HTT modulator 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 of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 024,052, filed on 13 May 2020, which is incorporated herein by reference in its entirety under Section 119(e) of the U.S. Patent Act.

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

[0003] Huntington's disease (HD) is a dominant, 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 global prevalence of 5 to 10 cases per 100,000 people and is the most common hereditary monogenic neurodegenerative disorder.

[0004] Neurodegenerative diseases and conditions, such as Huntington's disease, have a significant adverse impact on the lives of those affected. Current treatments for Huntington's disease are palliative, aiming to alleviate the severity of symptoms. There are no available treatments to palliatively treat the disease.

[0005] Huntington's disease is caused by the elongation of the CAG repeat domain in exon 1 of the huntingtin gene (HTT), which is expressed as a mutant huntingtin protein (mHTT) containing an extended polyglutamine region at the amino-terminal domain of the protein. Although HD is monogenic and autosomal dominant, the molecular pathway of its pathogenesis is not fully understood. Therefore, reducing mHTT is a clear therapeutic strategy that targets the gene product of the causative gene. In fact, several therapeutic strategies targeting mHTT reduction via the degradation of HTT RNA mediated by antisense oligonucleotides (ASOs) or AAV-miRs have progressed through clinical trials in HD, demonstrating a reduction in mHTT levels in the CSF of treated patients. [Overview of the project] [Problems that the invention aims to solve]

[0006] While these modalities show great promise, they are invasive (involving repeated intrathecal injections), not guaranteed to distribute throughout the brain to all affected areas, and do not address any peripheral dysfunction that may be caused by widespread mHTT. Therefore, small molecule HTT reducers that can be delivered non-invasively throughout the body are an attractive HTT-reducing treatment to pursue. Thus, small molecule modulators of the HTT protein are needed. Such molecules may find use in treating the symptoms of Huntington's disease and / or delaying disease progression. [Means for solving the problem]

[0007] This disclosure generally relates to the use of HTT as a small molecule modulator and therapeutic agent, for example, in the treatment of diseases, such as Huntington's disease.

[0008] Accordingly, compounds useful for the treatment of Huntington's disease, or isotopic enriched analogs of such compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are provided herein.

[0009] In certain embodiments, compounds that modulate proteins or protein fragments involved in neurodegenerative diseases, such as the HTT protein, are provided.

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

[0011] This disclosure also provides compositions comprising pharmaceutical compositions, kits comprising compounds, and methods for using (or administering) and preparing compounds. This disclosure further provides compounds or compositions thereof for use in methods of treating diseases or conditions at least partially mediated by proteins or protein fragments involved in neurodegenerative diseases. Furthermore, this disclosure provides the use of compounds or compositions thereof in the manufacture of pharmaceuticals for treating diseases or conditions at least partially mediated by proteins or protein fragments involved in neurodegenerative diseases. [Modes for carrying out the invention]

[0012] The following description illustrates exemplary embodiments of the Technology. However, it should be recognized that such descriptions are not intended to limit the scope of this disclosure, but rather are provided as exemplary embodiments.

[0013] definition Where used herein, the following words, phrases, and abbreviations are intended to have the meanings generally described below, unless the context in which they are used indicates otherwise.

[0014] The compounds described herein refer to compounds of formula I, Ia, Ib, Ic, IIa, IIb, IIc, IId, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, or any compound of any formula described herein, including the examples, or compounds of Table 1 or Table 1A, or their isotope-labeled analogs, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers.

[0015] A dash ("-") that is not between two letters or abbreviations is used to indicate a bond point to the parent structure in the case of a substituent. For example, -C(O)NH2 is bonded to the parent structure through a carbon atom. Dashes before or after chemical groups are for convenience, and chemical groups may be written with or without one or more dashes without losing their usual meaning. A wavy or dotted line drawn through a bond in a structure indicates a specific bond point. Unless chemically or structurally required, the order in which chemical groups are written or specified does not indicate or suggest anisotropy or stereochemistry.

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

[0017] In this specification, any reference to a value or parameter includes (and describes) embodiments relating to that value or parameter itself. In certain embodiments, the term "about" includes a specified amount ± 10%. In other embodiments, the term "about" includes a specified amount ± 5%. In certain other embodiments, the term "about" includes a specified amount ± 1%. Again, the term "about X" includes a description of "X". Again, the singular forms "a" and "the" include multiple references unless the context explicitly states otherwise. For example, a reference to "the compound" includes multiple such compounds, and a reference to "the assay" includes one or more assays and their equivalents known to those skilled in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 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 1~4It has an alkyl group. Examples 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 specified 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, etc., may also be referred to as "alkylene" or "arylene" groups, respectively. Also, unless explicitly indicated otherwise, when a combination of groups is referred to herein as one moiety, for example arylalkyl or aralkyl, the last-mentioned group contains the atom that attaches that moiety to the rest of the molecule.

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

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

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

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

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

[0025] "Ashiru" is -C(O)R y It refers to the base, and in the formula, R yThe elements are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

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

[0027] "Amino" is -NR y R z It refers to the base, and in the formula, R y and R z These are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be substituted as defined herein. In some embodiments, "amino" refers to an NH2 group.

[0028] "Amidino" is -C(NR y )(NR z 2) Refers to a unit, in the formula, R y and R zThese are independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may optionally be 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 condensed systems. As used herein, aryl refers to a ring with 6 to 20 carbon atoms (i.e., C 6~20 aryl) or 6-10 carbon ring atoms (i.e., C) 6~10 It has an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryls never include, nor overlap with, heteroaryls as defined below. When one or more aryl groups condense with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups condense with a heterocyclyl, the resulting ring system is a heterocyclyl.

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

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

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

[0033] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including condensed, crosslinked, and spirocyclic systems. The term "cycloalkyl" refers to a cycloalkenyl group (i.e., a cyclic group having at least one double bond) and at least one sp 3 This includes carbocyclic fused ring systems having ring carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyls have 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), 3-8 ring carbon atoms (i.e., C 3~8 Cycloalkyl) or 3-6 ring carbon atoms (i.e., C 3~6 They have cycloalkyl groups. Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, norborneyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring system that may include a fused aryl ring, regardless of its bond to the rest of the molecule. Moreover, cycloalkyls also include "spirocycloalkyls," such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl. If there are two positions for substitution on one carbon atom of the parent structure, the cycloalkyl as a substituent may include a spirocycloalkyl. The cycloalkyl group may be substituted at the carbon atom of the bond to the parent structure.

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

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

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

[0037] "Imino" is -C(NR y )R z It refers to the base, and in the formula, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of them may be optionally substituted as defined herein.

[0038] "Imido" is -C(O)NR y C(O)R z It refers to the base, and in the formula, R y and R z Each of these is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, and each of them may be optionally substituted as defined herein.

[0039] "Halogen" or "halo" refers to substituent elements in Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodine.

[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 halogens. For example, if a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogen moieties bonded. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may, though not required, be the same halogen. Perhaloalkyl groups are haloalkyl groups in which all hydrogen substituents are replaced by halos. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0041] A "haloalkoxy" refers to an alkoxy group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms, up to all hydrogen atoms including the upper limit, are replaced by halogens.

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

[0043] A "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any related hydrogen atoms) of the alkyl chain are independently replaced by the same or different heteroatomic groups, provided that the bond to the rest of the molecule passes through the carbon atoms. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatomic groups. Heteroatomic groups are not limited to, but include NR y Examples include -, -O-, -S-, -S(O)-, -S(O)2-, and here, R yThe elements are 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., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2CH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH3, etc.) and aminoalkyl groups (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2 CH2NR y CH3 etc, here, R y Examples include hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which may be optionally substituted as defined herein. As used herein, a heteroalkyl comprises 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] A "heteroaryl" refers to an aromatic group having a single ring or multiple fused rings, where 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) - ) may include a portion. When used herein, heteroaryls have 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) 3~8The heteroaryl comprises a heteroaryl ring and one to five ring heteroatoms, one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, each independently selected from nitrogen, oxygen, and sulfur. In certain examples, the heteroaryl ring may be a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having one to four ring heteroatoms, one to three ring heteroatoms, one to two ring heteroatoms, or one ring heteroatom, each 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, sinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, iso Examples include indolyl, isoquinolyl, isoxazolyl, naphthylidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 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, though not limited to them, include 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 via any of the rings in the fused system. Any aromatic ring system having one or more fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its bond to the rest of the molecule (i.e., via any one of the fused rings). Heteroaryls do not encompass or overlap with the aryls as defined above.

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

[0046] A "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur atom may be 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 intra- or extra-ring double bond), bridged heterocyclyl groups, condensed heterocyclyl groups, oxo-heterocyclyls (i.e., heterocyclyls 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 condensed, bridged, or spiro. Regardless of the listed substituents, unless otherwise stated, a heterocyclyl is one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - ) may include a portion. Heterocyclyls can be bonded through carbon atoms or heteroatoms if the bond valency allows. Furthermore, the term heterocyclyl encompasses any ring system containing a non-aromatic ring containing at least one heteroatom, regardless of its bond to the rest of the molecule, and this ring may be condensed into an aryl or heteroaryl ring. Heterocyclyls may have an aromatic charge resonance structure (e.g., pyridine-2(1H)-on-1-yl). As used herein, heterocyclyls include 3 to 14 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms or 5 to 6 ring atoms having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, and / or 2 to 12 ring carbon atoms (i.e., C 2~12 Heterocyclines), 2 to 10 ring carbon atoms (i.e., C 2~10 Heterocyclines), 2-8 ring carbon atoms (i.e., C 2~8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C3~12 Heterocyclines), 3-8 ring carbon atoms (i.e., C 3~8 Heterocycline) or ring carbon atoms (i.e., C) with 3-6 carbon atoms 3~6It may also contain heterocyclyl groups. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoin Examples include drill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxylanil, oxetanil, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, 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 bridging heterocyclyl rings, though not limited to, include 2,5-diazabicyclo[2.2.1]heptane and 2-oxa-5-azabicyclo[2.2.1]heptanyl. If there are two positions for substitution on one carbon atom of the parent structure, the heterocyclyl substituent may include a spiroheterocyclyl. Examples of condensed heterocyclyl rings, though not limited to them, include 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be linked via any of the rings in the condensation system.

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

[0048] "Oxime" refers to a -CR y (=NOH) group, where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which, as defined herein, may optionally be substituted.

[0049] "Sulfonyl" refers to a -S(O)2R y group, where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which, as defined herein, may optionally be substituted. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0050] "Sulfinyl" refers to a -S(O)R y group, where R y is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl, each of which, as defined herein, may optionally be substituted. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

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

[0052] The terms "optional" or "optionally" mean that the subsequently described event or situation may or may not occur, and the description includes examples where the event or situation occurs and examples where 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 are replaced by a non-hydrogen group such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino, aryl, arylalkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkoxy, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide or -Si(R y )3 (where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl) refers to a group that is replaced.

[0054] In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently substituted for deuterium, halo, cyano, hydroxyl, imino, nitro, azide, 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 Ure g , -NR g S(=O) 1~2 NR g R h ,=NSO2R g 、=NOR g -S(=O) 1~2 NR g R h This refers to a group that is replaced by -SF5 or -SCF3. In certain embodiments, "substituted" means that one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g-C(=O)NR g R h -CH2SO2R g or -CH2SO2NR g R h This also means the base that is replaced by R. g and R h The same or different, independently of 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 These two, together with the atom to which they are bonded, form a heterocyclyl ring which is optionally substituted by an alkyl group that is optionally substituted by an oxo, halo, or oxo, halo, amino, hydroxyl, or alkoxy group.

[0055] Polymers or similar amorphous structures, which can be achieved by defining substituents having an infinite number of further substituents (e.g., substituted aryls having a substituted alkyl group that is itself substituted by a substituted aryl group, further substituted by a substituted heteroalkyl group, etc.), are not intended to arise from the above definitions. Unless otherwise noted, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include compounds having substitution patterns that are chemically unrealizable or unisolated (e.g., a methyl group substituted by five fluorine atoms, or a heteroaryl group having three consecutive oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may also refer to other chemical groups as defined herein.

[0056] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0057] Any compounds or structures given herein are intended to represent the unlabeled form and the “isotope-enriched analog” of the compound. The isotope-enriched form of a compound may also be referred to as the “labeled form.” The isotope-enriched analog has the structure described herein, except that one or more atoms are enriched with isotopes having selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively 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, isotope-enriched analogs include compounds that have any degree of isotope enrichment exceeding the natural abundance of the isotope (e.g., on the Earth's surface). Various isotope-enriched compounds, for example, radioactive isotopes, for example, 3 H, 18 F, 11 C, 13 C and 14 Compounds incorporating C are included in this disclosure. 18 F, 3 H or 11 Compounds labeled with 1C 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 tomography (SPECT), or in radiation therapy for patients.

[0058] The term “isotope-enriched analog” includes “deuterated analogs” of the compounds described herein, in which one or more hydrogen atoms, for example, a hydrogen atom 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 mammals, particularly humans. 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 are 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 with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may result in certain therapeutic benefits arising from higher metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the scheme, or by substituting the non-isotope labeling reagent with readily available isotope enrichment reagents in the examples and preparations described below. Where a compound is described as a deuterated analog, the compound may be obtained using deuterium as a substituent.

[0060] The concentration of such heavy isotopes, 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, where a position is specifically designated as "H" or "hydrogen," that position is understood to contain hydrogen and its isotopes in their natural abundances.

[0061] In many cases, the compounds of this disclosure can form acid salts and / or base salts in the presence of an amino group and / or a carboxyl group, or similar groups.

[0062] Isotope-enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0063] In this specification, the term “pharmaceutically acceptable salt” of a compound refers to a salt that retains the bioefficiency and properties of a given compound and is not biologically or otherwise undesirable. Examples of “pharmaceutically acceptable” or “physiologically acceptable” salts of 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. When a compound is obtained as an acid addition salt, a free base can be obtained by basifying a solution of the acid acid. Conversely, when a compound is a free base (e.g., an amine), an addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize a variety of synthetic methodologies that may be used to prepare non-toxic, pharmaceutically acceptable addition salts. pharmaceutically acceptable acid addition salts of 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, and phosphoric acid. 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, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include salts of sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium.Salts derived from organic bases 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), tertiary alkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl)amines (i.e., Examples of suitable amines include N(substituted alkenyl)3, mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), cyclic amines (e.g., piperidine, piperazine, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines. Specific examples of suitable amines, though these are merely examples, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0064] Some of the compounds described herein may also exist as tautomers. For example, when a compound is described as containing an amide, it may also exist as an imido acid tautomer, and when a compound is described as containing a ketone, it may also exist as an enol tautomer. Regardless of which tautomer is shown, and regardless of the equilibrium between the tautomers, it will be understood by those skilled in the art that a compound contains both tautomers. Thus, for example, it will be understood that an amide-containing compound contains its imido acid tautomer, and an imido acid-containing compound contains its amide tautomer.

[0065] The compounds described herein may contain chiral centers and therefore may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which in the case of amino acids can be defined as (R-) or (S-) or (D)- or (L)- from the viewpoint of absolute configuration. The compounds described herein 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 they can be 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 racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). If a compound described herein contains a double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both cis and trans or E- and Z- geometric isomers.

[0066] A "stereoisomer" refers to a pair of compounds that are composed of the same atoms bonded together by the same bonds, but have different three-dimensional structures. Various stereoisomers and mixtures thereof, including "enantiomers," are considered, and enantiomers refer to stereoisomer compounds that are mirror images of each other and cannot be superimposed.

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

[0068] A “prodrug” is any molecule that, when administered to a mammalian subject, releases in vivo a parent drug presumed to be active, due to one of the compounds described herein. A prodrug may be a form of one of the compounds described herein that has been modified so that the modification can be cleaved in vivo to release the parent compound. A prodrug can be prepared by modifying a functional group present in one of the compounds described herein so that the modification can be cleaved in vivo, either through routine procedures or in vivo, to become the parent compound. Examples of prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group is bonded to any group, and this can be cleaved in vivo to regenerate the liberated hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of the hydroxyl functional group in the compounds described herein (e.g., acetate esters, formic acid esters, and benzoic acid ester derivatives), amides, guanidines, and carbamates (e.g., N,N-dimethylaminocarbonyl). 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," edited by H. Bundgaard, Elsevier, 1985; and "Bioreversible Carriers in Drug Design," edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is thus incorporated herein by reference in whole.

[0069] As used herein, the terms “group,” “part,” “radical,” “substituent,” and “fragment” are synonymous and are intended, for example, to indicate a part of a molecule that can be bonded to another part of the molecule through a specified bond or bond.

[0070] The term "activator" is used to describe a compound that has biological activity in the treatment, improvement, or prevention of a disease or condition. In some embodiments, an "activator" is a compound or its isotope-labeled analog, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers that has pharmaceutically useful properties. For example, an activator may be used for anti-neurodegenerative therapy.

[0071] The term “effective dose” means the amount of a compound, for example, described herein, that is sufficient to produce a desired response in an individual or patient. The term “therapeutic effective dose” means the amount that, when administered to a human or non-human patient, is effective in providing a therapeutic benefit, such as improvement of symptoms, slowing of disease progression, or prevention of disease. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of a disease described herein. The (therapeutic) effective dose may vary depending on the subject and the disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the mode of administration, which can be determined by a person skilled in the art.

[0072] The terms “huntingtin protein” or “HTT protein” as used herein refer 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 that encodes the HTT protein. 15 The genes are located on chromosome 4, specifically between base pairs 3,076,407 and 3,245,686.

[0073] The term "protein aggregate," as used herein, refers to an aggregate of proteins that may be insoluble fibrous amyloid, including, for example, misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). "Proteins involved in neurodegenerative diseases" may be proteins that, in wild-type or mutant form, can form such aggregates, or may be proteins involved in pathological processes related to neurodegenerative diseases.

[0074] In some embodiments, the term “neurodegenerative disease” refers to a disease or condition in which the function of the nervous system in question is impaired. Examples of neurodegenerative diseases are those described herein.

[0075] "Treatment" or "the act of taking treatment" a) Suppressing the disease (for example, reducing one or more symptoms resulting from the disease or condition, and / or reducing the extent of the disease or condition), b) Slowing down or preventing the onset of clinical symptoms related to the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)), and / or c) Eliminating the disease, i.e., reversing the clinical symptoms (e.g., improving the appearance of the disease, achieving partial or complete remission of the disease or condition, enhancing the effects of another medication, slowing the progression of the disease, improving quality of life, and / or extending survival). This refers to any treatment of the disease manifestation in a patient, including [specific treatments].

[0076] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk (e.g., those with genetic or epigenetic markers related to the disease or condition, those involved in activities or exposed to environmental conditions) or who have a family history of the disease or condition.

[0077] "Subject" or "patient" refers to an animal, such as a mammal, that is or will be the object of a procedure, observation, or experiment. The methods described herein may be useful in both human therapeutic and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.

[0078] The methods described herein can be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as within an animal or a human. In this context, the methods described herein may be used for therapeutic purposes in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include biological samples, including in vitro cell cultures and fluid or tissue samples obtained from organisms. 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 may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or administration of the compounds disclosed herein for a given efficacy, cell type, organism, and other parameters. Information gathered from such use may be used for experimental purposes or to establish protocols for in vivo treatment in a clinical setting. Other ex vivo uses in which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. The selected compounds may be further characterized to test their safety or acceptable dose in human or non-human subjects. Such properties can be tested using methods generally known to those skilled in the art.

[0079] It is understood that several particular properties described herein, described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, various properties described herein, described in the context of a single embodiment for brevity, may also be provided separately or in any preferred sub-combination. All combinations of embodiments relating to the chemical groups represented by the variable elements contained in Formula I are specifically incorporated herein, to the extent that such combinations produce stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), as every combination is explicitly enumerated individually. In addition, all sub-combinations of the chemical groups enumerated in embodiments describing such variable elements, as well as all sub-combinations of uses and pharmaceutically active properties described herein, are also specifically incorporated herein, as every sub-combination of the chemical groups, as well as every sub-combination of uses and pharmaceutically active properties, as every combination is explicitly enumerated individually. In addition, some embodiments include all combinations of one or more additional agents disclosed herein, as every combination is explicitly enumerated individually.

[0080] [Table 1] TIFF0007894498000002.tif251158TIFF0007894498000003.tif28158

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

[0082] [ka] or its isotope-enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers (wherein, X1 , X 2 , X 3 and X 4 CR 4 or N, where X 1 , X 2 , X 3 and X 4 There are at least two of them, but if there are three or fewer, then it is N. Each R 4 These are independently hydrogen, halo, hydroxyl, and C. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, Y 1 CR 5 or N, R 5 C 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 the available nitrogen atoms 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group. Y 2 Does not exist, or CR 6 or N, R 6 C 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 on the available nitrogen atom, C 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group. Y 3 CR 3 or N, R 3C 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 the available nitrogen atoms 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group. Each R 17 C is independent 1~4 Alkyl, or two R 17 However, it can link with any intervening atom to form a 3-6 member heterocycline. Z 1 and Z 2 Each of them is either C or N, Rings A and B together form a 9- or 10-membered bicyclic heteroaryl compound containing 1 to 3 ring nitrogen atoms. Ring B contains 1 to 3 heteroatoms selected from N, O, and S, and has a halo, hydroxyl, and C atoms on the available carbon atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C 1~6 Optionally substituted by 1 to 3 substituents independently selected from the haloalkoxy, with C on the available nitrogen atom. 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group. R 1 ha-L 1 -R 11 And here, 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 not present, R 11 is C 2~6 Alkinyl, C 3~10Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, where R 11 1 to 4 R 13 It is substituted depending on the base, R 12 is hydrogen or C 1~6 It is alkyl, Each R 13 These are independently halo, cyano, hydroxy, and R 16 C is replaced depending on the case. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl-C 1~6 Alkyl, R 16 C is replaced depending on the case. 6~10 Ariel, R 16 C is replaced depending on the case. 6~10 Aryl-C 1~6 Alkyl, R 16 Heteroaryls that are substituted in some cases, R 16 Heteroaryl-C which may be substituted depending on the circumstances. 1~6 Alkyl, R 16 Heterocyclines that are substituted in some cases, R 16 Heterocyclyl-C is sometimes substituted by 1~6 Alkyl, OR 14 -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2,-C 1~6 Alkilen-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 Selected from, Each R 14 C is independent 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Selected from aryl, heteroaryl and heterocyclyl, each R 14 1-6 halos, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~10 They are optionally substituted with cycloalkyl or -NHSO2-aryl-N(CH3)2. Each R 15 These are independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl. Each R 16 These are independently halo, cyano, hydroxy, -NH2, and -NHR 21 , -N(R 21 )2, C 1~6 Alkyl, C 1~6 Haloalkyl, OR 21 or C 3~10 It is a cycloalkyl, Each R 21 C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Selected from aryl, heteroaryl and heterocyclyl, each R 21 1 to 6 halos or C 1~3 It is sometimes substituted with alkoxy, R 2 is hydrogen or C1~6 (It is alkyl.) It will be provided.

[0083] In a particular embodiment, the compound of formula I

[0084] [ka] or its isotope-enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers (wherein, X 1 , X 2 , X 3 and X 4 CR 4 or N, where X 1 , X 2 , X 3 and X 4 There are at least two of them, but if there are three or fewer, then it is N. Y 1 CR 5 or N, Y 2 CR 6 or N, Y 3 CR 3 or N, Z 1 and Z 2 Each of them is either C or N, Rings A and B together form a 9- or 10-membered bicyclic heteroaryl compound containing 1 to 3 ring nitrogen atoms. Ring B contains 1 to 3 nitrogen atoms and has a halo, hydroxyl, and C atoms on the available carbon atoms. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is sometimes substituted by alkoxy, and C is present on the available nitrogen atoms. 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group. R 1 ha-L 1 -R 11 And here, L 1-O-, -S-, -S(O)-, -S(O)2-, -N(R 12 )-- and not exist, R 11 is C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, where R 11 1 to 4 R 13 It is substituted depending on the base, R 12 is hydrogen or C 1~6 It is alkyl, Each R 13 These are independently halo, cyano, hydroxy, and R 16 C is replaced depending on the case. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl-C 1~6 Alkyl, R 16 C is replaced depending on the case. 6~10 Ariel, R 16 C is replaced depending on the case. 6~10 Aryl-C 1~6 Alkyl, R 16 Heteroaryls that are substituted in some cases, R 16 Heteroaryl-C which may be substituted depending on the circumstances. 1~6 Alkyl, R 16 Heterocyclines that are substituted in some cases, R 16 Heterocyclyl-C is sometimes substituted by 1~6 Alkyl, OR 14 -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2,-C 1~6 Alkilen-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 Selected from, Each R 14 C 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Selected from aryl, heteroaryl and heterocyclyl, each R 14 It is sometimes replaced by 1 to 3 halos. Each R 15 These are independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl. Each R 16 These are independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino, or C 1~6 It is alkyl, R 2 is hydrogen or C 1~6 It is alkyl, R 3 C 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 C is independent 1~4 Alkyl, or two R17 However, it can link with any intervening atom to form a 3-6 member heterocycline. Each R 4 These are independently hydrogen, halo, hydroxyl, and C. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 5 C 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, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 (It is an alkoxy) It will be provided.

[0085] In a particular embodiment, ring B is a five-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0086] In a particular embodiment, ring B is a six-membered heteroaryl containing 1 to 3 nitrogen atoms.

[0087] In a particular embodiment, ring B is

[0088] [ka] (In the formula, R 7 , R 8 and R 9 Each of these is independently hydrogen, halo, hydroxyl, and C. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 Selected from (haloalkyl)

[0089] In a particular embodiment, ring B is

[0090] [ka] (In the formula, R 7 , R 8 and R 9 Each of these is independently hydrogen, halo, hydroxyl, and C. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 Selected from (haloalkyl)

[0091] In a particular embodiment, ring B is

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

[0093] In a particular embodiment, ring B is

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

[0095] In a particular embodiment, ring B is

[0096] [ka] (In the formula, R 7 , R 8 and R 9 Each of them is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 (It is an alkoxy) Selected from.

[0097] In a particular embodiment, the compound of formula Ia

[0098] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, wherein ring A, ring B, R 1 , R 2 , R 3 , Y 1 , Y 2 , Z 1 and Z 2 This is defined as herein.

[0099] In a particular embodiment, the compound of formula Ib

[0100] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, wherein ring A, ring B, R 1 , R 2 , R 3 , Y 1 , Y 2 , Z1 and Z 2 This is defined as herein.

[0101] In a particular embodiment, the compound of formula Ic

[0102] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, wherein ring A, ring B, R 1 , R 2 , R 3 , Y 1 , Y 2 , Z 1 and Z 2 This is defined as herein.

[0103] In a particular embodiment, the compound of formula IIa

[0104] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 7 , R 8 , X 1 , X 2 , X 3 , X 4 and Y 1 This is defined as herein.

[0105] In a particular embodiment, the compound of formula IIb

[0106] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 7 , R 10 , X 1 , X 2 , X 3 , X 4 and Y 1 This is defined as herein.

[0107] In a particular embodiment, the compound of formula IIc

[0108] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , X 1 , X 2 , X 3 , X 4 and Y 1 This is defined as herein.

[0109] In a particular embodiment, the compound of formula IId

[0110] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , X 1 , X 2 , X 3 , X4 and Y 1 This is defined as herein.

[0111] In a particular embodiment, the compound of formula IIIa

[0112] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 8 and Y 1 This is defined as herein.

[0113] In certain embodiments, compounds of formula IIIb

[0114] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 8 and Y 1 This is defined as herein.

[0115] In a particular embodiment, the compound of formula IIIc

[0116] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 8 and Y 1 This is defined as herein.

[0117] In a particular embodiment, compound of formula IIId

[0118] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 5 and R 10 This is defined as herein.

[0119] In a particular embodiment, the compound of formula IIIe

[0120] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 5 and R 10 This is defined as herein.

[0121] In certain embodiments, compounds of formula IIIf

[0122] [ka] Or an isotope-enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers is provided, where R 1 , R 2 , R 3 , R 5 and R 10 This is defined as herein.

[0123] In a particular embodiment, L1 It does not exist or -N(R 12 )-. In a particular embodiment, L 1 It does not exist.

[0124] In a particular embodiment, R 11 Ha, 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 Alkilen-NHR 14 , -C 1~6 Alkylene-N(R) 14 )2 and -C(O)OR 15 A heterocycline in which 1 to 4 groups are optionally substituted, independently selected from R, where each R 14 C is independent 1~6 Alkyl, C 3~10 Selected from cycloalkyl and heterocyclyl, each R 14 R is sometimes replaced by 1 to 3 halos, where R 15 is C 1~6 It is alkyl.

[0125] In a particular embodiment, R 11 is an unsubstituted heterocyclyl. In certain embodiments, R 11 It is a heterocyclyl substituted with methyl.

[0126] In a particular embodiment, R 11 teeth

[0127] [ka] And ring C has 1 to 4 R 13A 3- to 10-membered heterocycline containing 0, 1, or 2 additional ring nitrogen atoms, optionally substituted by a group. In certain embodiments, the ring C has 1-4 R 13 Substituted by the group

[0128] [ka] In a particular embodiment, ring C has 1 to 4 R 13 Substituted by the group

[0129] [ka] In a particular embodiment, ring C has 1 to 4 R 13 Substituted by the group

[0130] [ka] That is the case.

[0131] In a particular embodiment, ring C has 1 to 4 R 13 It is a 5- to 10-membered bicyclic heterocycline containing one additional ring nitrogen atom, which may be substituted by the group.

[0132] In a particular embodiment, ring C has 1 to 4 R 13 It is a 5- to 10-membered spirodicyclic heterocycline containing one additional ring nitrogen atom, which may be substituted by the group.

[0133] In a particular embodiment, ring C has 1 to 4 R 13 It is a 5- to 10-membered condensed bicyclic heterocycline containing one additional ring nitrogen atom, which may be substituted by the group.

[0134] In a particular embodiment, R 11 teeth

[0135] [ka] Selected from, each of which has 1 to 4 R 13 It is substituted depending on the context.

[0136] In a particular embodiment, R 11 teeth

[0137] [ka] Selected from, each of which has 1 to 4 R 13 It is substituted depending on the context.

[0138] In a particular embodiment, R 11 It 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 a particular embodiment, R 11These are independently fluoromethyl, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropane-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 It is optionally substituted with 1 to 4 groups selected from cyethyl-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 a particular embodiment, R 11These are independently 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropane-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 It may be substituted with 1 to 4 groups selected from pyr-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 a particular embodiment, R 11 It is optionally substituted by 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 a particular embodiment, X 1 , X 2 , X 3 and X 4 These two are N. In a particular embodiment, X 1 , X 2 , X 3 and X 4 One of them is N.

[0143] In a particular embodiment, Y 2 Does not exist, or CR 6 Or it is N.

[0144] In a particular embodiment, R 1 ha-L 1 -R 11 And here, 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 not present, R 11 is C 2~6 Alkinyl, C 3~10 Cycloalkyl, C 6~10 It is an aryl, heteroaryl, or heterocyclyl, where R 11 1 to 4 R 13 It is substituted depending on the context.

[0145] Some implementation methods, each R 13 These are independently halo, cyano, hydroxy, and R 16 C is replaced depending on the case. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Hydroxyalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl-C 1~6 Alkyl, R 16 C is replaced depending on the case. 6~10 Ariel, R 16 C is replaced depending on the case. 6~10 Aryl-C 1~6 Alkyl, R 16 Heteroaryls that are substituted in some cases, R 16 Heteroaryl-C which may be substituted depending on the circumstances. 1~6 Alkyl, R 16 Heterocyclines that are substituted in some cases, R 16 Heterocyclyl-C is sometimes substituted by 1~6 Alkyl, OR 14-NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2,-C 1~6 Alkilen-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 Selected from, each R 14 C is independent 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Selected from aryl, heteroaryl and heterocyclyl, each R 14 1-6 halos, C 1~3 Alkyl, C 1~3 Alkoxy, C 3~10 They are optionally substituted with cycloalkyl or -NHSO2-aryl-N(CH3)2, and each R 15 These are independently hydrogen, -OH, and C. 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, C 6~10 Each R is an aryl, heteroaryl, or heterocyclyl. 16 These are independently halo, cyano, hydroxy, -NH2, and -NHR 21 , -N(R 21 )2, C 1~6 Alkyl, C 1~6 Haloalkyl, OR 21 or C 3~10It is a cycloalkyl, and each R 21 C is independent 1~6 Alkyl, C 3~10 Cycloalkyl, C 6~10 Selected from aryl, heteroaryl and heterocyclyl, each R 21 1 to 6 halos or C 1~3 It is sometimes substituted with alkoxy compounds.

[0146] In a particular embodiment, R 2 It is hydrogen.

[0147] In a particular embodiment, R 3 is hydrogen. In a particular embodiment, R 3 is a halo. In a particular embodiment, R 3 is fluoro. In a particular embodiment, R 3 is C 1~6 It is alkyl. In a particular embodiment, R 3 is methyl. In a particular embodiment, R 3 is C 1~6 It is an alkoxy. In a particular embodiment, R 3 It is methoxy.

[0148] In a particular embodiment, each R 4 is hydrogen. In a particular embodiment, one R 4 That is the halo, and the rest is hydrogen.

[0149] In a particular embodiment, R 5 is hydrogen. In a particular embodiment, R 5 is C 1~6 It is an alkoxy. In a particular embodiment, R 5 It is methoxy.

[0150] In a particular embodiment, R 6 It is hydrogen.

[0151] In a particular embodiment, R 7 It is hydrogen.

[0152] In a particular embodiment, R 8 is C 1~6 It is alkyl. In a particular embodiment, R 8 It is methyl.

[0153] In a particular embodiment, R 9 is C 1~6 It is alkyl. In a particular embodiment, R 9 It is methyl.

[0154] In a particular embodiment, R 10 is C 1~6 It is alkyl. In a particular embodiment, R 10 It is methyl.

[0155] In a particular embodiment, L 1 It does not exist.

[0156] In a particular embodiment, Y 1 CR 5 In a particular embodiment, Y 1 is N. In a particular embodiment, Y 1 It is CH.

[0157] In a particular embodiment, Y 2 CR 6 In a particular embodiment, Y 2 is N. In a particular embodiment, Y 2 It is CH.

[0158] In a particular embodiment, Y 3 CR 3 In a particular embodiment, Y 3 It is CH.

[0159] In certain embodiments, ring B contains 1 to 3 heteroatoms independently selected from N, O, and S, and a halo, hydroxyl, and C on the available carbon atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy and C1~6 Optionally substituted by 1 to 3 substituents independently selected from the haloalkoxy, with C on the available nitrogen atom. 1~6 Alkyl or C 1~6 It may be substituted with a haloalkyl group.

[0160] In a particular embodiment, ring B is

[0161] [ka] That is the case.

[0162] In a particular embodiment, ring B is

[0163] [ka] That is the case.

[0164] In a particular embodiment, ring B is

[0165] [ka] That is the case.

[0166] In a particular embodiment, each R 13 Ha, C 1~6 Alkyl, R 16 C is replaced depending on the case. 3~10 Cycloalkyl, R 16 Heterocyclyl, -NH2, -NHR, which may be substituted depending on the circumstances. 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2,-C 1~6 Alkilen-NHR 14 , -C 1~6 Alkylene-N(R) 14 ) Selected independently from 2, where R 16 and R 14 R 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 Alkilen-NHR 14 and -C 1~6 Alkylene-N(R) 14 ) Selected independently from 2, where R 14 R is as defined herein. In certain embodiments, each R 13 Ha, C 1~6 Alkyl, -NH2, -NHR 14 , -N(R 14 )2, -C 1~6 Alkylene-NH2,-C 1~6 Alkilen-NHR 14 and -C 1~6 Alkylene-N(R) 14 ) Selected independently from 2, where R 14 R is as defined herein. In certain embodiments, R 13 The heterocyclyl contains one ring nitrogen atom. In certain embodiments, R 13 is R 16 A heterocycline which is optionally substituted by, where the heterocycline contains one ring nitrogen atom.

[0167] In a particular embodiment, R 13 -NH2, -NHR 14 or -C 1~6 Alkilen-NHR 14 And R 14 R is as defined herein. In certain embodiments, R 13 Ha-NHR 14 or -C 1~6 Alkilen-NHR 14 And R 14 R is as defined herein. In certain embodiments, R 13 Ha-NHR 14 or -C 1~6 Alkilen-NHR 14 And R 14 is C 3~10It is a cycloalkyl. In a particular embodiment, R 13 is -NH-cyclopropyl. In certain embodiments, R 13 is -NH-methyl. In certain embodiments, R 13 is -CH2-NH-cyclopropyl. In certain embodiments, R 13 is -CH2-NH-methyl. In certain embodiments, R 13 is R 16 It is a -CH2- heterocyclyl which is substituted in some cases, where R 16 This is defined as herein.

[0168] In a particular embodiment, R 14 is C 1~6 It is alkyl. In a particular embodiment, R 14 C is substituted with 1 to 6 fluorocarbons. 1~6 It is alkyl. In a particular embodiment, R 14 is methyl. In a particular embodiment, R 14 is C 3~10 It is a cycloalkyl. In a particular embodiment, R 14 It is cyclopropyl.

[0169] In a particular embodiment, R 15 is hydrogen or C 1~6 It is alkyl.

[0170] In a particular embodiment, R 16 is an amino, alkylamino, or dialkylamino. In certain embodiments, each R 16 These 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 Selected independently from cycloalkyl. In certain embodiments, each R 16 They are independent of Haro, C 1~6 Alkyl or R 21 And R21 This is defined as herein.

[0171] In a particular embodiment, the compound of formula I

[0172] [ka] or its isotope-enriched analog, pharmaceutically acceptable salt, prodrug, tautomer, stereoisomer or mixture of stereoisomers (wherein, X 1 , X 2 , X 3 and X 4 CR 4 or N, where X 1 , X 2 , X 3 and X 4 There are at least two of them, but if there are three or fewer, then it is N. Y 1 CR 5 or N, Y 2 CR 6 or N, Y 3 CR 3 or N, Z 1 and Z 2 Each of them is either C or N, Rings A and B together form a 9-membered bicyclic heteroaryl compound containing 1 to 3 ring nitrogen atoms. Ring B is

[0173] [ka] Selected from, R 1 ha-L 1 -R 11 And here, L 1 -O-, -S-, -S(O)-, -S(O)2-, -N(R 12 )-- and not exist, R 11 is C 3~10 Cycloalkyl, C 6~10Aryl, heteroaryl or heterocyclyl, where R 11 is optionally substituted by 1 to 4 R 13 groups, R 12 is hydrogen or C 1~6 alkyl, each R 13 is independently halo, cyano, hydroxy, C 16 alkyl optionally substituted by R 1~6 alkyl, C 1~6 haloalkyl, C 1~6 hydroxyalkyl, C 16 cycloalkyl optionally substituted by R 3~10 cycloalkyl-C 16 alkyl, C 3~10 aryl optionally substituted by R 1~6 aryl-C 16 alkyl, heteroaryl optionally substituted by R 6~10 heteroaryl-C 16 alkyl, heteroaryl optionally substituted by R 6~10 heterocyclyl optionally substituted by R 1~6 heterocyclyl-C 16 alkyl, OR 16 -NH2, -NHR 1~6 -N(R 16 )2, -C 16 alkylene-NH2, -C 1~6 alkylene-NHR 14 -C 14 alkylene-N(R 14 )2, -C(O)R 1~6 -C(O)OR 1~6 -C(O)NHR 14 -C(O)N(C 1~6 alkyl)R 14 -S(O)2R 15 -S(O)R 15 -S(O)2R 15 -S(O)R 1~4 -C(O)R 15 -C(O)OR 15 -C(O)NHR15 , -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 selected from, each R 14 is independently, C 1~6 alkyl, C 3~10 cycloalkyl, C 6~10 aryl, heteroaryl and heterocyclyl selected from, each R 14 is optionally substituted by 1 to 3 halos, each R 15 is 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 is independently halo, cyano, hydroxy, amino, alkylamino, dialkylamino or C 1~6 alkyl, R 2 is hydrogen or C 1~6 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, wherein each R 17 is independently C 1~4 alkyl, or two Rs 17 are linked together with any intervening atoms to form a 3- to 6-membered heterocyclyl, each R<000093​1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 5 C 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, hydroxyl, C 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 7 , R 8 and R 9 Each of these is independently hydrogen, halo, hydroxyl, and C. 1~6 Alkyl, C 1~6 Haloalkyl or C 1~6 It is an alkoxy, R 10 is hydrogen, C 1~6 Alkyl or C 1~6 A haloalkyl product is provided.

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

[0175] In a particular embodiment, a method is provided for treating Huntington's disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein.

[0176] In a particular embodiment, a method is provided for treating Huntington's disease in a patient in need, comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition described herein in combination with a second activator.

[0177] Compounds selected from Table 1, or their isotopic enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are also provided:

[0178] [Table 2] TIFF0007894498000036.tif202170TIFF0007894498000037.tif244170TIFF0007894498000038.tif249170TIFF0007894498000039.tif245170TIFF0007894498000040.tif231170TIFF0007894498000041.tif250170TIFF0007894498000042.tif218170TIFF0007894498000043.tif226170TIFF0007894498000044.tif246170TIFF0007894498000045.tif223170TIFF0007894498000046.tif250170TIFF0007894498000047.tif248170TIFF0007894498000048.tif221170TIFF0007894498000049.tif250170TIFF0007894498000050.tif244170TIFF0007894498000051.tif234170TIFF0007894498000052.tif218170TIFF0007894498000053.tif233170TIFF0007894498000054.tif236170TIFF0007894498000055.tif237170TIFF0007894498000056.tif229170TIFF0007894498000057.tif241170TIFF0007894498000058.tif252170TIFF0007894498000059.tif252170TIFF0007894498000060.tif225170TIFF0007894498000061.tif245170TIFF0007894498000062.tif240170TIFF0007894498000063.tif238170TIFF0007894498000064.tif239170TIFF0007894498000065.tif243170TIFF0007894498000066.tif252170TIFF0007894498000067.tif244170TIFF0007894498000068.tif234170TIFF0007894498000069.tif44156.

[0179] Compounds selected from Table 1A, or their isotopic enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers are also provided:

[0180] [Table 3] TIFF0007894498000071.tif236163TIFF0007894498000072.tif245163TIFF0007894498000073.tif254163TIFF000 7894498000074.tif249164TIFF0007894498000075.tif250162TIFF0007894498000076.tif228162TIFF00078944980 00077.tif255162TIFF0007894498000078.tif255161TIFF0007894498000079.tif254164TIFF0007894498000080.t if255162TIFF0007894498000081.tif234163TIFF0007894498000082.tif252164TIFF0007894498000083.tif255162 TIFF0007894498000084.tif254163TIFF0007894498000085.tif239164TIFF0007894498000086.tif253164TIFF000 7894498000087.tif244164TIFF0007894498000088.tif224165TIFF0007894498000089.tif255164TIFF00078944980 00090.tif239164TIFF0007894498000091.tif249163TIFF0007894498000092.tif255163TIFF0007894498000093.t if255164TIFF0007894498000094.tif255164TIFF0007894498000095.tif248165TIFF0007894498000096.tif201164

[0181] Signs and treatment methods The compounds described herein may be useful, at least in part, for treating diseases or conditions mediated by proteins involved in neurodegenerative diseases. In some embodiments, the compounds described herein may be useful, at least in part, for detecting diseases or conditions mediated by HTT proteins. In some embodiments, treatment of diseases or conditions mediated by proteins involved in neurodegenerative diseases may include administration of the compounds described herein. Treatment may include simultaneous administration of the compounds described herein and one or more other activators and / or therapeutic agents.

[0182] In some embodiments, a method is provided for treating or preventing, at least in part, a neurodegenerative disease or condition mediated by proteins in which such treatment is necessary, the method comprising administering to the patient a therapeutically effective amount of a compound described herein.

[0183] Examples of 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 diseases in which elongated polyglutamine (polyQ) in the protein encoded by an extended CAG repeat region results. This family also includes dentatorubral-pallidoluysian atrophy (DRPLA), spinal cord and medulla oblongata muscular atrophy (SBMA), and spinocerebellar degeneration (SCA). In HD, selective neurodegeneration of gamma-aminobutyrate-releasing spinoid neurons in the striatum is observed, but neuronal loss in many other brain regions has also been reported. Symptoms of HD include loss of motor control, mental symptoms, and memory and / or cognitive impairment.

[0185] Huntingtin protein (HTT protein) is a 348 kDa polydomain protein containing polymorphic glutamine / proline-rich domains at its amino terminus. These are encoded by IT. 15 The number of CAG repeats in the gene varies from 6 to 35 in healthy individuals; more than 36 repeats indicate an HD allele. The length of the CAG increase correlates inversely with the age of disease onset, with cases of juvenile onset characterized by an increase of more than 60 repeats. Penetration decreases between 36 and 39 repeats. See McColgan P et al., Huntington's disease: a clinical review, Eur. J. Neurology, 2017, vol. 25, pp. 24-34, which is incorporated in its entirety herein by reference. Longer polyQ domains are thought to induce structural changes in HTT proteins, leading to the formation of intracellular aggregates that appear as nuclear inclusions in many HTT proteins. However, aggregates can also form outside the nucleus. HTT proteins are present in the nucleus, cell body, dendrites, and nerve terminals of neurons, and are also associated with several organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0186] A diagnosis of Huntington's disease is based on a confirmed family history or positive genetic testing and the onset of motor impairment 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 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 before the onset of the disease, a period known as the pre-disease stage.

[0187] The stages of Huntington's disease (HD) are described, for example, in Winder, JY et al., Assessment Scales for Patients with Advanced Huntington's Disease: Comparison of the UHDRS and UHDRS-FAP, Mov Disord Clin Pract., September-October 2018; Vol. 5 (No. 5): pp. 527-533, which is incorporated in its entirety by reference herein. HD is classified into early stages (stage 1 or 2 TFC score), intermediate stages (stage 3 TFC score), or late stages (stage 4 or 5 TFC score). For example, see Shouldon, I. et al., Huntington disease: Clinical care and evaluation, Neurology, 1979, Vol. 29 (No. 1), p. 1; and Shouldon, I., Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs, Neurology, 1981, Vol. 31 (No. 10), pp. 1333-1335. The part of the brain most affected by HD, and therefore most likely to contain abnormalities in the HTT protein, is the group of nerve cells at the base of the brain, collectively known as the basal ganglia. The basal ganglia organize the body's muscle-driven movements, or "motor movements." The main components of the basal ganglia are the caudate nucleus and putamen (collectively 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 motor disorders. Normal basal ganglia function requires fine-tuning of neuronal excitability within each nucleus to determine the degree of motor smoothing or inhibition at any given moment. This is mediated by the complex structure of the striatum, where intermediate spine neuron excitability is controlled by several presynaptic and postsynaptic mechanisms and interneuronal activity, and fixed by several repetitive or internal basal ganglia circuits. The motor circuits of the basal ganglia have two entry points, the striatum and the subthalamic nuclei, and an output port, the globus pallidus internal segment, which connects to the cortex via the motor thalamus.

[0189] The compounds described herein may inhibit neuronal degeneration when administered to a subject. In some embodiments, inhibition of neuronal degeneration may include inhibition of axons or neuronal degeneration in neurons. Such inhibition may affect the entire neuron or a portion thereof, for example, the neuronal cell body, axons, and dendrites. This can be evaluated, for example, by analysis of the function of the nervous system according to methods known in the art.

[0190] Administration of the compounds described herein may result in relief of one or more symptoms of the diseases or conditions described herein, for example, a reduction of at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%). The diseases or conditions may include: disorders of the nervous system secondary to a disease, condition, or therapy having a primary effect other than on the nervous system; damage to the nervous system caused by physical, mechanical, or chemical trauma; autoimmune neurodegeneration; neurodegeneration secondary to infection; and / or ocular neurodegeneration. Symptoms of neurodegeneration include, for example, tremors, bradykinesia, ataxia, loss of balance, depression, cognitive decline, short-term memory loss, long-term memory loss, confusion, personality changes, language problems, loss of sensory cognition, touch hypersensitivity, numbness in the hands and feet, muscle weakness, muscle paralysis, muscle spasms, muscle cramps, marked 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, color vision impairment, reduced recovery of visual function after exposure to bright light, and loss of visual contrast sensitivity.

[0191] Administration of the compounds described herein can result in a reduction of at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%) of the number of degenerating neurons (or their neuronal bodies, axons, or dendrites) in a neuronal population or subject compared to the number of degenerating neurons (or their neuronal bodies, axons, or dendrites) in a neuronal population or subject that has not been administered one or more of the compounds described herein.

[0192] Neurons can transmit 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 the types of neurons that can be used in the treatments of this 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 used in the treatments of this disclosure include astrocytes and microglia.

[0193] Neurodegenerative diseases are diseases or conditions in which the function of the nervous system is impaired. Examples of neurodegenerative diseases include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia, Batten disease (also known as Spillmayer-Voigt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington's disease, dementia associated with HIV, Kennedy disease, Krabbe disease, and others. Examples include Lewy body dementia, Machad-Joseph disease (spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration, spinal muscular atrophy, Steele-Richardson-Olsewski disease, insulin resistance, or tabes dorsalis.

[0194] In some embodiments, the disease or condition is selected from Huntington's disease (HD), dentatorubral-pallidoluysian atrophy, muscular atrophy of the spinal cord and medulla oblongata, spinocerebellar degeneration, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cavernous malformations of the brain, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal lesions, diabetes mellitus, chronic and / or neuropathic pain, stroke, ischemia, retinopathy, spinal muscular atrophy (SMA), erectile dysfunction, nephropathy (non-hypertension), hypertensive nephropathy, hypertension (hypertension), optic nerve lesions, hepatic fibrosis, lupus, post-transplant liver failure, encephalomyelitis, epilepsy, and glioblastoma.

[0195] Furthermore, the compounds described herein can be used to prevent or treat memory loss. Types of memory that may be affected by loss and therefore can be treated by this 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 to belong to Category I, Category II, or Category III.

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

[0198] The use of the compounds described herein for the manufacture of pharmaceuticals for use in the diagnosis, prevention, or treatment of the diseases or conditions described herein is also provided. For example, the disease or condition may be Huntington's disease.

[0199] Pharmaceutical composition and administration thereof The compounds provided herein may be administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions containing the compounds described herein and pharmaceutically acceptable excipients are also provided herein.

[0200] Suitable pharmaceutically acceptable excipients include, for example, inert solid diluents and fillers, diluents containing sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in methods well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker & CT Rhodes).

[0201] The pharmaceutical composition may be formulated for administration by various methods, including, for example, oral, rectal, oral cavity, nasal cavity, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

[0202] Pharmaceutical compositions may be formulated for administration by injection. Forms into which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions having sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, glucose, or sterile aqueous solutions, and similar pharmaceutical excipients.

[0203] The pharmaceutical composition may be in the form of an aqueous or oily suspension for sterile injection. This suspension may be formulated according to known techniques using appropriate dispersants or wetting and suspending agents. The sterile injection preparation may also be an injectable sterile solution or suspension in a non-toxic, parenterally acceptable vehicle, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles that can be used may be water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally used as solvents or suspensions. Any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used for this purpose. In addition, fatty acids, such as oleic acid, may be useful in the preparation of injections. Such solutions may be formulated with appropriate salts as a 0.01% to 10% isotonic solution, pH 5 to 7.

[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 buffers, 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] A pharmaceutical composition, such as a pharmaceutical composition 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 placed within certain tissues, including blood. Suitable examples of sustained-release carriers include semipermeable polymer matrices in common product forms, e.g., 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 disclosure of which is 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 usually diluted with excipients and / or encapsulated in a carrier, which may be in the form of capsules, sachets, paper or other containers. If the excipient functions as a diluent, it may be in the form of a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, injectable sterile solutions, and packaged sterile powders.

[0208] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The pharmaceutical composition may further contain lubricants, such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives, such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners; 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 using 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 manner disclosed herein utilizes a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of controlled amounts of the compounds described herein. The construction and use of transdermal patches for drug delivery are well known in the art. Such patches can be constructed for continuous, pulsed, or on-demand delivery of drugs.

[0210] To prepare solid compositions, such as tablets, the compounds described herein can be mixed with pharmaceutical excipients to form solid pre-formulation compositions containing a homogeneous mixture. When these pre-formulation compositions are described as homogeneous, the compounds are uniformly dispersed throughout the composition, allowing the composition to be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0211] Tablets or pills of the compounds described herein can be coated or otherwise mixed to provide a dosage form that offers the benefit of long-lasting action or protection from the acidic conditions of the stomach. For example, tablets or pills may contain an internal and an external component, the latter in the form of an outer coating over the former. The two components may be separated by an enteric coating that acts to resist degradation in the stomach, allowing the internal component to reach the intestines intact or delaying its release. Various materials can be used for such enteric coatings or coatings, including several polymer acids and mixtures of polymer 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, liquids, emulsions, syrups, or elixirs. Furthermore, pharmaceutical compositions containing the compounds described herein may also be presented as dried products for preparation using water or other suitable vehicles before use. Such liquid preparations may contain conventional additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats), non-aqueous vehicles that may contain 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 inhalation may include liquid and suspension formulations, as well as powders, in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients, such as those described herein. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic action. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be coupled to a face mask tent or an intermittent positive pressure breathing device. Liquid, 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 or pharmaceutical compositions described herein may be administered in appropriate doses determined by an informed physician. The compounds or pharmaceutical compositions may be administered in single or multiple doses, and in a single or multiple dosage form (e.g., two tablets or three capsules). For any particular subject, the appropriate dose depends on a variety of factors, including the activity of the specific compound used, the subject's age, weight, overall health, sex, diet, administration time, route of administration, elimination rate, activators used in combination, and the severity of the specific disease or condition. For example, the dose can be expressed as several milligrams of the compound described herein per kilogram of body weight (mg / kg) per day. A dose of about 0.1 to about 150 mg / kg may be appropriate. In some embodiments, a dose of about 0.1 to about 100 mg / kg may be appropriate. In some embodiments, appropriate doses may be approximately 0.0001 to 100 mg of the compound per kg of body weight per day, approximately 0.001 to 50 mg per kg of body weight, or approximately 0.01 to 10 mg of the compound per kg of body weight per day. In some embodiments, the dose may be administered multiple times per day, for example, once per day, twice per day, or three times per day. In some embodiments, the dose may be administered every two days, every three days, every four days, or once per week. Normalization according to the body weight of the subject is particularly useful when adjusting doses between subjects of wide-ranging sizes, such as when using a drug in both children and adults, or when converting a dose effective in non-human subjects, such as dogs, to a dose suitable for human subjects.

[0215] kit Kits comprising the compounds described herein and appropriate packaging are also provided herein. In certain embodiments, the kit further includes instructions for use. In one embodiment, the kit includes the compounds described herein, as well as labels and / or instructions for the use of the compounds in the treatment of diseases or conditions described herein.

[0216] Manufacturing articles containing the compounds described herein in appropriate containers are also provided herein. The containers may be vials, bottles, ampoules, pre-filled syringes and / or intravenous bags.

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

[0218] The methods described herein include methods for detecting, treating, or preventing diseases or conditions described herein, such as Huntington's disease, and comprising administering the compounds described herein and one or more additional activators to a subject simultaneously or sequentially. In methods using simultaneous administration, the agents may be present in a combined composition or administered separately. When used in combination with one or more additional activators, the compounds described herein may be administered before, concurrently with, or after the administration of the additional activators. Administration may be carried out by one or different routes.

[0219] Pharmaceutical compositions are also provided that include the compounds described herein and one or more additional agents used in the treatment of Huntington's disease, such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, escitalopram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. Similarly, packaged pharmaceutical compositions are also provided that contain the compounds described herein, and one or more additional agents used in the treatment of Huntington's disease, for example, 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 activator 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] Methods for treating or preventing Alzheimer's disease, comprising treating memory and / or cognitive impairment associated with Alzheimer's disease, are also provided, comprising administering to a subject, simultaneously or sequentially, the compounds described herein and one or more additional agents. In some embodiments, the activator is Reminyl®, Cognex®, Aricept®, Exelon®, Akatinol®, Neotropin®, Eldepryl®, Estrogen, or Clioquinol.

[0221] In some embodiments, the compounds described herein may be administered together with activators for treating Parkinson's disease, such as L-dopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and rislide), 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 may be administered together with activators 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 their respective variations, as will be apparent from the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods can be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. Where available, reagents can be purchased commercially from, for example, Sigma Aldrich or other chemical suppliers.

[0223] The compounds described herein can be prepared, for example, from readily available starting materials using the following general methods and procedures. It should be noted that, unless otherwise specified, other process conditions may also be used, provided that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through predetermined optimization procedures.

[0224] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as appropriate conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006), Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience and the literature cited therein.

[0225] Furthermore, the compounds described herein may contain one or more asymmetric ("chiral") centers. Therefore, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-rich mixtures. All such stereoisomers (and stereoisomer-rich mixtures) are included within the scope of this disclosure unless otherwise noted. Pure stereoisomers (or stereoisomer-rich mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, etc. If pure or enantiomer-rich compounds are desired, chiral chromatography and / or starting materials that are pure or enantiomer-rich can be used as conventionally 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 available from suppliers such as Sigma Aldrich and Alfa Aesar. Others can be prepared by procedures or obvious variations thereof described in standard reference books, such as Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplement (Elsevier Science Publishers, 1989), organic Reactions, Vols. 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0227] The terms “solvent,” “inert organic solvent,” and “inert solvent” refer to solvents that are inert under the conditions of the reaction described herein (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Generally, when the term inert is used herein in relation to a solvent, it refers to a material that does not undergo a reaction to form the target compound of interest through a reaction that forms a carbon-carbon bond. Unless otherwise specified, the solvents used in the reactions of this disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.

[0228] The term "appropriate amount" means adding enough to achieve the stated function, for example, to bring the solution to the desired volume (i.e., 100%).

[0229] It should also be recognized that in each of the following schemes, the addition of any substituent may result in the formation 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] Isotope labeling, for example, the incorporation of a deuterium atom into the compounds described herein, can be carried out by reacting suitable starting materials(s) with a reagent containing a radioactive isotope. The method can generally be carried out by any method known to those skilled in the art, including those provided herein, following the same principles as standard organic chemical reactions.

[0231] Scheme 1 provides an exemplary synthetic route for the synthesis of the compounds provided herein (e.g., compounds of formula I). ​​Compounds of formula I, or other formulas or compounds disclosed herein, are typically prepared by first preparing 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 the compound of formula I proceeds according to scheme 1. The synthesis of the compound of formula I can be carried out by coupling compound Va with compound Vb to form compound Vc, coupling compound Vc with compound Vd, and preparing the compound of formula I by one or more subsequent steps.

[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 in this specification. A 1 , A 2 , and A 3 are as 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 can be linked to compound Vb by formation of an amide bond via the leaving group in A 1 and the amine of compound Vb (as shown in Scheme 1). A 1 may be a suitable leaving group, such as a halide, pseudohalide, carboxylic acid or carboxylate (carboylate). Compound Va can be activated in A 1 by an activator (e.g., chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, HATU, HBTU) for activating the carboxyl group, optionally in the presence of a base (e.g., 1-methylimidazole, triethylamine, diisopropylethylamine) and in a suitable solvent (e.g., a polar aprotic solvent such as acetonitrile, DMF, or dichloromethane). Alternatively, in A 1 [[]]the carboxylate can first be activated with an activator (e.g., oxalyl chloride) and then combined with compound Vb in the presence of a base (e.g., triethylamine, diisopropylethylamine). In such embodiments, it is not necessary to isolate the activated form of compound Va (e.g., when A 1 is a halide, such as chloride), and the reaction can be carried out in one pot.

[0236] In Scheme 1, the compound of formula I can be prepared. Therefore, compound Vc can be coupled by a coupling reaction, for example, by the addition of a nucleophile, for example, A 2 In this embodiment, compound Vc can be coupled with compound Vd in a coupling reaction by nucleophilic aromatic substitution. 2 A may be a suitable leaving group (e.g., a halide, e.g., a chloride or fluoride, or a pseudohalogen, e.g., a sulfonyl), 3 R may be a hydrogen atom, or 1 If present as an anion, it may also be a cation (e.g., sodium ion, potassium ion). Nucleophilic aromatic substitution may be carried out by heating (e.g., to a temperature of 50-200°C) in the presence of a base (e.g., triethylamine, cesium carbonate, NaH, potassium carbonate, pyridine) and in a suitable solvent (e.g., dioxane, DMF, acetonitrile, DMSO). Alternatively, compound Vc may be coupled with compound Vd in a coupling reaction (e.g., a metal-catalyzed coupling reaction). In such embodiments, for example, A 2 R may be a leaving group (for example, a halide, for example, a chloride or bromide, or a pseudohalogen, for example, a sulfonyl), 1 It may also contain a suitable coupling functional group (e.g., a carbon-carbon double bond), A 3 is A 2 A complementary coupling partner may be (e.g., a hydrogen atom or a tin or boron-containing group). The reaction may be carried out using a catalyst (e.g., bis(triphenylphosphine)palladium(II) dichloride) and optionally in the presence of a base (e.g., sodium carbonate).

[0237] In some embodiments, A 2 is R 1 This may be the case, and compound Vc can also be directly converted to the compound 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 these may also exist in a protected form, for example, as an amine or hydroxyl group. Amine protecting groups include those known in the art and those described herein, for example, 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 the compound of formula I.

[0239] Those skilled in the art will recognize that any of the compounds Va, Vb, Vc, or Vd may be available from suppliers for specific embodiments. Alternative synthesis of compounds Va, Vb, Vc, or Vd may be as described herein or known to those skilled in the art.

[0240] [Examples] The following embodiments are included to illustrate specific embodiments of the present disclosure. Those skilled in the art will see that the techniques disclosed in the following embodiments represent techniques that function well in the practice of the present disclosure and can therefore be judged to constitute a specific form for such practice. However, those skilled in the art will see that, in light of the present disclosure, many can be modified in the specific embodiments disclosed without departing from the intent and scope of the present disclosure, and similar or equivalent results can still be obtained.

[0241] Analysis method Acidic QC method AcHSSC18 - Standard acidic 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 ULC-MS

[0248] [Table 7]

[0249] 10cm_Bicarb_AQ - Standard basic ULC-MS

[0250] [Table 8]

[0251] General Procedure The compounds were named using the Chemdraw 18.1 structural naming tool. All reactions involving air or humidity-sensitive reagents were carried out under a nitrogen atmosphere using dry solvents and glassware.

[0252] Examples 1-140 Examples 1-140 were performed according to the following method: Method A: Ester hydrolysis The ester, methanol (11 mL / mmol), water (1.08 mL / mmol), and LiOH·H2O (1 equivalent) were combined and stirred at room temperature for 17 hours, followed by 3 days at 50°C. The reaction mixture was evaporated to dryness to obtain the corresponding lithium carboxylate salt. Method B: HBTU coupling Lithium carboxylate salt, amine (1.0 equivalent), HBTU (1.0 equivalent), triethylamine (12 equivalents), 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 Boc-protected amine, methanol (20 mL / mmol), and 4N HCl (20 mL / mmol) in dioxane were combined and stirred at room temperature for 2 to 17 hours. The reaction mixture was evaporated to dryness and purified by preparative HPLC. method ds N Ar substitution A substituted aryl halide, amine (1 equivalent), cesium carbonate (1.1 equivalents), and DMF (5 mL / mmol) were combined in a sealed tube and heated at 100°C for 1 to 5 days. The reaction mixture was cooled to room temperature. The cesium salt was removed by filtration, and the filtrate was evaporated to dryness to obtain the crude product, which was used directly in the next step. Method D2 S N Ar substitution A substituted aryl halide, amine (1 equivalent), triethylamine (1.1 equivalents), and MeCN (5 mL / mmol) were combined in a sealed tube and heated at 60°C for 1 to 5 days. The reaction mixture was evaporated to dryness to obtain the crude product, which could be purified or used directly in the next step. Method E TFA Boc deprotection Boc-protected amine, dichloromethane (4 mL / mmol), and TFA (23 equivalents) were combined and stirred for 1 day. The reaction mixture was evaporated to dryness and purified by preparative HPLC. Method F CuI coupling conditions Benzamide, aryl halide (1.05 equivalents), copper(I) iodide (0.10 equivalents), potassium carbonate (1.5-2.5 equivalents), and DMEDA (0.20 equivalents) in toluene (2 mL / mmol) were degassed, sealed, and heated at 100°C for 20-114 hours. After this time, the reaction mixture was filtered through Celite and concentrated under reduced pressure. Method G t-BuBrettPhos Conditions Benzamide, aryl halide (1.05 equivalents), tert-BuBrettPhos-Pd-G3 (0.10 equivalents), and K3PO4 (1.4-2.4 equivalents) were placed in a stem block tube. Toluene (3 mL / mmol) was added, and the reaction mixture was degassed. The reaction mixture was heated at 110°C for 18-114 hours. After this time, the reaction mixture was filtered through Celite and concentrated under reduced pressure. Method H TCFH coupling TCFH (1.20 equivalents) was added to MeCN (3 mL / mmol) containing acid (1.0 equivalent), amine (1.30 equivalents), and 1-methylimidazole (2.5-3.5 equivalents) while stirring at room temperature for 16 hours. Method I: Tri-tert-butylphosphine Buchwald conditions Aryl bromide, amine (2 equivalents), Pd(PtBu3)2 (0.2 equivalents), and Cs2CO3 (3 equivalents) were suspended in dioxane (3 mL / mmol), and the mixture was purged with N2 for 10 minutes. The tube was sealed and heated at 100°C for 16 hours. 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 Aryl bromide, amine (1 equivalent), Pd2(dba)3 (0.1 equivalent), rac-BINAP (0.2 equivalents), and Cs2CO3 (4 equivalents) were suspended in DMF (3 mL / mmol), and the mixture was purged with N2 for 10 minutes. The tube was sealed and heated at 100°C for 16 hours. 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 equivalent), and Cs2CO3 (3 equivalents) t The mixture was suspended in BuOH (20 mL / mmol) and purged with N2 for 10 minutes. The tube was sealed and heated at 100°C for 16 hours. 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 1 equivalent of arylamine, 1.3 equivalents of di-tert-butyl dicarbonate, and 0.298 M of ethyl acetate were combined, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the layers were separated. The aqueous layer was washed with ethyl acetate (×2), and the combined organic layer was washed with brine, dried (on phase separation filter paper), and concentrated under vacuum. Method M: Aminopyridinium salt formation Substituted pyridine (1 equivalent) was dissolved in DMF (0.13 M), and O-(2,4-dinitrophenyl)hydroxylamine (1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. Method N 1,3 bipolar addition Aminopyridinium salt (1 equivalent), ethyl 2-butinoate (1.1 equivalents), and K2CO3 (1.5 equivalents) were dissolved in DMF (0.088 M), and the reaction mixture was stirred overnight at room temperature. Method O: HBr decarboxylation One equivalent of ester was dissolved in 48% by weight hydrobromic acid (0.2 M) in H2O, and the reaction mixture was stirred at 100°C for 4 hours. Method P: Pd-catalyzed amidation Lactam (1 equivalent), heteroaryl chloride (1 equivalent), and Cs2CO3 (1.5 equivalents) were suspended in dioxane (0.2 M), and the mixture was purged with N2 for 10 minutes. Then, Pd2(dba)3 (0.2 equivalents) and xanthophos (0.2 equivalents) were added, the tube was sealed, and the mixture was heated at 100°C for 16 hours. After cooling to room temperature, the mixture was evaporated to dryness, loaded onto silica in DCM / MeOH, and purified by silica gel chromatography. Method Q: Reductive amination of formaldehyde Amine (1 equivalent), formaldehyde (37% solution, 50 equivalents), methanol (1 mL), and sodium triacetoxyborohydride (2 equivalents) (1.5 equivalents) were combined, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried, and evaporated. The crude substance was purified by achiral SFC or preparative HPLC.

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

[0254] [ka] 5-Chloro-2-pyrazinecarboxylic acid (960 mg, 6.05 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridine-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 under vacuum to obtain 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide, which was used crudely 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]pyrazine-6-yl)pyrazine-2-carboxamide

[0256] [ka] 5-Chloro-2-pyrazinecarboxylic acid (1466 mg, 9.25 mmol), 2,8-dimethylimidazo[1,2-a]pyrazine-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 the mixture was stirred for 16 hours. The reaction mixture was then filtered, and the solid was dried under vacuum to obtain 5-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)pyrazine-2-carboxamide, which was used crudely 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-indazole-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 hours. The reaction mixture was then diluted with Â, washed with water (3 ×) and brine (1 ×), evaporated to dryness on silica, and purified by flash chromatography. The minor of the two main 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), Â1 (15 mL), and methanol (15 mL) were combined and passed through an H-cube equipped with a 10% Pd / C cartridge at a flow rate of 1 mL per minute, 40°C, and a pressure of 40 bar using a pump. The reaction mixture was evaporated to dryness to obtain 6-ethoxy-2-methyl-2H-indazole-5-amine, which was used crudely in the next step.

[0260] Intermediate 4: 6-Methoxy-2-methyl-2H-indazole-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 Â, washed with water (×3) and brine (×1), evaporated to dryness on silica, and purified by flash chromatography to obtain two regioisomers. 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), siRNA (15 mL), and MeOH (15 mL) were combined and then pumped at a rate of 1 ml per minute through an H-Cube equipped with a 10% Pd / C cartridge under 50 bar hydrogen at 40°C. The reaction mixture was evaporated to dryness to obtain 6-methoxy-2-methyl-2H-indazole-5-amine, which was used crudely in the next reaction: MS (ES+) 178 (M+H).

[0263] Intermediate 5: N-isopropylpyrrolidine-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 NaHCO3 solution, extracted with dichloromethane, dried (MgSO4), and evaporated to dryness to obtain tert-butyl 3-(isopropylamino)pyrrolidine-1-carboxylate, which was used crudely in the next step.

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

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

[0267] [ka] 1310 mg, 7.07 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 80 mL of dihydrochloride (DCM) and 1120 mg, 7.78 mmol, 1.10 equivalents of 3,3-difluorocyclobutan-1-amine, and sodium triacetoxyborohydride (4650 mg, 21.9 mmol, 3.10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with NaHCO3 (aqueous solution) and extracted three times with DCM. The combined organic layers were dried (MgSO4) and concentrated under vacuum to obtain crude tert-butyl 3-((3,3-difluorocyclobutyl)amino)pyrrolidine-1-carboxylate, which was used without further purification.

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

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

[0270] [ka] 1310 mg, 7.70 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 10 mL of dimethyl chloride (DCM) and 568 mg, 7.78 mmol, 1.10 equivalents of oxetane-3-amine, and sodium triacetoxyborohydride (3140 mg, 14.84 mmol, 2.10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with aqueous solution of NaHCO3 and washed three times with DCM. The combined organic layers were washed with saturated brine, dried (on phase separation filter paper), and concentrated under vacuum to obtain crude tert-butyl 3-(oxetane-3-ylamino)pyrrolidine-1-carboxylate, which was used without further purification.

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

[0272] Intermediate 8: (3R * ,4S * )-N-Cyclopropyl-4-Fluoro-N-Methylpyrrolidine-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 at 50°C for 2 days. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 aqueous solution, extracted with dichloromethane (2×), dried (MgSO4), evaporated to dryness, and tert-butyl (3R * ,4R * )-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylate was obtained and used crudely 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. 50% Deoxo-Fluor® (0.32 mL, 0.86 mmol) was added dropwise to THF at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was quenched by adding saturated sodium bicarbonate and extracted with DCM (×2). The organic layer was dried (MgSO4), the solvent was removed under vacuum, and tert-butyl (3R * ,4S * )-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine-1-carboxylate was obtained and used crudely in the next step.

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

[0276] Intermediate 9:(3aR * ,6aS * )-3-Cyclopropylhexahydro-2H-pyrrolo[3,4-d]oxazole-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 at 50°C for 48 hours. The reaction mixture was cooled to room temperature and quenched by adding saturated sodium bicarbonate. The aqueous layer was extracted with DCM (×2), and the organic layer was dried (MgSO4). The solvent was removed under vacuum to obtain crude tert-butyl (3R * ,4R * )-3-(cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylate was obtained and used in the next step without further purification.

[0278] Crude material from the preceding 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 mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the crude tert-butyl (3R) was obtained. * ,4R * )-3-((tert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine-1-carboxylate was obtained and 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). 50% Deoxo-Fluor® (487 mg, 1.10 mmol) in THF was added dropwise at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was quenched by the addition of saturated sodium bicarbonate and extracted with DCM (×2). The organic layer was dried (MgSO4), the solvent was removed under vacuum, and tert-butyl(3aR) was extracted.* ,6aS * )-3-cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazole-5-carboxylate was obtained. The substance was used without further purification.

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

[0281] Intermediate 10: 8-Methoxy-2-methylimidazo[1,2-a]pyrazine-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 substance was purified by silica gel column chromatography (gradient elution, 0-100% ethyl acetate in cyclohexane) to obtain 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), K2CO3 (1.71 g, 12.39 mmol), N,N'-dimethylethylenediamine (73 mg, 0.826 mmol), and toluene (11 mL) were placed in a sealed tube and degassed by blowing nitrogen for 5 minutes. The mixture was then hot-block heated at 100°C for 42 hours. After cooling to room temperature, LC-MS analysis showed partial conversion. The reaction mixture was evaporated to dryness on silica and purified by flash chromatography eluting with 1-9% MeOH in ethylacetate to obtain N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-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 (4M in dioxane, 4.3 mL, 17.25 mmol) was added to N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-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 obtain the title compound.

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

[0285] [ka] 1000 mg, 5.40 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 10 mL of DCM and 0.62 mL, 5.94 mmol, 1.10 equivalents of tert-butylamine, and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with NaHCO3 (aqueous solution) and washed three times with DCM. The combined organic layer was washed with saturated brine, dried (on phase separation filter paper), and concentrated under vacuum to obtain 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 equivalent) was dissolved in methanol (10 mL), and 4 M HCl in dioxane (13.5 mL, 54.05 mmol, 10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to obtain crude N-(tert-butyl)pyrrolidine-3-amine·2HCl, which was used without further purification.

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

[0288] [ka] 1000 mg (5.40 mmol, 1 equivalent) of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 10 mL of dimethyl chloride (DCM) and 0.41 mL (5.94 mmol, 1.10 equivalents) of cyclopropylamine, and sodium triacetoxyborohydride (2400 g, 11.34 mmol, 2.10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with aqueous solution of NaHCO3 and washed three times with DCM. The combined organic layers were washed with saturated brine, dried (on phase separation filter paper), and concentrated under vacuum to obtain 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 equivalent) was dissolved in methanol (10 mL), and 4 M HCl in dioxane (13.5 mL, 53.91 mmol, 10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum to obtain crude N-cyclopropylpyrrolidine-3-amine·2HCl, which was used without further purification.

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

[0291] [ka] 1000 mg, 5.40 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in 10 mL of dimethylamine (DCM) and 0.42 mL, 5.94 mmol, 1.10 equivalents of cyclopropanemethylamine, and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equivalents) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with aqueous solution of NaHCO3 and extracted three times with DCM. The combined organic layers were washed with saturated brine, dried (on phase separation filter paper), and concentrated under vacuum to obtain 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 equivalent) was dissolved in methanol (10 mL), and 4 M HCl (13.9 mL, 55.75 mmol, 10 equivalents) in dioxane was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and the residue was loaded into a 10 g SCX cartridge (pre-prepared with MeOH) in MeOH. Elution was performed with MeOH (2 CV) and then with 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated under vacuum to obtain crude N-(cyclopropylmethyl)pyrrolidine-3-amine, which was used without further purification.

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

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

[0295] 1.38 g, 5.40 mmol of tert-butyl 3-morpholinopyrrolidine-1-carboxylate was dissolved in methanol (10 mL), and 13.5 mL, 53.99 mL of 4 M HCl in dioxane were added at room temperature. The reaction mixture was stirred for 18 hours, and the solvent was removed under vacuum to obtain the crude product. This product was purified by elution with MeOH (2 CV) and then 2.3 M NH3 / MeOH (3 CV) using a 10 g SCX cartridge (pre-prepared with MeOH). The ammonia fraction was concentrated under vacuum to obtain crude 4-(pyrrolidine-3-yl)morpholine, which was used without further purification.

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

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

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

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

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

[0301] 1.82 g, 4.74 mmol of tert-butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine-1-carboxylate was dissolved in methanol (5 mL), and 20.0 mL, 80 mmol of 4 M HCl in dioxane was added at room temperature. The reaction mixture was stirred for 18 hours, and the solvent was removed under vacuum to obtain crude N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-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 gradually added 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 mixture was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was placed in ELISA and washed with water and brine. The organic layer was concentrated under vacuum to obtain 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine, which was used without further purification.

[0304] Intermediate 18: N-(pyrrolidine-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 hours. The reaction mixture was then quenched with saturated aqueous NaHCO3 solution, extracted with dichloromethane, dried (MgSO4), and evaporated to dryness to obtain tert-butyl 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylate (2.29 g) as a clear oily substance, which was used crudely in the next step.

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

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

[0308] [ka] 200 mg, 0.83 mmol of tert-butyl 3-((isopropylamino)methyl)pyrrolidine-1-carboxylate was dissolved in 3 ml of DMF, and then sodium hydride (60%, 50 mg, 1.24 mmol) and iodomethane (51 µl, 0.83 mmol) were added at room temperature, and the mixture was stirred for 65 hours. The reaction mixture was then quenched with 4% aqueous LiCl solution, extracted with ethyl acetate (x2), dried on phase separation paper, and evaporated to dryness to obtain 190 mg of tert-butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate as a clear oily substance, which was used crudely in the next step.

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

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

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

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

[0313] [ka] According to Method L Boc protection, 3-methoxypyridine-4-amine (370 mg, 2.98 mmol, 1 equivalent) was purified. The crude product was purified using silica chromatography with an elution gradient of 0-100% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain tert-butyl(3-methoxypyridine-4-yl)carbamate (590 mg, 88%) as a white solid. LCMS (ES+) 225 (M+H)+

[0314] Method M was performed according to the aminopyridinium salt formation from tert-butyl(3-methoxypyridine-4-yl)carbamate (590 mg, 2.63 mmol, 1 equivalent). LC-MS showed consumption of the starting material and a new peak with the exact target mass ion (240). The reaction mixture was proceeded to the next step without post-treatment (assuming 100% yield).

[0315] Method N followed the 1,3 bipolar addition procedure from 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridine-1-ium-2,4-dinitrophenolate (1114 mg, 2.63 mmol, 1 equivalent). The reaction mixture was concentrated on silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-75% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain 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] Method O: Following HBr decarboxylation, ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (169 mg, 0.484 mmol, 1 equivalent) was used. The reaction mixture was concentrated under vacuum to obtain crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine.2HBr as a brown oil. Without further purification, the process proceeded to the next step.

[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] According to Method L Boc protection, 3-fluoropyridine-4-amine (925 mg, 8.25 mmol, 1 equivalent) was purified. The crude product was purified using silica chromatography with an elution gradient of 0-100% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain tert-butyl(3-fluoropyridine-4-yl)carbamate (1453 mg, 83%) as a white solid. LCMS (ES+) 213 (M+H)+

[0319] Method M was performed according to the aminopyridinium salt formation process using tert-butyl(3-fluoropyridine-4-yl)carbamate (503 mg, 2.37 mmol, 1 equivalent). LC-MS showed a new peak containing consumption of the starting material and the precise target mass ion (228). The reaction mixture was proceeded to the next step without workup (assuming 100% yield).

[0320] Method N: Following 1,3 bipolar addition, the reaction mixture was prepared from 1-amino-4-((tert-butoxycarbonyl)amino)-3-fluoropyridine-1-ium-2,4-dinitrophenolate (1278 mg, 3.11 mmol, 1 equivalent). The reaction mixture was concentrated on silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-20% siRNA in cyclohexane. The fractions containing the target mass were combined, and the solvent was removed under vacuum to obtain 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 product was re-purified using silica chromatography with an elution gradient of 0-18% siRNA in cyclohexane to obtain 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]pyridine-5-amine.2HBr

[0324] [ka] Method O: Decarboxylation of HBr was performed from ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (127 mg, 0.376 mmol, 1 equivalent). The reaction mixture was concentrated under vacuum to obtain crude 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-amine.2HBr as a brown solid. The next step was performed 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] According to Method L Boc protection, 3-methylpyridine-4-amine (600 mg, 5.55 mmol, 1 equivalent) was purified. The crude product was purified using silica chromatography with an elution gradient of 0-100% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain tert-butyl(3-methylpyridine-4-yl)carbamate (939 mg, 81%) as a white solid. LCMS (ES+) 209 (M+H)+

[0327] Method M was performed according to the aminopyridinium salt formation process using tert-butyl(3-fluoropyridine-4-yl)carbamate (939 mg, 4.51 mmol, 1 equivalent). LC-MS showed a new peak containing consumption of the starting material and the precise target mass ion (224). The reaction mixture was proceeded to the next step without post-treatment (assuming 100% yield).

[0328] Method N was performed using 1,3 bipolar addition from 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridine-1-ium-2,4-dinitrophenolate (1835 mjg, 4.51 mmol, 1 equivalent). The reaction mixture was concentrated on silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-50% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain 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]pyridine-5-amine.2HBr

[0332] [ka] Method O: Following HBr decarboxylation, ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (250 mg, 0.750 mmol, 1 equivalent) was used. The reaction mixture was concentrated under vacuum to obtain crude 2,6-dimethylpyrazolo[1,5-a]pyridine-5-amine 2HBr as a brown oily substance. The process proceeded to the next step without further purification.

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

[0334] [ka] According to Method L Boc protection, tert-butyl(3-ethoxypyridine-4-yl)carbamate was obtained from 3-ethoxypyridine-4-amine (2200 mg, 15.9 mmol, 1 equivalent) as a yellow solid. The next step was performed without further purification.

[0335] Method M was performed according to the aminopyridinium salt formation process using tert-butyl(3-ethoxypyridine-4-yl)carbamate (4200 mg, 17.6 mmol, 1 equivalent). LC-MS showed a new peak containing consumption of the starting material and the precise target mass ion (254). The reaction mixture was proceeded to the next step without post-treatment (assuming 100% yield).

[0336] Method N 1,3 bipolar addition was performed from 1-amino-4-((tert-butoxycarbonyl)amino)-3-ethoxypyridine-1-ium-2,4-dinitrophenolate (7702 mg, 17.626 mmol, 1 equivalent). The reaction mixture was concentrated on silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-60% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain 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] Method O: Following HBr decarboxylation, ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 0.941 mmol, 1 equivalent) was used. The reaction mixture was concentrated under vacuum to obtain crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine, 2HBr, as a brown oil. The crude was loaded into a 5 g SCX cartridge (pre-prepared with MeOH). The residue was eluted with MeOH, and then with 7 M NH3 in MeOH. The ammonia fraction was concentrated under vacuum to obtain 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine as a light brown oil. Without further purification, the process proceeded to the next step.

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

[0339] [ka] 5-bromo-1H-indazole-6-ol (900 mg, 4.22 mmol, 1 equivalent), sodium chlorodifluoroacetate (1288 mg, 8.45 mmol, 2 equivalents), and Cs2CO3 (2065 mg, 6.34 mmol, 1.5 equivalents) were dissolved in DMF (10 mL), and the reaction mixture was stirred in a sealed tube at 100 °C for 18 hours. siRNA and H2O were added, and the layers were separated. The aqueous layer was washed with siRNA (×2), and the combined organic layers were washed with brine, dried (on phase separation filter paper), and concentrated under vacuum. The crude product was purified by silica chromatography using an elution gradient of 5-100% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain 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 equivalent) was dissolved in RINKAN (50 mL), and trimethyloxonium tetrafluoroborate (413 mg, 2.79 mmol, 1.5 equivalents) was added. The RM was stirred at room temperature for 16 hours. RINKAN and H2O were added, and the layers were separated. The aqueous layer was washed with RINKAN (×2), and the combined organic layers were washed with brine, dried (on phase separation filter paper), and concentrated under vacuum to obtain 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 equivalent), diphenylmethanymine (0.24 mL, 1.44 mmol, 1 equivalent), Cs2CO3 (706 mg, 2.16 mmol, 1.5 equivalents), Pd(OAc)2 (32 mg, 0.14 mmol, 0.1 equivalent), and rac-BINAP (90 mg, 0.14 mmol, 0.1 equivalent) were combined in THF (5 mL), and the mixture was purged with N2 for 15 minutes. The reaction mixture was stirred in a sealed tube at 80°C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous phase was extracted with SiO(×3). The combined organic phase was washed with brine, dried (on phase separation filter paper), and the solvent was removed under vacuum. The crude product was purified using silica chromatography and an elution gradient of 0-75% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain N-(6-(difluoromethoxy)-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethaneimine. Although impurities were still present, the process proceeded to the next step without further purification.

[0342] N-(6-(difluoromethoxy)-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethanymine (220 mg, 0.48 mmol, 1 equivalent) was dissolved in MeOH (10 mL), and 4M HCl (0.48 mL, 1.91 mmol, 4 equivalents) was added to dioxane. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain 6-(difluoromethoxy)-2-methyl-2H-indazole-5-amine,2HCl as a red solid. The process proceeded to the next step without further purification.

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

[0344] [ka] Method H₂C₄TCFH coupling was performed from 5-chloropyrazine-2-carboxylic acid (321 mg, 2.02 mmol, 1 equivalent) and 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine.2HBr (858 mg, 2.02 mmol, 1 equivalent). The reaction mixture was diluted with H₂O, and the solid was filtered. The solid was washed with MeCN:H₂O (1:2) (×3) to obtain 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-yl)pyrazine-2-carboxamide (327 mg, purity 80%, 40%) as a yellow solid. LCMS (ES+) 318 (M+H)+

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

[0346] [ka] 5-Bromo-3-fluoropyridine-2-amine (2 g, 10.47 mmol) and ethyl bromopyruvate (1.4 mL, 11.52 mmol) were dissolved in ethanol (50 mL) and heated under reflux for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum to obtain a residue. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The ethyl acetate layer was dried (MgSO4), and the solvent was removed under vacuum to obtain a residue, which was purified using silica chromatography with an elution gradient of 0-50% ethyl acetate / cyclohexane to obtain 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. 12.88 mL, 12.88 mmol, 1 M DIBAL in toluene was added dropwise, and the reaction mixture was heated to room temperature over 18 hours. The reaction mixture was cooled to 0°C in an ice bath and quenched by adding water. The aqueous layer was extracted with HCl × 3, and the organic layer was dried (MgSO4). The solvent was removed under vacuum to obtain the residue, which was purified using silica chromatography with an elution gradient of 0-100% HCl / cyclohexane to obtain the title compound as a clear oil (1.1 g, 73%).

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

[0349] [ka] (R)-3-(aminomethyl)-1-Boc-pyrrolidine (1000 mg, 4.99 mmol, 1.00 equivalent), (1-ethoxycyclopropoxy)trimethylsilane (1.0 mL, 4.99 mmol, 1.00 equivalent), and methyl alcohol (50.00 mL) were combined. Sodium borohydride cyanohydride (345 mg, 5.49 mmol, 1.10 equivalents) was added, followed by acetic acid (0.20 mL). The reaction mixture was then heated in a hot block at 55°C for 2 days. The reaction mixture was cooled to room temperature. Diluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO4), and concentrated under vacuum to obtain 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 crudely 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 equivalent), methyl alcohol (10 mL), and 4M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.01 equivalents) was combined and stirred at room temperature for 23 hours. The reaction mixture was then concentrated under vacuum and partitioned between dichloromethane and a 15% NaOH aqueous solution. The organic layer was concentrated under vacuum to obtain a mixture of N-[[(3S)-pyrrolidine-3-yl]methyl]cyclopropanamine dihydrochloride and (S)-N-cyclopropyl-N-(pyrrolidine-3-ylmethyl)cyclopropanamine dihydrochloride as a clear, rubbery substance (718 mg), which was used as is in the next step.

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

[0352] Di-tert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.00 equivalent) was added to the reaction mixture from the preceding step and stirred at room temperature for 2 hours. The crude reaction mixture was concentrated on silica under vacuum and purified by flash chromatography to obtain methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidine-1-yl]pyrazine-2-carboxylate as a clear, rubbery substance (682 mg). This was used directly in the next step. LCMS (ES+) 377 (M+H)+

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

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

[0355] [ka] N-[[(3R)-pyrrolidine-3-yl]methyl]cyclopropanamine dihydrochloride was prepared using the same chemical action as its enantiomer, N-[[(3S)-pyrrolidine-3-yl]methyl]cyclopropanamine dihydrochloride, and used directly in the next step.

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

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

[0358] 1.11 g, 4.91 mmol, 1.00 equivalent of tert-butyl(3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate, 10.00 mL of methyl alcohol, and 5.0 mL, 20.0 mmol, 4.07 equivalents of 4M hydrogen chloride in dioxane were combined and stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum to obtain (3R)-N-cyclopropylpyrrolidine-3-amine dihydrochloride as a white semi-solid (985 mg), which was used as is in the next step.

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

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

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

[0362] Intermediate 35: N-(azetidine-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 sodium bicarbonate aqueous solution (200 mL) was added to the reaction mixture and vigorously stirred for 10 minutes. The organic layer was collected, washed with water and brine, then passed through a phase separator and concentrated to dryness to obtain the title compound as a clear oil (5.1 g, 83%), which was then used directly in the next step.

[0364] tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate (3.00 g, 13.3 mmol, 1.00 equivalent) and trifluoroacetic acid (5.1 mL, 66.3 mmol, 5.00 equivalent) were combined in dichloromethane (30 mL) and stirred at room temperature for 72 hours. The reaction mixture was concentrated under vacuum, loaded into an SCX cartridge, and washed with DCM / MeOH (1:1). The compound was released using 7M ammonia (5:5:1) in DCM / MeOH / MeOH, concentrated to dryness, and N-(azetidine-3-ylmethyl)cyclopropanamine was obtained as a colorless oil (1.19 g, 71%). Note: Multiple elutions were necessary 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-(azetidine-3-yl)-1-methylpiperidine hydrochloride

[0366] [ka] A mixture of tert-butyl 3-(piperidine-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 obtain a crude off-white rubbery substance, which was used without further purification (tert-butyl 3-(1-methylpiperidine-3-yl)azetidine-1-carboxylate, 330 mg).

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

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

[0369] [ka] A mixture of tert-butyl 3-(piperidine-3-yl)azetidine-1-carboxylate (250 mg, 1.04 mmol), 1-(ethoxycycloproxy)trimethylsilane (0.23 mL, 1.14 mmol), and sodium borohydride cyanohydride in methanol (10 mL) and acetic acid (0.1 mL) was heated at 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 obtain the crude substance as orange rubber, which was then proceeded to without further purification (tert-butyl 3-(1-cyclopropylpiperidine-3-yl)azetidine-1-carboxylate, 224 mg). MS (ES+) 281.2 [M+H] + .

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

[0371] Intermediate 38: 5-Chloro-N-(6-ethoxy-2-methyl-indazole-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), iodomethane (0.76 mL, 12.2 mmol) was added dropwise, and the reaction mixture was stirred overnight. The reaction mixture was diluted with siRNA and water, the organic layer was separated, and further extracted with siRNA. The combined organic layers were washed with brine, dried over sodium sulfate, decanted, and concentrated under reduced pressure. The crude substance was purified by flash column chromatography (0-100% siRNA in cyclohexane, 80 g column). The product-containing fraction was concentrated under reduced pressure to obtain the title compound as a light brown solid (586 mg, yield 23%). 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), 10% palladium (279 mg, 2.62 mmol) on carbon was added, and the reaction mixture was heated overnight at 70°C. After 24 hours, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain a brown, rubbery substance, and the crude material was used directly in the next step without further purification (460 mg, yield 92%). 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-indazole-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, the filter cake was collected, and dried under reduced pressure to obtain 5-chloro-N-(6-ethoxy-2-methyl-indazole-5-yl)pyrazine-2-carboxamide as a yellow powder (410 mg, yield 51%). 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-(azetidine-3-ylmethyl)cyclopropanamine dihydrochloride

[0376] [ka] A suspension of tert-butyl 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.44 mmol) and des-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 obtain a colorless oil, which was used without further purification (480 mg, 97% yield).

[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 overnight at room temperature under nitrogen. 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 obtain a crude substance: pale yellow rubber (250 mg, yield 87%).

[0378] A solution of tert-butyl 3-[(cyclopropylamino)methyl]-3-fluoroazetidine-1-carboxylate (250 mg, 1.02 mmol) in 4M hydrogen chloride (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 obtain a crude substance as a light brown solid, which was used without further purification (210 mg, yield 95%).

[0379] Intermediate 40: 1-(azetidine-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 sodium bicarbonate aqueous solution (15 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 obtain tert-butyl 3-[(3-methoxyazetidine-1-yl)methyl]azetidine-1-carboxylate as a clear oily substance (700 mg), which was used without further purification.

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

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

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

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

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

[0386] [ka] A mixture of 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (prepared according to WO2015 / 197503, 991 mg, 4.38 mmol) and CuSO4 (401 mg, 2.51 mmol) in 35% aqueous ammonia (8 mL) was heated to 90°C for 3 hours under microwave irradiation. After cooling to room temperature, the substance 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 added to a 70 g SCX cartridge and eluted with 100 mL of MeOH, and then with 150 mL of 2.3 M NH3 / MeOH. The ammonia fraction was concentrated, and the residue was purified by silica gel column chromatography (gradient elution, 0-20% MeOH / DCM) to obtain 2,8-dimethylimidazo[1,2-a]pyrazine-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]pyridine-6-yl)pyrazine-2-carboxamide

[0388] [ka] 3-Chloro-5-nitropyridine-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 obtain the desired product (91% purity, 1.5 g, quantitative). LCMS (ES) + ) 212 (M+H) + , RT 1.35 minutes.

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

[0390] 8-chloro-2-methylimidazo[1,2-a]pyridine-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) were stirred under nitrogen at room temperature for 16 hours. The reaction mixture was concentrated, diluted with DCM, and washed with aqueous sodium bicarbonate. The organic layer was concentrated on silica and purified by elution with cyclohexane / siRNA (0-100% gradient) by column chromatography. Appropriate fractions were combined and concentrated under vacuum to obtain 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]pyridine-6-yl)pyrazine-2-carboxamide)

[0392] [ka] 5-Bromo-3-methoxypyridine-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 hours. The reaction mixture was diluted 3:1 DCM / IPA and washed with brine. The organic layer was concentrated under vacuum to obtain 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-methylimidazo[1,2-a]pyridine (1.01 g, 4.19 mmol), copper(I) iodide (0.16 g, 0.838 mmol), potassium carbonate (0.87 g, 6.28 mmol), ammonium hydroxide solution (0.26 mL, 6.28 mmol), L-proline (0.19 g, 1.68 mmol), and DMSO (10.00 mL) were added to the reaction flask. The reaction vessel was sealed and heated at 90°C for 16 hours. The reaction mixture was passed through an SCX cartridge using MeOH and NH3 in MeOH (7M), and the appropriate fraction was concentrated under vacuum to obtain the desired product (1.19 g, 99%). LCMS (ES) + ) 179 (M+H) + .

[0394] 8-methoxy-2-methylimidazo[1,2-a]pyridine-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) were stirred under nitrogen at room temperature for 16 hours. The reaction mixture was concentrated, diluted in 3:1 DCM:IPA, and washed with brine. The crude product was purified by column chromatography using cyclohexane / siRNA (0-100% gradient) to obtain 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide (909 mg, 87%). LCMS (ES + ) 317 (M+H) + .

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

[0396] [ka] HBTU (1.88 g, 4.96 mmol, 1.00 equivalent), triethylamine (3.5 mL, 24.8 mmol, 5.00 equivalent), 5-chloro-2-pyrazinecarboxylic acid (0.79 g, 4.96 mmol, 1.00 equivalent), N,N-dimethylformamide (10.00 mL), and 7-fluoro-2-methyl-indazole-5-amine hydrochloride (1.00 g, 4.96 mmol, 1.00 equivalent) were combined and stirred at room temperature for 17 hours. LC-MS showed the absence of the expected chlorinated substance; instead, an HOBt adduct was formed. The reaction mixture was partitioned between HCl and water. The aqueous layer was washed multiple times with HCl. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated under vacuum. Note: A significant amount of HOBt adduct remained in the aqueous layer. The substance was purified by flash silica chromatography (gradient elution c-hex to ethyl acetate) to obtain 5-(benzotriazole-1-yloxy)-N-(7-fluoro-2-methyl-indazole-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-indazole-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 mixture was heated at 45 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered through a glass sintered material, and the collected solid was washed with ELISA. The collected liquid was concentrated under vacuum to obtain 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 mixture was heated at 90°C for 5 days. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica chromatography using 0-40% siRNA / cyclohexane to obtain 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 amounts, and once the addition was complete, the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with water, extracted with siRNA, and the layers were separated. The combined organic phases were dried on magnesium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by column chromatography on silica gel and eluted with 0-50% siRNA in cyclohexane to obtain 5-bromo-7-fluoro-2-methyl-2H-indazole as an off-white solid (2.42 g, 55%).

[0401] 5-bromo-7-fluoro-2-methylindazole (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 mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to room temperature, the solid was filtered, and washed with ethyl acetate. The filtrate was concentrated under vacuum to obtain the residue. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate / cyclohexane 0-100%, to obtain an oily substance (3 g). 1 ¹H NMR analysis primarily revealed that the starting material, 5-bromo-7-fluoro-2-methyl-indazole, was converted to N-(7-fluoro-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethaneimine with a conversion rate of 35%.

[0402] An impure substance (3.00 g, 4.58 mmol, assumed purity 35%) 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(diphenylphosphin)-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 mixture was heated at 80°C for 24 hours. The reaction mixture was cooled to room temperature, the solid was filtered, and washed with phenylethylamine. The filtrate was concentrated under vacuum to obtain an oily residue. The residue was purified by elution with 0-100% siRNA / cyclohexane using column chromatography on silica gel to obtain N-(7-fluoro-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethaneimine as an off-white solid (2.56 g, >100%).

[0403] N-(7-fluoro-2-methyl-indazole-5-yl)-1,1-diphenyl-methanymine (2.56 g, 7.77 mmol) was suspended in methyl alcohol (10 mL), and 4N hydrogen chloride (19 mL, 77.7 mmol) in dioxane was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum to obtain a pale yellow solid. SiO4 was added, and the resulting slurry was stirred for approximately 10 minutes. The solid was filtered and washed with further SiO4 to obtain the title compound as an off-white solid (1.66 g, 95%). LCMS (ES+) 166 (M+H)+

[0404] Intermediate 43: tert-butylcyclopropyl((2-oxopyrrolidine-3-yl)methyl)carbamate

[0405] [ka] 3-(hydroxymethyl)pyrrolidine-2-one (780 mg, 6.77 mmol) was added dropwise to a stirred solution of dichloromethane (50 mL) and triethylamine (1.9 mL, 13.5 mmol) at room temperature, with methanesulfonyl chloride (0.58 mL, 7.45 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding water, and the layers were separated using a phase separator. DCM was removed under vacuum to obtain (2-oxopyrrolidine-3-yl)methylmethanesulfonate as a white solid (800 mg, 61%).

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

[0407] 3-[(cyclopropylamino)methyl]pyrrolidine-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 mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum to obtain a residue, which was purified by silica chromatography (10 g, eluted with siRNA) to obtain the title compound as a clear oil (420 mg, 58%).

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

[0409] [ka] 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 7-fluoro-2-methyl-indazole-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 mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by adding water, and the aqueous layer was extracted with dichloromethane (DCM). The layers were separated using a phase separator, and the DCM was removed under vacuum to obtain 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-indazole-5-yl)pyrazine-2-carboxamide

[0411] [ka] 5-Chloropyrazine-2-carbonyl chloride (223 mg, 1.26 mmol) and 2H-indazole-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 mixture was stirred at room temperature for 3 hours.

[0412] The reaction mixture was quenched with water, and the aqueous layer was extracted three times using DCM. The layers were separated using a phase separator, and the solvent was removed under vacuum to obtain 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]oxazole-6-yl)pyrazine-2-carboxamide

[0414] [ka] 4-Fluoro-2-methyl-1,3-benzoxazole-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 formed solid was filtered and washed with acetonitrile and water. The solid was dried overnight in a vacuum oven to obtain the title compound as an off-white solid (250 mg, 67%). It was used in the next step without further purification.

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

[0417] [ka] tert-butyl N-(azetidine-3-ylmethyl)carbamate (675 mg, 3.62 mmol), methyl 5-chloro-2-pyrazine carboxylate (625 mg, 3.62 mmol), cesium carbonate (2373 mg, 7.28 mmol), and 1,4-dioxane (25 mL) were combined and heated overnight under reflux. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was placed in a DCM, washed with water, and the layers were separated using a phase separator. The DCM was removed under vacuum to obtain the residue. The residue was purified by column chromatography on silica gel (25 g, eluted with 0-100% ethyl ethyl in cyclohexane) to obtain a yellow oily substance (870 mg, 74%).

[0418] Methyl 5-[3-[(tert-butoxycarbonylamino)methyl]azetidine-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 mixture was stirred at room temperature for 1 hour. Iodomethane (0.048 mL, 0.776 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with MeOH (to avoid ester hydrolysis), and the solvent was removed under vacuum to obtain an oily residue. This residue was used in the next step without further purification. Methyl 5-[3-[[tert-butoxycarbonyl(methyl)amino]methyl]azetidine-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 mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum, 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 SiO₂ × 4. The organic layer was separated and dried by passing it through hydrophobic frit. The solvent was removed under vacuum, and the title compound was obtained as a clear oil (155 mg, 61%). It was used in the next step without further purification.

[0419] Intermediate 48: 7-Fluoro-2,8-dimethylimidazo[1,2-a]pyridine-6-amine.HCl

[0420] [ka] 4-Fluoro-3-methylpyridine-2-amine (500 mg, 3.96 mmol, 1.00 equivalent), 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 obtain a brown solid, which was used crudely in the next step. LCMS (ES+) 205 / 207 (M+H)+.

[0421] 5-Bromo-4-fluoro-3-methylpyridine-2-amine (813 mg, 3.96 mmol) (crude product from the preceding 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 overnight in a hot block at 85°C. An off-white precipitate was observed. The reaction mixture was cooled to room temperature, concentrated under vacuum, and partitioned between approximately 10% NaOH aqueous solution and dichloromethane. The organic phase was dried (MgSO4) and concentrated under vacuum to obtain 6-bromo-7-fluoro-2,8-dimethylimidazo[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-dimethylimidazo[1,2-a]pyridine (856 mg, 3.52 mmol), and tetrahydrofuran (20 mL) were combined. The reaction mixture was degassed by blowing nitrogen over it for 5 minutes. The reaction tube was sealed and hot-block heated to 85°C over the weekend. The reaction mixture was filtered through a Celite plug to remove the cesium salts and rinsed with ethyl acetate. The organic phase was concentrated on silica under vacuum and purified by flash chromatography. The starting material and target appeared to flow simultaneously. 622 mg, light brown solid. LC-MS basic, retention time = 1.42 min, 243 / 245 M+H starting material, retention time = 1.70 min, 344 M+H target. Used directly in the next step.

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

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

[0425] [ka] To a solution of intermediate 1 (150 mg, 0.49 mmol) in dioxane (1 mL), tert-butyl(R)-3-ethylpiperazine-1-carboxylate (263 mg, 1.23 mmol) was added. Triethylamine (0.1 mL, 0.74 mmol) was added, and the reaction mixture was heated in a microwave at 140°C for 30 minutes. The solvent was removed under vacuum, and the residue was purified using silica chromatography and a 0-10% ethyl acetate / cyclohexane elution gradient to obtain tert-butyl(R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-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]pyridine-6-yl)carbamoyl)pyrazine-2-yl)piperazine-1-carboxylate (140 mg, 0.29 mmol) in methanol (2 mL), 4 M hydrochloric acid (10 mL) in dioxane was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the resulting crude product was purified by reverse-phase HPLC to obtain the target TFA salt. The TFA salt was dissolved in methanol / DCM 1:1, and MP-carbonate was added. The mixture was allowed to stand for 18 hours. The MP-carbonate was filtered, and the solvent was removed under vacuum to obtain 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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0428] [Table 9] TIFF0007894498000155.tif254170TIFF0007894498000156.tif254170TIFF0007894498000157.tif95170

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

[0430] [ka] The compound was prepared using general method D and the following amounts of: Intermediate 1 (127 mg, 0.41 mmol), N-(pyrrolidine-3-ylmethyl)cyclopropanamine dihydrochloride (87 mg, 0.41 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (3 mL). The crude substance was purified by preparative HPLC to obtain the title compound. LC-MS (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0432] [Table 10] TIFF0007894498000160.tif249170TIFF0007894498000161.tif248170TIFF0007894498000162.tif246170TIFF0007894498000163.t if247170TIFF0007894498000164.tif250170TIFF0007894498000165.tif236170TIFF0007894498000166.tif254170TIFF0007894498 000167.tif251170TIFF0007894498000168.tif230170TIFF0007894498000169.tif251170TIFF0007894498000170.tif232170TIFF00 07894498000171.tif249170TIFF0007894498000172.tif222170TIFF0007894498000173.tif251170TIFF0007894498000174.tif14170

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

[0434] [ka] Intermediate 2 (100 mg, 0.3 mmol), 1-(pyrrolidine-3-ylmethyl)pyrrolidine dihydrochloride (94 mg, 0.23 mmol), Cs2CO3 (487 mg, 1 mmol), and DMF (3 mL) were combined in a sealed tube and hot-block heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, the cesium salt was removed by filtration, and the reaction mixture was purified by preparative HPLC to obtain the title compound. LC-MS (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0436] [Table 11] TIFF0007894498000177.tif246170TIFF0007894498000178.tif224170TIFF0007894498000179.tif232170

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

[0438] [ka] Methyl 5-chloropyrazine-2-carboxylate (173 mg, 1 mol), N-Boc piperazine (186 mg, 1 mmol), Cs2CO3 (650 mg, 2 mmol), and DMF (5 mL) were combined in a sealed tube and hot-block heated at 100°C for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water (x2) and brine, and evaporated to dryness to obtain methyl 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)pyrazine-2-carboxylate, which was used crudely in the next step. MS (ES+) 323 (M+H).

[0439] Methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, LiOH·H2O (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 obtain lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, which was used crudely in the next step. MS (ES+) 309 (M+H).

[0440] 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate lithium (157 mg, 0.5 mmol), 2,8-dimethylimidazo[1,2-a]pyrazine-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 obtain tert-butyl4-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)piperazin-1-carboxylate. MS (ES+) 453 (M+H).

[0441] 10.6 mg of tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)piperazine-1-carboxylate, 2 mL of dichloromethane, and 1 mL of TFA were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and then added to MeOH. Na2CO3 was added and the mixture was stirred for 5 minutes. The reaction product was then filtered, the filtrate was evaporated to dryness, and the compound was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 353 (M+H)+, RT 1.86 min (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0443] [Table 12] TIFF0007894498000182.tif245170TIFF0007894498000183.tif203170

[0444] Further analogues were prepared from commercially available or synthesized amines using the same chemical action, however, 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-amine was used instead of 2,8-dimethylimidazo[1,2-a]pyrazine-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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0445] [Table 13] TIFF0007894498000185.tif245170TIFF0007894498000186.tif247170TIFF0007894498000187.tif40170

[0446] [Example 83] (R)-5-(3-(ethylamino)pyrroridine-1-yl)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-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 one 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 mixture was stirred for 1 hour. The reaction mixture was evaporated to dryness to obtain 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)pyrazine-2-carboxamide, which was used crudely in the next step.

[0448] 5-Chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)pyrazine-2-carboxamide (125 mg, 0.28 mmol), (R)-N-ethylpyrrolidine-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 at 100°C for 2 hours. The reaction mixture was then cooled to room temperature, the cesium salt was removed by filtration, and the filtrate was purified by preparative HPLC to obtain the title compound. LC-MS (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 analogues were prepared using the same chemical action and suitable amines. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0450] [Table 14]

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

[0452] [ka] 5-(4-(tert-butoxycarbonyl)piperazine-1-yl)pyrazine-2-carboxylate lithium (157 mg, 0.5 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridine-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 obtain tert-butyl4-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H).

[0453] 80 mg of tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)piperazine-1-carboxylate, 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 added to MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and the compound was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 356 (M+H)+, RT 1.67 min (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]pyrazine-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide and [Example 88] N-(2,8-dimethylimidazo[1,2-a]pyridine-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide

[0455] [ka] Methyl 5-chloropyrazine-2-carboxylate (665 mg, 3.85 mmol), tert-butyl ((3R * ,4S * (-4-fluoropyrrolidine-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 at 100°C for 18 hours. The reaction mixture was then diluted with ethyl acetate, washed with water (3 ×) and brine (1 ×), evaporated to dryness, and methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate was obtained and used crudely without further purification.

[0456] Methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-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 the addition of MeI (0.14 mL, 2.22 mmol). The reaction mixture was stirred for 22 hours, then diluted with ethyl acetate and washed with water (3 ×) and brine (1 ×). The organic layer was evaporated to dryness and methyl 5-((3R * ,4S *A solid of )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate was obtained and used crudely without further purification.

[0457] Methyl 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate, LiOH·H2O (85 mg, 2.03 mmol), methanol (20 mL), and water (2 mL) were combined and stirred at 45°C for 23 hours. Then, the reaction mixture was evaporated to dryness and 5-((3R * ,4S * Lithium )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate was obtained and used crudely without further purification.

[0458] 5-((3R * ,4S * Lithium tert-butoxycarbonyl(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate, 2,8-dimethylimidazo[1,2-a]pyrazine-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 obtain tert-butyl((3R * ,4S * )-4-fluoro-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate was obtained and used without further purification.

[0459] tert-butyl((3R * ,4S *)-4-fluoro-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate, methanol (3 mL), and 4N HCl (3 mL) in dioxane 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 was evaporated to dryness. The crude solid was purified by preparative HPLC, followed by chiral preparative HPLC. Cis isomer, enantiomer 1 N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analysis 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]pyridine-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (Analysis 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). I obtained it.

[0460] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0461] [Table 15]

[0462] Further analogs can be found using the same chemical reaction: 5-((3R * ,4S * )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate lithium or 5-((3R * ,4R *The preparations were made using lithium )-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate and 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-amine. In some cases, a Boc-protected amine was 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was optionally specified.

[0463] [Table 16]

[0464] [Example 92] (S)-5-([1,3'-bipyrrolidine]-1'-yl)-N-(6-methoxy-2-methyl-2H-indazole-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 at 100°C for 16 hours. The reaction mixture was filtered to remove the cesium salt and rinsed with phenylethylamine. The combined organic filtrate was evaporated to dryness to obtain methyl(S)-5-([1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxylate, which was used crudely without further purification.

[0466] Methyl(S)-5-([1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxylate, LiOH·H2O (126 mg, 3 mmol), MeOH (50 mL), and water (5 mL) were combined and heated at 45°C for 16 hours. The reaction mixture was then evaporated to dryness to obtain lithium (S)-5-([1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxylate, which was used crudely without further purification.

[0467] (S)-5-([1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxylate lithium (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 obtain the title compound. LC-MS (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'-bipyrrolidine]-1'-yl)-N-(6-ethoxy-2-methyl-2H-indazole-5-yl)pyrazine-2-carboxamide

[0469] [ka] (S)-5-([1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxylate lithium (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 overnight at room temperature. The reaction mixture was purified by preparative HPLC to obtain the title compound. LC-MS (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)pyrroridine-1-yl)-N-(6-methoxy-2-methyl-2H-indazole-5-yl)pyrazine-2-carboxamide

[0471] [ka] 5-((3R * ,4S *)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate lithium (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 obtain tert-butyl((3R * ,4S * )-4-fluoro-1-(5-((6-methoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate was obtained and used without further purification.

[0472] tert-butyl((3R * ,4S * The title compound was obtained by deprotecting )-4-fluoro-1-(5-((6-methoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate using general method C (HCl Boc deprotection). LC-MS (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]pyridine-6-yl)-5-(pyrrolidine-3-yloxy)pyrazine-2-carboxamide

[0474] [ka] 100 mg, 0.53 mmol of tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate in 2 mL of DMF was added to a suspension of NaH (32 mg, 0.801 mmol) in 1 mL of DMF, and the reaction mixture was stirred at room temperature for 30 minutes. Intermediate 1 (163 mg, 0.534 mmol) was added, and the reaction mixture was heated at 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 MgSO4 and evaporated to dryness. The crude mixture was purified by flash chromatography to obtain tert-butyl(S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)oxy)pyrrolidine-1-carboxylate. MS (ES+) 457 (M+H).

[0475] 63 mg, 0.14 mmol of tert-butyl(S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)oxy)pyrrolidine-1-carboxylate, methanol (1 mL), and 4N HCl in dioxane (0.35 mL, 1.38 mmol) were combined and stirred at room temperature for 17 hours. The reaction mixture was evaporated to dryness, and the crude product was purified by preparative HPLC to obtain the title compound. LC-MS (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by preparative HPLC.

[0477] [Table 17]

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

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

[0480] 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidine-1-yl)pyrazine-2-carboxylic acid (343 mg, 1.02 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridine-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 mixture was stirred overnight at room temperature. The solvent was removed under vacuum to obtain the crude product. Purification using silica chromatography with an elution gradient of 0-100% ethyl acetate / cyclohexane yielded tert-butyl((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)-4-methylpyrrolidine-3-yl)(methyl)carbamate. MS (ES+) 484 (M+H).

[0481] 610 mg, 1.02 mmol) of tert-butyl((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)-4-methylpyrrolidine-3-yl)(methyl)carbamate was dissolved in methanol (2 mL), and 10 mL of 4 M HCl in dioxane was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum to obtain the crude product. The crude product was purified by elution using a 5 g SCX cartridge (pre-prepared with MeOH) with 1:1 MeOH / DCM (2 CV), followed by 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated under vacuum to obtain the residue. Further purification by reverse-phase HPLC was performed to obtain the title compound. LCMS (ES+) 384.2 (M+H)+, RT 1.72 min (analytical method AcHSSC18); 11H 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 and unclear.

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

[0483] [Table 18] TIFF0007894498000201.tif216170TIFF0007894498000202.tif246170

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

[0485] [ka]

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

[0487] Methyl(R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-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. Next, the reaction mixture was diluted with ethyl acetate, washed with water (3x) and brine (1x), dried (MgSO4), and evaporated to dryness to obtain a mixture of methyl(R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate and methyl(R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate, which was used crudely without further purification.

[0488] A mixture of methyl(R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate and methyl(R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate (169 mg), LiOH·H2O (19 mg, 0.45 mmol), methanol (15 mL), and water (2 mL) was heated in a hot block at 45°C for 18 hours. Next, the reaction mixture was evaporated to dryness to obtain a mixture of (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate lithium and (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate lithium, which was used crudely without further purification.

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

[0490] 65.1 mg of tert-butyl(R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)cyclopropyl)(methyl)carbamate, methanol (3 mL), and 3 mL of 4N HCl in dioxane were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to obtain (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxamide. LC-MS (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] 41.9 mg of tert-butyl(R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyrrolidine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)cyclopropyl)carbamate, methanol (3 mL), and 4N HCl (3 mL) in dioxane were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to obtain (R)-5-(3-(1-aminocyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyrrolidine-6-yl)pyrazine-2-carboxamide. LC-MS (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-indazole-5-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide

[0493] [ka] Intermediate 3 (0.32 mmol), lithium (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-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 obtain tert-butyl(R)-(1-(5-((6-ethoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-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-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate, methanol (3 mL), and 4N HCl (3 mL) in dioxane were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, placed in MeOH, stirred over sodium carbonate for 5 minutes, and filtered through an isolute NH2 resin cartridge. The filtrate was evaporated to dryness to obtain the title compound. LC-MS (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] Further analogues were prepared using Method H (TCFH coupling) starting from (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylic acid and specified amines. 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). The final product was isolated by SCX and / or preparative HPLC.

[0496] [Table 19]

[0497] Example 110: (R)-5-(3-(ethylamino)pyrrolidine-1-yl)-N-(6-methoxy-2-methyl-2H-indazole-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 mixture was then evaporated to dryness to obtain 5-chloro-N-(6-methoxy-2-methyl-2H-indazole-5-yl)pyrazine-2-carboxamide, which was used crudely without further purification. MS (ES+) 318 / 320 (M+H).

[0499] 5-Chloro-N-(6-methoxy-2-methyl-2H-indazole-5-yl)pyrazine-2-carboxamide (150 mg, 0.25 mmol), (R)-N-ethylpyrrolidine-3-amine (28 mg, 0.25 mmol), Cs2CO3 (325 mg, 1 mmol), and DMF (2 mL) were combined in a sealed tube and hot-block heated at 100°C for 1 hour. The reaction mixture was cooled to room temperature, the cesium salt was removed by filtration, and the reaction mixture was purified by preparative HPLC to obtain the title compound. LC-MS (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC.

[0501] [Table 20]

[0502] [Example 112] (R)-5-(3-(cyclopropylamino)pyrroridine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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). NaBH3CN (162 mg, 2.58 mmol) was added, followed by AcOH (0.2 mL). The reaction mixture was then heated at 55°C for 16 hours. The reaction mixture was then diluted with dichloromethane, washed with saturated NaHCO3 aqueous solution, dried in (MgSO4), and evaporated to dryness to obtain tert-butyl(R)-3-(cyclopropylamino)pyrrolidine-1-carboxylate, which was used crudely in the next step.

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

[0505] (R)-N-cyclopropylpyrrolidine-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 at 100°C for 20 hours. The cesium salt was then filtered off, and the filtrate was purified by preparative HPLC to obtain the title compound. LC-MS (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 analogues were prepared from commercially available or synthesized amines using the same chemical reaction. The final products were isolated by preparative HPLC.

[0507] [Table 21]

[0508] [Example 114] 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(5-fluoro-2-methyl-1,3-benzoxazole-6-yl)pyrazine-2-carboxamide (enantiomer 1 + enantiomer 2)

[0509] [ka] According to Method H, from 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylic acid (126 mg, 0.361 mmol, 1 equivalent) and 5-fluoro-2-methylbenzo[d]oxazole-6-amine (60 mg, 0.361 mmol, 1 equivalent) in DMF (2.0 mL), the reaction mixture was diluted with water, the solid was filtered, and washed with 1:1 MeCN / H2O. The solid was purified using silica chromatography with an elution gradient of 0-10% siRNA in cyclohexane. The fractions containing the desired substance were combined, and the solvent was removed under vacuum to obtain tert-butylcyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazole-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate. LCMS (ES+) 497 (M+H)+.

[0510] According to Method E, TFA Boc deprotection, tert-butylcyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazole-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate (26 mg, 0.0511 mmol). The reaction mixture was concentrated under vacuum, and the residue was added to a 2 g SCX cartridge and eluted with 2 column volumes of methanol, then 3 column volumes of 2 M ammonia-methanol solution. The ammonia fraction was concentrated under vacuum to obtain 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(5-fluoro-2-methyl-1,3-benzoxazole-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)pyrrolidine-1-yl]-N-(2,6-dimethylindazole-5-yl)pyrazine-2-carboxamide (enantiomer 1 + enantiomer 2)

[0512] [ka] According to Method H, from 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylic acid (140 mg, 0.403 mmol, 1 equivalent) and 2,6-dimethyl-2H-indazole-5-amine (65 mg, 0.403 mmol, 1 equivalent) in DMF (2.0 mL), the reaction mixture was diluted with water, the solid was filtered, and washed with 1:1 MeCN / H2O to obtain crude tert-butylcyclopropyl(1-(5-((2,6-dimethyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate, which was then proceeded to without further purification.

[0513] According to Method E, TFA Boc deprotection, tert-butylcyclopropyl(1-(5-((2,6-dimethyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate (36 mg, 0.0732 mmol) was used. The reaction mixture was concentrated under vacuum, and the residue was added to a 2 g SCX cartridge and eluted with 2 column volumes of methanol, followed by 3 column volumes of 2 M ammonia-methanol solution. The ammonia fraction was concentrated under vacuum, and the residue was purified by reverse-phase HPLC to obtain 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2,6-dimethylindazole-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)pyrroridine-1-yl]-N-(2,7-dimethylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide (enantiomer 1 + enantiomer 2)

[0515] [ka] According to Method H, lithium 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylate (97 mg, 0.273 mmol) was reacted with 2,7-dimethylimidazo[1,2-a]pyridine-6-amine (44 mg, 0.273 mmol) in DMF (2.0 mL). The reaction mixture was diluted with water, the solid was filtered, washed with 1:1 MeCN / H2O, and purified by reverse-phase HPLC to obtain tert-butylcyclopropyl(1-(5-((2,7-dimethylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate. LCMS (ES+) 492 (M+H)+.

[0516] According to Method E, tert-butylcyclopropyl(1-(5-((2,7-dimethylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate (9.4 mg, 0.020 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum, and the residue was added to a 2 g SCX cartridge. Elution was performed with 2 column volumes of methanol, followed by 3 column volumes of 2 M ammonia-methanol solution. The ammonia fraction was concentrated under vacuum to obtain the title compound. LC-MS (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]pyridine-6-yl)-5-(3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxamide

[0518] [ka] 1.0 g, 5.37 mmol of tert-butyl(R)-3-aminopyrrolidine-1-carboxylate and 2.29 g, 16.1 mmol of ethyl trifluoroethyl acetate were stirred in 20 mL of ethanol at 60°C for 17 hours. The reaction mixture was concentrated to dryness, and the crude tert-butyl(R)-3-(2,2,2-trifluoroacetamide)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-trifluoroacetamide)pyrrolidine-1-carboxylate (5.37 mmol) in THF (10 mL), borane·THF (21.5 mL, 1 M, 21.5 mmol) was added dropwise. After the addition, the mixture was refluxed for 17 hours. The reaction mixture was cooled to room temperature, saturated NH4Cl aqueous solution (20 mL) was added, and then the mixture was heated to 60°C for 2 hours. The mixture was concentrated, and the resulting aqueous solution was extracted with ELISA (2 × 30 mL). The organic layer was collected, dried (MgSO4), filtered, and concentrated. It was purified by flash silica column chromatography (gradient, DCM to DCM / MeOH / MeOH in 7 M NH3 [89:10:1]) to obtain 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 hours. The mixture was concentrated to dryness, and the crude (R)-N-(2,2,2-trifluoroethyl)pyrrolidine-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), (R)-N-(2,2,2-trifluoroethyl)pyrrolidine-3-amine·HCl (87 mg, 0.36 mmol) and Cs2CO3 (533 mg, 1.64 mmol) were added. The mixture was stirred at 100°C for 17 hours and then cooled to room temperature. The reaction mixture was partitioned between RINKAN (10 mL) and water (10 mL). The organic layer was separated from the aqueous layer and extracted with a further RINKAN (10 mL). The combined organic layers were washed with water (3 × 30 mL), dried, filtered, and concentrated to dryness. The title compound was obtained by preparative HPLC. LCMS (ES+) 438 (M+H)+, RT 2.64 min (Analytical method AcHSSC18); 1 ¹H 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 is obscured by a water peak.

[0522] [Example 118] N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-bipyrrolidine]-1'-yl)pyrazine-2-carboxamide and [Example 119] N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-bipyrrolidine]-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 at 50°C for 5 days. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), evaporated to dryness on silica, and purified by flash chromatography using 1% NH4OH / 10% MeOH / CH2Cl2 to obtain tert-butyl(3'R) * ,4'R * )-4'-hydroxy-[1,3'-bipyrrolidine]-1'-carboxylate was obtained and used crudely 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 mixture was quenched with saturated NaHCO3 aqueous solution and extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), evaporated to dryness, and tert-butyl (3'R) was used. * ,4'S *)-4'-fluoro-[1,3'-bipyrrolidine]-1'-carboxylate was obtained and used crudely in the next step.

[0525] tert-butyl(3'R) * ,4'S * (3'R)-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. * ,4'S * )-4'-fluoro-1,3'-bipyrrolidine·2HCl was obtained and used crudely 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 at 100°C for 6 hours. The reaction mixture was cooled to room temperature, the cesium salt was removed by filtration, and the filtrate was purified by preparative HPLC, followed by chiral preparative HPLC, to obtain the following. Example 118, cis isomer, enantiomer 1 N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-bipyrrolidine]-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]pyridine-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-bipyrrolidine]-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 analogues were prepared using the same chemical action and appropriate amines. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0528] [Table 22]

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

[0530] [ka] A mixture of tert-butyl(R)-methyl(pyrrolidine-3-yl)carbamate (400 mg, 2.0 mmol), methyl 5-chloropyrazine-2-carboxylate (350 mg, 2.0 mmol), Cs2CO3 (976 mg, 3.0 mmol), and DMF (6 mL) was heated in a sealed tube at 110°C for 17 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, and the organic layer was concentrated under vacuum to obtain methyl(R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylate.

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

[0532] According to Method F, tert-butyl(R)-(1-(5-carbamoylpyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate (308 mg, 0.96 mmol) and 5-bromo-6-fluoro-2-methyl-2H-indazole (229 mg, 1.0 mmol) were coupled. The crude product was purified by preparative HPLC to obtain tert-butyl(R)-(1-(5-((6-fluoro-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate.

[0533] According to Method E, tert-butyl(R)-(1-(5-((6-fluoro-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate (78 mg, 0.17 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum, the residue was placed in MeOH, stirred with Na2CO3 for 5 minutes, filtered, and the filtrate was purified by preparative HPLC to obtain 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]pyrazine-6-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrazine-2-carboxamide

[0535] [ka] According to Method F, tert-butyl(R)-(1-(5-carbamoylpyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate (150 mg, 0.47 mmol) and intermediate 17 (119 mg, 0.49 mmol) were coupled. The crude product was purified by preparative HPLC to obtain tert-butyl(R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate.

[0536] According to Method E, tert-butyl(R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)(methyl)carbamate (24 mg, 0.050 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum, the residue was placed in MeOH, stirred with Na2CO3 for 5 minutes, filtered, and the filtrate was purified by preparative HPLC to obtain 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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0538] [Table 23]

[0539] [Example 125] N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-(piperidine-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), 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) were added. Bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03 mmol) was added, the reaction tube was sealed, and the mixture was heated at 100°C for 22 hours. The reaction mixture was cooled to room temperature, the solvent was removed under vacuum to obtain the residue, which was purified by silica chromatography to yield tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-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]pyridine-6-yl)carbamoyl)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in ethyl acetate (15 mL) was hydrogenated for 6 hours in a recycling mode at 1 mL / min, 40°C, and 40 bar using an H-cube and a 20% Pd(OH)2 / C cartridge. Subsequently, LC-MS analysis showed nearly complete conversion. After removing the solvent under vacuum, tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)piperidine-1-carboxylate was obtained and used in the next step without further purification.

[0542] The following were prepared using general method E and the following amounts: tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-2-yl)piperidine-1-carboxylate, DCM (3 mL), and TFA (1 mL). The reaction mixture was evaporated to dryness, placed in MeOH, treated with Na2CO3, and then filtered. Purification by reverse-phase HPLC, followed by achiral SFC, yielded N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-(piperidine-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]pyridine-6-yl)-2-(piperazine-1-yl)pyrimidine-5-carboxamide

[0544] [ka] 2-Chloropyrimidine-5-carboxylic acid (159 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-amine, 2HCl (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 obtain 2-((1H-benzo[d][1,2,3]triazole-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrimidine-5-carboxamide. MS (ES+) 405 (M+H).

[0545] 2-((1H-benzo[d][1,2,3]triazole-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), Cs2CO3 (162 mg, 0.5 mmol), and DMF (4 mL) were combined in a sealed tube and hot-block heated at 100°C for 3 days. The reaction mixture was purified by preparative HPLC to obtain tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidine-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H).

[0546] 27.5 mg of tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrimidine-2-yl)piperazine-1-carboxylate, 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 placed in MeOH. Na2CO3 was added and the mixture was stirred for 5 minutes. The reaction product was then filtered, the filtrate was evaporated to dryness, and the compound was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 356 (M+H)+, RT 1.61 min (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]pyrazine-6-yl)-2-(3-(methylamino)pyrrolidine-1-yl)pyrimidine-5-carboxamide

[0548] [ka] Methyl 2-chloropyrimidine-5-carboxylate (345 mg, 2 mmol), tert-butyl(R)-methyl(pyrrolidine-3-yl)carbamate (400 mg, 2 mmol), Cs2CO3 (975 mg, 3 mmol), and DMF (10 mL) were combined in a sealed tube and hot-block heated at 100°C for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water (x4) and brine (x1), and evaporated to dryness to obtain methyl(R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-5-carboxylate. MS RT (ES+) 337 (M+H).

[0549] Methyl(R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-5-carboxylate (400 mg, 1.19 mmol), LiOH·H2O (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 obtain lithium (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-5-carboxylate, which was used crudely in the following reaction: MS (ES+) 323 (M+H).

[0550] (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-5-carboxylate lithium (200 mg, 0.62 mmol), 2,8-dimethylimidazo[1,2-a]pyrazine-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 obtain tert-butyl(R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrimidine-2-yl)pyrrolidine-3-yl)(methyl)carbamate. MS (ES+) 467 (M+H).

[0551] 49 mg of tert-butyl(R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrimidine-2-yl)pyrrolidine-3-yl)(methyl)carbamate, 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 added to MeOH. Na2CO3 was added and stirred for 5 minutes. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and the compound was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 367 (M+H)+, RT 1.73 min (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical reaction.

[0553] [Table 24]

[0554] [Example 129] (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-2-(3-(methylamino)pyrrolidine-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]pyridine-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 obtain 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrimidine-5-carboxamide, which was used crudely 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-methylpyrrolidine-3-amine (23 mg, 0.23 mmol), Cs2CO3 (325 mg, 1 mmol), and DMF (2 mL) were combined in a sealed tube and hot-block heated at 100°C for 16 hours. The reaction mixture was cooled to room temperature, the cesium salt was removed by filtration, and the reaction mixture was purified by preparative HPLC to obtain the title compound. LC-MS (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] Further analogues were prepared from commercially available or synthesized amines using the same chemical action. 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). The final product was isolated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily specified.

[0558] [Table 25] TIFF0007894498000225.tif226170

[0559] [Example 136] (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)-2-(3-(ethylamino)pyrrolidine-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]pyrazine-6-amine (324 mg, 2 mmol), dichloromethane (30 mL), and triethylamine (2 mL) were added, and the reaction mixture was stirred for 2 hours. The reaction mixture was then evaporated to dryness to obtain 2-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)pyrimidine-5-carboxamide, which was used crudely in the next step.

[0561] 2-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)pyrimidine-5-carboxamide (156 mg, 0.5 mmol), (R)-N-ethylpyrrolidine-3-amine (57 mg, 0.5 mmol), cesium carbonate (325 mg, 1 mmol), and DMF (3 mL) were combined in a sealed tube and hot-block heated at 100°C for 2 hours. The reaction mixture was then cooled to room temperature, the cesium salt was removed by filtration, and the filtrate was purified by preparative HPLC to obtain the title compound. LC-MS (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-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrimidine-5-carboxamide and [Example 138] 2-((3R,4S)-3-(ethylamino)-4-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrimidine-5-carboxamide

[0563] [ka] 2.17 g, 10.64 mmol of cis-tert-butyl-3-amino-4-fluoropyrrolidine-1-carboxylate, 40 mL of dichloromethane, 2 mL of triethylamine, and 2.55 g, 11.7 mmol of di-tert-butyl decarbonate were combined and stirred at room temperature for 18 hours. The reaction mixture was then evaporated to dryness to obtain tert-butyl (3R * ,4S * )-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate was obtained and used crudely 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 ethyl acetate, washed with water (4 ×) and brine (1 ×), evaporated to dryness, and tert-butyl (3R * ,4S * )-3-((tert-butoxycarbonyl)(ethyl)amino)-4-fluoropyrrolidine-1-carboxylate was obtained and used crudely in the next step without further purification.

[0565] tert-butyl(3R) * ,4S * (3R)-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. Then the reaction mixture was evaporated to dryness. * ,4S * )-N-ethyl-4-fluoropyrrolidine-3-amine·2HCl was obtained and used crudely in the next step without further purification.

[0566] (3R * ,4S * )-N-ethyl-4-fluoropyrrolidine-3-amine·2HCl (133 mg, 0.65 mmol), 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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 hot-block heated at 100°C for 20 hours. The reaction mixture was then cooled to room temperature, the cesium salt was removed by filtration, and the filtrate was purified by preparative HPLC, followed by chiral preparative HPLC to obtain the following. Cis isomer, enantiomer 1 2-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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] Further analogues were prepared using the same chemical reaction.

[0568] [Table 26]

[0569] Examples 140-141 Examples 140-141 were performed as follows: Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. All non-aqueous reactions were carried out under a dry nitrogen atmosphere (unless otherwise noted). Proton nuclear magnetic resonance spectra were obtained at 300 MHz with a Bruker AVANCE300 spectrometer, 500 MHz with a Bruker AVANCE500 spectrometer, or 500 MHz with a Bruker ASCEND500 spectrometer. Spectra are shown in ppm(δ) and coupling constants, and J values ​​are 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 Shimadzu 2020 UP-LCMS instrument. UPLC analyses were obtained by elution using an Acquity UPLC BEH C18 column, 1.7 μm (2.1 × 75 mm), according to solvent gradient method 1. HPLC analysis was performed using a Phenomenex C18 Kinetex column, 5 μm (4.6 × 150 mm), and elution was performed according to solvent gradient method 2. Detection was performed by UV at 254 and 215 nm. UPLC-MS data was obtained using standard methods: (a) low pH, Waters CSHC18 column (1.7 μm, 2.1 × 50 mm), column temperature 55°C, sample concentration 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 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]pyridine-6-yl)-6-(3-(methyl-amino)pyrroridine-1-yl)pyridazine-3-carboxamide

[0579] [ka] To a solution of (R)-6-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyridazine-3-carboxylic acid (0.050 g, 0.16 mmol) and 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-amine (0.026 g, 0.16 mmol) in N,N-dimethylformamide (5.0 mL), N,N-diisopropylethylamine (0.13 mL, 0.78 mmol) was added, followed by 1-[bis(dimethyl-amino)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 sodium bicarbonate aqueous solution (30 mL). The resulting suspension was extracted with ethyl acetate (3 × 30 mL), 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 obtain tert-butyl(R)-(1-(6-((8-fluoro-2-methylimido-azo[1,2-a]pyridine-6-yl)carbamoyl)pyridazin-3-yl)pyrrolidine-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]pyridine-6-yl)carbam-oil)pyridazin-3-yl)pyrrolidine-3-yl)(methyl)carbamate (0.061 g, 0.13 mmol) in dichloromethane (4.5 mL), trifluoroacetic acid (0.50 mL, 6.5 mmol) was added, and the mixture was stirred at room temperature for 90 minutes. After this time, volatile substances were removed under reduced pressure, and the resulting residue was placed in 80:18:2 dichloromethane / methanol / ammonium hydroxide and concentrated again (2 × 25 mL). The crude product was purified by chromatography (silica gel, gradient elution from dichloromethane to 80:18:2 dichloromethane / methanol / ammonium hydroxide). The obtained product was combined with another batch and ground with 90:10 heptane / dichloromethane to obtain (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-6-(3-(methylamino)pyrrolidine-1-yl)pyridazine-3-carboxamide. Melting point 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 = >99% (AUC) at 3.00 min, 254, and 215 nm.

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

[0582] [ka] Pyridine (0.031 mL, 0.39 mmol) and tert-butyl(R)-methyl(pyrrolidine-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 sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The obtained residue was purified by chromatography (gradient elution from silica gel and dichloromethane to 95:5 dichloromethane / methanol) to obtain methyl(R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-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)pyrrolidine-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, volatile substances were removed under vacuum, 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, the resulting solid was filtered, washed with water, and dried under vacuum to obtain (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)-pyrrolidine-1-yl)pyrimidine-2-carboxylic acid. The aqueous layer was extracted with 3:1 chloroform / 2-propanol (3 × 20 mL), the combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a second yield of (R)-5-(3-((tert-butoxycarbonyl)(methyl)-amino)pyrrolidine-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]triazole-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)pyrrolidine-1-yl)pyrimidine-2-carboxylic acid (0.094 g, 0.29 mmol) and 2,8-dimethylimidazo[1,2-a]pyrazine-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 formed solid was filtered, washed with water (10 mL), and dried in vacuum to obtain tert-butyl(R)-(1-(2-((2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)carbamoyl)pyrimidine-5-yl)pyrrolidine-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]pyrazine-6-yl)carbamoyl)pyrimidine-5-yl)pyrrolidine-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 under vacuum, dichloromethane (40 mL) was added, and the mixture was concentrated again to dryness. The resulting residue was dissolved in dichloromethane (40 mL) and washed with saturated sodium bicarbonate aqueous solution (50 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by chromatography (gradient elution from silica gel and dichloromethane to 85:14:1 dichloromethane / methanol / ammonium hydroxide) to obtain (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)-5-(3-(methylamino)pyrrolidine-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 under vacuum to obtain (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazine-6-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrimidine-2-carboxamide. Melting point 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]pyridine-6-yl)-5-(3-(piperidine-2-yl)azetidine-1-yl)pyrazine-2-carboxamide 2-(azetidine-3-yl)-1-benzylpiperidine

[0587] [ka] Next, benzyl bromide (0.37 mL, 3.12 mmol) was added to a solution of tert-butyl 3-(piperidine-2-yl)azetidine-1-carboxylate (500 mg, 2.08 mmol) in DCM (7 mL), followed by saturated sodium carbonate solution (7 mL). 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 phase was passed through phase separation paper and evaporated to dryness. The crude product was purified using silica chromatography and an elution gradient of 0-100% [siRNA+MeOH with 5% NH3] / cyclohexane to obtain tert-butyl 3-(1-benzylpiperidine-2-yl)azetidine-1-carboxylate.

[0588] 540 mg, 1.63 mmol of tert-butyl 3-(1-benzylpiperidine-2-yl)azetidine-1-carboxylate 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 obtain an oily substance, which was then partitioned between DCM and an aqueous sodium carbonate solution. The aqueous layer was extracted with DCM (×1), and the combined organic phase was passed through phase separation paper and evaporated to dryness to obtain 2-(azetidine-3-yl)-1-benzylpiperidine.

[0589] [ka] For 22 hours, the following amounts were added according to Method D: 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide (119 mg, 0.39 mmol), 2-(azetidine-3-yl)-1-benzylpiperidine (90 mg, 0.39 mmol), cesium carbonate (191 mg, 0.59 mmol), and DMF (2 mL). Then, an aqueous solution of LiCl (4%) was added to the reaction mixture and extracted with DCM (×2). The organic layer was then dried on phase separation paper and evaporated to dryness. The crude product was purified by silica chromatography using an elution gradient of 25-100% siRNA / cyclohexane, followed by NH3(7N) / siRNA in 0-1% MeOH. Next, the substance was purified by chiral SFC to obtain 5-(3-(1-benzylpiperidine-2-yl)azetidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide (enantiomer 1).

[0590] Enantiomer 1,5-(3-(1-benzylpiperidine-2-yl)azetidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide (34 mg, 0.068 mmol) was dissolved in MeOH (1 mL) and degassed for 20 minutes by spraying with N2 gas. Then, Pd / C (10%, 5 mg) was added, followed by 1-methyl-1,4-cyclohexadiene (76 μL, 0.68 mmol), and the resulting mixture was heated at 60°C for 3 hours. Further 1-methyl-1,4-cyclohexadiene (76 μL, 0.68 mmol) was added, and the mixture was left at 60°C overnight. Additional 1-methyl-1,4-cyclohexadiene (76 μL, 0.68 mmol) and Pd / C (10%, 5 mg) were added, and the mixture was left to stand overnight at 60°C, after which complete conversion was achieved. The mixture was filtered through Celite, washed with a large amount of MeOH, and evaporated to obtain the crude residue, which was purified by reverse-phase HPLC to obtain (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-5-(3-(piperidine-2-yl)azetidine-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)pyrrolidine-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridine-5-yl)pyrazine-2-carboxamide (enantiomer 1 + enantiomer 2) 2-Methylpyrazolo[1,5-a]pyridine-5-amine

[0592] [ka] 5-Bromo-2-methylpyrazolo[1,5-a]pyridine (120 mg, 0.569 mmol, 1 equivalent), benzophenone imine (0.095 mL, 0.569 mmol, 1 equivalent), rac-BINAP (35 mg, 0.0569 mmol, 0.1 equivalent), Pd(OAc)2 (13 mg, 0.0569 mmol, 0.1 equivalent), and cesium carbonate (278 mg, 0.853 mmol, 1.5 equivalents) were suspended in THF, and the reaction mixture was purged with N2 for 15 minutes. The tube was sealed, and the reaction mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature, diluted with water, and washed with RINKAN (×3). The combined organic layer was washed with brine, dried, and the solvent was removed under vacuum. The crude product was purified by silica chromatography using an elution gradient of 5-60% RINKAN in cyclohexane. The fractions containing the desired compound were combined, and the solvent was removed under vacuum to obtain N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-1,1-diphenylmethaneimine. LCMS (ES+) 312 (M+H)+

[0593] 185 mg (0.529 mmol, 1 equivalent) of 2-methylpyrazolo[1,5-a]pyridine-5-amine was dissolved in 2.0 mL of MeOH, and 1.3 mL (5.29 mmol, 10 equivalents) of 4 M HCl in dioxane was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and the residue was added to an SCX cartridge. Elution was performed with 2 columns of methanol, followed by 3 columns of 2 M ammonia-methanol solution. The ammonia fraction was concentrated under vacuum to obtain 2-methylpyrazolo[1,5-a]pyridine-5-amine. LCMS (ES+) 148 (M+H)+

[0594] [ka] According to Method H, from 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylic acid (188 mg, 0.530 mmol, 1 equivalent) and 2-methylpyrazolo[1,5-a]pyridine-5-amine (78 mg, 0.530 mmol, 1 equivalent) in DMF (2.0 mL), the reaction mixture was diluted with water, the solid was filtered, and washed with 1:2 MeCN / H2O to obtain tert-butylcyclopropyl(1-(5-((2-methylpyrazolo[1,5-a]pyridine-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate, which was then removed without further purification and proceeded to the next step.

[0595] According to Method E, tert-butylcyclopropyl(1-(5-((2-methylpyrazolo[1,5-a]pyridine-5-yl)carbamoyl)pyrazine-2-yl)pyrrolidine-3-yl)carbamate (71 mg, 0.149 mmol) was used. The reaction mixture was concentrated under vacuum, and the residue was added to a 2 g SCX cartridge and eluted with two columns of methanol, then three columns of 2 M ammonia-methanol solution. The ammonia fraction was concentrated under vacuum to obtain crude 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridine-5-yl)pyrazine-2-carboxamide, which was purified by HPLC to obtain 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridine-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-butyl3-(6-((2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyridazine-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]pyridine-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 hours. The crude solution containing 6-chloro-N-(2-methylimidazo[1,2-a]pyridine-6-yl)pyridazine-3-carboxamide was used without further purification.

[0598] 6-Chloro-N-(2-methylimidazo[1,2-a]pyridine-6-yl)pyridazin-3-carboxamide (1 mL of solution from the preceding 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) were stirred in DMF (1 mL) at 110°C for 1.5 hours. After cooling to room temperature, the solid was removed by filtration, and the filtrate was purified by preparative HPLC to obtain tert-butyl 3-(6-((2-methylimidazo[1,2-a]pyridine-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]pyrazine-6-yl)-2-methoxy-6-(piperazine-1-yl)nicotinamide

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

[0601] 6-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazine-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 at 100°C for 17 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to obtain the title compound. LC-MS (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]pyridine-6-yl)-2-methoxy-6-(piperazine-1-yl)nicotinamide

[0603] [ka] 6-chloro-2-methoxynicotinic acid (188 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridine-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 hours. The reaction mixture was diluted with Â, washed with water (2 ×), and evaporated to dryness to obtain 6-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)-2-methoxynicotinamide, which was used crudely in the next step.

[0604] The crude product from the preceding step, piperazine (86 mg, 1 mmol), triethylamine (1 mL), and dioxane (10 mL) were combined in a sealed tube and heated at 100°C for 17 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to obtain the title compound. LC-MS (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]pyridine-6-yl)-6-(4-methylpiperazine-1-yl)nicotinamide

[0606] [ka] 6-(4-methylpiperazin-1-yl)pyridine-3-carboxylic acid (50 mg, 0.23 mmol), 2-methylimidazo[1,2-a]pyridine-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 obtain the title compound. LC-MS (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]pyridine-6-yl)pyrazine-2-carboxamide, (S)-5-(3-((cyclopropylamino)methyl)pyrrolinidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide

[0608] [ka] N-(pyrrolidine-3-ylmethyl)cyclopropanamine 2HCl (488 mg, 2.29 mmol), 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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 at 100°C for 4 hours. The cesium salt was then filtered off, and the filtrate was purified by preparative HPLC, followed by chiral preparative HPLC, to obtain the following: Example 148 Enantiomer 1 5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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 analogues were prepared from commercially available or synthesized amines using the same chemical reaction. The final products were isolated by preparative HPLC.

[0610] [Table 31]

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

[0612] [ka] 5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)pyrazine-2-carboxamide was reacted with formaldehyde (37 wt% in H2O, 10-15% methanol, 1.5 mL) and sodium triacetoxyborohydride (168 mg, 0.794 mmol), and the mixture was stirred at room temperature for 18 hours. The mixture was then partitioned between DCM and an aqueous sodium bicarbonate solution. The aqueous phase was then re-extracted with DCM (×1), and the combined organic phase was passed through phase separation paper and evaporated to dryness to obtain the crude residue. The crude product was purified using silica chromatography and an elution gradient of NH3(7N) / siRNA in 0-4% MeOH. The substance was then purified by chiral SFC, followed by HPLC chromatography, to obtain the following: Example 151 Enantiomer 1 5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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] Further analogues were prepared using the same chemical action and either commercially available or specified amines as described in the intermediates section. When a Boc-protected amine was used, its Boc group was later removed with TFA or HCl using standard method C or C.

[0614] [Table 32] TIFF0007894498000247.tif254170TIFF0007894498000248.tif251170TIFF0007894498000249.tif251170TIFF0007894498000250.tif251170 TIFF0007894498000251.tif251170TIFF0007894498000252.tif252170TIFF0007894498000253.tif214170TIFF0007894498000254.tif220170

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

[0616] [ka] (R)-5-(3-(1-aminocyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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 borocyanohydride (11 mg, 0.18 mmol) was added. Acetic acid (20 μL) was added, and the reaction mixture was heated overnight at 50°C. The reaction mixture was cooled to room temperature, the solvent was removed under vacuum to obtain the residue, which was purified by preparative HPLC to obtain (R)-5-(3-(1-(cyclopropylamino)cyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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]pyridine-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]pyridine-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 mixture was cooled to room temperature, filtered, and purified by achiral reverse-phase HPLC (Xbridge Phenyl 19×150mm, 10μm 40~100% MeOH / H2O (10mM NH4CO3), 20mL / min, room temperature) to obtain N-(8-fluoro-2-methylimidazo[1,2-a]pyridine-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]pyridine-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]pyridine-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 mixture was cooled to room temperature, filtered, and the solid was washed with phenylethylamine. The combined filtrate was concentrated under reduced pressure to obtain the crude substance, which was then carried out without further purification, assuming a quantitative yield. MS (ES+) 496.3 [M+H] + .

[0621] To a solution of tert-butyl 2-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridine-6-yl)carbamoyl)pyrazine-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 mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The crude substance was purified by reverse-phase HPLC (Xbridge Phenyl 19×150 mm, 10 μm 20-80% MeOH / H2O (10 mM NH4...

Claims

1. Compounds of formula Ia 【Chemistry 1】 or its isotope-enriched analog, pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers (in the formula, Y 1 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 is optionally substituted on available nitrogen atoms by C 1～6 alkyl or C 1～6 haloalkyl, Y 2 CR 6 or N, R 6 C 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 the available nitrogen atoms, C 1～6 Alkyl or C 1～6 It may be substituted with a haloalkyl group. R 3 C 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 C is available on nitrogen atoms. 1～6 Alkyl or C 1～6 It may be substituted with a haloalkyl group. Each R 17 C is independent 1～4 Alkyl, or two R 17 However, it can link with any intervening atom to form a 3- to 6-membered heterocycline. Z 1 and Z 2 Each of them is C, Rings A and B together form a 9-membered bicyclic heteroaryl compound containing 1 to 3 ring nitrogen atoms. Ring B is 【Chemistry 2】 And, R 8 is C 1～6 It is alkyl, R 1 ha-L 1 -R 11 And here, 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 not present, R 11 1 to 4 R 13 It is a heterocyclyl which is substituted by a group depending on the case. R 12 is hydrogen or C 1～6 It is alkyl, Each R 13 is independently halo, cyano, hydroxy, R 16 -substituted C 1～6 alkyl, C 1～6 haloalkyl, C 16 hydroxyalkyl, R 16 -substituted C 3～10 cycloalkyl, R 16 -substituted C 3～10 cycloalkyl-C<000007]1>alkyl, R 16 -substituted C 6～10 aryl, R 16 -substituted C 6～10 aryl-C 1～6 alkyl, R 16 -substituted heteroaryl, R / 16 -substituted heteroaryl-C 1～6 alkyl, R 16 -substituted heterocyclyl, R 16 -substituted heterocyclyl-C 1～6 alkyl, OR 14 , -NH 2 , -NHR 14 , -N(R 14 )<00()0087>, -C 1～6 alkylene-NH 2 , -C 1～6 alkylene-NHR 14 , -C 1～6 alkylene-N(R 14 )<00()0094>, -C(O)R<000009)5>, -C(O)OR 15 , -C(O)NHR<0000()97>, -C(O)N(C 1～4 alkyl)R 15 [[ID= / 6]] 2 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 Selected from, Each R 14 C is independent 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 Selected from 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 It is sometimes replaced by, Each R 15 These are independently hydrogen, -OH, and C 1～6 Alkyl, C 1～6 Haloalkyl, C 3～10 Cycloalkyl, C 6～10 It is an aryl, heteroaryl, or heterocyclyl. Each R 16 These are independently halo, cyano, hydroxy, and -NH 2 , -NHR 21 , -N(R 21 ) 2 , C 1～6 Alkyl, C 1～6 Haloalkyl, OR 21 or C 3～10 It is a cycloalkyl, Each R 21 C 1～6 Alkyl, C 3～10 Cycloalkyl, C 6～10 Selected from aryl, heteroaryl and heterocyclyl, each R 21 1 to 6 halos or C 1～3 It is sometimes substituted with alkoxy, R 2 is hydrogen or C 1～6 (It is alkyl.)

2. R 11 Hello, 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 Alkilen-NHR 14 , -C 1～6 Alkylene-N(R) 14 ) 2 and -C(O)OR 15 A heterocycline in which 1 to 4 groups are optionally substituted, independently selected from R, where each R 14 C 1～6 Alkyl, C 3～10 Selected from cycloalkyl and heterocyclyl, each R 14 R is sometimes replaced by 1 to 3 halos, where R 15 C 1～6 The compound according to claim 1, wherein it is alkyl.

3. R 11 but 【Transformation 3】 And ring C has 1 to 4 R 13 The compound according to claim 1, which is a 3- to 10-membered heterocycline containing 0, 1, or 2 additional ring nitrogen atoms, which are optionally substituted by a group.

4. Ring C has 1 to 4 R 13 The compound according to claim 3, which is a 5- to 10-membered bicyclic heterocycline containing one additional ring nitrogen atom, which is optionally substituted by a group.

5. Ring C has 1 to 4 R 13 The compound according to claim 3, which is a 5- to 10-membered spirodicyclic heterocycline containing one additional ring nitrogen atom, which is optionally substituted by a group.

6. Ring C has 1 to 4 R 13 The compound according to claim 3, which is a 5- to 10-membered condensed bicyclic heterocycline containing one additional ring nitrogen atom, which is optionally substituted by a group.

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

8. R 11 Fluoromethyl, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropane-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, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl The compound according to claim 1, optionally substituted with 1 to 4 groups independently selected from ropyl-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.

9. R 3 A compound according to any one of claims 1 to 8, wherein the compound is a halo.

10. R 3 A compound according to any one of claims 1 to 9, wherein is fluoro.

11. R 3 The compound according to any one of claims 1 to 8, wherein is methyl.

12. R 3 The compound according to any one of claims 1 to 8, wherein is methoxy.

13. R 5 The compound according to any one of claims 1 to 12, wherein is hydrogen.

14. R 5 C 1～6 A compound according to any one of claims 1 to 12, wherein the compound is an alkoxy.

15. R 5 The compound according to any one of claims 1 to 12, wherein is methoxy.

16. R 8 The compound according to any one of claims 1 to 15, wherein is methyl.

17. L 1 A compound according to any one of claims 1 to 16, wherein the compound is not present.

18. Y 1 CR 5 The compound according to any one of claims 1 to 17.

19. Y 1 A compound according to any one of claims 1 to 17, wherein is N.

20. Y 2 CR 6 The compound according to any one of claims 1 to 19.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, or an isotopic enriched analog thereof, a pharmaceutically acceptable salt, a tautomer, a stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable excipient.

22. An agent for treating Huntington's disease, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 20 or the pharmaceutical composition described in claim 21.

23. An agent for treating Huntington's disease, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to claim 21, in combination with a second activator.

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