined and stirred at room temperature for 17 h. LCMS indicated the absence of the expected chlorinated material; instead, the HOBt adduct had formed. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed multiple times with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. Note: A significant amount of the HOBt adduct remained in the aqueous layer. The material was purified by flash silica chromatography (gradient elution c-hex to EtOAc) to give 5-(benzotriazol-1-yloxy)-N-(7-fluoro-2-methyl-indazol-5-yl)pyrazine-2-carboxamide as a pale yellow solid (586 mg, 28%). LCMS (ES+) 405 (M+H) + . 1 H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 9.16 (s, 1H), 8.82 (s, 1H), 8.48 (d, J=2.7 Hz, 1H), 8.25 - 8.20 (m, 2H), 7.87 (d, J=8.3 Hz, 1H), 7.71 (dd, J=7.6, 7.6 Hz, 1H), 7.62 - 7.57 (m, 2H), 4.20 (s, 3H).

[0397] Intermediate 42: 7-Fluoro-2-methyl-2H-indazol-5-amine hydrochloride

[0398] [ka] 5-Bromo-2,3-difluorobenzaldehyde (5 g, 22.6 mmol), methoxyamine hydrochloride (2.27 g, 27.1 mmol), and potassium carbonate (6.88 g, 49.8 mmol) were added to ethylene glycol dimethyl ether (100 mL). The reaction was heated to 45° C. for 18 hours. The reaction was cooled to room temperature, filtered through a glass sinter, and the collected solid was washed with EtOAc. The collected liquid was concentrated in vacuo to give 5-bromo-2,3-difluorobenzaldehyde O-methyloxime as a pale yellow solid (6.82 g, 100%).

[0399] 5-Bromo-2,3-difluorobenzaldehyde O-methyloxime (5.66 g, 22.6 mmol) was dissolved in 1,4-dioxane (150 mL) and hydrazine (3.6 mL, 0.113 mol) was added. The reaction was heated at 90° C. for 5 days. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by silica chromatography EtOAc / cyclohexane 0-40% to give 5-bromo-7-fluoro-2H-indazole as an off-white solid (3.83 g, 71%).

[0400] 5-Bromo-7-fluoro-1H-indazole (3.83 g, 17.8 mmol) was dissolved in ethyl acetate (100 mL) and cooled to 0 °C using an ice bath. Trimethyloxonium tetrafluoroborate (3.95 g, 26.7 mmol) was added in small portions, and once the addition was complete, the reaction was allowed to warm to room temperature. The reaction was stirred for 18 hours at room temperature. The reaction was quenched with water, extracted with EtOAc, and the layers were separated. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel, eluting with 0 to 50% EtOAc in cyclohexane to give 5-bromo-7-fluoro-2-methyl-2H-indazole as an off-white solid (2.42 g, 55%).

[0401] 5-Bromo-7-fluoro-2-methyl-indazole (2.42 g, 10.6 mmol) was dissolved in degassed tetrahydrofuran (100 mL) and cesium carbonate (5.16 g, 15.8 mmol), palladium(II) acetate (0.24 g, 1.06 mmol), (rac)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.66 g, 1.06 mmol), and benzophenone imine (1.8 mL, 10.6 mmol) were added. The reaction tube was purged with nitrogen and sealed. The reaction was heated at 80°C for 18 hours. The reaction was cooled to room temperature, and the solid was filtered and washed with EtOAc. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography on silica gel eluting with 0 to 100% EtOAc / cyclohexane to give 3 g of an oil. 1 H NMR analysis showed mainly starting material, 5-bromo-7-fluoro-2-methyl-indazole, with 35% conversion to N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine.

[0402] The impure material (3.00 g, 4.58 mmol, assumed 35% purity) was dissolved in degassed tetrahydrofuran (80 mL) and cesium carbonate (2.24 g, 6.88 mmol), palladium(II) acetate (0.21 g, 0.917 mmol), (rac)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.57 g, 0.917 mmol), and benzophenone imine (0.92 mL, 5.50 mmol) were added. The reaction tube was purged with nitrogen and sealed. The reaction was heated at 80 °C for 24 h. The reaction was cooled to room temperature, and the solid was filtered and washed with EtOAc. The filtrate was concentrated in vacuo to give a residual oil. The residue was purified by column chromatography on silica gel eluting with 0-100% EtOAc / cyclohexane to give N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethanimine as an off-white solid (2.56 g, >100%).

[0403] N-(7-Fluoro-2-methyl-indazol-5-yl)-1,1-diphenyl-methanimine (2.56 g, 7.77 mmol) was suspended in methyl alcohol (10 mL) and 4N hydrogen chloride in dioxane (19 mL, 77.7 mmol) was added at room temperature. The reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give a pale yellow solid. EtOAc was added and the formed slurry was stirred for about 10 minutes. The solid was filtered and washed with more EtOAc to give the title compound as an off-white solid (1.66 g, 95%). LCMS (ES+) 166 (M+H)+

[0404] Intermediate 43: tert-butyl cyclopropyl((2-oxopyrrolidin-3-yl)methyl)carbamate

[0405] [ka] To a stirred solution of 3-(hydroxymethyl)pyrrolidin-2-one (780 mg, 6.77 mmol) in dichloromethane (50 mL) and triethylamine (1.9 mL, 13.5 mmol) at room temperature was added dropwise methanesulfonyl chloride (0.58 mL, 7.45 mmol). The reaction was stirred for 18 hours at room temperature. The reaction was quenched by the addition of water, and the layers were separated using a phase separator. The DCM was removed in vacuo to give (2-oxopyrrolidin-3-yl)methyl methanesulfonate as a white solid (800 mg, 61%).

[0406] (2-Oxopyrrolidin-3-yl)methyl methanesulfonate (800 mg, 4.14 mmol) was dissolved in acetonitrile (15 mL) and triethylamine (1.7 mL, 12.4 mmol) was added, followed by cyclopropylamine (1.7 mL, 24.8 mmol). The reaction tube was sealed and heated in a microwave for 2 hours at 120° C. The solvent was removed in vacuo to give a residue that was purified by SCX chromatography (5 g, eluted with MeOH / DCM 50% followed by 10% 7N NH3 / MeOH in MeOH). The ammonia fractions were combined and the solvent was removed in vacuo to give 3-((cyclopropylamino)methyl)pyrrolidin-2-one as a yellow oil (438 mg, 69%).

[0407] 3-[(Cyclopropylamino)methyl]pyrrolidin-2-one (438 mg, 2.84 mmol) was dissolved in dichloromethane (30 mL). Di-tert-butyl dicarbonate (0.72 mL, 3.12 mmol) and 4-(dimethylamino)pyridine (17 mg, 0.142 mmol) were added. The reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give a residue that was purified by silica chromatography (10 g, eluted with EtOAc) to give the title compound as a clear oil (420 mg, 58%).

[0408] Intermediate 44: 5-chloro-N-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0409] [ka] 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 7-fluoro-2-methyl-indazol-5-amine hydrochloride (254 mg, 1.26 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (0.53 mL, 3.78 mmol) was added, and the reaction was stirred at room temperature for 3 hours. The reaction was quenched by the addition of water, and the aqueous layer was extracted with DCM. The layers were separated using a phase separator, and the DCM was removed in vacuo to give the title compound as a light brown solid (280 mg, 65%). It was used in the next step without further purification.

[0410] Intermediate 45: 5-chloro-N-(1H-indazol-5-yl)pyrazine-2-carboxamide

[0411] [ka] 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 2H-indazol-5-amine (168 mg, 1.26 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (0.53 mL, 3.78 mmol) was added at room temperature, and the reaction was stirred at room temperature for 3 hours.

[0412] The reaction was quenched with water and the aqueous layer was extracted three times with DCM. The layers were separated using a phase separator and the solvent was removed in vacuo to give the title compound as a brown solid (305 mg, 79%). It was used in the next step without further purification.

[0413] Intermediate 46: 5-chloro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)pyrazine-2-carboxamide

[0414] [ka] 4-Fluoro-2-methyl-1,3-benzoxazol-6-amine (200 mg, 1.20 mmol), 5-chloro-2-pyrazinecarboxylic acid (191 mg, 1.20 mmol), and 1-methylimidazole (0.29 mL, 3.60 mmol) were suspended in acetonitrile (10 mL). Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (400 mg, 1.43 mmol) was added, and the suspension was stirred at room temperature for 18 hours.

[0415] The solid that formed was collected by filtration and washed with acetonitrile and water. The solid was dried in a vacuum oven overnight to give the title compound as an off-white solid (250 mg, 67%), which was used in the next step without further purification.

[0416] Intermediate 47: 5-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)azetidin-1-yl)pyrazine-2-carboxylic acid

[0417] [ka] tert-Butyl N-(azetidin-3-ylmethyl)carbamate (675 mg, 3.62 mmol), methyl 5-chloro-2-pyrazinecarboxylate (625 mg, 3.62 mmol), cesium carbonate (2373 mg, 7.28 mmol), and 1,4-dioxane (25 mL) were combined and heated at reflux overnight. The reaction was cooled to room temperature, and the solvent was removed in vacuo. The residue was taken up in DCM, washed with water, and the layers were separated using a phase separator. The DCM was removed in vacuo to give a residue. The residue was purified by column chromatography on silica gel (25 g, eluting with 0-100% EtOAc in cyclohexane) to give a yellow oil (870 mg, 74%).

[0418] Methyl 5-[3-[(tert-butoxycarbonylamino)methyl]azetidin-1-yl]pyrazine-2-carboxylate (250 mg, 0.776 mmol) was dissolved in N,N-dimethylformamide (5 mL) and sodium hydride (60%, 34 mg, 0.853 mmol) was added. The reaction was stirred at room temperature for 1 hour. Iodomethane (0.048 mL, 0.776 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with MeOH (to avoid ester hydrolysis) and the solvent was removed in vacuo to give a residual oil. This was used in the next step without further purification. Methyl 5-[3-[[tert-butoxycarbonyl(methyl)amino]methyl]azetidin-1-yl]pyrazine-2-carboxylate (261 mg, 0.776 mmol) was dissolved in methyl alcohol (2 mL) and water (1 mL) and lithium hydroxide monohydrate (33 mg, 0.776 mmol) was added. The reaction was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (2 mL). The pH was adjusted to pH = 3 with 1 M HCl and the aqueous layer was extracted with 4 portions of EtOAc. The organic layer was separated and dried by passing through a hydrophobic frit. The solvent was removed in vacuo to give the title compound as a clear oil (155 mg, 61%). It was used in the next step without further purification.

[0419] Intermediate 48: 7-Fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-amine.HCl

[0420] [ka] 4-Fluoro-3-methyl-pyridin-2-amine (500 mg, 3.96 mmol, 1.00 equiv), N-bromosuccinimide (706 mg, 3.96 mmol), and dichloromethane (20 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness to give a brown solid, which was used crude in the next step. LCMS (ES+) 205 / 207 (M+H)+.

[0421] 5-Bromo-4-fluoro-3-methyl-pyridin-2-amine (813 mg, 3.96 mmol) (crude from the previous step), 1-bromo-2,2-dimethoxypropane (0.80 mL, 5.95 mmol), pyridinium p-toluenesulfonate (100 mg, 0.396 mmol), and 2-propanol (15 mL) were combined in a sealed tube and heated to 85 °C on a hot block overnight. An off-white precipitate was observed. The reaction mixture was cooled to room temperature, concentrated in vacuo, and partitioned between approximately 10% aqueous NaOH and dichloromethane. The organic phase was dried (MgSO4) and concentrated in vacuo to give 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine (856 mg) as a brown solid. LCMS (ES+) 243 / 245 (M+H)+. 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J=6.3 Hz, 1H), 7.25 (s, 1H), 2.53 (d, J=2.5 Hz, 3H), 2.44 (s, 3H).

[0422] Cesium carbonate (1721 mg, 5.28 mmol), palladium(II) acetate (79 mg, 0.352 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (219 mg, 0.352 mmol), 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine (856 mg, 3.52 mmol), and tetrahydrofuran (20 mL) were combined, and the reaction mixture was degassed by bubbling nitrogen through for 5 minutes. The reaction tube was sealed and heated to 85 °C on a hot block over the weekend. The reaction mixture was filtered through a Celite plug to remove cesium salts and rinsed with EtOAc. The organic phase was concentrated in vacuo onto silica and purified by flash chromatography. The starting material and target appeared to co-flow. 622 mg, light brown solid. LCMS basic, retention time = 1.42 min, 243 / 245 M+H starting material, retention time = 1.70 min, 344 M+H target. Used directly in next step.

[0423] A mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine and N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methanimine (622 mg, from the previous step), methyl alcohol (5 mL), and 4 M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) was combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to give 767 mg of a light brown solid. LCMS analysis indicated a mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine and 7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-amine.HCl. LCMS basic, retention time = 1.04 min, 180 M+H target, retention time = 1.42 min, 243 / 245 bromide in starting material. Used directly in next step.

[0424] [Example 1] (R)-5-(2-ethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0425] [ka] To a solution of Intermediate 1 (150 mg, 0.49 mmol) in dioxane (1 mL) was added tert-butyl (R)-3-ethylpiperazine-1-carboxylate (263 mg, 1.23 mmol). Triethylamine (0.1 mL, 0.74 mmol) was added, and the reaction was heated in a microwave at 140 °C for 30 minutes. The solvent was removed in vacuo, and the residue was purified by silica chromatography using an elution gradient of 0-10% ethyl acetate / cyclohexane to give tert-butyl (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate. MS (ES+) 484 (M+H).

[0426] To a solution of tert-butyl (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate (140 mg, 0.29 mmol) in methanol (2 mL) was added 4 M hydrochloric acid in dioxane (10 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude product was purified by reverse-phase HPLC to give the target TFA salt. The TFA salt was dissolved in methanol / DCM 1:1 and MP-carbonate was added. The mixture was left for 18 h. The MP-carbonate was filtered and the solvent removed in vacuo to give the title compound. LCMS (ES+) 384 (M+H)+, RT 1.85 min (analytical method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.77 (s, 1H), 8.31 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.60 (dd, J=1.1, 12.7 Hz, 1H), 4.47 - 4.44 (m, 1H), 4.32 (d, J=12.9 Hz, 1H), 3.14 - 2.98 (m, 3H), 2.81 (dd, J=2.9, 12.5 Hz, 1H), 2.70 - 2.64 (m, 1H), 2.39 (s, 3H), 1.92 - 1.74 (m, 2H), 0.89 (t, J=7.5 Hz, 3H).

[0427] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0428] [Table 9] TIFF2025160356000155.tif254170TIFF2025160356000156.tif254170TIFF2025160356000157.tif95170

[0429] [Example 12] 5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2)

[0430] [ka] Prepared using general method D and the following amounts: Intermediate 1 (127 mg, 0.41 mmol), N-(pyrrolidin-3-ylmethyl)cyclopropanamine dihydrochloride (87 mg, 0.41 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (3 mL). The crude material was purified by preparative HPLC to give the title compound. LCMS (ES+) 410.2 (M+H)+, RT 3.59 min (analytical method BicarbBEHC18). 1 H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.95 (d, J=1.7 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.1 Hz, 1H), 7.65 (dd, J=0.8, 3.1 Hz, 1H), 7.33 (dd, J=1.6, 13.1 Hz, 1H), 3.51 - 3.40 (m, 2H), 3.32 - 3.24 (m, 1H), 3.03 - 2.95(m, 2H), 2.49 - 2.36(m, 2H), 2.10 (s, 3H), 1.90 - 1.82 (m, 2H), 1.55 - 1.46 (m, 1H), 0.17 - 0.12(m, 2H), 0.04 - -0.04 (m, 2H).

[0431] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0432] [Table 10] TIFF2025160356000160.tif249170TIFF2025160356000161.tif248170TIFF2025160356000162.tif246170TIFF2025160356000163.t if247170TIFF2025160356000164.tif250170TIFF2025160356000165.tif236170TIFF2025160356000166.tif254170TIFF2025160356 000167.tif251170TIFF2025160356000168.tif230170TIFF2025160356000169.tif251170TIFF2025160356000170.tif232170TIFF20 25160356000171.tif249170TIFF2025160356000172.tif222170TIFF2025160356000173.tif251170TIFF2025160356000174.tif14170

[0433] [Example 52] N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2)

[0434] [ka] Intermediate 2 (100 mg, 0.3 mmol), 1-(pyrrolidin-3-ylmethyl)pyrrolidine dihydrochloride (94 mg, 0.23 mmol), CsCO (487 mg, 1 mmol), and DMF (3 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 16 h. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration, and the reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 421.2 (M+H)+, RT 2.04 min (analytical method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 9.15 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 3.79 - 3.66 (m, 2H), 3.57 - 3.49 (m, 1H), 3.33 - 3.24 (m, 1H), 2.71 (s, 3H), 2.52 (t, J=1.9 Hz, 6H), 2.50 - 2.42 (m, 6H), 2.40 (s, 3H), 2.15 - 2.13 (m, 1H), 1.71 (s, 6H).

[0435] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0436] [Table 11] TIFF2025160356000177.tif246170TIFF2025160356000178.tif224170TIFF2025160356000179.tif232170

[0437] [Example 65] N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(piperazin-1-yl)pyrazine-2-carboxamide

[0438] [ka] Methyl 5-chloropyrazine-2-carboxylate (173 mg, 1 mol), N-Boc piperazine (186 mg, 1 mmol), CsCO (650 mg, 2 mmol), and DMF (5 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 4 h. The reaction mixture was diluted with EtOAc, washed with water (×2), brine, and evaporated to dryness to give methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, which was used crude in the next step. MS (ES+) 323 (M+H).

[0439] Methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, LiOH HO (50 mg), methanol (20 mL), and water (2 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness to give lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, which was used crude in the next step. MS (ES+) 309 (M+H).

[0440] Lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate (157 mg, 0.5 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (81 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL), and DMF (2 mL) were combined and stirred at room temperature for 3 days. The reaction mixture was then purified by preparative HPLC to give tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate. MS (ES+) 453 (M+H).

[0441] tert-Butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate (10.6 mg), dichloromethane (2 mL), and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and then taken up in MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction was then filtered, and the filtrate was evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 353 (M+H)+, RT 1.86 minutes (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 9.15 (s, 1H), 8.75 (d, J=1.1 Hz, 1H), 8.37 (d, J=1.1 Hz, 1H), 8.01 (s, 1H), 3.71 - 3.67 (m, 4H), 2.82 (dd, J=5.1, 5.1 Hz, 4H), 2.71 (s, 3H), 2.40 (s, 3H).

[0442] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0443] [Table 12] TIFF2025160356000182.tif245170TIFF2025160356000183.tif203170

[0444] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry, but coupled with 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine instead of 2,8-dimethylimidazo[1,2-a]pyrazine-6-amine. In some cases, Boc-protected amines were used; in these cases, the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, where chirality was arbitrarily assigned.

[0445] [Table 13] TIFF2025160356000185.tif245170TIFF2025160356000186.tif247170TIFF2025160356000187.tif40170

[0446] [Example 83] (R)-5-(3-(ethylamino)pyrrolidin-1-yl)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide

[0447] [ka] 5-Chloropyrazine-2-carboxylic acid (246 mg, 1.55 mmol) and dichloromethane (10 mL) were combined at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.27 mL, 3.1 mmol) was added, followed by 1 drop of DMF. The reaction mixture was stirred for 21 hours and then evaporated to dryness. Intermediate 10 (276 mg, 1.55 mmol), dichloromethane (30 mL), and triethylamine (2 mL) were added, and the reaction was stirred for 1 hour. The reaction mixture was evaporated to dryness to give 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide, which was used crude in the next step.

[0448] 5-Chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazine-2-carboxamide (125 mg, 0.28 mmol), (R)-N-ethylpyrrolidin-3-amine (32 mg, 0.28 mmol), cesium carbonate (325 mg, 1 mmol), and DMF (3 mL) were combined in a sealed tube and heated to 100 °C for 2 h. The reaction mixture was then cooled to room temperature, the cesium salts were removed by filtration, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 397 (M+H)+, RT 1.9 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.48 - 9.46 (m, 1H), 8.89 (s, 1H), 8.74 (d, J=1.1 Hz, 1H), 8.02 (d, J=1.3 Hz, 1H), 7.94 (s, 1H), 4.07 (s, 3H), 3.71 - 3.52 (m, 3H), 3.43 - 3.38 (m, 2H), 2.64 - 2.56 (m, 2H), 2.35 (s, 3H), 2.19 - 2.08 (m, 1H), 1.88 - 1.88 (m, 2H), 1.04 (dd, J=7.2, 7.2 Hz, 3H).

[0449] Further analogs were prepared using the same chemistry and the appropriate amine. Some enantiomers were separated by chiral SFC, where chirality was arbitrarily assigned.

[0450] [Table 14]

[0451] [Example 86] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperazin-1-yl)pyrazine-2-carboxamide

[0452] [ka] Lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate (157 mg, 0.5 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (83 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL), and DMF (2 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to give tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H).

[0453] tert-Butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylate (80 mg), dichloromethane (2 mL), and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and then taken up in MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction was then filtered, and the filtrate was evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 356 (M+H)+, RT 1.67 minutes (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.0 Hz, 1H), 8.32 (s, 1H), 7.89 (d, J=2.6 Hz, 1H), 7.57 (dd, J=1.5, 13.0 Hz, 1H), 3.65 (dd, J=5.1, 5.1 Hz, 4H), 3.41 (dd, J=5.1, 5.1 Hz, 4H), 2.35 (s, 3H).

[0454] [Example 87] N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide and [Example 88] N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0455] [ka] Methyl 5-chloropyrazine-2-carboxylate (665 mg, 3.85 mmol), tert-butyl ((3R * ,4S * )-4-fluoropyrrolidin-3-yl)carbamate (786 mg, 3.85 mmol), cesium carbonate (1.25 g, 3.85 mmol) and DMF (10 mL) were combined in a sealed tube and heated to 100° C. for 18 h. The reaction mixture was then diluted with EtOAc, washed with water (3×), brine (1×) and evaporated to dryness to give methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0456] Methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate (630 mg, 1.85 mmol) and DMF (15 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 89 mg, 2.22 mmol) was added to the stirred reaction mixture, followed by MeI (0.14 mL, 2.22 mmol). The reaction mixture was stirred for 22 h, then diluted with EtOAc and washed with water (3×) and brine (1×). The organic layer was evaporated to dryness to give methyl 5-((3R * ,4S *)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate was obtained as a solid which was used crude without further purification.

[0457] Methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate, LiOH·HO (85 mg, 2.03 mmol), methanol (20 mL), and water (2 mL) were combined and stirred at 45 °C for 23 h. The reaction mixture was then evaporated to dryness to give 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-lithium carboxylate, which was used crude without further purification.

[0458] 5-((3R * ,4S * Lithium 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (162 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (5 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was then purified by preparative HPLC to give tert-butyl ((3R * ,4S * )-4-fluoro-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, which was used without further purification.

[0459] tert-Butyl ((3R * ,4S *)-4-Fluoro-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, methanol (3 mL) and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, dissolved in MeOH, stirred with Na2CO3 for 5 minutes, filtered through an Isolute NH2 resin cartridge and the filtrate evaporated to dryness. The crude solid was purified by preparative HPLC followed by chiral preparative HPLC to give cis isomer, enantiomer 1 N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 5.39 (d, J=52.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.81 (dd, J=12.7, 39.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.24 - 3.18 (m, 1H), 2.71 (s, 3H), 2.44 - 2.39 (m, 6H), 2.01 - 2.01 (m, 1H). cis isomer, enantiomer 2 N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analytical Method AcHSSC18); 1H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 9.15 (s, 1H), 8.78 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 5.39 (d, J=52.3 Hz, 1H), 4.05 - 3.92 (m, 2H), 3.81 (dd, J=12.7, 39.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.24 - 3.18 (m, 1H), 2.71 (s, 3H), 2.44 - 2.39 (m, 6H), 2.01 - 2.01 (m, 1H). obtained.

[0460] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0461] [Table 15]

[0462] Further analogs were prepared using the same chemistry using 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate lithium or 5-((3R * ,4R *)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate and lithium 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily assigned.

[0463] [Table 16]

[0464] [Example 92] (S)-5-([1,3'-bipyrrolidin]-1'-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0465] [ka] Methyl 5-chloropyrazine-2-carboxylate (473 mg, 2.74 mmol), (S)-1,3'-bipyrrolidine (384 mg, 2.74 mmol), cesium carbonate (1.14 g, 3.5 mmol), and DMF (10 mL) were combined in a sealed tube and heated to 100°C for 16 h. The reaction mixture was filtered to remove cesium salts and rinsed with EtOAc. The combined organic filtrate was evaporated to dryness to give methyl (S)-5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0466] Methyl (S)-5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, LiOH HO (126 mg, 3 mmol), MeOH (50 mL), and water (5 mL) were combined and heated to 45 °C for 16 h. The reaction mixture was then evaporated to dryness to give lithium (S)-5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0467] (S)-Lithium 5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate (161 mg, 0.6 mmol), Intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL), and DMF (2 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 422 (M+H)+, RT 2.45 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.06 (s, 1H), 8.76 (d, J=1.1 Hz, 1H), 8.69 (s, 1H), 8.23 ​​(s, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.11 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.83 - 3.69 (m, 2H), 3.56 - 3.48 (m, 1H), 3.39 (dd, J=6.9, 11.8 Hz, 1H), 2.89 - 2.89 (m, 1H), 2.56 (d, J=3.6 Hz, 4H), 2.20 - 2.19 (m, 1H), 2.01 - 1.97 (m, 1H), 1.73 (dd, J=5.0, 5.0 Hz, 4H).

[0468] [Example 93] (S)-5-([1,3'-bipyrrolidin]-1'-yl)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0469] [ka] (S)-Lithium 5-([1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxylate (95 mg, 0.36 mmol), Intermediate 3 (69 mg, 0.36 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL), and DMF (2.5 mL) were combined and stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 436.5 (M+H)+, RT 2.6 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ10.14 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.09 (s, 1H), 4.22 (q, J=6.9 Hz, 2H), 4.09 (s, 3H), 3.83 - 3.69 (m, 1H), 3.55 - 3.48 (m, 1H), 3.20 (s, 1H), 2.90 - 2.82 (m, 2H), 2.19 - 2.13 (m, 2H), 1.96 (dd, J=3.6, 8.2 Hz, 2H), 1.75 - 1.69 (m, 4H), 1.51 - 1.46 (m, 3H).

[0470] [Example 94] 5-((3S * ,4R * )-3-Fluoro-4-(methylamino)pyrrolidin-1-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0471] [ka] 5-((3R * ,4S *Lithium (3R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidin-1-yl)pyrazine-2-carboxylate (187 mg, 0.54 mmol), Intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL), and DMF (3 mL) were combined and stirred at room temperature for 3 hours. The reaction mixture was then purified by preparative HPLC to give tert-butyl ((3R * ,4S * )-4-fluoro-1-(5-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, which was used without further purification.

[0472] tert-Butyl ((3R * ,4S * )-4-Fluoro-1-(5-((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate was deprotected using general method C (HCl Boc deprotection) to give the title compound. LCMS (ES+) 400 (M+H)+, RT 2.3 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ10.07 (s, 1H), 8.78 (s, 1H), 8.69 (s, 1H), 8.23 ​​(s, 1H), 8.12 (s, 1H), 7.12 (s, 1H), 5.39 (d, J=55.2 Hz, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 4.04 - 3.70 (m, 4H), 3.20 (dd, J=10.2, 10.2 Hz, 1H), 2.42 (s, 3H).

[0473] [Example 95] (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(pyrrolidin-3-yloxy)pyrazine-2-carboxamide

[0474] [ka] tert-Butyl (S)-3-hydroxypyrrolidine-1-carboxylate (100 mg, 0.53 mmol) in DMF (2 mL) was added to a suspension of NaH (32 mg, 0.801 mmol) in DMF (1 mL), and the reaction was stirred at room temperature for 30 minutes. Intermediate 1 (163 mg, 0.534 mmol) was added, and the reaction was heated to 90° C. for 5.5 hours. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (×2), and the combined organic solution was dried over MgSO and evaporated to dryness. The crude mixture was purified by flash chromatography to give tert-butyl (S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)oxy)pyrrolidine-1-carboxylate. MS (ES+) 457 (M+H).

[0475] tert-Butyl (S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)oxy)pyrrolidine-1-carboxylate (63 mg, 0.14 mmol), methanol (1 mL), and 4 N HCl in dioxane (0.35 mL, 1.38 mmol) were combined and stirred at room temperature for 17 hours. The reaction mixture was evaporated to dryness, and the crude material was purified by preparative HPLC to give the title compound. LCMS (ES+) 357 (M+H)+, RT 1.62 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 8.90 (s, 1H), 8.38 (s, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.5, 13.0 Hz, 1H), 5.50 (dd, J=5.8, 5.8 Hz, 1H), 3.68 - 3.52 (m, 1H), 3.15 (dd, J=5.2, 12.5 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.88 - 2.81 (m, 1H), 2.35 (s, 3H), 2.19 - 2.05 (m, 1H), 1.91 - 1.87 (m, 1H).

[0476] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by preparative HPLC.

[0477] [Table 17]

[0478] [Example 97] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3R,4R)-3-methyl-4-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0479] [ka] Tert-butyl ((3R,4R)-4-methylpyrrolidin-3-yl)carbamate (251 mg, 1.25 mmol) and methyl 5-chloropyrazine-2-carboxylate (216 mg, 1.25 mmol) were dissolved in DMF (4 mL) and the reaction was heated to 100° C. for 18 hours. The reaction was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The solvent was removed in vacuo to give the crude product. The crude was purified using silica chromatography, elution gradient 0-100% EtOAc / cyclohexane to give methyl 5-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-methylpyrrolidin-1-yl)pyrazine-2-carboxylate. MS (ES+) 337 (M+H). Methyl 5-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-methylpyrrolidin-1-yl)pyrazine-2-carboxylate (344 mg, 1.02 mmol) was dissolved in DMF (2 mL) and cooled in an ice bath. Sodium hydride / 60% in mineral oil (45 mg, 1.12 mmol) was added and the reaction was stirred for 15 minutes. Methyl iodide (145 mg, 1.02 mmol) was added and the reaction was allowed to warm to room temperature over 3 hours. LCMS showed starting material. Additional sodium hydride / 60% in mineral oil (45 mg, 1.12 mmol) was added, followed by methyl iodide (145 mg, 1.02 mmol) and the reaction was stirred for a further 18 hours. Water (1 mL) was added, followed by sodium hydroxide (82 mg, 1.04 mmol) and the reaction was stirred for 18 hours. The reaction was acidified to pH=5 with 1M HCl and the aqueous layer was extracted with 3× EtOAc. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidin-1-yl)pyrazine-2-carboxylic acid. MS (ES+) 337 (M+H).

[0480] 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidin-1-yl)pyrazine-2-carboxylic acid (343 mg, 1.02 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (168 mg, 1.02 mmol) were dissolved in DMF (2 mL). HBTU (426 mg, 1.12 mmol) and trimethylamine (0.5 mL) were added, and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo to give the crude product. Purification by silica chromatography using an elution gradient of 0-100% EtOAc / cyclohexane gave tert-butyl ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidin-3-yl)(methyl)carbamate. MS (ES+) 484 (M+H).

[0481] tert-Butyl ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidin-3-yl)(methyl)carbamate (610 mg, 1.02 mmol) was dissolved in methanol (2 mL) and 4 M HCl in dioxane (10 mL) was added. The reaction was stirred overnight at room temperature. The solvent was removed in vacuo to give the crude product. The crude was purified by SCX 5 g SCX cartridge (pre-conditioned with MeOH) eluting with 1:1 MeOH / DCM (2 CV) then 2.3 M NH3 / MeOH (3 CV). The ammoniacal fractions were concentrated in vacuo to give a residue. Further purification by reverse phase HPLC gave the title compound. LCMS (ES+) 384.2 (M+H)+, RT 1.72 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.57 (dd, J=1.6, 13.1 Hz, 1H), 3.70 - 3.63 (m, 2H), 3.26-3.08 (m, 3H), 2.32 (m, 6H), 1.02 (d, J=5.9 Hz, 3H). NH is obscured by the DMSO peak.

[0482] The following examples were prepared using similar procedures starting from methyl 5-chloropyrazine-2-carboxylate and the specified amine. The final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, where chirality was arbitrarily assigned.

[0483] [Table 18] TIFF2025160356000201.tif216170TIFF2025160356000202.tif246170

[0484] [Example 106] (R)—N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxamide and [Example 107] (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0485] [ka]

[0486] Methyl 5-chloropyrazine-2-carboxylate (191 mg, 1.1 mmol), tert-butyl (R)-(1-(pyrrolidin-3-yl)cyclopropyl)carbamate (250 mg, 1.1 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (4 mL) were combined in a sealed tube and heated to 100° C. on a hot block for 23 h. The reaction mixture was then diluted with EtOAc, washed with water (3×), brine (1×), and evaporated to dryness to give methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0487] Methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate (341 mg, 0.91 mmol) and DMF (10 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 45 mg, 1.13 mmol) was added, followed by MeI (0.07 mL, 1.13 mmol), and stirring was continued for 10 days. The reaction mixture was then diluted with EtOAc, washed with water (3x), brine (1x), dried (MgSO4) and evaporated to dryness to give a mixture of methyl (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0488] A mixture of methyl (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate (169 mg), LiOH·HO (19 mg, 0.45 mmol), methanol (15 mL), and water (2 mL) was combined and heated to 45°C in a hot block for 18 hours. The reaction mixture was then evaporated to dryness to give a mixture of lithium (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and lithium (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, which was used crude without further purification.

[0489] A mixture of lithium (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate and lithium (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxylate, 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (74 mg, 0.45 mmol), HBTU (171 mg, 0.45 mmol), triethylamine (0.5 mL), and DMF (2 mL) was combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to give: tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)cyclopropyl)(methyl)carbamate, which was used without further purification. tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)cyclopropyl)carbamate, which was used without further purification.

[0490] tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)cyclopropyl)(methyl)carbamate (65.1 mg), methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 410 (M+H)+, RT 1.93 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.7, 13.0 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.46 - 3.42 (m, 1H), 3.13 (dd, J=10.2, 10.2 Hz, 1H), 2.73 - 2.68 (m, 1H), 2.35 (s, 3H), 2.29 (s, 3H), 2.00 (s, 1H), 1.65 (s, 1H), 0.51 (s, 4H).

[0491] tert-Butyl (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)cyclopropyl)carbamate (41.9 mg), methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 396 (M+H)+, RT 1.9 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.74 (d, J=1.1 Hz, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.7, 13.1 Hz, 1H), 3.82 - 3.69 (m, 2H), 3.50 - 3.41 (m, 2H), 2.35 (s, 3H), 2.09 (d, J=8.3 Hz, 1H), 2.00 (s, 1H), 1.93 (d, J=9.8 Hz, 1H), 0.49 (d, J=6.4 Hz, 4H).

[0492] [Example 108] (R)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0493] [ka] Intermediate 3 (0.32 mmol), (R)-lithium 5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate (100 mg, 0.32 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL), and DMF (2.5 mL) were combined and stirred at room temperature for 18 hours. The reaction mixture was then purified by preparative HPLC to afford tert-butyl (R)-(1-(5-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate as an off-white solid, which was used without further purification.

[0494] tert-Butyl (R)-(1-(5-((6-ethoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate, methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, then taken up in MeOH, stirred over sodium carbonate for 5 minutes, and then filtered through an Isolute NH2 resin cartridge. The filtrate was evaporated to dryness to give the title compound. LCMS (ES+) 396 (M+H)+, RT 2.5 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.79 (d, J=1.3 Hz, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.13 (s, 1H), 4.27 (q, J=7.0 Hz, 2H), 4.13 (s, 3H), 3.73 - 3.60 (m, 3H), 3.45 - 3.40 (m, 1H), 3.34 - 3.32 (m, 1H), 2.38 - 2.34 (m, 3H), 2.17 - 2.09 (m, 1H), 1.94 - 1.91 (m, 2H), 1.53 (dd, J=6.9, 6.9 Hz, 3H).

[0495] Additional analogs were prepared using Method H (TCFH coupling) starting from (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid and the specified amine. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC.

[0496] [Table 19]

[0497] Example 110: (R)-5-(3-(ethylamino)pyrrolidin-1-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0498] [ka] 5-Chloropyrazine-2-carboxylic acid (159 mg, 1 mmol) and dichloromethane (10 mL) were combined under a nitrogen atmosphere. Oxalyl chloride (0.17 mL, 2 mmol) was added, followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness. Intermediate 4 (1.08 mmol), dichloromethane (20 mL), and triethylamine (2 mL) were added, and the reaction mixture was stirred for 1.5 hours. The reaction was then evaporated to dryness to give 5-chloro-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide, which was used crude without further purification. MS (ES+) 318 / 320 (M+H).

[0499] 5-Chloro-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide (150 mg, 0.25 mmol), (R)-N-ethylpyrrolidin-3-amine (28 mg, 0.25 mmol), CsCO (325 mg, 1 mmol), and DMF (2 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 1 h. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration, and the reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 396 (M+H)+, RT 2.36 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.75 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.23 ​​(s, 1H), 8.04 (d, J=1.3 Hz, 1H), 7.11 (s, 1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.71 - 3.52 (m, 3H), 3.42 - 3.37 (m, 2H), 2.63 - 2.58 (m, 2H), 2.17 - 2.09 (m, 1H), 1.86 - 1.81 (m, 2H), 1.04 (dd, J=7.1, 7.1 Hz, 3H).

[0500] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC.

[0501] [Table 20]

[0502] [Example 112] (R)-5-(3-(cyclopropylamino)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0503] [ka] (R)-(+)-1-Boc-3-aminopyrrolidine (400 mg, 2.15 mmol) and (1-ethoxycyclopropoxy)trimethylsilane (0.48 mL, 2.37 mmol) were combined in MeOH (30 mL). NaBHCN (162 mg, 2.58 mmol) was added, followed by AcOH (0.2 mL). The reaction mixture was then heated to 55° C. for 16 h. The reaction was then diluted with dichloromethane, washed with saturated aqueous NaHCO, dried (MgSO), and evaporated to dryness to give tert-butyl (R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate, which was used crude in the next step.

[0504] tert-Butyl (R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate (455 mg, 2 mmol), MeOH (15 mL), and 4 N HCl in dioxane (15 mL) were combined and stirred at room temperature for 24 h. The reaction mixture was then evaporated to dryness to give (R)-N-cyclopropylpyrrolidin-3-amine 2HCl, which was used crude in the next step.

[0505] (R)-N-Cyclopropylpyrrolidin-3-amine.2HCl (500 mg), Intermediate 1 (400 mg, 1.3 mmol), cesium carbonate (1.63 g, 5 mmol), and DMF (7 mL) were combined and heated to 100 °C for 20 h. The cesium salts were then filtered off, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 396 (M+H)+, RT 1.75 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.23 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.93 (d, J=2.5 Hz, 1H), 7.60 (dd, J=1.5, 13.0 Hz, 1H), 3.78 - 3.53 (m, 4H), 3.51 - 3.42 (m, 1H), 2.61 - 2.58 (m, 1H), 2.39 (s, 3H), 2.21 - 2.12 (m, 2H), 1.99 - 1.99 (m, 1H), 0.45 (d, J=6.6 Hz, 2H), 0.33 - 0.25 (m, 2H).

[0506] Further analogs were prepared from commercially available or synthesized amines using the same chemistry. Final products were isolated by preparative HPLC.

[0507] [Table 21]

[0508] [Example 114] 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(5-fluoro-2-methyl-1,3-benzoxazol-6-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2)

[0509] [ka] From 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid (126 mg, 0.361 mmol, 1 equiv.) and 5-fluoro-2-methylbenzo[d]oxazol-6-amine (60 mg, 0.361 mmol, 1 equiv.) in DMF (2.0 mL) according to Method H. The reaction mixture was diluted with water, and the solid was filtered and washed with 1:1 MeCN / HO. The solid was purified by silica chromatography using an elution gradient of 0-10% EtOAc in cyclohexane. Fractions containing the desired material were combined, and the solvent removed in vacuo to give tert-butyl cyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate. LCMS (ES+) 497 (M+H)+.

[0510] From tert-butyl cyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (26 mg, 0.0511 mmol) following Method E TFA Boc deprotection. The reaction mixture was concentrated in vacuo and the residue was applied to a 2 g SCX cartridge and eluted with 2 column volumes of methanol followed by 3 column volumes of 2M ammonia in methanol. The ammonia fraction was concentrated in vacuo to give 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(5-fluoro-2-methyl-1,3-benzoxazol-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 397 (M+H)+, RT 4.57 min (Analytical Method BicarbBEHC18). 1H NMR (400 MHz, DMSO) δ 9.91 (d, J=2.4 Hz, 1H), 8.75 (s, 1H), 8.47 (d, J=6.5 Hz, 1H), 8.04 (s, 1H), 7.71 (d, J=10.9 Hz, 1H), 3.74 - 3.50 (m, 4H), 3.45 (s, 1H), 2.63 (s, 3H), 2.19 - 2.10 (m, 2H), 1.96 (s, 1H), 0.43 (d, J=6.7 Hz, 2H), 0.32 - 0.23 (m, 2H).

[0511] [Example 115] 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2,6-dimethylindazol-5-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2)

[0512] [ka] From 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid (140 mg, 0.403 mmol, 1 equiv.) and 2,6-dimethyl-2H-indazol-5-amine (65 mg, 0.403 mmol, 1 equiv.) in DMF (2.0 mL) according to Method H. The reaction mixture was diluted with water, and the solid was filtered and washed with 1:1 MeCN / HO to give crude tert-butyl cyclopropyl(1-(5-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate, which was carried on without further purification.

[0513] From tert-butyl cyclopropyl(1-(5-((2,6-dimethyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (36 mg, 0.0732 mmol) following Method E TFA Boc deprotection. The reaction mixture was concentrated in vacuo and the residue was applied to a 2 g SCX cartridge and eluted with 2 column volumes of methanol followed by 3 column volumes of 2M ammonia in methanol. The ammonia fraction was concentrated in vacuo and the residue purified by reverse phase HPLC to give 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2,6-dimethylindazol-5-yl)pyrazine-2-carboxamide. LCMS (ES+) 392 (M+H)+, RT 2.38 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 8.26 - 8.22 (m, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 4.18 (s, 3H), 3.77 - 3.55 (m, 4H), 3.51 - 3.45 (m, 1H), 2.43 (s, 3H), 2.21 - 2.15 (m, 2H), 2.01 - 1.99 (m, 1H), 0.48 (d, J=6.6 Hz, 2H), 0.36 - 0.28 (m, 2H).

[0514] [Example 116] 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2)

[0515] [ka] According to Method H, lithium 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate (97 mg, 0.273 mmol) was reacted with 2,7-dimethylimidazo[1,2-a]pyridin-6-amine (44 mg, 0.273 mmol) in DMF (2.0 mL). The reaction mixture was diluted with water, and the solid was filtered, washed with 1:1 MeCN / HO, and purified by reverse-phase HPLC to give tert-butyl cyclopropyl(1-(5-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate. LCMS (ES+) 492 (M+H)+.

[0516] According to Method E, tert-butyl cyclopropyl (1-(5-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (9.4 mg, 0.020 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo and the residue was applied to a 2 g SCX cartridge and eluted with 2 column volumes of methanol followed by 3 column volumes of 2M ammonia in methanol. The ammonia fractions were concentrated in vacuo to give the title compound. LCMS (ES+) 392 (M+H)+, RT 3.95 min (Analytical Method BicarbBEHC18). 1 H NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 8.65 (d, J=1.3 Hz, 1H), 7.87 (d, J=1.3 Hz, 1H), 7.44 (s, 1H), 7.23 (s, 1H), 3.76 - 3.45 (m, 4H), 3.42 - 3.37 (m, 1H), 2.31 (d, J=0.8 Hz, 3H), 2.29 (d, J=0.7 Hz, 3H), 2.26 - 2.12 (m, 2H), 2.01 - 1.91 (m, 1H), 0.47 - 0.44 (m, 2H), 0.35 - 0.31 (m, 2H).

[0517] [Example 117] (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-((2,2,2-trifluoroethyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0518] [ka] tert-Butyl (R)-3-aminopyrrolidine-1-carboxylate (1.0 g, 5.37 mmol) and ethyl trifluoroacetate (2.29 g, 16.1 mmol) were stirred in ethanol (20 mL) at 60° C. for 17 hours. The reaction mixture was concentrated to dryness, and the crude tert-butyl (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate was used in the next step. LCMS (ES+) 283 (M+H). + .

[0519] To a stirred solution of tert-butyl (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate (5.37 mmol) in THF (10 mL) was added borane·THF (21.5 mL, 1 M, 21.5 mmol) dropwise. After the addition, the mixture was refluxed for 17 h. The reaction mixture was cooled to room temperature, saturated aqueous NH₄Cl (20 mL) was added, and then heated to 60°C for 2 h. The mixture was concentrated, and the resulting aqueous solution was extracted with EtOAc (2 × 30 mL). The organic layer was collected, dried (MgSO₄), filtered, and concentrated. Purification by flash silica column chromatography (gradient, DCM to DCM / MeOH / 7 M NH₃ in MeOH [89:10:1]) gave tert-butyl (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylate. LCMS (ES+) 213 (M+H) + .

[0520] tert-Butyl (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylate (600 mg, 3.29 mmol) and HCl in dioxane (4 M, 4 mL, 16 mmol) were stirred in MeOH (10 mL) for 17 h. The mixture was concentrated to dryness, and the crude (R)-N-(2,2,2-trifluoroethyl)pyrrolidin-3-amine HCl was used in the next step.

[0521] To a stirred solution of Intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL) was added (R)-N-(2,2,2-trifluoroethyl)pyrrolidin-3-amine·HCl (87 mg, 0.36 mmol) and Cs2CO3 (533 mg, 1.64 mmol). The mixture was stirred at 100 °C for 17 h and then cooled to room temperature. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated from the aqueous layer and extracted with additional EtOAc (10 mL). The combined organic layers were washed with water (3 × 30 mL), dried (MgSO4), filtered, and concentrated to dryness. Purification by preparative HPLC afforded the title compound. LCMS (ES+) 438 (M+H)+, RT 2.64 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.19 (d, J=1.2 Hz, 1H), 8.75 (s, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.90 (t, J=8 Hz, 1H), 7.56 (dd, J=1.6, 13.2 Hz, 1H), 3.68 - 3.49 (m, 4H), 3.41 - 3.21 (m, 2H), 2.82 - 2.73 (m, 1H), 2.34 (s, 3H), 2.20 - 2.11 (m, 1H), 2.01 - 1.85 (m, 1H), one proton obscured by a water peak.

[0522] [Example 118] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxamide and [Example 119] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxamide

[0523] [ka] tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.25 g, 6.75 mmol), pyrrolidine (6.816 g, 95.84 mmol), and water (12 mL) were combined in a sealed tube and heated to 50 °C for 5 days. The reaction was quenched with saturated aqueous NaHCO and extracted with dichloromethane (2x). The combined organic layers were dried (MgSO) and evaporated to dryness onto silica, which was purified by flash chromatography eluting with 1% NHOH / 10% MeOH / CHCl to give tert-butyl (3'R * ,4'R * )-4'-hydroxy-[1,3'-bipyrrolidine]-1'-carboxylate was obtained, which was used crude in the next step.

[0524] tert-Butyl (3'R * ,4'R * )-4'-hydroxy-[1,3'-bipyrrolidine]-1'-carboxylate (200 mg, 0.78 mmol), dichloromethane (10 mL), and Deoxy-fluor® (50% in THF) (0.32 mL, 0.86 mmol) were combined at room temperature under a nitrogen atmosphere and stirred for 2 days. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4) and evaporated to dryness to give tert-butyl (3'R * ,4'S *)-4'-fluoro-[1,3'-bipyrrolidine]-1'-carboxylate was obtained, which was used crude in the next step.

[0525] tert-Butyl (3'R * ,4'S * )-4'-fluoro-[1,3'-bipyrrolidine]-1'-carboxylate, methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred for 16 hours. The reaction mixture was evaporated to dryness to give (3'R * ,4'S * )-4'-Fluoro-1,3'-bipyrrolidine·2HCl was obtained, which was used crude in the next step without further purification.

[0526] (3'R * ,4'S * )-4'-Fluoro-1,3'-bipyrrolidine 2HCl, Intermediate 1 (200 mg, 0.65 mmol), cesium carbonate (800 mg, 2.45 mmol), and DMF (4 mL) were combined in a sealed tube and heated to 100 °C for 6 h. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration, and the filtrate was purified by preparative HPLC followed by chiral preparative HPLC to give: Example 118, cis isomer, enantiomer 1 N-(8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxamide. LCMS (ES+) 428 (M+H)+, RT 1.82 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.58 (dd, J=1.6, 13.0 Hz, 1H), 5.47 (td, J=1.9, 51.0 Hz, 1H), 3.97 - 3.78 (m, 4H), 3.20 - 3.15 (m, 1H), 2.66 - 2.59 (m, 4H), 2.35 (s, 3H), 1.71 (dd, J=4.5, 4.5 Hz, 4H). Example 119, cis isomer, enantiomer 2 N-(8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-bipyrrolidin]-1'-yl)pyrazine-2-carboxamide. LCMS (ES+) 428 (M+H)+, RT 1.82 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ10.47 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.08 (s, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.58 (dd, J=1.6, 13.0 Hz, 1H), 5.47 (td, J=1.9, 51.0 Hz, 1H), 3.97 - 3.78 (m, 4H), 3.20 - 3.15 (m, 1H), 2.66 - 2.59 (m, 4H), 2.35 (s, 3H), 1.71 (dd, J=4.5, 4.5 Hz, 4H).

[0527] Further analogs were prepared using the same chemistry and appropriate amines. Some enantiomers were separated by chiral SFC, where chirality was arbitrarily assigned.

[0528] [Table 22]

[0529] [Example 121] (R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0530] [ka] A mixture of tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (400 mg, 2.0 mmol), methyl 5-chloropyrazine-2-carboxylate (350 mg, 2.0 mmol), CsCO (976 mg, 3.0 mmol), and DMF (6 mL) was heated to 110° C. in a sealed tube for 17 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine, and the organic layer was concentrated in vacuo to give methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate.

[0531] A mixture of methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate (671 mg) and ammonia in methanol (4 N, 20 mL) was heated to 90° C. for 19 hours. The reaction was cooled to room temperature and concentrated in vacuo to give tert-butyl (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate.

[0532] Tert-butyl (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (308 mg, 0.96 mmol) and 5-bromo-6-fluoro-2-methyl-2H-indazole (229 mg, 1.0 mmol) were coupled according to Method F. The crude material was purified by preparative HPLC to give tert-butyl (R)-(1-(5-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate.

[0533] According to Method E, tert-butyl (R)-(1-(5-((6-fluoro-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (78 mg, 0.17 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo, and the residue was taken up in MeOH and stirred with Na2CO3 for 5 min, filtered, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 370 (M+H)+, RT 2.37 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.82 (d, J=2.8 Hz, 1H), 8.75 (d, J=1.0 Hz, 1H), 8.49 (d, J=7.9 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.51 (d, J=12.1 Hz, 1H), 4.16 (s, 3H), 3.69 - 3.56 (m, 4H), 2.32 (s, 3H), 2.17 - 2.04 (m, 1H), 1.99 - 1.80 (m, 2H).

[0534] [Example 122] (R)-N-(8-Methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0535] [ka] Tert-butyl (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (150 mg, 0.47 mmol) and Intermediate 17 (119 mg, 0.49 mmol) were coupled according to Method F. The crude material was purified by preparative HPLC to give tert-butyl (R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate.

[0536] According to Method E, tert-butyl (R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (24 mg, 0.050 mmol) was treated with TFA. The reaction mixture was concentrated in vacuo, and the residue was taken up in MeOH and stirred with Na2CO3 for 5 min, filtered, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 383 (M+H)+, RT 1.9 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.47 (s, 1H), 8.89 (s, 1H), 8.74 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 4.07 (s, 3H), 3.65 - 3.54 (m, 4H), 2.35 (s, 3H), 2.31 (s, 3H), 2.10 (s, 1H), 1.94 - 1.94 (m, 2H).

[0537] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0538] [Table 23]

[0539] [Example 125] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperidin-4-yl)pyrazine-2-carboxamide

[0540] [ka] To a solution of Intermediate 1 (200 mg, 0.65 mmol) in dioxane (15 mL) and water (2 mL) was added sodium carbonate (500 mg, 4.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (202 mg, 0.65 mmol). Bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) was added, and the reaction tube was sealed and heated at 100° C. for 22 h. The reaction was cooled to room temperature and the solvent removed in vacuo to give a residue which was purified by silica chromatography to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. MS (ES+) 453 (M+H).

[0541] A solution of tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in ethyl acetate (15 mL) was hydrogenated using an H-cube and a 20% Pd(OH) / C cartridge in recycle mode at 1 mL / min, 40 °C, and 40 bar for 6 h, after which LCMS analysis showed almost complete conversion. The solvent was removed in vacuo to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperidine-1-carboxylate, which was used in the next step without further purification.

[0542] Prepared using general method E and the following amounts: tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperidine-1-carboxylate, DCM (3 mL), and TFA (1 mL). The reaction mixture was evaporated to dryness, taken up in MeOH, treated with Na2CO3, and then filtered. Purification by reverse phase HPLC followed by achiral SFC gave N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperidin-4-yl)pyrazine-2-carboxamide. LCMS (ES+) 355.2 (M+H)+, RT 1.61 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ10.92 - 10.90 (m, 1H), 9.23 (d, J=1.6 Hz, 2H), 8.76 (s, 1H), 7.94 (d, J=2.8 Hz, 1H), 7.57 (dd, J=2.0, 12.9 Hz, 1H), 3.10 - 3.00 (m, 3H), 2.63 (dd, J=10.5, 12.0 Hz, 2H), 2.36 (s, 3H), 1.84 - 1.81 (m, 2H), 1.70 (dq, J=3.9, 12.2 Hz, 2H).

[0543] [Example 126] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperazin-1-yl)pyrimidine-5-carboxamide

[0544] [ka] 2-Chloropyrimidine-5-carboxylic acid (159 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine. HCl (238 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (0.5 mL), and DMF (4 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to give 2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide. MS (ES+) 405 (M+H).

[0545] 2-((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide (113 mg, 0.28 mmol), N-Boc piperazine (52 mg, 0.28 mmol), CsCO (162 mg, 0.5 mmol), and DMF (4 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 3 days. The reaction mixture was purified by preparative HPLC to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H).

[0546] tert-Butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (27.5 mg), dichloromethane (2 mL), and TFA (1 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness and then taken up in MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction was then filtered, and the filtrate was evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 356 (M+H)+, RT 1.61 minutes (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.22 - 10.21 (m, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.89 (s, 2H), 7.91 (d, J=2.8 Hz, 1H), 7.28 (dd, J=1.4, 12.7 Hz, 1H), 3.81 - 3.77 (m, 4H), 2.76 (dd, J=5.0, 5.0 Hz, 4H), 2.45 (s, 1H), 2.35 (s, 3H).

[0547] [Example 127] (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrimidine-5-carboxamide

[0548] [ka] Methyl 2-chloropyrimidine-5-carboxylate (345 mg, 2 mmol), tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (400 mg, 2 mmol), CsCO (975 mg, 3 mmol), and DMF (10 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 1 h. The reaction mixture was diluted with EtOAc, washed with water (×4), brine (×1), and evaporated to dryness to give methyl (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-5-carboxylate. MS RT (ES+) 337 (M+H).

[0549] Methyl (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-5-carboxylate (400 mg, 1.19 mmol), LiOH HO (55 mg, 1.3 mmol), MeOH (20 mL), and water (2 mL) were combined and heated in a hot block at 50 °C for 3 days. The reaction mixture was then evaporated to dryness to give lithium (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-5-carboxylate, which was used crude in the next reaction. MS (ES+) 323 (M+H).

[0550] (R)-Lithium 2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-5-carboxylate (200 mg, 0.62 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (100 mg, 0.62 mmol), HBTU (235 mg, 0.62 mmol), triethylamine (0.5 mL), and DMF (3 mL) were combined and stirred at room temperature for 1.5 hours. The reaction mixture was then purified by preparative HPLC to give tert-butyl (R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate. MS (ES+) 467 (M+H).

[0551] tert-Butyl (R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (49 mg), dichloromethane (3 mL), and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and then taken up in MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction was then filtered, and the filtrate was evaporated to dryness and purified by preparative HPLC to give the title compound. LCMS (ES+) 367 (M+H)+, RT 1.73 minutes (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.18 (s, 1H), 8.95 (s, 2H), 7.96 (s, 1H), 3.69 - 3.57 (m, 3H), 3.40 (dd, J=4.2, 11.7 Hz, 1H), 3.29 - 3.23 (m, 1H), 2.73 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.12 - 2.03 (m, 1H), 1.90 - 1.80 (m, 2H).

[0552] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry.

[0553] [Table 24]

[0554] [Example 129] (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(3-(methylamino)pyrrolidin-1-yl)pyrimidine-5-carboxamide

[0555] [ka] 2-Chloropyrimidine-5-carboxylic acid (500 mg, 3.15 mmol) and dichloromethane (10 mL) were combined under a nitrogen atmosphere. Oxalyl chloride (0.55 mL, 6.3 mmol) was added, followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness. 8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (750 mg, 3.15 mmol), dichloromethane (30 mL), and triethylamine (3 mL) were added, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was then evaporated to dryness to give 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide, which was used crude in the next reaction. MS (ES+) 306 / 308 (M+H).

[0556] 2-Chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide (150 mg, 0.23 mmol), (S)-N-methylpyrrolidin-3-amine (23 mg, 0.23 mmol), CsCO (325 mg, 1 mmol), and DMF (2 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 16 h. The reaction mixture was cooled to room temperature, the cesium salts were removed by filtration, and the reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 370 (M+H)+, RT 1.61 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.94 (d, J=1.6 Hz, 1H), 8.89 (s, 2H), 7.84 (d, J=2.8 Hz, 1H), 7.28 (dd, J=1.5, 12.7 Hz, 1H), 3.76 - 3.59 (m, 3H), 3.42 (dd, J=4.6, 11.7 Hz, 1H), 3.35 - 3.28 (m, 1H), 2.37 (d, J=0.7 Hz, 3H), 2.36 (s, 3H), 2.24 - 2.08 (m, 1H), 1.90 - 1.81 (m, 1H).

[0557] Additional analogs were prepared from commercially available or synthesized amines using the same chemistry. In some cases, Boc-protected amines were used, in which case the Boc group was removed at the end of the synthetic sequence using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). Final products were isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrarily assigned.

[0558] [Table 25] TIFF2025160356000225.tif226170

[0559] [Example 136] (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(3-(ethylamino)pyrrolidin-1-yl)pyrimidine-5-carboxamide

[0560] [ka] 2-Chloropyrimidine-5-carboxylic acid (317 mg, 2 mmol) and dichloromethane (5 mL) were combined at room temperature under a nitrogen atmosphere. Oxalyl chloride (0.35 mL, 4 mmol) was added, followed by one drop of DMF. The reaction mixture was stirred for 21 hours and then evaporated to dryness. 2,8-Dimethylimidazo[1,2-a]pyrazin-6-amine (324 mg, 2 mmol), dichloromethane (30 mL), and triethylamine (2 mL) were added, and the reaction was stirred for 2 hours. The reaction mixture was then evaporated to dryness to give 2-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrimidine-5-carboxamide, which was used crude in the next step.

[0561] 2-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrimidine-5-carboxamide (156 mg, 0.5 mmol), (R)-N-ethylpyrrolidin-3-amine (57 mg, 0.5 mmol), cesium carbonate (325 mg, 1 mmol), and DMF (3 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 2 h. The reaction mixture was then cooled to room temperature, the cesium salts were removed by filtration, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 381 (M+H)+, RT 1.79 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.69 (s, 1H), 9.17 (s, 1H), 8.95 (s, 2H), 7.97 (s, 1H), 3.73 - 3.53 (m, 3H), 3.40 - 3.36 (m, 2H), 2.73 (s, 3H), 2.64 - 2.55 (m, 2H), 2.40 (s, 3H), 2.14 - 2.05 (m, 1H), 1.88 - 1.78 (m, 2H), 1.04 (dd, J=7.1, 7.1 Hz, 3H).

[0562] [Example 137] 2-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide and [Example 138] 2-((3R,4S)-3-(ethylamino)-4-fluoropyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide

[0563] [ka] Cis-tert-butyl-3-amino-4-fluoropyrrolidine-1-carboxylate (2.17 g, 10.64 mmol), dichloromethane (40 mL), triethylamine (2 mL), and di-tert-butyl dicarbonate (2.55 g, 11.7 mmol) were combined and stirred at room temperature for 18 hours. The reaction mixture was then evaporated to dryness to give tert-butyl (3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate, which was used crude in the next step without further purification.

[0564] tert-Butyl (3R * ,4S *)-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate and DMF (20 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 511 mg, 12.77 mmol) was added, followed by EtI (1 mL, 12.77 mmol). The reaction mixture was stirred for 3 days, then diluted with EtOAc, washed with water (4×), brine (1×), and evaporated to dryness to give tert-butyl (3R * ,4S * )-3-((tert-butoxycarbonyl)(ethyl)amino)-4-fluoropyrrolidine-1-carboxylate, which was used crude in the next step without further purification.

[0565] tert-Butyl (3R * ,4S * )-3-((tert-butoxycarbonyl)(ethyl)amino)-4-fluoropyrrolidine-1-carboxylate, methanol (15 mL) and 4N HCl in dioxane (15 mL) were combined and stirred for 16 hours. The reaction mixture was then evaporated to dryness to give (3R * ,4S * )-N-ethyl-4-fluoropyrrolidin-3-amine·2HCl was obtained, which was used crude in the next step without further purification.

[0566] (3R * ,4S * )-N-Ethyl-4-fluoropyrrolidin-3-amine·2HCl (133 mg, 0.65 mmol), 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide (200 mg, 0.65 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (3 mL) were combined in a sealed tube and heated to 100 °C on a hot block for 20 h. The reaction mixture was then cooled to room temperature, the cesium salts were removed by filtration, and the filtrate was purified by preparative HPLC followed by chiral preparative HPLC to give the following: cis isomer, enantiomer 1 2-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide. LCMS (ES+) 402.3 (M+H)+, RT 1.62 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.06 (d, J=1.6 Hz, 1H), 8.92 (d, J=4.0 Hz, 2H), 7.92 (d, J=2.8 Hz, 1H), 7.29 (dd, J=1.7, 12.6 Hz, 1H), 5.30 (td, J=3.1, 54.4 Hz, 1H), 4.05 - 3.89 (m, 2H), 3.78 (ddt, J=3.0, 18.3, 20.3 Hz, 1H), 3.58 - 3.44 (m, 1H), 3.20 (dd, J=10.7, 10.7 Hz, 1H), 2.77 - 2.59 (m, 2H), 2.35 (s, 3H), 2.06 - 2.05 (m, 1H), 1.08 (dd, J=7.1, 7.1 Hz, 3H). cis isomer, enantiomer 2 2-((3R,4S)-3-(ethylamino)-4-fluoropyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide. LCMS (ES+) 402 (M+H)+, RT 1.62 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 9.06 (d, J=1.6 Hz, 1H), 8.92 (d, J=4.0 Hz, 2H), 7.92 (d, J=2.8 Hz, 1H), 7.29 (dd, J=1.7, 12.6 Hz, 1H), 5.30 (td, J=3.1, 54.4 Hz, 1H), 4.05 - 3.89 (m, 2H), 3.78 (ddt, J=3.0, 18.3, 20.3 Hz, 1H), 3.58 - 3.44 (m, 1H), 3.20 (dd, J=10.7, 10.7 Hz, 1H), 2.77 - 2.59 (m, 2H), 2.35 (s, 3H), 2.06 - 2.05 (m, 1H), 1.08 (dd, J=7.1, 7.1 Hz, 3H).

[0567] Additional analogs were prepared using the same chemistry.

[0568] [Table 26]

[0569] Examples 140-141 Examples 140-141 were carried out as follows: Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. All non-aqueous reactions were performed under an atmosphere of dry nitrogen (unless otherwise noted). Proton nuclear magnetic resonance spectra were obtained on a Bruker AVANCE300 spectrometer at 300 MHz, a Bruker AVANCE500 spectrometer at 500 MHz, or a Bruker ASCEND500 spectrometer at 500 MHz. Spectra are given in ppm (δ) and coupling constants, with J values ​​reported in hertz (Hz). Tetramethylsilane was used as an internal standard for proton nuclear magnetic resonance. Mass spectra and LCMS analyses were obtained using a Waters Acquity SQD (ESI, UP-LCMS) or a Shimadzu 2020 UP-LCMS instrument. UPLC analyses were obtained using an Acquity UPLC BEH C18 column, 1.7 μm (2.1 × 75 mm), eluted according to solvent gradient method 1. HPLC analysis was obtained using a Phenomenex C18 Kinetex column, 5 μm (4.6 × 150 mm), eluted according to solvent gradient method 2. Detection was by UV at 254 and 215 nm. UPLC-MS data were obtained using standard methods: (a) low pH, Waters CSHC18 column (1.7 μm, 2.1 × 50 mm), column temperature 55 °C, sample concentration of 0.5 mM in DMSO, ESI mass detection, UV DAD detection in the wavelength range 210-400 nm, and elution according to solvent gradient method 3, or (b) high pH, ​​Waters UPLC Xbridge BEH C18 column (2.5 μm, 2.1 × 50 mm), column temperature 45 °C, sample concentration of 0.5 mM in DMSO, ESI mass detection, UV DAD detection in the wavelength range 210-400 nm, and elution according to solvent gradient method 4.

[0570] Method 1

[0571] [Table 27]

[0572] Method 2

[0573] [Table 28]

[0574] Method 3

[0575] [Table 29]

[0576] Method 4

[0577] [Table 30]

[0578] [Example 140] (R)-N-(8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-(methyl-amino)pyrrolidin-1-yl)pyridazine-3-carboxamide

[0579] [ka] To a solution of (R)-6-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyridazine-3-carboxylic acid (0.050 g, 0.16 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (0.026 g, 0.16 mmol) in N,N-dimethylformamide (5.0 mL) was added N,N-diisopropylethylamine (0.13 mL, 0.78 mmol), followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 0.071 g, 0.19 mmol). The mixture was stirred at room temperature for 16 hours. After this time, water (30 mL) was added, followed by saturated aqueous sodium bicarbonate (30 mL). The resulting suspension was extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were washed with brine (2 × 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, dichloromethane to 95:5 dichloromethane / methanol, gradient elution) to give tert-butyl (R)-(1-(6-((8-fluoro-2-methylimido-azo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)pyrrolidin-3-yl)(methyl)carbamate. 1 H NMR (500 MHz, CDCl3) δ 9.71 (s, 1H), 9.04 (d, J = 1.5 Hz, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 11.0 Hz, 1.5 Hz, 1H), 6.77 (d, J = 9.5 Hz, 1H), 5.00-4.80 (m, 1H), 4.06-3.73 (m, 2H), 3.72-3.42 (m, 2H), 2.86 (s, 3H), 2.48 (s, 3H), 2.23-2.17 (m, 2H), 1.50 (s, 9H); MS (ESI) m / z 470 [M + H] + .

[0580] To a solution of tert-butyl (R)-(1-(6-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbam-oyl)pyridazin-3-yl)pyrrolidin-3-yl)(methyl)carbamate (0.061 g, 0.13 mmol) in dichloromethane (4.5 mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol), and the mixture was stirred at room temperature for 90 minutes. After this time, the volatiles were removed under reduced pressure, and the resulting residue was taken up in 80:18:2 dichloromethane / methanol / ammonium hydroxide and reconcentrated (2 x 25 mL). The crude product was purified by chromatography (silica gel, dichloromethane to 80:18:2 dichloromethane / methanol / ammonium hydroxide, gradient elution). The resulting product was combined with another batch and triturated with 90:10 heptane / dichloromethane to give (R)—N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-(methylamino)pyrrolidin-1-yl)pyridazine-3-carboxamide, mp 198-200°C, decomposition. 1 H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.21 (d, J = 1.5 Hz, 1H), 7.92 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 13.0, MS (ESI) m / z 370 [M + H] + ; HPLC: Method 2, t R = 3.00 min, >99% (AUC) at 254 and 215 nm.

[0581] [Example 141] (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)-pyrrolidin-1-yl)pyrimidine-2-carboxamide

[0582] [ka] Pyridine (0.031 mL, 0.39 mmol) and tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (0.128 g, 0.641 mmol) were added to a solution of methyl 5-fluoropyrimidine-2-carboxylate (0.050 g, 0.32 mmol) in dimethyl sulfoxide (0.4 mL), and the mixture was stirred at room temperature for 1 hour and at 80° C. for 18 hours. After this time, the mixture was cooled, water (8 mL) was added, and the mixture was added to saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by chromatography (silica gel, dichloromethane to 95:5 dichloromethane / methanol, gradient elution) to give methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-2-carboxylate. 1 H NMR (500 MHz, CDCl3) δ 8.14 (s, 2H), 4.96 (br s, 1H), 4.02 (s, 3H), 3.64-3.59 (m, 2H), 3.46-3.41 (m, 1H), 3.34-3.30 (m, 1H), 2.84 (s, 3H), 2.31-2.16 (m, 2H), 1.49 (s, 9H); MS (ESI) m / z 337 [M + H] + .

[0583] A solution of lithium hydroxide monohydrate (0.013 g, 0.32 mmol) in water (6.9 mL) was added to a solution of methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-2-carboxylate (0.107 g, 0.318 mmol) in tetrahydrofuran (6.9 mL), and the mixture was stirred at room temperature for 16 hours. After this time, the volatiles were removed in vacuo, and water (5 mL) was added. The mixture was washed with dichloromethane (10 mL). The pH of the aqueous layer was adjusted to 3 with 2.0 N hydrochloric acid, and the solid that formed was collected by filtration, washed with water, and dried in vacuo to give (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)-pyrrolidin-1-yl)pyrimidine-2-carboxylic acid. The aqueous layer was extracted with 3:1 chloroform / 2-propanol (3 x 20 mL), the combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give a second crop of (R)-5-(3-((tert-butoxycarbonyl)(methyl)-amino)pyrrolidin-1-yl)pyrimidine-2-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (br s, 1H), 8.20 (s, 2H), 4.80 (br s, 1H), 3.61-3.53 (m, 2H), 3.40-3.35 (m, 2H), 2.75 (s, 3H), 2.17-2.07 (m, 2H), 1.42 (s, 9H); MS (ESI) m / z 323 [M + H] + .

[0584] N,N-Diisopropylethylamine (0.203 mL, 1.17 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.166 g, 0.437 mmol) were added to a solution of (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrimidine-2-carboxylic acid (0.094 g, 0.29 mmol) and 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (0.047 g, 0.29 mmol) in N,N-dimethylformamide (2.4 mL), and the mixture was stirred at room temperature for 16 hours. After this time, water (20 mL) was added. The solid that formed was collected by filtration, washed with water (10 mL), and dried in vacuo to give tert-butyl (R)-(1-(2-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-5-yl)pyrrolidin-3-yl)(methyl)carbamate. 1 H NMR (500 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.17 (s, 1H), 8.29 (s, 2H), 8.01 (s, 1H), 4.82 (br s, 1H), 3.65-3.57 (m, 2H), 3.44-3.28 (m, MS (ESI) m / z 467 [M + H] + .

[0585] Trifluoroacetic acid (0.348 mL, 4.54 mmol) was added to a solution of tert-butyl (R)-(1-(2-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-5-yl)pyrrolidin-3-yl)(methyl)carbamate (0.106 g, 0.227 mmol) in dichloromethane (4.7 mL), and the mixture was stirred at room temperature for 2 hours. After this time, the solvent was removed in vacuo, dichloromethane (40 mL) was added, and the mixture was again concentrated to dryness. The resulting residue was dissolved in dichloromethane (40 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by chromatography (silica gel, dichloromethane to 85:14:1 dichloromethane / methanol / ammonium hydroxide, gradient elution) to give (R)—N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-carboxamide. The product was dissolved in dichloromethane (4 mL), the solution was added to hexane (100 mL), and the suspension was concentrated in vacuo to give (R)—N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrimidine-2-carboxamide. mp 266-268 °C. 1 H NMR (500 MHz, DMSO-d6) δ 9.96 (br s, 1H), 9.17 (s, 1H), 8.24 (s, 2H), 8.01 (s, 1H), 3.56-3.40 (m, 3H), 3.23-3.20 (m, 1H), 2.70 (s, MS (ESI) m / z 367 [M + H] + ; UPLC: Method 1, t R = 2.69 min, 98.7% (AUC) at 254 nm and >99% (AUC) at 215 nm; UPLC-MS: Method 4, t R = 0.83 min, >99% (AUC), MS (ESI) m / z 367 [M + H]+ .

[0586] [Example 142] (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(piperidin-2-yl)azetidin-1-yl)pyrazine-2-carboxamide 2-(azetidin-3-yl)-1-benzylpiperidine

[0587] [ka] To a solution of tert-butyl 3-(piperidin-2-yl)azetidine-1-carboxylate (500 mg, 2.08 mmol) in DCM (7 mL) was then added benzyl bromide (0.37 mL, 3.12 mmol), followed by saturated sodium carbonate solution (7 mL), and the resulting mixture was stirred at room temperature for 19 hours. The mixture was then partitioned between DCM and water. The aqueous phase was re-extracted (×1), and the combined organic phases were passed through phase separator paper and evaporated to dryness. The crude material was purified using silica chromatography, eluting with a gradient of 0–100% [EtOAc + 5% NH3 in MeOH] / cyclohexane to give tert-butyl 3-(1-benzylpiperidin-2-yl)azetidine-1-carboxylate.

[0588] tert-Butyl 3-(1-benzylpiperidin-2-yl)azetidine-1-carboxylate (540 mg, 1.63 mmol) was dissolved in a mixture of DCM (5 mL) and TFA (5 mL), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was evaporated to dryness to give an oil, which was partitioned between DCM and aqueous sodium carbonate. The aqueous layer was extracted with DCM (×1), and the combined organic phases were passed through phase separator paper and evaporated to dryness to give 2-(azetidin-3-yl)-1-benzylpiperidine.

[0589] [ka] Method D was followed for 22 hours with the following amounts: 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (119 mg, 0.39 mmol), 2-(azetidin-3-yl)-1-benzylpiperidine (90 mg, 0.39 mmol), cesium carbonate (191 mg, 0.59 mmol), and DMF (2 mL). Aqueous LiCl (4%) was then added to the reaction mixture, which was extracted with DCM (×2). The organic layer was then dried through phase separator paper and evaporated to dryness. The crude product was purified using silica chromatography with an elution gradient of 25–100% EtOAc / cyclohexane, followed by 0–1% NH3 (7N) in MeOH / EtOAc. The material was then purified by chiral SFC to give 5-(3-(1-benzylpiperidin-2-yl)azetidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (enantiomer 1).

[0590] Enantiomer 1, 5-(3-(1-benzylpiperidin-2-yl)azetidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (34 mg, 0.068 mmol) was dissolved in MeOH (1 mL) and degassed by sparging with N gas for 20 minutes. Pd / C (10%, 5 mg) was then added, followed by 1-methyl-1,4-cyclohexadiene (76 uL, 0.68 mmol), and the resulting mixture was heated to 60° C. for 3 hours. Additional 1-methyl-1,4-cyclohexadiene (76 uL, 0.68 mmol) was added and left at 60° C. overnight. Additional 1-methyl-1,4-cyclohexadiene (76 uL, 0.68 mmol) and Pd / C (10%, 5 mg) were added and again left overnight at 60 °C, after which complete conversion was achieved. The mixture was filtered through Celite, washed with copious amounts of MeOH, and evaporated to give a crude residue which was purified by reverse-phase HPLC to give (S)—N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(piperidin-2-yl)azetidin-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 410 (M+H)+, RT 1.81 min (Analytical Method AcHSSC18); 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.73 (d, J=1.3 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.86 (d, J=1.3 Hz, 1H), 7.56 (dd, J=1.6, 13.1 Hz, 1H), 4.26 - 4.17 (m, 2H), 4.10 (dd, J=5.6, 9.1 Hz, 1H), 4.00 (dd, J=5.7, 9.0 Hz, 1H), 3.06 (d, J=11.0 Hz, 1H), 2.90 - 2.85 (m, 1H), 2.80 - 2.74 (m, 1H), 2.69 - 2.60 (m, 1H), 2.35 (s, 3H), 1.79 - 1.78 (m, 1H), 1.71 - 1.68 (m, 1H), 1.61 - 1.59 (m, 1H), 1.42 - 1.34 (m, 2H), 1.13 - 1.05 (m, 1H).

[0591] [Example 143] 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (Enantiomer 1 + Enantiomer 2) 2-Methylpyrazolo[1,5-a]pyridin-5-amine

[0592] [ka] 5-Bromo-2-methylpyrazolo[1,5-a]pyridine (120 mg, 0.569 mmol, 1 equiv.), benzophenone imine (0.095 mL, 0.569 mmol, 1 equiv.), rac-BINAP (35 mg, 0.0569 mmol, 0.1 equiv.), Pd(OAc) (13 mg, 0.0569 mmol, 0.1 equiv.), and cesium carbonate (278 mg, 0.853 mmol, 1.5 equiv.) were suspended in THF, and the reaction mixture was purged with N for 15 min. The tube was sealed, and the reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, and washed with EtOAc (×3). The combined organic layers were washed with brine, dried, and the solvent removed in vacuo. The crude product was purified using silica chromatography, eluting with a gradient of 5–60% EtOAc in cyclohexane. Fractions containing the desired compound were combined and the solvent removed in vacuo to give N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-1,1-diphenylmethanimine. LCMS (ES+) 312 (M+H)+

[0593] 2-Methylpyrazolo[1,5-a]pyridin-5-amine (185 mg, 0.529 mmol, 1 equiv.) was dissolved in MeOH (2.0 mL) and 4 M HCl in dioxane (1.3 mL, 5.29 mmol, 10 equiv.) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was applied to a 2 g SCX cartridge and eluted with 2 column volumes of methanol followed by 3 column volumes of 2 M ammonia in methanol. The ammonia fraction was concentrated in vacuo to give 2-methylpyrazolo[1,5-a]pyridin-5-amine. LCMS (ES+) 148 (M+H)+

[0594] [ka] From 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid (188 mg, 0.530 mmol, 1 equiv.) and 2-methylpyrazolo[1,5-a]pyridin-5-amine (78 mg, 0.530 mmol, 1 equiv.) in DMF (2.0 mL) according to Method H. The reaction mixture was diluted with water, and the solid was filtered and washed with 1:2 MeCN / HO to give tert-butyl cyclopropyl(1-(5-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate, which was carried on to the next step without further purification.

[0595] From tert-butyl cyclopropyl (1-(5-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate (71 mg, 0.149 mmol) according to Method E. The reaction mixture was concentrated in vacuo and the residue was applied to a 2 g SCX cartridge and eluted with 2 column volumes of methanol, then 3 column volumes of 2 M ammonia in methanol. The ammoniacal fractions were concentrated in vacuo to give crude 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide, which was purified by HPLC to give 5-[3-(cyclopropylamino)pyrrolidin-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (enantiomer 1 + enantiomer 2). LCMS (ES+) 378 (M+H)+, RT 4.32 min (analytical method BicarbBEHC18). 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.56 (s, 1H), 8.29 (d, J=7.6 Hz, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 7.07 (dd, J=2.0, 7.6 Hz, 1H), 6.08 (s, 1H), 3.56 - 3.25 (m, 6H), 2.16 (s, 3H), 1.98 - 1.93 (m, 2H), 1.79 (s, 1H), 0.26 (d, J=6.6 Hz, 2H), 0.15 - 0.06 (m, 2H).

[0596] [Example 144] tert-Butyl 3-(6-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0597] [ka] 6-Chloropyridazine-3-carboxylic acid (270 mg, 1.7 mmol), 2-methylimidazo[1,2-a]pyridin-6-amine (250 mg, 1.7 mmol), HBTU (683 mg, 1.8 mmol), and triethylamine (1 mL, 7.2 mmol) were dissolved in DMF (6 mL) and stirred at room temperature for 24 h. The solution containing crude 6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridazine-3-carboxamide was used without further purification.

[0598] 6-Chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridazine-3-carboxamide (1 mL of the solution from the previous step, approximately 0.24 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64 mg, 0.3 mmol), and cesium carbonate (98 mg, 0.3 mmol) in DMF (1 mL) were stirred at 110° C. for 1.5 hours. After cooling to room temperature, the solids were removed by filtration, and the filtrate was purified by preparative HPLC to give tert-butyl 3-(6-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LCMS (ES+) 464 (M+H)+, RT 2.75 min (Analytical method 10cm_Formic acid_AQ). 1 H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 9.32 (s, 1H), 8.04 - 8.00 (m, 1H), 7.80 (s, 1H), 7.63 (dd, J=1.8, 9.6 Hz, 1H), 7.47 (d, J=9.6 Hz, 1H), 7.41 (d, J=9.6 Hz, 1H), 4.36 (s, 2H), 4.28 (d, J=12.4 Hz, 2H), 3.21 (d, J=12.0 Hz, 2H), 2.37 (s, 3H), 1.99 - 1.94 (m, 2H), 1.72 (d, J=4.6 Hz, 2H), 1.50 (s, 9H).

[0599] Comparative Example Comparative Example 145 N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide

[0600] [ka] 6-Chloro-2-methoxynicotinic acid (188 mg, 1 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (162 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (4 mL) were combined and stirred for 17 h. The reaction was diluted with EtOAc, washed with water (2×), and evaporated to dryness to give 6-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxynicotinamide, which was used crude in the next step.

[0601] 6-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxynicotinamide (70 mg, 0.21 mmol), piperazine (45 mg, 0.52 mmol), triethylamine (1 mL), and dioxane (6 mL) were combined in a sealed tube and heated to 100 °C for 17 h. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 382 (M+H)+, RT 2.07 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 9.19 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.08 (s, 3H), 3.59 (dd, J=5.0, 5.0 Hz, 4H), 2.80 (dd, J=5.0, 5.0 Hz, 4H), 2.70 (s, 3H), 2.39 (s, 3H).

[0602] Comparative Example 146 N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide

[0603] [ka] 6-Chloro-2-methoxynicotinic acid (188 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine.2HCl (238 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (4 mL) were combined and stirred for 17 h. The reaction was diluted with EtOAc, washed with water (2×), and evaporated to dryness to give 6-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide, which was used crude in the next step.

[0604] The crude product from the previous step, piperazine (86 mg, 1 mmol), triethylamine (1 mL), and dioxane (10 mL) were combined in a sealed tube and heated to 100 °C for 17 h. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 385 (M+H)+, RT 1.89 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 9.68 (s, 1H), 9.11 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.88 (d, J=2.8 Hz, 1H), 7.37 (dd, J=1.6, 12.9 Hz, 1H), 6.50 (d, J=8.8 Hz, 1H), 4.03 (s, 3H), 3.57 (dd, J=5.0, 5.0 Hz, 4H), 2.79 (dd, J=5.0, 5.0 Hz, 4H), 2.35 (s, 3H).

[0605] Comparative Example 147 N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide

[0606] [ka] 6-(4-Methylpiperazin-1-yl)pyridine-3-carboxylic acid (50 mg, 0.23 mmol), 2-methylimidazo[1,2-a]pyridin-6-amine (33 mg, 0.23 mmol), HBTU (95 mg, 0.25 mmol), DMF (1 mL), and triethylamine (0.25 mL) were combined and stirred at room temperature for 18 hours. The reaction mixture was then purified by preparative HPLC to give the title compound. LCMS (ES+) 351 (M+H)+, RT 2.89 min (analytical method BicarbBEHC18). 1 H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 9.19 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.10 (dd, J=2.6, 9.1 Hz, 1H), 7.74 (s, 1H), 7.44 (d, J=9.5 Hz, 1H), 7.35 (dd, J=2.0, 9.5 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 3.65 (dd, J=5.0, 5.0 Hz, 4H), 2.41 (dd, J=5.1, 5.1 Hz, 4H), 2.33 (s, 3H), 2.23 (s, 3H).

[0607] [Examples 148 and 149] (R)-5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, (S)-5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0608] [ka] N-(pyrrolidin-3-ylmethyl)cyclopropanamine.2HCl (488 mg, 2.29 mmol), 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (700 mg, 2.29 mmol), cesium carbonate (2.98 g, 9.16 mmol) and DMF (8 ml) were combined and heated to 100° C. for 4 hours. The cesium salts were then filtered off and the filtrate was purified by preparative HPLC followed by chiral preparative HPLC to give: Example 148 Enantiomer 1 5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 410 (M+H)+, RT 1.83 min (Analytical Method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.22 (d, J=1.6 Hz, 1H), 8.77 (d, J=1.3 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.8, 13.0 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.58 - 3.45 (m, 1H), 3.28 (dd, J=7.3, 11.0 Hz, 1H), 2.76 - 2.63 (m, 3H), 2.37 (s, 3H), 2.17 - 2.08 (m, 2H), 1.79 - 1.74 (m, 1H), 0.40 (dd, J=1.6, 6.6 Hz, 2H), 0.27 - 0.23 (m, 2H). Example 149 Enantiomer 2 5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 410 (M+H)+, RT 1.83 min (Analytical Method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.22 (d, J=1.6 Hz, 1H), 8.77 (d, J=1.3 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.59 (dd, J=1.8, 13.0 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.58 - 3.45 (m, 1H), 3.28 (dd, J=7.3, 11.0 Hz, 1H), 2.76 - 2.63 (m, 3H), 2.37 (s, 3H), 2.17 - 2.08 (m, 2H), 1.79 - 1.74 (m, 1H), 0.40 (dd, J=1.6, 6.6 Hz, 2H), 0.27 - 0.23 (m, 2H).

[0609] Further analogs were prepared from commercially available or synthesized amines using the same chemistry. Final products were isolated by preparative HPLC.

[0610] [Table 31]

[0611] [Examples 151 and 152] (R)-5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide, (S)-5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0612] [ka] 5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide was reacted with formaldehyde (37% wt in HO, 10-15% methanol, 1.5 mL) and sodium triacetoxyborohydride (168 mg, 0.794 mmol) and stirred at room temperature for 18 hours. The mixture was then partitioned between DCM and aqueous sodium bicarbonate. The aqueous phase was then re-extracted with DCM (×1) and the combined organic phases were passed through phase separator paper and evaporated to dryness to give the crude residue. The crude material was purified using silica chromatography, eluting with a gradient of 0-4% NH in MeOH (7N) / EtOAc. The material was then purified by chiral SFC followed by HPLC chromatography to give: Example 151 Enantiomer 1 5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 424 (M+H)+, RT 1.92 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.6, 13.2 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.57 - 3.49 (m, 1H), 3.23 (dd, J=6.8, 11.1 Hz, 1H), 2.35 (s, 3H), 2.31 (s, 3H), 2.15 - 2.09 (m, 1H), 1.75 - 1.63 (m, 2H), 0.48 - 0.43 (m, 2H), 0.36 - 0.27 (m, 2H). Example 152 Enantiomer 2 5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 424 (M+H)+, RT 1.92 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.75 (d, J=1.3 Hz, 1H), 7.98 (d, J=1.4 Hz, 1H), 7.90 (dd, J=0.8, 3.2 Hz, 1H), 7.57 (dd, J=1.7, 13.1 Hz, 1H), 3.73 - 3.64 (m, 2H), 3.57 - 3.50 (m, 1H), 3.22 (dd, J=6.7, 11.0 Hz, 1H), 2.65 - 2.59 (m, 1H), 2.52 (t, J=1.8 Hz, 0H), 2.35 (s, 3H), 2.31 (s, 3H), 2.15 - 2.07 (m, 1H), 1.73 - 1.63 (m, 2H), 0.48 - 0.42 (m, 2H), 0.36 - 0.27 (m, 2H).

[0613] Additional analogs were prepared using the same chemistry and defined amines, either commercially available or described in the Intermediates section. When Boc-protected amines were used, the Boc group was subsequently removed with TFA or HCl using standard methods C or C.

[0614] [Table 32] TIFF2025160356000247.tif254170TIFF2025160356000248.tif251170TIFF2025160356000249.tif251170TIFF2025160356000250.tif251170 TIFF2025160356000251.tif251170TIFF2025160356000252.tif252170TIFF2025160356000253.tif214170TIFF2025160356000254.tif220170

[0615] [Example 170] (R)-5-(3-(1-(cyclopropylamino)cyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0616] [ka] (R)-5-(3-(1-aminocyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (60 mg, 0.15 mmol) was dissolved in methanol (2 mL) and (1-ethoxycyclopropoxy)trimethylsilane (29 mg, 0.21 mmol), and sodium cyanoborohydride (11 mg, 0.18 mmol) was added. Acetic acid (20 μL) was added, and the reaction was heated at 50 °C overnight. The reaction was cooled to room temperature and the solvent removed in vacuo to give a residue which was purified by preparative HPLC to give (R)-5-(3-(1-(cyclopropylamino)cyclopropyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 436 (M+H)+, RT 1.98 min (analytical method AcHSSC18); 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.23 (d, J=1.5 Hz, 1H), 8.78 (d, J=1.3 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.93 (d, J=2.3 Hz, 1H), 7.61 (dd, J=1.5, 13.1 Hz, 1H), 3.88 - 3.76 (m, 2H), 3.54 - 3.46 (m, 1H), 3.23 - 3.16 (m, 1H), 2.92 - 2.66 (m, 2H), 2.39 - 2.38 (m, 3H), 2.20 - 2.14 (m, 1H), 2.06 (s, 1H), 1.76 - 1.63 (m, 1H), 0.63 - 0.54 (m, 4H), 0.44 - 0.40 (m, 2H), 0.30 - 0.25 (m, 2H).

[0617] [Example 171] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide

[0618] [ka] A mixture of 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (55 mg, 0.18 mmol), 6-methyl-2,6-diazaspiro[3.5]nonane dihydrochloride (50 mg, 0.24 mmol) and cesium carbonate (235 mg, 0.722 mmol) in DMF (1.5 mL) was heated to 100° C. and stirred overnight. The reaction was cooled to room temperature, filtered, and subjected to achiral reverse-phase HPLC purification (Xbridge Phenyl 19 x 150 mm, 10 μm 40-100% MeOH / HO (10 mM NHCO), 20 mL / min, room temperature) to give N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(6-methyl-2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide. LCMS (ES+) 410.3 [M+H] + , RT 1.83 min (Analysis method AcHSSC18). 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.72 (d, J=1.3 Hz, 1H), 7.90 - 7.87 (m, 2H), 7.56 (dd, J=1.6, 13.1 Hz, 1H), 3.90 (d, J=9.0 Hz, 2H), 3.86 (d, J=9.0 Hz, 2H), 2.50 - 2.40 (m, 2H), 2.35 (s, 3H), 2.29 - 2.21 (m, 2H), 2.21 (s, 3H), 1.70 - 1.60 (m, 2H), 1.57 - 1.50 (m, 2H).

[0619] [Example 172] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide

[0620] [ka] A mixture of 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (89 mg, 0.29 mmol), tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate hydrochloride (100 mg, 0.38 mmol), and cesium carbonate (382 mg, 1.17 mmol) in DMF (3 mL) was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, filtered, and the solid was washed with EtOAc. The combined filtrate was concentrated under reduced pressure to give the crude material, which was carried forward without further purification, assuming quantitative yield. MS (ES+) 496.3 [M+H] + .

[0621] To a solution of tert-butyl 2-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (145 mg, 0.293 mmol) in methanol (2.5 mL), hydrogen chloride (4 M in dioxane, 2.4 mL, 9.75 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (Xbridge Phenyl 19 x 150 mm, 10 μm 20-80% MeOH / HO (10 mM NHCO), 20 mL / min, room temperature) to give N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)pyrazine-2-carboxamide. LCMS (ES+) 396.0 [M+H] + , RT 1.80 min (Analysis method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.19 (d, J=1.5 Hz, 1H), 8.72 (d, J=1.3 Hz, 1H), 7.90 - 7.86 (m, 2H), 7.58 (d, J=1.5 Hz, 1H), 7.56 (dd, J=1.6, 13.1 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 3.90 (d, J=8.9 Hz, 2H), 3.83 (d, J=8.9 Hz, 2H), 2.84 (s, 2H), 2.67 - 2.61 (m, 2H), 2.35 (s, 3H), 1.80 - 1.71 (m, 2H), 1.50 - 1.41 (m, 2H).

[0622] [Example 173] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyrazine-2-carboxamide

[0623] [ka] 2,2,6,6-Tetramethyl-4-piperidinol (116 mg, 0.974 mmol) was added to a suspension of NaH (60% in oil) (55 mg, 1.38 mmol) in DMF (3 ml), and the reaction was stirred at room temperature for 30 minutes. 5-Chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide (100 mg, 0.33 mmol) was added, and the reaction was heated to 95°C for 1 hour. The reaction mixture was evaporated to dryness. The crude mixture was purified by flash chromatography using a kP-NH column, followed by preparative HPLC purification to give the title compound. LCMS (ES+) 427 (M+H)+, RT 2.02 min (analytical method AcHSSC18). 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 9.24 (d, J=1.6 Hz, 1H), 8.90 (d, J=1.3 Hz, 1H), 8.37 (d, J=1.3 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.6, 13.1 Hz, 1H), 5.61 - 5.53 (m, 1H), 2.35 (s, 3H), 2.03 (dd, J=4.0, 12.0 Hz, 2H), 1.29 (dd, J=11.5, 11.5 Hz, 2H), 1.23 (s, 6H), 1.12 (s, 6H).

[0624] [Example 174] 5-(5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide

[0625] [ka] N-(8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide (100 mg, 0.262 mmol) was dissolved in methanol (8 mL), (1-ethoxycyclopropyloxy)trimethylsilane (48 mg, 0.275 mmol), NaBHCN (18 mg, 0.29 mmol), and acetic acid (0.2 mL) were added, and the reaction was heated to 55° C. for 18 hours. Additional portions of (1-ethoxycyclopropyloxy)trimethylsilane (48 mg, 0.275 mmol) and NaBHCN (18 mg, 0.29 mmol) were added, and heating was continued for another 18 hours. The reaction was cooled to room temperature, and potassium carbonate (500 mg, 3.6 mmol) was added. The solvent was removed in vacuo, and the crude mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated, dried (MgSO4), and evaporated to dryness. The crude material was purified by preparative HPLC to give 5-(5-cyclopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide. LCMS (ES+) 422 (M+H)+, RT 1.82 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 9.19 (d, J=1.6 Hz, 1H), 8.75 (d, J=1.1 Hz, 1H), 8.00 (d, J=1.3 Hz, 1H), 7.90 (d, J=2.8 Hz, 1H), 7.57 (dd, J=1.6, 13.1 Hz, 1H), 3.83 (dd, J=8.3, 11.5 Hz, 2H), 3.42 (dd, J=3.3, 11.5 Hz, 2H), 2.96 (dd, J=7.5, 7.5 Hz, 2H), 2.77 (dd, J=6.9, 9.2 Hz, 2H), 2.69 - 2.62 (m, 2H), 2.35 (s, 3H), 1.67 - 1.61 (m, 1H), 0.43 - 0.37 (m, 2H), 0.33 - 0.27 (m, 2H).

[0626] [Example 175] (R)-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0627] [ka] To a solution of methyl 5-chloropyrazine-2-carboxylate (500 mg, 2.9 mmol) in dioxane (10 mL) was added tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate (696 mg, 3.48 mmol). Triethylamine (0.61 mL, 4.35 mmol) was added, and the reaction was heated in a microwave at 140 °C for 30 minutes. The solvent was removed in vacuo, and a portion of the residue was purified by flash chromatography using an elution gradient of 20 to 100% EtOAc in cyclohexane to give methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate lithium salt. LCMS (AQ6 general acidic elution) RT 1.54 min, (ES+) 337 (M+H). 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 7.89 (s, 1H), 4.89 - 4.80 (m, 1H), 3.93 (s, 3H), 3.83 - 3.76 (m, 2H), 3.58 - 3.45 (m, 2H), 2.82 (s, 3H), 2.27 - 2.13 (m, 2H), 1.48 (s, 9H).

[0628] Methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylate (194 mg, 0.577 mmol, 1 equiv) was dissolved in MeOH (5 mL) and HO (0.5 mL), lithium hydroxide monohydrate (36 mg, 0.865 mmol, 1.50 equiv) was added, and the reaction mixture was stirred for 16 h. An additional portion of lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the reaction mixture was stirred at 45 °C for 1 h. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The resulting material was used without further purification. LCMS (AQ6 general acidic elution) RT 1.4 min, (ES+) 323 (M+H).

[0629] 6,8-Dimethylimidazo[1,2-a]pyrazin-2-amine (50 mg, 0.31 mmol), methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid lithium salt (99 mg, 0.31 mmol), HBTU (129 mg, 0.339 mmol), triethylamine (0.064 mL, 0.46 mmol), and DMF (1 mL) were combined and stirred at room temperature for 18 hours. An additional portion of HBTU (160 mg, 0.422 mmol) was added, and the reaction was heated to 50° C. for 2.5 hours. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated, and the crude material was purified by flash chromatography eluting with a gradient of 20-100% EtOAc in cyclohexane followed by 10% ethanol / ethyl acetate, then by flash chromatography eluting with a gradient of 20-100% EtOAc on KP-NH to give tert-butyl (R)-(1-(5-((6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate. LCMS (AQ6 general acidic elution) RT 1.53 min, (ES+) 467 (M+H).

[0630] tert-Butyl (R)-(1-(5-((6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)carbamoyl)pyrazin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (35 mg, 0.07 mmol), methanol (1 mL), dioxane (1 mL), and 4N HCl in dioxane (0.5 mL, 2.0 mmol) were combined and stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness, and the crude material was dissolved in methanol (2 mL), stirred with potassium carbonate, re-evaporated, and purified by preparative HPLC to give the title product. LCMS (ES+) 367 (M+H)+, RT 1.88 min (Analytical Method AcHSSC18); 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.76 (d, J=1.3 Hz, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 8.03 (d, J=1.4 Hz, 1H), 3.69 - 3.59 (m, 3H), 3.42 - 3.38 (m, 1H), 2.68 (s, 3H), 2.38 (s, 3H), 2.32 (s, 3H), 2.15 - 2.08 (m, 2H), 1.90 (s, 1H).

[0631] [Example 176] (R)-N-(6-Methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)-5-(3-(methylamino)pyrrolidin-1-yl)pyrazine-2-carboxamide

[0632] [ka] Method H: From (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidin-1-yl)pyrazine-2-carboxylic acid (156 mg, 0.485 mmol, 1 equiv.) and 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine 2HBr (164 mg, 0.485 mmol, 1 equiv.) according to TCFH coupling. The reaction mixture was diluted with HO and the solid was filtere...

Claims

1. Compounds of Formula I 【Chemical 1】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein: 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, 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 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 on available nitrogen atoms, C 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 is 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 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, and heterocyclyl; each R 21 1 to 6 halos or C 1～3 optionally substituted with alkoxy; R 2 is hydrogen or C 1～6 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.

3. The compound of claim 1 of formula Ib 【Chemistry 3】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

4. The compound of claim 1 of formula Ic 【Chemistry 4】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

5. The compound of claim 1 of formula IIa 【Chemistry 5】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

6. The compound of claim 1 of formula IIb 【Chemistry 6】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

7. The compound of claim 1 of formula IIIa 【Chemistry 7】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

8. The compound of claim 1 of formula IIIb 【Chemistry 8】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

9. The compound of claim 1 of formula IIIc 【Chemistry 9】 or an isotopically enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

10. 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 10. The compound of any one of claims 1 to 9, wherein the compound is alkyl.

11. R 11 but 【Chemistry 10】 and ring C is one to four R 13 11. The compound of any one of claims 1 to 10, which is a 3- to 10-membered heterocyclyl containing 0, 1 or 2 additional ring nitrogen atoms, optionally substituted by a group.

12. Ring C is one to four R 13 12. The compound of claim 11, which is a 5-10 membered bicyclic heterocyclyl containing one additional ring nitrogen atom, optionally substituted with a group.

13. Ring C is one to four R 13 12. The compound of claim 11, which is a 5-10 membered spiro bicyclic heterocyclyl containing one additional ring nitrogen atom, optionally substituted with a group.

14. Ring C is one to four R 13 12. The compound of claim 11, which is a 5-10 membered fused bicyclic heterocyclyl containing one additional ring nitrogen atom, optionally substituted with a group.

15. R 11 but 【Chemistry 11】 【change】 each of which is selected from 1 to 4 R 13 11. The compound of claim 1, optionally substituted by a group.

16. R 11 where: fluoro, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoroprop-1-ylamino)methyl, cyclopropyl, 1-(cyclopropylamino)-1-cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperdinyl, 1-cyclopropyl-2-piperdinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert-butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylamino 16. The compound of any one of claims 1 to 15, optionally substituted by one to four groups independently selected from 3-methyl, N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylaminomethyl, N-isopropyl-N-aminomethyl, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanylamino, (3-methoxy-1-azetidinyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, 4-morpholinylmethyl, and tert-butoxycarbonyl.

17. R 3 17. The compound of any one of claims 1 to 16, wherein is halo.

18. R 3 18. The compound of any one of claims 1 to 17, wherein is fluoro.

19. R 3 17. The compound of any one of claims 1 to 16, wherein is methyl.

20. R 3 17. The compound of any one of claims 1 to 16, wherein is methoxy.

21. Each R 4 21. The compound of any one of claims 1 to 20, wherein is hydrogen.

22. R 5 22. The compound of any one of claims 1 to 21, wherein is hydrogen.

23. R 5 C 1～6 22. The compound of any one of claims 1 to 21, which is alkoxy.

24. R 5 22. The compound of any one of claims 1 to 21, wherein is methoxy.

25. R 7 25. The compound of any one of claims 1 to 24, wherein is hydrogen.

26. R 8 26. The compound of any one of claims 1 to 25, wherein is methyl.

27. L 1 27. The compound of any one of claims 1 to 26, wherein is absent.

28. Y 1 is CR 5 28. The compound of any one of claims 1 to 27, wherein

29. Y 1 28. The compound of any one of claims 1 to 27, wherein is N.

30. Y 2 is CR 6 30. The compound of any one of claims 1 to 29, wherein

31. Y 3 is CR 3 31. The compound of any one of claims 1 to 30, wherein

32. Ring B 【Chemistry 12】 32. The compound of any one of claims 1 to 31, wherein:

33. Ring B 【Chemistry 13】 32. The compound of any one of claims 1 to 31, wherein:

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

35. 35. A pharmaceutical composition comprising a compound of any one of claims 1 to 34, or an isotopically enriched analogue, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

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

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

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