Htt modulators for the treatment of huntington's disease

Abstract

This article provides specific compounds that can be used as HTT modulators. These compounds may be used to treat Huntington's disease.

Description

[0001] Cross-referencing of related patent applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 024,052, filed May 13, 2020, pursuant to 35 U.S. SC §119(e), which is hereby incorporated by reference in its entirety. Technical Field

[0003] This disclosure relates to methods for preventing and / or treating neurodegenerative diseases or conditions. Background Technology

[0004] Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric deficits, as well as neurodegeneration and brain atrophy that begins in the striatum and cerebral cortex and extends to other subcortical brain regions. With a global prevalence of 5–10 cases per 100,000 people, HD is the most common inherited monogenic neurodegenerative disease.

[0005] Neurodegenerative diseases and conditions such as Huntington's disease have a profound negative impact on the lives of those affected. Current treatment for Huntington's disease is palliative, aiming to reduce the severity of symptoms. There are currently no available treatments to alleviate the disease.

[0006] Huntington's disease is caused by an extension of the CAG repeat domain in exon 1 of the huntingtin protein (HTT) gene, expressed as a mutant huntingtin protein (mHTT) containing extended polyglutamine bundles in the N-terminal domain of the protein. Even though HD is a single-gene and autosomal dominant disease, the molecular pathways underlying its pathogenesis remain incompletely understood. Therefore, reducing mHTT is a well-defined therapeutic strategy targeting the gene product of the pathogenic gene. In fact, several therapeutic strategies targeting mHTT reduction via antisense oligonucleotide (ASO) or AAV-miR-mediated HTT RNA degradation are being advanced in clinical trials for HD, and reductions in mHTT levels in the CSF of treated patients have been demonstrated.

[0007] While these methods show great promise, they are invasive (involving repeated intrathecal injections); their distribution throughout the brain to all affected areas is uncertain; and they do not address any peripheral functional impairments that may result from the widespread distribution of mHTT. Therefore, small molecule HTT-lowering agents that can be delivered systematically and non-invasively would be the attractive HTT-lowering therapy in pursuit. Consequently, there is a need for small molecule modulators of the HTT protein. Such molecules could be used to treat the symptoms of Huntington's disease and / or delay its progression. Summary of the Invention

[0008] The present invention discloses generally small molecule modulators of HTT and their use as therapeutic agents in, for example, the treatment of diseases such as Huntington's disease.

[0009] Therefore, this article provides compounds that can be used to treat Huntington's disease, or isotopically enriched analogs of said compounds, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers.

[0010] In some embodiments, compounds are provided that regulate proteins or protein fragments (such as HTT protein) associated with neurodegenerative diseases.

[0011] In some embodiments, a pharmaceutical composition is provided comprising the compound described herein or an isotopically enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers, and a pharmaceutically acceptable excipient.

[0012] This disclosure also provides compositions including pharmaceutical compositions, kits containing said compounds, and methods for using (or administering) and preparing said compounds. This disclosure further provides methods for using compounds or compositions thereof to treat diseases or conditions at least partially mediated by proteins or protein fragments associated with neurodegenerative diseases. Furthermore, this disclosure provides the use of said compounds or compositions thereof in the manufacture of medicaments for treating diseases or conditions at least partially mediated by proteins or protein fragments associated with neurodegenerative diseases. Detailed Implementation

[0013] The following description illustrates exemplary embodiments of the invention. However, it should be understood that such description is not intended to be a limitation on the scope of this disclosure, but rather is provided as a description of exemplary embodiments.

[0014] definition

[0015] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings stated below, unless the context in which they are used indicates otherwise.

[0016] The compounds described herein refer to any compound of any formula described herein or its isotopically labeled analogues, pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, or mixtures of stereoisomers. Any compound of any formula described herein includes those of formula I, Ia, Ib, Ic, IIa, IIb, IIc, IId, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, or any compound described anywhere herein (including examples) or the compounds in Table 1 or Table 1A.

[0017] A dash ("-") not located between two letters or symbols is used to indicate the attachment point of a substituent to the parent structure. For example, -C(O)NH2 is attached to the parent structure via a carbon atom. Dashes at the beginning or end of chemical groups are for convenience; chemical groups may or may not be depicted with one or more dashes without losing their general meaning. Wavy or dashed lines drawn across bonds in the structure indicate designated attachment points. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0018] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms, excluding other substitutions. For example, "C 1-6 "alkyl" indicates an alkyl group having 1 to 6 carbon atoms.

[0019] References to the value or parameter “about” herein include (and describe) embodiments relating to that value or parameter itself. In some embodiments, the term “about” includes an indicated amount ±10%. In other embodiments, the term “about” includes an indicated amount ±5%. In some other embodiments, the term “about” includes an indicated amount ±1%. Furthermore, references to the term “about X” include a description of “X”. Additionally, the singular forms “an” and “the” include plural references unless the context clearly specifies otherwise. Thus, for example, references to “the compound” include a plurality of such compounds, and references to “the assay” include references to one or more assays known to those skilled in the art and their equivalents.

[0020] "alkyl" refers to an unbranched saturated hydrocarbon chain or a branched saturated hydrocarbon chain. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 9 carbon atoms (i.e., C1646) 1-9 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl 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 named by its chemical name or identified by its 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).

[0021] Alternative chemical names known to those skilled in the art may be used instead of the terms provided herein. For example, divalent groups such as divalent "alkyl" groups or divalent "aryl" groups may also be referred to as "alkylene" or "arylene" groups, respectively. Furthermore, unless otherwise expressly stated, combinations of groups are referred to herein as a portion, such as arylalkyl or aralkyl, where the group mentioned below contains an atom through which the portion is attached to the remainder of the molecule.

[0022] "Alkenyl" refers to an alkyl group that contains at least one carbon-carbon double bond and has 2 to 20 carbon atoms (i.e., C64 ... 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 groups include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl) and isoprenyl.

[0023] "Alkynyl" refers to an alkyl group that contains at least one carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C36, C46, ​​C56, C6 ... 2-20 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, 2-8 acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C46) 2-4 (Alkyne group). The term "alkynyl group" also includes those groups that have one triple bond and one double bond.

[0024] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0025] "alkylamino" refers to the group "alkyl-NH-". Examples of alkylamino groups include, for example, methylamino, ethylamino, isopropylamino, tert-butylamino, and n-hexylamino. "Dialkylamino" refers to the group "(alkyl)2N-". Examples of dialkylamino groups include, for example, dimethylamino, diethylamino, (isopropyl)(methyl)amino, (n-pentyl)(tert-butyl)amino, and din-hexylamino.

[0026] "alkylthio" refers to the group "alkyl-S-". "alkylsulfinyl" refers to the group "alkyl-S(O)-". "alkylsulfonyl" refers to "alkyl-S(O)2-".

[0027] "Acyl" refers to the group -C(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl groups include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0028] "Amide group" refers to the "C-amide group" (which refers to the group -C(O)NR). y R z ) and "N-amide" group (which refers to the -NR group) y C(O)R z ), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted, or R y and R z Together they form cycloalkyl or heterocyclic groups; each of which may optionally be substituted, as defined herein.

[0029] "Amino" refers to the -NR group. y R z , where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. In some embodiments, "amino" refers to the NH2 group.

[0030] "Amino group" refers to the group -C(NRy)(NRz2), where R y Rz is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0031] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 carbon atoms). 6-20 aryl group or 6 to 10 carbon ring atoms (i.e., C46) 6-10 Aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracene. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic.

[0032] "Arylalkyl" or "arylalkyl" refers to the group "aryl-alkyl-".

[0033] "Carbamoyl" refers to the "O-carbamoyl" group (which refers to the group -OC(O)NR). y R z ) and the "N-carbamoyl" group (which refers to the -NR group) y C(O)OR z ), where R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0034] "Carboxylic ester" or "ester" refers to -OC(O)R x and -C(O)OR x Of the two, R x It is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0035] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp... 3 A carbocyclic fused-ring system with cyclic carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyl groups have 3 to 20 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups), or 3 to 6 cyclic carbon atoms (i.e., C164-C ... 3-6Cycloalkyl. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenylcycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Furthermore, the term cycloalkyl is intended to cover any non-aromatic ring system that may include a fused aryl ring, regardless of its attachment to the rest of the molecule. Additionally, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl. A cycloalkyl group as a substituent may include spirocycloalkyl when there are two substitution positions on a carbon atom in the parent structure. Cycloalkyl groups may be substituted at the carbon atom to which they are attached to the parent structure.

[0036] "Cycloalkoxy" refers to the "-O-cycloalkyl" group.

[0037] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”.

[0038] "Guidinyl" refers to -NR y C(=NR z (NR) y R z ), where each R y and R z Independently, it is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0039] "Imine" refers to the group -C(NR) y )R z , where R y and R z Each of these elements is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0040] "Imidin group" refers to the group -C(O)NR y C(O)R z , where R y and R z Each of these elements is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0041] "Halogen" or "halogen group" refers to a substituent atom in Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0042] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms (up to and including all hydrogen atoms) are replaced by a halogen. For example, when a residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. A perhaloalkyl group is a haloalkyl group in which each hydrogen substituent is replaced by a halogen. Examples of haloalkyl groups include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0043] "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 and including all hydrogen atoms) are replaced by halogens.

[0044] "Hydroxyalkyl" refers to an alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by hydroxyl groups.

[0045] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) of the alkyl chain are each independently replaced by the same or different heteroatom groups, provided that the attachment point to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched saturated chains or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, -S(O)2-, etc., where Ry is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be 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, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2OCH3, etc.), and aminoalkyl groups (-CH2NR). y CH3、-CH(CH3)NR y CH3、-CH2CH2NR yCH3、-CH2CH2NR y CH2CH2NR y CH3, etc., of which R y It is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. As used herein, 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.

[0046] "Heteroaryl" refers to an aromatic group having a monocyclic or multiple fused rings and containing one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, and may contain one or more (e.g., 1 to 3) N-oxides (-O... - The heteroaryl group, as used herein, comprises 1 to 20 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8The heteroaryl group comprises 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. In some cases, the heteroaryl group comprises a 5-10 membered ring system, a 5-7 membered ring system, or a 5-6 membered ring system, each independently having 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomum, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinel, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthuronyl, benzooxazolyl, benzothienyl (benzothienyl), benzotriazolyl, imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothienyl, furanyl, isothiazolyl, imidazole The fused heteroaryl group includes, but is not limited to, benzo[d]thiazolyl, indolyl, indolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphridinyl, oxadiazolyl, oxazolyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purine, pyrroloyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]phenylthio, indolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group can be linked via any ring of the fused system. Any aromatic ring system having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its attachment to the rest of the molecule (i.e., through any one of the fused rings). A heteroaryl does not encompass aryl groups as defined above or overlap with aryl groups as defined above.

[0047] "Heteroarylenealkyl" refers to the group "heteroarylene-alkyl-".

[0048] "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group containing one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur atom is optionally oxidized to form an N-oxide, a sulfinyl (-S(O)-), or a sulfoxide (-S(O)2-). The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one inner ring or exocyclic double bond), bridged heterocyclic groups, fused heterocyclic groups, oxoheterocyclic groups (i.e., heterocyclic groups containing at least one oxo group), and spiro-heterocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, wherein the polycyclic group can be fused, bridged, or spirocyclic. Regardless of the listed substituents, heterocyclic groups can contain one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) groups. - Unless otherwise stated, heterocyclic groups can be bonded by carbon atoms or heteroatoms, where valence permits. Furthermore, the term heterocyclic group encompasses any ring system, including a non-aromatic ring containing at least one heteroatom, which may be fused to an aryl ring or a heteroaryl ring, regardless of its attachment to the rest of the molecule. Heterocyclic groups may have an aromatic charged resonance structure (e.g., pyridin-2(1H)-keto-1-yl). As used herein, heterocyclic groups may comprise 3 to 14 ring atoms, 3 to 10 ring atoms, 3 to 6 ring atoms, or 5 to 6 ring atoms and / or 2 to 12 ring carbon atoms (i.e., C14 to C24). 2-12 Heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclic groups), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6Heterocyclic groups; having 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom. Examples of heterocyclic groups include, for example, azirrocyclobutyl, azirrocyclopentenyl, benzo[b][1,4]dioxacycloheptatrienyl, 1,4-benzodioxyl, benzopyranyl, benzodioxinyl, benzopyranoneyl, benzofuranoneyl, dioxyl, dihydropyranyl, hydrogenpyranyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, furanoneyl, imidazolinyl, imidazoalkyl, dihydroindolyl, indolazinyl, isodihydroindolyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- Oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolylalkyl, ethylene oxide, oxacyclobutyl, phenothiazinyl, phenothiazinyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazolyl, tetrahydrofuranyl, tetrahydropyranyl, trithiaalkyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic rings include, for example, bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of bridging heterocyclic rings include, but are not limited to, 2,5-diazabicyclo[2.2.1]heptane and 2-oxa-5-azabicyclo[2.2.1]heptyl. When there are two substitution positions on a carbon atom in the parent structure, the heterocyclic group as a substituent can include a spiroheterocyclic group. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, dihydroindolyl, and isoyindolyl, wherein the heterocyclic group can be bonded via either ring of the fused system.

[0049] "Heterocyclic alkyl" refers to the group "heterocyclic-alkyl-".

[0050] "Oxime" refers to the group -CR y (=NOH), where R y It is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

[0051] "Sulfonyl" refers to the group -S(O)2R y , where R yIt is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of sulfonyl groups are methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl.

[0052] "Sulinate group" refers to the group -S(O)R y , where R y It is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, phenylsulfinyl, and toluenesulfonyl.

[0053] "Sulfanamide group" refers to the group -SO2NR. y R z and -NR y SO2R z , where R y and R z Each of these elements is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may optionally be substituted as defined herein.

[0054] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. Furthermore, the term "optionally substituted" refers to unsubstituted or substituted groups.

[0055] As used herein, the term "substituted" refers to a group in which any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a non-hydrogen group, said non-hydrogen group being, for example but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidyl, aryl, arylalkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkoxy, cycloalkylalkyl, guanidinyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, -NHNH2, =NNH2, imino, imide, hydroxyl, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thio, N-oxide, or -Si(R y )3, where each R y It is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

[0056] In some embodiments, "substituted" refers to a group in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by the following groups: deuterium, halogen, cyano, hydroxyl, imino, nitro, azide, oxo, thio, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkyl, haloalkyl, cycloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NR g R h -NR g C(=O)R h -NR g C(=O)NR g R h -NR g C(=O)OR h -NR g S(=O) 1-2 R h -C(=O)R g -C(=O)OR g -OC(=O)OR g -OC(=O)R g -C(=O)NR g R h -OC(=O)NR g R h -OR g -SR g -S(=O)R g -S(=O)2R g -OS (=O) 1-2 R g -S (=O) 1-2 OR g -NR g S(=O) 1-2 NR g R h =NSO2R g =NOR g -S (=O) 1-2 NR g R h -SF5 or -SCF3. In some embodiments, "substituted" also means a group in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g 、or -CH2SO2NR g Rh Alternative. In the above text, R g and R h It is the same or different and independently is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, heterocyclic alkyl, heteroaryl and / or heteroarylalkyl, or R g and R h and R i The two atoms in the ring, together with the atoms to which they are attached, form a heterocyclic ring optionally substituted with an oxo group or a halogen group, or an alkyl group optionally substituted with an oxo group, a halogen group, an amino group, a hydroxyl group, or an alkoxy group.

[0057] Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., substituted aryl groups with substituted alkyl groups, said substituted alkyl groups being themselves substituted by substituted aryl groups, said substituted aryl groups being further substituted by substituted heteroalkyl groups, etc.) are not intended to be generated by the above definition. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of an aryl group substituted by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition is not intended to cover compounds having chemically infeasible or inseparable substitution patterns (e.g., methyl groups substituted by five fluorine atoms or heteroaryl groups having three consecutive oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein.

[0058] In some implementations, as used herein, the phrase "one or more" refers to 1 to 5. In some implementations, as used herein, the phrase "one or more" refers to 1 to 3.

[0059] Any compound or structure described herein is intended to represent the unlabeled form of the compound and "isotopically enriched analogues". The isotopically enriched form of the compound may also be referred to as "labeled". Isotopically enriched analogues have the structures described herein, except that one or more atoms are enriched in the form of 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, such as... 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. Typically, isotopically enriched analogs include compounds with any isotopic enrichment exceeding the natural abundance of the isotope (e.g., on the Earth's surface). This disclosure includes various isotopically labeled compounds, such as those doped with radioactive isotopes like... 3 H, 18 F, 11 C 13 C and 14 Those in C. (Use) 18 F, 3 H or 11 C-labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or basal tissue distribution assays), or in the treatment of patients with radiotherapy.

[0060] The term “isotope-enriched analogues” includes “deuterated analogues” of the compounds described herein, wherein one or more hydrogen atoms are replaced by deuterium (as in the case of hydrogen atoms on carbon atoms). These compounds can exhibit increased metabolic resistance and, therefore, can be used to increase 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.

[0061] The deuterium-labeled or substituted therapeutic compounds of this disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties involving distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, and / or improved therapeutic index. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by substituting a non-isotope-labeled reagent with an readily available isotope-labeled reagent, by performing the procedures disclosed in the scheme or in the examples and preparations described below. When a compound is described as a deuterated analog, the compound can be plotted with deuterium as a substituent.

[0062] The concentration of such heavier isotopes (especially deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, said position is understood to have hydrogen and its isotopes in their natural abundance.

[0063] In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0064] Also provided are isotopically enriched analogs, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, and mixtures of stereoisomers of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0065] The term "pharmaceutically acceptable salt" for compounds described herein refers to a salt that retains the biological efficacy and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" for compounds described herein includes, for example, acid addition salts obtained by interacting a compound having a basic functional group with an acid, and base addition salts obtained by interacting a compound having an acidic functional group with a base. If the compound is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the compound is a free base (e.g., of an amine), the addition salt can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize the various synthetic methods that can 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, phosphoric acid, etc. 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. For example, salts derived from inorganic bases include sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), and substituted... Alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), cyclic amines (e.g., piperidine, piperazine, 1,4-diazabicyclo[2.2.2]octane), aromatic amines (e.g., pyridine, quinoline), or mixed amines, etc. Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0066] Some of the compounds described herein can exist as tautomers. For example, when a compound is drawn as containing an amide, it can exist as an imine tautomer, and when a compound is drawn as containing a ketone, it can also exist as an enol tautomer. Regardless of which tautomer is shown, and regardless of the equilibrium properties between the tautomers, those skilled in the art will understand that the compound comprises both tautomers. Thus, for example, the amide-containing compound is understood to include its imine tautomer, and the imine-containing compound is understood to include its amide tautomer.

[0067] The compounds described herein may include asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers. In absolute stereochemistry, for amino acids, these enantiomers, diastereomers, and other stereoisomers may be defined as (R)- or (S)-, or as (D)- or (L)-. The compounds described herein are intended to include all these possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Where the compounds described herein contain double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both cis and trans geometric isomers or both E and Z geometric isomers.

[0068] "Stereoisomer" refers to one of a series of compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures. Various stereoisomers and mixtures thereof, including "enantiomers," are considered, where enantiomers are stereoisomeric compounds that are mirror images of each other and cannot be superimposed.

[0069] A “diastereomer” is one of a series of stereoisomers having at least two asymmetric atoms that are not mirror images of each other.

[0070] A “prodrug” is any molecule that, when administered to a mammalian subject, releases in vivo the presumed active parent drug of the compound described herein. A prodrug can be in the form of a compound described herein modified in such a way that the modification can be cleaved in vivo to release the parent compound. A prodrug can be prepared by modifying functional groups present in the compound described herein such that the modification is cleaved into the parent compound in conventional operation or in vivo. Prodrugs include compounds described herein in which the hydroxyl, amino, carboxyl, or thiol groups of the compound described herein are bonded to any group, and the prodrug can be cleaved in vivo to regenerate free hydroxyl, amino, or thiol groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetates, formates, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc., of the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in the following literature: T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Volume 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 these references is incorporated in its entirety by citation.

[0071] As used herein, the terms “group,” “part,” “free radical,” “substituent,” and “fragment” are synonymous and are intended to refer to a molecular part that can be attached to other parts of the molecule, for example, by indicated attachment points or bonds.

[0072] The term "active agent" is used to refer to a compound that has biological activity in treating, improving, or preventing a disease or condition. In some embodiments, an "active agent" is a compound with pharmaceutical efficacy or its isotopically labeled analogue, a pharmaceutically acceptable salt, a solvate, a prodrug, a stereoisomer, or a mixture of stereoisomers. For example, an active agent can be an anti-neurodegenerative therapeutic agent.

[0073] The term "effective amount" means, for example, an amount of a compound described herein that is sufficient to produce the desired response in an individual or patient. The term "therapeutic effective amount" means an amount that, when administered to a human or non-human patient, effectively provides a therapeutic benefit (such as improvement of symptoms, slowing disease progression, or prevention of disease, for example), such as an amount sufficient to alleviate the symptoms of the disease described herein. Therapeutic effective amounts can 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 method of administration, which can be determined by those skilled in the art.

[0074] As used herein, the term "huntington protein" or "HTT protein" refers to the protein encoded by the human huntington protein gene (HTT gene), located at position 16.3 on the short (p) arm of chromosome 4. More precisely, the HTT protein is encoded by the IT gene. 15 The gene is located on chromosome 4 from base pair 3,076,407 to base pair 3,245,686.

[0075] As used herein, the term "protein aggregate" refers to an aggregate of proteins, which can be, for example, an insoluble fibrinomyoid protein containing misfolded HTT protein molecules ("HTT protein aggregates") or misfolded β-amyloid protein molecules ("β-amyloid aggregates"). "Proteins involved in neurodegenerative diseases" can be proteins capable of forming such aggregates in their wild-type or mutant forms, or proteins involved in pathological processes associated with neurodegenerative diseases.

[0076] In some implementations, the term "neurodegenerative disease" refers to a disease or condition in which the function of the subject's nervous system is impaired. Examples of neurodegenerative diseases include those described herein.

[0077] "Treatment" (or "treating") refers to any treatment of a patient's disease condition, including...

[0078] a) Suppress the disease (e.g., reduce one or more symptoms caused by the disease or condition and / or reduce the severity of the disease or condition);

[0079] b) Slowing down or preventing the development of clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., migration) of the disease or condition); and / or

[0080] c) Alleviating the disease, i.e. causing the disappearance of clinical symptoms (e.g., improving the disease state, providing partial or complete relief of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving quality of life and / or prolonging survival).

[0081] "Prevention" or "preventing" means any treatment that prevents the development of clinical symptoms of a disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of developing the disease or condition (e.g., carrying a genetic or epigenetic marker, engaging in an activity, or being exposed to environmental conditions associated with the disease or condition) or who have a family history of the disease or condition.

[0082] "Subject" or "patient" refers to an animal, such as a mammal, that has been or will be a subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and veterinary applications. In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a human.

[0083] The methods described herein can be applied in vivo or in vitro cell populations. “In vivo” means within a living individual, such as in an animal or human. In this context, the methods described herein can be used therapeutically in an individual. “In vitro” means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples (including fluid or tissue samples obtained from an individual). Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal schedule and / or dosage of the compounds of this disclosure for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in clinical settings to establish in vivo treatment regimens. Other in vitro uses of the compounds and compositions described herein are described below or will become apparent to those skilled in the art. Selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods well known to those skilled in the art.

[0084] It should also be understood that certain features described herein in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, multiple features described herein in the context of a single embodiment may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables included in Formula I are specifically included herein, to the extent that such combinations result in stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity) as if each combination were individually and explicitly listed. Furthermore, all sub-combinations of chemical groups listed in embodiments describing such variables, as well as all sub-combinations of uses and medical indications described herein, are also specifically included herein, as if each sub-combination of chemical groups and sub-combinations of uses and medical indications were individually and explicitly listed. In addition, some embodiments include each combination of one or more additional pharmaceutical agents disclosed herein, as if each combination were individually and explicitly listed.

[0085] List of abbreviations and acronyms

[0086]

[0087]

[0088] compound

[0089] This document provides compounds for regulating HTT. In some embodiments, a compound of formula I is provided:

[0090]

[0091] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein:

[0092] X 1 X 2 X 3 and X 4 It is CR 4 Or N, where X 1 X 2 X 3 and X 4 At least two but no more than three of them are N;

[0093] Each R 4 Independently, it is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0094] Y 1It is CR 5 Or N;

[0095] R 5 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, C 1-6 Haloalkoxy, heterocyclic, -NH2, -NHR 17 or -N(R) 17 )2, and optionally on the available nitrogen atom 1-6 alkyl or 1-6 Halogenated alkyl substitution;

[0096] Y 2 It doesn't exist; it's CR. 6 Or N;

[0097] R 6 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, C 1-6 Haloalkoxy, heterocyclic, -NH2, -NHR 17 or -N(R) 17 )2, and optionally C on the available nitrogen atom. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution; and

[0098] Y 3 It is CR 3 Or N;

[0099] R 3 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, C 1-6 Haloalkoxy, heterocyclic, -NH2, -NHR 17 or -N(R) 17 )2, and optionally on the available nitrogen atom 1-6 alkyl or 1-6 Halogenated alkyl substitution;

[0100] Each R 17 C is independent 1-4 Alkyl, or two R 17 It can be linked with any intermediate atom to form a 3- to 6-membered heterocyclic group;

[0101] Z1 and Z 2 Each of them is either C or N;

[0102] Ring A and ring B together form a 9-membered or 10-membered bicyclic heteroaryl group containing 1 to 3 cyclic nitrogen atoms;

[0103] Ring B contains 1 to 3 heteroatoms selected from N, O, and S, and optionally has 1 to 3 heteroatoms independently selected from halogen, hydroxyl, C on one or more available carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Substitution of haloalkoxy groups, and optionally, carbon atom substitution at a available nitrogen atom. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0104] R 1 Yes -L 1 -R 11 L 1 It is -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, and R 11 It is C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl or heterocyclic, wherein R 11 Optionally by 1 to 4 R 13 Group substitution;

[0105] R 12 Is it hydrogen or C? 1-6 alkyl;

[0106] Each R 13 Independently selected from halogen, cyano, hydroxyl groups, optionally surrounded by R 16 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally R 16 Replacement C 3-10 cycloalkyl, optionally R 16 Replacement C 3-10 cycloalkyl-C 1-6 Alkyl, optionally R 16 Replacement C 6-10 Aryl, optional R 16 Replacement C 6-10Aryl-C 1-6 Alkyl, optionally R 16 Substituted heteroaryl groups, optionally R 16 Substituted heteroaryl-C 1-6 Alkyl, optionally R 16 Substituted heterocyclic groups, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, OR 14 -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2、-C(O)R 15 -C(O)OR 15 -C(O)NHR 15 -C(O)N(C 1-4 Alkyl)R 15 -S(O)2R 15 -S(O)R 15 -NHC(O)R 15 -N(C 1-4 Alkyl)C(O)R 15 -NHS(O)R 15 -N(C 1-4 Alkyl)S(O)R 15 -NHS(O)2R 15 、 and -N(C 1-4 Alkyl)S(O)2R 15 ;

[0107] Each R 14 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, and heterocyclic; and each R 14 Optionally, it is divided into one to six halogen groups, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or -NHSO2-aryl-N(CH3)2 substitution;

[0108] Each R 15 Independently, it is hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, or heterocyclic;

[0109] Each R 16 Independently, it can be a halogen group, cyano group, hydroxyl group, -NH2, or -NHR group. 21 -N(R) 21 2. C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 21 Or C 3-10 cycloalkyl;

[0110] Each R 21 Selected independently 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, and heterocyclic groups, and each R 21 Optionally, it is coated with one to six halogen groups or C 1-3 Alkoxy substitution; and

[0111] R 2 Is it hydrogen or C? 1-6 alkyl.

[0112] In some embodiments, a compound of formula I is provided:

[0113]

[0114] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein:

[0115] X 1 X 2 X 3 and X 4 It is CR 4 Or N, where X 1 X 2 X 3 and X 4 At least two but no more than three of them are N;

[0116] Y 1 It is CR 5 Or N;

[0117] Y 2 It is CR 6 Or N;

[0118] Y 3 It is CR 3 Or N;

[0119] Z 1 and Z 2 Each of them is either C or N;

[0120] Ring A and ring B together form a 9- or 10-membered bicyclic heteroaryl group containing 1 to 3 cyclic nitrogen atoms; and

[0121] Ring B contains 1 to 3 nitrogen atoms, and optionally is occupied by a halogen group, hydroxyl group, or C atom on a usable carbon atom. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy substitution, and optionally C on a available nitrogen atom. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution;

[0122] R 1 Yes -L 1 -R 11 L 1 It is -O-, -S-, -S(O)-, -S(O)2-, -N(R) 12 - or does not exist, and R 11 It is C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl or heterocyclic, wherein R 11 Optional land area is divided into 1-4 R 13 Group substitution;

[0123] R 12 Is it hydrogen or C? 1-6 alkyl;

[0124] Each R 13 Independently selected from halogen, cyano, hydroxyl groups, optionally surrounded by R 16 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally R 16 Replacement C 3-10 cycloalkyl, optionally R 16 Replacement C 3-10 cycloalkyl-C 1-6 Alkyl, optionally R 16 Replacement C 6-10 Aryl, optional R 16 Replacement C 6-10 Aryl-C 1-6 Alkyl, optionally R 16 Substituted heteroaryl groups, optionally R 16 Substituted heteroaryl-C 1-6 Alkyl, optionally R 16 Substituted heterocyclic groups, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, OR 14 -NH2, -NHR 14 -N(R)14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2、-C(O)R 15 -C(O)OR 15 -C(O)NHR 15 -C(O)N(C 1-4 Alkyl)R 15 -S(O)2R 15 -S(O)R 15 -NHC(O)R 15 -N(C 1-4 Alkyl)C(O)R 15 -NHS(O)R 15 -N(C 1-4 Alkyl)S(O)R 15 -NHS(O)2R 15 、 and -N(C 1-4 Alkyl)S(O)2R 15 ;

[0125] Each R 14 Selected independently 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, and heterocyclic groups, and each R 14 It may be optionally replaced by one to three halogen groups;

[0126] Each R 15 Independently, it is hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, or heterocyclic;

[0127] Each R 16 It is independently a halogenated group, cyano group, hydroxyl group, amino group, alkylamino group, dialkylamino group, or C group. 1-6 alkyl;

[0128] R 2 Is it hydrogen or C? 1-6 alkyl;

[0129] R 3 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, heterocyclic, -NH2, -NHR17 or -N(R) 17 )2;

[0130] Each R 17 C is independent 1-4 Alkyl, or two R 17 It can be linked with any intermediate atom to form a 3- to 6-membered heterocyclic group;

[0131] Each R 4 Independently, it is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0132] R 5 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, heterocyclic, -NH2, -NHR 17 -N(R) 17 )2; and

[0133] R 6 It is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0134] In some embodiments, ring B is a 5-membered heteroaryl group containing 1 to 3 nitrogen atoms.

[0135] In some embodiments, ring B is a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms.

[0136] In some implementations, ring B is selected from...

[0137]

[0138] Where R 7 R 8 and R 9 Each of these is independently a hydrogen, halogen, hydroxyl, or C group. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy groups; and R 10 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0139] In some implementations, ring B is selected from...

[0140]

[0141] Where R 7 R 8 and R 9 Each of these is independently a hydrogen, halogen, hydroxyl, or C group. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy groups; and R 10 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0142] In some implementations, ring B is selected from...

[0143]

[0144] Where R 7 R 8 and R 9 Each of these is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy groups; and

[0145] R 10 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0146] In some implementations, ring B is selected from...

[0147]

[0148] Where R 7 and R 8 Each of these is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy groups; and R 10 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0149] In some implementations, ring B is selected from...

[0150]

[0151] Where R 7 R 8 and R 9 Each of these is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkyl group.

[0152] In some embodiments, compounds of formula Ia are provided:

[0153]

[0154] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein ring a, ring B, and ring R... 1 R 2 R 3 Y 1 Y 2 Z 1 and Z 2 As defined in this article.

[0155] In some embodiments, compounds of formula Ib are provided:

[0156]

[0157] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein ring a, ring B, and ring R... 1 R 2 R 3 Y 1 Y 2 Z 1 and Z 2 As defined in this article.

[0158] In some embodiments, compounds of formula Ic are provided:

[0159]

[0160] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein ring a, ring B, and ring R... 1 R 2 R 3 Y 1 Y 2 Z 1 and Z 2 As defined in this article.

[0161] In some embodiments, compounds of formula IIa are provided:

[0162]

[0163] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R3 R 7 R 8 X 1 X 2 X 3 X 4 and Y 1 As defined in this article.

[0164] In some embodiments, compounds of formula IIb are provided:

[0165]

[0166] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 7 R 10 X 1 X 2 X 3 X 4 and Y 1 As defined in this article.

[0167] In some embodiments, compounds of formula IIc are provided:

[0168]

[0169] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 7 R 8 R 9 X 1 X 2 X 3 X 4 and Y 1 As defined in this article.

[0170] In some embodiments, compounds of formula IId are provided:

[0171]

[0172] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 7 R8 R 9 X 1 X 2 X 3 X 4 and Y 1 As defined in this article.

[0173] In some embodiments, compounds of formula IIIa are provided:

[0174]

[0175] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 8 and Y 1 As defined in this article.

[0176] In some embodiments, compounds of formula IIIb are provided:

[0177]

[0178] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 8 and Y 1 As defined in this article.

[0179] In some embodiments, compounds of formula IIIc are provided:

[0180]

[0181] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 8 and Y 1 As defined in this article.

[0182] In some embodiments, compounds of formula IIId are provided:

[0183]

[0184] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R1 R 2 R 3 R 5 and R 10 As defined in this article.

[0185] In some embodiments, compounds of formula IIIe are provided:

[0186]

[0187] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 5 and R 10 As defined in this article.

[0188] In some embodiments, compounds of formula IIIf are provided:

[0189]

[0190] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein R 1 R 2 R 3 R 5 and R 10 As defined in this article.

[0191] In some implementations, L 1 It does not exist or -N(R) 12 In some implementations, L 1 It does not exist.

[0192] In some implementations, R 11 It is optionally composed of 1 to 4 independently selected halogen groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heteroaryl, heterocyclic, heterocyclic-C 1-6 Alkyl, -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2 and -C(O)OR 15 The heterocyclic group substituted with the group; wherein each R 14Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl and heterocyclic groups, and each R 14 Optionally replaced by one to three halogen groups; and wherein R 15 It is C 1-6 alkyl.

[0193] In some implementations, R 11 It is an unsubstituted heterocyclic group. In some embodiments, R 11 It is a heterocyclic group substituted with a methyl group.

[0194] In some implementations, R 11 yes Where ring C is arbitrarily divided by 1 to 4 Rs 13 A 3- to 10-membered heterocyclic group containing 0, 1, or 2 additional cyclic nitrogen atoms. In some embodiments, the ring C is replaced by 1 to 4 R atoms. 13 Group substitution In some implementations, ring C is composed of 1 to 4 R... 13 Group substitution In some implementations, ring C is composed of 1 to 4 R... 13 Group substitution

[0195] In some implementations, ring C is optionally divided by 1 to 4 R 13 A 5- to 10-membered bicyclic heterocyclic group containing an additional cyclic nitrogen atom.

[0196] In some implementations, ring C is optionally divided by 1 to 4 R 13 A 5- to 10-membered spirobicyclic heterocyclic group containing an additional cyclic nitrogen atom.

[0197] In some implementations, ring C is optionally divided by 1 to 4 R 13 A 5- to 10-membered fused bicyclic heterocyclic group containing an additional cyclic nitrogen atom.

[0198] In some implementations, R 11 Selected from Each of these is arbitrarily divided by 1 to 4 Rs. 13 Group substitution.

[0199] In some implementations, R 11 Selected from Each of these is arbitrarily divided by 1 to 4 Rs. 13 Group substitution.

[0200] In some implementations, R 11 Optionally substituted with 1 to 4 groups independently selected from fluorine, methyl, ethyl, trifluoromethyl, cyclopropyl, 1-pyrrolyl, N-morpholinyl, N-pyrrolylalkyl, N-pyrrolylmethyl, cyclopropylamino, amino, aminomethyl, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanebutylamino, and tert-butoxycarbonyl.

[0201] In some implementations, R 11 Optionally, the atom is selected independently from 1 to 4 molecules, namely fluorine, methyl, ethyl, methoxyethoxy, trifluoromethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropyl-1-ylamino)methyl, cyclopropyl, 1-(cyclopropylamino)-1-cyclopropyl, 1-pyrrolidinyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperidinyl, 1-cyclopropyl-2-piperidinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, N-tert-butoxycarbonyl-N-cyclopropylaminomethyl, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N ... The groups substituted with methylaminomethyl, N-methoxyethyl-N-cyclopropylaminomethyl, N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylamino, N-isopropyl-N-aminomethyl, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanebutylamino, (3-methoxy-1-azacyclobutyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, 4-morpholinylmethyl, and tert-butoxycarbonyl groups.

[0202] In some implementations, R 11Optionally, it is selected from 1 to 4 independently from 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropyl-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 Substitution of groups such as N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, isopropylaminomethyl, N-isopropyl-N-aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, (3-methoxy-1-azacyclobutyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl and 4-morpholinylmethyl.

[0203] In some implementations, R 11 Optionally substituted with 1 to 4 groups independently selected from amino, methylamino, ethylamino, isopropylamino, tert-butylamino, n-butylamino, cyclopropylamino, N-cyclopropyl-N-methylamino, 3,3-difluorocyclobutylamino, tetrahydropyranylamino and oxetane-butylamino.

[0204] In some implementations, X 1 X 2 X 3 and X 4 The two in are N. In some implementations, X 1 X 2 X 3 and X 4 One of them is N.

[0205] In some implementations, Y 2 It does not exist; it is CR. 6 Or N.

[0206] In some implementations, R 1 Yes -L 1 -R 11 L 1 It is -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, and R 11 It is C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10aryl, heteroaryl or heterocyclic, wherein R 11 Optionally by 1 to 4 R 13 Group substitution.

[0207] In some implementations, each R 13 Independently selected from halogen, cyano, hydroxyl groups, optionally surrounded by R 16 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally R 16 Replacement C 3-10 cycloalkyl, optionally R 16 Replacement C 3-10 cycloalkyl-C 1-6 Alkyl, optionally R 16 Replacement C 6-10 Aryl, optional R 16 Replacement C 6-10 Aryl-C 1-6 Alkyl, optionally R 16 Substituted heteroaryl groups, optionally R 16 Substituted heteroaryl-C 1-6 Alkyl, optionally R 16 Substituted heterocyclic groups, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, OR 14 -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2、-C(O)R 15 -C(O)OR 15 -C(O)NHR 15 -C(O)N(C 1-4 Alkyl)R 15 -S(O)2R 15 -S(O)R 15 -NHC(O)R 15 -N(C 1-4 Alkyl)C(O)R 15 -NHS(O)R 15 -N(C 1-4 Alkyl)S(O)R 15 -NHS(O)2R 15 and -N(C 1-4 Alkyl)S(O)2R 15; Each R 14 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, and heterocyclic; and each R 14 Optionally, it is divided into one to six halogen groups, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-10 Cycloalkyl or -NHSO2-aryl-N(CH3)2 substitution; each R 15 Independently, it is hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, or heterocyclic; each R 16 Independently, it can be a halogen group, cyano group, hydroxyl group, -NH2, or -NHR group. 21 -N(R) 21 2. C 1-6 Alkyl, C 1-6 Halogenated alkyl, OR 21 Or C 3-10 cycloalkyl; and each R 21 Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl and heterocyclic, and each R 21 Optionally, it is coated with one to six halogen groups or C 1-3 Alkyl-substituted.

[0208] In some implementations, R 2 It is hydrogen.

[0209] In some implementations, R 3 It is hydrogen. In some implementations, R 3 It is a halogen group. In some implementations, R 3 It is fluorine. In some implementations, R 3 It is C 1-6 Alkyl group. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is C 1-6 Alkyl group. In some embodiments, R 3 It is a methoxy group.

[0210] In some implementations, each R 4 It is hydrogen. In some implementations, an R 4 It is a halogen group, and the rest are hydrogen.

[0211] In some implementations, R 5It is hydrogen. In some implementations, R 5 It is C 1-6 Alkyl group. In some embodiments, R 5 It is a methoxy group.

[0212] In some implementations, R 6 It is hydrogen.

[0213] In some implementations, R 7 It is hydrogen.

[0214] In some implementations, R 8 It is C 1-6 Alkyl group. In some embodiments, R 8 It is a methyl group.

[0215] In some implementations, R 9 It is C 1-6 Alkyl group. In some embodiments, R 9 It is a methyl group.

[0216] In some implementations, R 10 It is C 1-6 Alkyl group. In some embodiments, R 10 It is a methyl group.

[0217] In some implementations, L 1 It does not exist.

[0218] In some implementations, Y 1 It is CR 5 In some implementations, Y 1 It is N. In some implementations, Y 1 It is CH.

[0219] In some implementations, Y 2 It is CR 6 In some implementations, Y 2 It is N. In some implementations, Y 2 It is CH.

[0220] In some implementations, Y 3 It is CR 3 In some implementations, Y 3 It is CH.

[0221] In some embodiments, ring B contains one to three heteroatoms independently selected from N, O, and S, and optionally is surrounded by one to three heteroatoms independently selected from halogen groups, hydroxyl groups, C groups, and S groups on one or more available carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6Substitution of haloalkoxy groups, and optionally, carbon atom substitution at a available nitrogen atom. 1-6 Alkyl or C 1-6 Halogenated alkyl substitution.

[0222] In some implementations, ring B is

[0223] In some implementations, ring B is

[0224] In some implementations, ring B is

[0225] In some implementations, each R 13 Independently selected from halogen groups, C 1-6 Alkyl, optionally R 16 Replacement C 3-10 cycloalkyl, optionally R 16 Substituted heterocyclic groups, -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2, where R 16 and R 14 As defined herein. In some implementations, each R 13 Independently selected from -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 and -C 1-6 Alkylene-N(R) 14 )2, where R 14 As defined herein. In some implementations, each R 13 Independently selected from halogen groups, C 1-6 Alkyl, -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 and -C 1-6 Alkylene-N(R) 14 )2, where R 14 As defined herein. In some implementations, R 13 The heterocyclic group contains a cyclic nitrogen atom. In some embodiments, R 13Is it arbitrarily R 16 A substituted heterocyclic group, wherein the heterocyclic group comprises a cyclic nitrogen atom.

[0226] In some implementations, R 13 It is -NH2, -NHR 14 or -C 1-6 Alkylene-NHR 14 And R 14 As defined herein. In some implementations, R 13 Yes - NHR 14 or -C 1-6 Alkylene-NHR 14 And R 14 As defined herein. In some implementations, R 13 Yes - NHR 14 or -C 1-6 Alkylene-NHR 14 And R 14 It is C 3-10 Cycloalkyl. In some embodiments, R 13 It is -NH-cyclopropyl. In some embodiments, R 13 It is -NH-methyl. In some embodiments, R 13 It is -CH2-NH-cyclopropyl. In some embodiments, R 13 It is -CH2-NH-methyl. In some embodiments, R 13 Is it arbitrarily R 16 Substituted -CH2-heterocyclic group, wherein R 16 As defined in this article.

[0227] In some implementations, R 14 It is C 1-6 Alkyl group. In some embodiments, R 14 It is C replaced by one to six fluorine molecules. 1-6 Alkyl group. In some embodiments, R 14 It is methyl. In some embodiments, R 14 It is C 3-10 Cycloalkyl. In some embodiments, R 14 It is cyclopropyl.

[0228] In some implementations, R 15 Is it hydrogen or C? 1-6 alkyl.

[0229] In some implementations, R 16 It is an amino, alkylamino, or dialkylamino group. In some embodiments, each R... 16 Independently -NH2, -NHR 21or -N(R) 21 )2; and each R 21 Selected independently from C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 Cycloalkyl. In some embodiments, each R 16 Independently, it is a halogen group, C 1-6 Alkyl or OR 21 And R 21 As defined in this article.

[0230] In some embodiments, a compound of formula I is provided:

[0231]

[0232] Or its isotopically enriched analogues, pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers, or mixtures of stereoisomers, wherein:

[0233] X 1 X 2 X 3 and X 4 It is CR 4 Or N, where X 1 X 2 X 3 and X 4 At least two but no more than three of them are N;

[0234] Y 1 It is CR 5 Or N;

[0235] Y 2 It is CR 6 Or N;

[0236] Y 3 It is CR 3 Or N;

[0237] Z 1 and Z 2 Each of them is either C or N;

[0238] Ring A and ring B together form a 9-membered bicyclic heteroaryl group containing 1 to 3 cyclic nitrogen atoms; and

[0239] Ring B is selected from

[0240]

[0241] R 1 Yes -L 1 -R 11 L 1It is -O-, -S-, -S(O)-, -S(O)2-, -N(R) 12 - or does not exist, and R 11 It is C 3-10 cycloalkyl, C 6-10 aryl, heteroaryl or heterocyclic, wherein R 11 Optional land area is divided into 1-4 R 13 Group substitution;

[0242] R 12 Is it hydrogen or C? 1-6 alkyl;

[0243] Each R 13 Independently selected from halogen, cyano, hydroxyl groups, optionally surrounded by R 16 Replacement C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, optionally R 16 Replacement C 3-10 cycloalkyl, optionally R 16 Replacement C 3-10 cycloalkyl-C 1-6 Alkyl, optionally R 16 Replacement C 6-10 Aryl, optional R 16 Replacement C 6-10 Aryl-C 1-6 Alkyl, optionally R 16 Substituted heteroaryl groups, optionally R 16 Substituted heteroaryl-C 1-6 Alkyl, optionally R 16 Substituted heterocyclic groups, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, OR 14 -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2、-C(O)R 15 -C(O)OR 15 -C(O)NHR 15 -C(O)N(C 1-4 Alkyl)R 15 -S(O)2R 15 -S(O)R 15 -NHC(O)R 15 -N(C 1-4Alkyl)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 ;

[0244] Each R 14 Selected independently 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, and heterocyclic groups, and each R 14 It may be optionally replaced by one to three halogen groups;

[0245] Each R 15 Independently, it is hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, C 6-10 Aryl, heteroaryl, or heterocyclic;

[0246] Each R 16 It is independently a halogenated group, cyano group, hydroxyl group, amino group, alkylamino group, dialkylamino group, or C group. 1-6 alkyl;

[0247] R 2 Is it hydrogen or C? 1-6 alkyl;

[0248] R 3 It is hydrogen, cyano, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, heterocyclic, -NH2, -NHR 17 or -N(R) 17 )2;

[0249] Each R 17 C is independent 1-4 Alkyl, or two R 17 It can be linked with any intermediate atom to form a 3- to 6-membered heterocyclic group;

[0250] Each R 4 Independently, it is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0251] R 5 It is hydrogen, cyano, halogen, hydroxyl, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl thio, C 1-6 Alkoxy, heterocyclic, -NH2, -NHR 17 -N(R) 17 )2;

[0252] R 6 It is hydrogen, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0253] R 7 R 8 and R 9 Each of these is independently a hydrogen, halogen, hydroxyl, or C group. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 alkoxy groups; and

[0254] R 10 It is hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0255] In some embodiments, a pharmaceutical composition is provided comprising the compound described herein or an isotopically enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer, or a mixture of stereoisomers, and a pharmaceutically acceptable excipient.

[0256] In some embodiments, a method for treating Huntington's disease in a patient in need is provided, the method comprising administering to the patient a therapeutically effective amount of the compound or pharmaceutical composition described herein.

[0257] In some embodiments, a method for treating Huntington's disease in a patient in need is provided, the method comprising administering to the patient a therapeutically effective amount of a combination of the compound or pharmaceutical composition described herein and a second active agent.

[0258] Also provided are a compound or an isotopically enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer selected from Table 1, or a mixture of stereoisomers:

[0259] Table 1

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290] Also provided are a compound or an isotopically enriched analog thereof, a pharmaceutically acceptable salt, a prodrug, a tautomer, a stereoisomer selected from Table 1A, or a mixture of stereoisomers:

[0291] Table 1A

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] Indications and Treatments

[0318] The compounds described herein can be used to treat diseases or conditions mediated at least partially by proteins associated with neurodegenerative diseases. In some embodiments, the compounds described herein can be used to detect diseases or conditions mediated at least partially by HTT proteins. In some embodiments, treatment of diseases or conditions mediated at least partially by proteins associated with neurodegenerative diseases may include administration of the compounds described herein. Treatment may include co-administration of the compounds described herein with one or more other active agents and / or therapies.

[0319] In some embodiments, a method is provided for treating or preventing a disease or condition in a patient in need that is at least partially mediated by a protein associated with neurodegenerative diseases, the method comprising administering to the patient a therapeutically effective amount of the compound described herein.

[0320] Examples of diseases or conditions are as follows.

[0321] Huntington's disease (HD)

[0322] Huntington's disease (HD) is a hereditary, progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric deficits, as well as neurodegeneration and brain atrophy. Atrophy may begin in the striatum and cerebral cortex and extend to other subcortical brain regions. HD belongs to a family of neurodegenerative diseases in which extended bundles of CAG repeat sequences result in long segments of polyglutamine (polyQ) encoded proteins. This family also includes dentate nucleus-rubella-globus pallidus Lewy body atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA). In HD, selective neurodegeneration of γ-aminobutyric acid-releasing spinous projection neurons in the striatum has been observed, but neuronal loss in many other brain regions has also been reported. Symptoms of HD include loss of motor control, psychiatric symptoms, memory, and / or cognitive impairment.

[0323] Huntington proteins (HTT proteins) are 348 kDa multidomain proteins containing a polymorphic glutamine / proline-rich domain at their amino terminus. In healthy individuals, the IT molecules encoding these domains... 15The number of CAG repeat sequences in the gene ranges from 6 to 35; 36 or more repeat sequences define the HD allele. The length of CAG extension is negatively correlated with the age of disease onset, with adolescent-onset cases characterized by extensions of more than 60 repeat sequences. Decreased penetrance was observed between 36 and 39 repeat sequences. See McColgan P et al., Huntington's disease: clinical review, Eur. J. Neurology, 2017, Vol. 25, 24-34, which is incorporated herein by reference in its entirety. It is believed that longer poly-Q domains induce conformational changes in the HTT protein, leading to its formation of intracellular aggregates, which in many cases manifest as nuclear inclusions. However, it can also form aggregates outside the nucleus. The HTT protein is present in the nucleus, cell body, dendrites, and nerve endings of neurons and is also associated with many organelles, including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0324] The diagnosis of Huntington's disease is based on a confirmed family history or positive genetic testing, and the onset of motor dysfunction as defined by the Total Motor Score (TMS) of the Unified HD Rating Scale (UHDRS). This score ranges from 0 (no motor abnormalities suggestive of HD) to 4 (≥99% due to HD), with a score of 4 defining a motor episode or “obvious” HD. However, up to 10–15 subtle motor, cognitive, and psychiatric deficits can be identified prior to obvious disease onset, and this is known as the pre-obvious stage of the disease.

[0325] 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. 2018 Sep-October; 5(5):527–533, which is incorporated herein by reference in its entirety. HD can be divided into early stages (stage 1 or 2 TFC scores), intermediate stages (stage 3 TFC scores), or late stages (stage 4 or 5 TFC scores). See, for example, Shoulson, I. et al., Huntington disease: Clinicalcare and evaluation, Neurology, 1979, Vol. 29(1), 1; Shoulson, I., Huntington disease: functional capacities in patients treated with neuroleptic and antidepressant drugs, Neurology, 1981, Vol. 31(10), 1333–35. The part of the brain most affected by hemorrhage (HD) and therefore considered most likely to contain HTT protein abnormalities is a group of nerve cells at the base of the brain, collectively known as the basal ganglia. The basal ganglia organize muscle-driven body movement, or "motor locomotion." The main components of the basal ganglia are the caudate and putamen (collectively known as the striatum) and the globus pallidus (external and internal regions). The substantia nigra and subthalamic nucleus are usually also included as part of the basal ganglia.

[0326] The basal ganglia are a group of subcortical nuclei primarily responsible for motor control, as well as other functions such as motor learning, executive function, behavior, and emotion. Disruption of the basal ganglia network is believed to contribute to several motor disorders. Normal function of the basal ganglia requires fine-tuning of neuronal excitability within each nucleus to determine the degree of motor facilitation or inhibition at any given time. This is mediated by the complex organization of the striatum, where the excitability of medium-sized spinous neurons is controlled by several presynaptic and postsynaptic mechanisms and interneuronal activity, and is ensured by several periodic or internal basal ganglia circuits. The motor circuits of the basal ganglia have two entry points—the striatum and the hypothalamic nucleus—and one output—the globus pallidus—which connects to the cerebral cortex via the motor thalamus.

[0327] The compounds described herein can inhibit neuronal degeneration when administered to a subject. In some embodiments, inhibition of neuronal degeneration may include inhibition of axonal or neuronal degeneration within a neuron. This inhibition can affect the entire neuron or a portion thereof, such as the neuronal cell body, axon, and dendrites. This can be assessed, for example, by analyzing neural function according to methods known in the art.

[0328] Administration of the compounds described herein can result in a rescue effect of at least 10% reduction (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 100%) of one or more symptoms of the disease or condition described herein. The disease or condition can be a neurological disorder secondary to a disease, condition, or therapy that has a major effect outside 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, tremor, bradykinesia, ataxia, loss of balance, depression, cognitive decline, short-term memory loss, long-term memory loss, confusion, personality changes, speech difficulties, loss of sensory perception, tactile sensitivity, numbness in the extremities, muscle weakness, muscle paralysis, muscle cramps, muscle spasms, significant changes in eating habits, excessive fear or worry, insomnia, delusions, hallucinations, fatigue, back pain, chest pain, digestive problems, headache, rapid heart rate, dizziness, blurred vision, shadows or missing areas of vision, distorted vision, impaired color vision, reduced recovery of visual function after exposure to bright light, and decreased visual contrast sensitivity.

[0329] The 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%) in the number of degenerated neurons (or their bodies, axons, or dendrites) in a neuronal population or in a subject, compared to the number of degenerated neurons (or their bodies, axons, or dendrites) in a neuronal population or in a subject who have not been administered one or more of the compounds described herein.

[0330] Neurons 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 (called interneurons) connect neurons within the central nervous system (brain and spinal cord). Certain specific examples of neuron types that can receive treatment according to the invention include cerebellar granule neurons, dorsal root ganglion neurons, PNS neurons (e.g., sensory neurons), and cortical neurons. Other examples of cell types that can receive treatment according to this disclosure include astrocytes and microglia.

[0331] Neurodegenerative diseases are illnesses or conditions in which the nervous system of a subject is impaired. Examples of neurodegenerative diseases include, for example, Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), telangiectasia, Baton's disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan's disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann's disease, etc. -Scheinker syndrome, Huntington's disease, HIV-related dementia, Kennedy's disease, Krabbe's disease, Kuru disease, Lewy body dementia, Machado-Joseph disease (type 3 spinocerebellar ataxia), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prions, Reversom disease, Sandhoff's disease, Schilder's disease, subacute combined spinal cord degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia, spinal muscular atrophy, Steele-Richardson-Olszewski disease, insulin resistance or tabes dorsalis.

[0332] In some implementations, the disease or condition is selected from Huntington's disease (HD), dentate nucleus-rubella-lewy body atrophy, spinal and bulbar muscular atrophy, spinocerebellar ataxia, spinal cord and / or brain injury, chronic pulmonary hypertension, Parkinson's disease, amyotrophic lateral sclerosis, cavernous malformation, cardiovascular disease, Alzheimer's disease (AD), glaucoma, multiple sclerosis (MS), corneal disease, diabetes, chronic and / or neuropathic pain, stroke, local ischemia, retinopathy, spinal muscular atrophy (SMA), erectile dysfunction, kidney disease (non-hypertensive), hypertensive nephropathy, hypertension (hypertension), optic neuropathy, liver fibrosis, lupus, post-transplant liver failure, encephalomyelitis, epilepsy, and glioblastoma.

[0333] Furthermore, the compounds described herein can be used to prevent or treat memory loss. Types of memory that can be affected by loss and therefore treated according to this disclosure include episodic memory, semantic memory, short-term memory, and long-term memory.

[0334] 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, prions, and spinocerebellar ataxia. In some embodiments, the neurodegenerative disease is classified as a trinucleotide repeat disorder. In some embodiments, the trinucleotide repeat disorder is classified as belonging to Class I, Class II, or Class III.

[0335] In some implementations, the neurodegenerative disease is Huntington's disease.

[0336] The use of the compounds described herein in the manufacture of medicaments for 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.

[0337] Pharmaceutical Compositions and Their Administration

[0338] The compounds described herein can be administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable excipients are also provided herein.

[0339] Suitable pharmaceutically acceptable excipients may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (GS Banker and CTRhodes, editors).

[0340] The pharmaceutical composition can be formulated for administration by various methods, including, for example, oral, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhaler.

[0341] The pharmaceutical composition may be formulated for administration by injection. Forms in which the pharmaceutical composition described herein may be incorporated for 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.

[0342] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenteral acceptable medium, such as a solution in 1,3-butanediol. Acceptable media that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are typically used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids (such as oleic acid) may be used in the preparation of the injectable. Such solutions may be formulated with appropriate salts as 0.01%–10% isotonic solutions (pH 5–7).

[0343] The compounds described herein can be administered parenterally in a sterile medium. Parentertal administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection, or infusion techniques. Depending on the medium and concentration used, the compounds described herein can be suspended or dissolved in the medium. Advantageously, adjuvants (such as local anesthetics, preservatives, and buffers) can be dissolved in the medium. In many pharmaceutical compositions for parentertal administration, the carrier constitutes at least 90% by weight of the total composition. In some embodiments, the carrier for parentertal administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

[0344] For example, a pharmaceutical composition for injection may contain cyclodextrin. Cyclodextrin may be, for example, hydroxypropyl cyclodextrin or sulfobutyl ether cyclodextrin. Cyclodextrin may be, for example, α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

[0345] The compounds described herein can also be administered via microspheres, liposomes, other microparticle delivery systems, or sustained-release formulations placed in certain tissues, including blood. Suitable examples of sustained-release carriers include semi-permeable polymer matrices in the form of shared formulations, such as suppositories or microcapsules. Examples can be found, for example, in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, AR, Lippincott Williams and 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.

[0346] The pharmaceutical composition can be formulated for oral administration. The pharmaceutical composition may be in the form of, for example, capsules or tablets. Oral formulations may include enteric coatings. In preparing the pharmaceutical composition, the compounds described herein are typically diluted with excipients and / or encapsulated in a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the excipient is used as a diluent, it can be in the form of a solid, semi-solid, or liquid material, acting as a medium, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0347] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, astragalus gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The pharmaceutical composition may additionally contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; protective agents such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0348] The pharmaceutical compositions can be formulated using procedures known in the art to provide a rapid, sustained, or delayed release of the active ingredient after administration to a subject. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems for polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be configured for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0349] To prepare solid compositions (such as tablets), the compounds described herein can be mixed with pharmaceutical excipients to form a solid preformed composition containing a homogeneous mixture. When these preformed compositions are referred to as homogeneous, the compounds can be uniformly dispersed throughout the composition, allowing the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0350] The compounds described herein can be coated or otherwise formulated into tablets or pills to provide a dosage form with the advantage of prolonged action or to protect the tablets or pills from the acidic conditions of the stomach. For example, the tablets or pills may comprise an internal dose component and an external dose component, the latter in the form of a coating over the former. The two components may be separated by an enteric coating layer, which resists disintegration in the stomach and allows the internal component to enter the intestine intact or delays release. A variety of materials can be used as such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0351] For example, the compounds described herein can be incorporated into oral liquid formulations, such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs. Furthermore, pharmaceutical compositions containing the compounds described herein can be presented as dry products for reconstitution with water or other suitable media prior to use. Such liquid formulations 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), emulsifiers (e.g., lecithin, dehydrated sorbitol monooleate, or gum arabic), non-aqueous media (which may include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethanol), and preservatives (e.g., methylparaben or propylparaben and sorbic acid).

[0352] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered orally or via nasal inhalation to produce local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a face mask curtain or intermittent positive pressure ventilation machine. Solution, suspension, or powder compositions may be administered from a device for delivery of preparations in a suitable manner, preferably orally or intranasally.

[0353] The compounds or pharmaceutical compositions thereof described herein may be administered at an appropriate dose as determined by an informed physician. The compounds or pharmaceutical compositions may be administered in single or multiple doses, and in single or multiple dose forms (e.g., two tablets or three capsules). For any given subject, the appropriate dose will depend on a variety of factors, including the activity of the specific compound used by the subject, age, weight, general health condition, sex, diet, time of administration, route of administration, excretion rate, active agents used in combination, and the severity of the specific disease or condition. For example, a dose may be expressed as milligrams of the compound described herein per kilogram of the subject's body weight per day (mg / kg). A dose of about 0.1 to about 150 mg / kg may be appropriate. In some embodiments, a dose of about 0.1 to about 100 mg / kg may be appropriate. In some embodiments, a dose from about 0.0001 to about 100 mg / kg body weight per day, from about 0.001 to about 50 mg of the compound / kg body weight, or from about 0.01 to about 10 mg of the compound / kg body weight may be appropriate. In some implementations, the dose may be administered multiple times daily, such as once daily, twice daily, or three times daily. In some implementations, the dose may be administered every two days, every three days, every four days, or once weekly. Standardization based on the subject's weight is particularly useful when adjusting the dose among subjects of varying sizes, such as when using the drug in both children and adults, or when converting an effective dose in non-human subjects (such as dogs) to a dose suitable for human subjects.

[0354] Reagent test kit

[0355] This document also provides a kit containing the compounds described herein and suitable packaging. In some embodiments, the kit further includes instructions for use. In one aspect, the kit contains the compounds described herein along with a label and / or instructions for use in the treatment of the diseases or conditions described herein.

[0356] This document also provides articles comprising the compounds described herein in suitable containers. These containers may be vials, jars, ampoules, pre-loaded syringes, and / or intravenous bags.

[0357] Combination therapy

[0358] In some embodiments, the compounds described herein are applied in combination with one or more additional active agents.

[0359] The methods described herein include methods for detecting, treating, or preventing the diseases or conditions described herein (e.g., Huntington's disease), the methods comprising administering to a subject, simultaneously or sequentially, a compound described herein and one or more additional active agents. In the simultaneous administration method, the agents may be present in a combined composition or may be administered alone. When used in combination with one or more additional active agents, the compound described herein may be administered before, in parallel with, or after the administration of the additional active agent. Administration may be performed via the same or different routes.

[0360] A pharmaceutical composition is also provided comprising the compounds described herein and one or more other agents for the treatment of Huntington's disease, such as, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, ethapram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenzylquinazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. Similarly, a packaged pharmaceutical composition is also provided, the packaged pharmaceutical composition comprising a pharmaceutical composition containing the compounds described herein and another composition comprising one or more additional agents for the treatment of Huntington's disease, said additional agents being, for example, but not limited to, carbamazepine, clonazepam, diazepam, fluoxetine, ethapram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenzylquinazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, and risperidone. In some embodiments, the active agent is carbamazepine, clonazepam, diazepam, fluoxetine, ethapram, valproate, lamotrigine, amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulpiride, quetiapine, clozapine, or risperidone.

[0361] Also provided are methods for treating or preventing Alzheimer's disease, including treating memory and / or cognitive impairment associated with Alzheimer's disease, said methods comprising administering, simultaneously or sequentially, the compounds described herein and one or more additional agents to a subject. In some embodiments, the active agent is Neotropin TM , Silegilan or Keqingnuo.

[0362] In some embodiments, the compounds described herein may be administered in combination with active agents for the treatment of Parkinson's disease, such as L-DOPA, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline, apomorphine, and ergot urea), dopa decarboxylase inhibitors (e.g., levodopa, benzylhydrazine, and carbidopa), and / or MAO-B inhibitors (e.g., selegiline and rasagiline). In some embodiments, the compounds described herein may be administered in combination with active agents for the treatment of Alzheimer's disease, such as acetylcholinesterase inhibitors (e.g., donepezil, galantamine, and rivastigmine) and / or NMDA receptor antagonists (e.g., memantine).

[0363] Compound Synthesis

[0364] The compounds described herein can be prepared using the methods disclosed herein and their conventional modifications, which will be readily apparent given the disclosure herein and methods well-known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be carried out as illustrated in the following examples. Reagents, if available, can be commercially available, for example from Sigma Aldrich or other chemical suppliers.

[0365] The compounds described herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, unless otherwise stated, other method conditions may also be used, provided that typical or preferred method conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0366] 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, and suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, several protecting groups are described in the following literature: Wuts, PGM, Greene, TW, and Greene, TW (2006), Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein.

[0367] Furthermore, the compounds described herein may contain one or more asymmetric (“chiral”) centers. Therefore, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched with stereoisomers, if desired. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, photoactive starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral resolving agents, etc. When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials can be employed as conventionally used in the art or as described in the examples.

[0368] The starting materials used in the following reactions are typically known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Sigma Aldrich, Alfa Aesar, etc. Other materials can be prepared by procedures described in standard reference texts such as Fieser and Fieser's *Reagents for Organic Synthesis*, Volumes 1–15 (John Wiley and Sons, 1991), Rodd's *Chemistry of Carbon Compounds*, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989), *Organic Reactions*, Volumes 1–40 (John Wiley and Sons, 1991), March's *Advanced Organic Chemistry* (John Wiley and Sons, 5th edition, 2001), and Larock's *Comprehensive Organic Transformations* (VCH Publishers Inc., 1989).

[0369] The terms “solvent,” “inert organic solvent,” and “inert solvent” refer to solvents that are inert under the reaction conditions described herein (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Generally, the term “inert” as used herein with respect to solvents means a material that does not undergo a reaction for forming the target compound by forming carbon-carbon bonds. Unless otherwise specified, the solvents used in the reactions described herein are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.

[0370] The term "qs" refers to the amount added sufficient to achieve the function (e.g., to bring the solution to the desired volume (i.e., 100%)).

[0371] It should also be understood that in each of the following schemes, the addition of any substituent may result in the production of multiple isomers (including, but not limited to, enantiomers or one or more diastereomers), any or all of which can be isolated and purified using conventional techniques.

[0372] Incorporating isotopic labeling (e.g., deuterium atoms) into the compounds described herein can be carried out by reacting one or more suitable starting materials with a reagent containing a radioactive isotope. The method generally follows the same principles as standard organic chemical reactions and can be performed by any method known to those skilled in the art, including those provided in this disclosure.

[0373] Scheme 1 provides an exemplary synthetic route for synthesizing compounds provided herein (e.g., compounds of Formula I). ​​Compounds of Formula I or other formulas or compounds disclosed herein are generally prepared by first providing formulas Va and Vb, and then attaching the desired substituents using suitable conditions (e.g., amide bond formation, nucleophilic aromatic substitution, or cross-coupling).

[0374] In some embodiments, the synthesis of compounds of formula I is carried out according to scheme 1. The synthesis of compounds 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 then preparing compounds of formula I through one or more subsequent steps.

[0375] Option 1

[0376]

[0377] In Scheme 1, R 1 R 2 R 3 X 1 X 2 X 3X 4 Y 1 and Y 2 As defined in this article. A 1 A 2 and A 3 As defined below, and Z 3 -Z 4 -Z 5 It is N-CR 7 =CR 8 Or C = CR 7 -NR 10 .

[0378] In scheme 1, compound Va can be obtained through A 1 The leaving group at the site forms an amide bond with the amine in compound Vb and is thus linked to compound Vb (as shown in Scheme 1). A 1 It can be a suitable leaving group, such as a halide, halide-like compound, carboxylic acid, or carboxylate. Compound Va can be activated by an activator (e.g., chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, HATU, HBTU) in A. 1 Activation is optionally performed in the presence of a base (e.g., 1-methylimidazole, triethylamine, diisopropylethylamine) and in a suitable solvent (e.g., a polar aprotic solvent such as acetonitrile, DMF, or dichloromethane). Alternatively, A 1 The carboxylate can be first activated by 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 separate the activated form of compound Va (e.g., where A...). 1 It is a halide (such as a chloride), and the reaction can be carried out in a container.

[0379] In Scheme 1, compounds of Formula I can be prepared. Therefore, compound Vc can combine with compound Vd in a coupling reaction, for example, via A. 2 The compound Vc undergoes nucleophilic addition (e.g., nucleophilic aromatic substitution). In such embodiments, A 2 It can be a suitable leaving group (e.g., a halide (such as a chloride or fluoride) or a halide-like group (such as a sulfonyl group)), and A 3 It can be a hydrogen atom, or R in it. 1It exists as anion or cation (such as sodium or potassium ions). Nucleophilic aromatic substitution can be carried out 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) under heating (e.g., to temperatures from 50°C to 200°C). Alternatively, compound Vc can be combined with compound Vd in a coupling reaction (e.g., a metal-catalyzed coupling reaction). In such embodiments, for example, A 2 It can be a leaving group (e.g., a halide (such as a chloride or bromide) or a halide-like group (such as a sulfonyl group)), and R 1 It can contain suitable coupling functional groups (e.g., carbon-carbon double bonds) and A 3 It could be A 2 The complementary coupling partner (e.g., a hydrogen atom or a tin- or boron-containing group). The reaction can be carried out with a catalyst (e.g., bis(triphenylphosphine)palladium(II) chloride) and optionally in the presence of a base (e.g., sodium carbonate).

[0380] In some implementation schemes, A 2 It can be R 1 Furthermore, compound Vc can be directly converted into compound I (without reacting with compound Vd).

[0381] In compounds Va, Vb, Vc, and / or Vd, R 1 R 2 R 3 X 1 X 2 X 3 X 4 Y 1 Y 2 Z 4 and Z 5 Any of the protecting groups can be present in a protected form, for example, at an amine or hydroxyl group. Amine protecting groups include those known in the art and described herein, including, for example, a tert-butoxycarbonyl group. In such embodiments, additional deprotection steps may be required. For example, when the protecting group is tert-butoxycarbonyl, an acidic deprotection step (e.g., using HCl or TFA in dioxane) may be required to prepare a compound of formula I.

[0382] Those skilled in the art will understand that, for a particular embodiment, any one of compounds Va, Vb, Vc, or Vd is available from a commercial supplier. Alternative synthesis of compounds Va, Vb, Vc, or Vd may be carried out as described herein or as known to those skilled in the art.

[0383] Example

[0384] The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art will understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific patterns constituting its practice. However, based on this disclosure, those skilled in the art will understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of this disclosure and still obtaining the same or similar results.

[0385] Analytical methods

[0386] Acidic QC methods

[0387] AcHSSC18 - Standard Acid UPLC-MS

[0388]

[0389]

[0390] 10cm_Formic_AQ-Standard Acid UPLC-MS

[0391]

[0392] Acid 1-Standard Acid UPLC-MS

[0393]

[0394] Alkaline QC method

[0395] Bicarb BEHC18 - Standard Alkaline UPLC-MS

[0396]

[0397]

[0398] 10cm_Bicarb_AQ-Standard Alkaline UPLC-MS

[0399]

[0400] General Program

[0401] Compounds were named using the Chemdraw 18.1 structural nomenclature tool. All reactions involving air- or moisture-sensitive reagents were carried out under a nitrogen atmosphere using dry solvents and glassware.

[0402] Example 1-140

[0403] Examples 1-140 were carried out according to the following method:

[0404] Method A: Ester hydrolysis

[0405] 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 stirring at 50 °C for 3 days. The reaction mixture was evaporated to dryness to give the corresponding lithium carboxylate.

[0406] Method B HBTU Coupling

[0407] Lithium carboxylate, amine (1.0 equivalent), HBTU (1.0 equivalent), triethylamine (12 equivalent), 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.

[0408] Method C: HCl Boc Deprotection

[0409] The Boc-protected amine, methanol (20 mL / mmol), and 4N HCl (20 mL / mmol) in dioxane were combined and stirred at room temperature for 2–17 hours. The reaction mixture was evaporated to dryness and purified by preparative HPLC.

[0410] Method DS N Ar replacement

[0411] The substituted aryl halide, amine (1 equivalent), cesium carbonate (1.1 equivalent), and DMF (5 mL / mmol) were combined in a sealed tube and heated to 100 °C for 1–5 days. The reaction mixture was cooled to room temperature. The cesium salt was removed by filtration, and the filtrate was evaporated to dryness to give the crude product, which was used directly in the next step.

[0412] Method D2 S N Ar replacement

[0413] The substituted aryl halide, amine (1 equivalent), triethylamine (1.1 equivalent), and MeCN (5 mL / mmol) were combined in a sealed tube and heated to 60 °C for 1–5 days. The reaction mixture was evaporated to dryness to give a crude product, which could be purified or used directly in the next step.

[0414] Method E TFA Boc Deprotection

[0415] The 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.

[0416] Method F CuI Coupling Conditions

[0417] The benzamide, aryl halide (1.05 equivalents), copper iodide (I) (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. The reaction mixture was then filtered through diatomaceous earth and concentrated under reduced pressure.

[0418] Method G t-BuBrettPhos condition

[0419] Benzamide, an aryl halide (1.05 equivalents), tert-BuBrettPhos-Pd-G3 (0.10 equivalents), and K3PO4 (1.4–2.4 equivalents) were placed in a stemblock 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. Afterward, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure.

[0420] Method H TCFH Coupling

[0421] TCFH (1.20 equivalents) was added to the acid (1.0 equivalents), amine (1.30 equivalents), and 1-methylimidazole (2.5-3.5 equivalents) in MeCN (3 mL / mmol) at room temperature and stirred for 16 h.

[0422] Method I: Tri-tert-butylphosphine Buchwald conditions

[0423] 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 min. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, washed with DCM, and the filtrate was concentrated to dryness.

[0424] Method J Pd2(dba)3Buchwald condition

[0425] Aryl bromide, amine (1 equivalent), Pd2(dba)3 (0.1 equivalent), rac-BINAP (0.2 equivalent), and Cs2CO3 (4 equivalent) were suspended in DMF (3 mL / mmol), and the mixture was purged with N2 for 10 min. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, washed with MeOH, and the filtrate was concentrated to dryness.

[0426] Method K RuPhos Pd G2 Buchwald condition

[0427] Aryl bromide, amine (2 equivalents), RuPhos Pd G2 (0.1 equivalents), and Cs2CO3 (3 equivalents) were suspended in... t The mixture was placed in BuOH (20 mL / mmol) and purged with N2 for 10 minutes. The tube was sealed and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was filtered through diatomaceous earth, washed with MeOH, and the filtrate was concentrated to dryness.

[0428] Method L Boc protection

[0429] Arylamine (1 equivalent), di-tert-butyl dicarbonate (1.3 equivalent), and EtOAc (0.298 M) 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 EtOAc (x2), and the combined organic matter was washed with brine, dried (using phase separation filter paper), and concentrated under vacuum.

[0430] Method for the formation of M-aminopyridine onium salts

[0431] The substituted pyridine (1 equivalent) was dissolved in DMF (0.13 M), and O-(2,4-dinitrophenyl)hydroxylamine (1.1 equivalent) was added. The reaction mixture was stirred at room temperature for 16 h.

[0432] Method N1,3 dipole addition

[0433] The aminopyridinium salt (1 equivalent), ethyl 2-butyrate (1.1 equivalent), and K2CO3 (1.5 equivalent) were dissolved in DMF (0.088 M), and the reaction mixture was stirred overnight at room temperature.

[0434] Method: O HBr decarboxylation

[0435] The ester (1 equivalent) was dissolved in 0.2 M hydrobromic acid (H2O) at 48 wt.%, and the reaction mixture was stirred at 100 °C for 4 h.

[0436] Method P Pd-catalyzed amidation

[0437] Lactam (1 eq), heteroaryl chloride (1 equivalent), and Cs₂CO₃ (1.5 equivalent) were suspended in dioxane (0.2 M), and the mixture was purged with N₂ for 10 min. Then, Pd₂(dba)₃ (0.2 equivalent) and Xantphos (0.2 equivalent) were added, the tube was sealed, and heated to 100 °C for 16 h. After cooling to room temperature, the mixture was evaporated to dryness, loaded onto silica in DCM / MeOH, and purified by silica gel chromatography.

[0438] Method Q: Formaldehyde Reduction Amination

[0439] Amine (1 equivalent), formaldehyde (37% solution, 50 equivalent), methanol (1 mL), and sodium triacetoxyborohydride (2 equivalents) (1.5 equivalents) were combined, and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried, and evaporated. The crude material was purified by achiral SFC or preparative HPLC.

[0440] Intermediate 1: 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0441]

[0442] 5-Chloro-2-pyrazinic acid (960 mg, 6.05 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (1000 mg, 6.05 mmol), chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate (2038 mg, 7.25 mmol), 1-methylimidazolium (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 give 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide, the crude product of which was used for the next step. MS (ES+) 306 (M+H), 1 H NMR(400MHz, CDCl3)9.37(1H,s),9.26(1H,d,J=1.4Hz),9.08(1H,d,J=1.8Hz),8.60 (1H,d,J=1.4Hz), 7.46(1H,d,J=2.8Hz), 6.87(1H,dd,J=1.8,10.8Hz), 2.49(3H,s).

[0443] Intermediate 2: 5-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrazin-2-carboxamide

[0444]

[0445] 5-Chloro-2-pyrazinic acid (1466 mg, 9.25 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (1500 mg, 9.25 mmol), chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate (3114 mg, 11.10 mmol), 1-methylimidazolium (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 stirred for 16 hours. The reaction mixture was then filtered and the solid was dried under vacuum to give 5-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrazin-2-carboxamide, the crude product of which was used for the next step. MS(ES+)302(M+H),1HNMR(400MHz,CDCl3)9.82(s,1H),9.25(d,J=1.4Hz,1H) ,9.14(s,1H),8.62(d,J=1.4Hz,1H),7.50(s,1H),2.85(s,3H),2.52(s,3H).

[0446] Intermediate 3: 6-ethoxy-2-methyl-2H-indazole-5-amine

[0447]

[0448] 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 EtOAc, washed with water (3x) and brine (1x), evaporated to dryness on silica, and purified by rapid chromatography. The minor peak among the two main peaks was 6-ethoxy-2-methyl-5-nitro-2H-indazole, which was used directly in the next step.

[0449] 6-Ethoxy-2-methyl-5-nitro-2H-indazole (117 mg, 0.53 mmol), EtOAc (15 mL), and methanol (15 mL) were combined and pumped through an H-cube with 10% Pd / C at a flow rate of 1 mL / min, 40 °C, and 40 bar. The reaction mixture was evaporated to dryness to give 6-ethoxy-2-methyl-2H-indazole-5-amine, the crude product of which was used in the next step.

[0450] Intermediate 4: 6-Methoxy-2-methyl-2H-indazole-5-amine

[0451]

[0452] 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 and stirred for 3 days at room temperature under a nitrogen atmosphere. The reaction mixture was then diluted with EtOAc, washed with water (x3) and brine (x1), evaporated to dryness on silica, and purified by rapid chromatography to give two regiomeric products. The minor regiomeric product corresponds to 6-methoxy-2-methyl-5-nitro-2H-indazole. MS(ES+)208(M+H). 1 H NMR (400MHz, DMSO) δ8.56(s,1H),8.42(s,1H),7.25(s,1H),4.18(s,3H),3.92(s,3H).

[0453] 6-Methoxy-2-methyl-5-nitro-2H-indazole (224 mg, 1.08 mmol), EtOAc (15 mL), and MeOH (15 mL) were combined and then pumped at 1 mL / min through an H-Cube with a 10% Pd / C box at 50 bar hydrogen and 40 °C. The reaction mixture was evaporated to dryness to give 6-methoxy-2-methyl-2H-indazole-5-amine, the crude product of which was used for subsequent reactions. MS (ES+) 178 (M+H).

[0454] Intermediate 5: N-isopropylpyrrolidine-3-amine·2HCl

[0455]

[0456] 1.31 g (7.07 mmol) of tert-butyl 3-oxopyrrolidine-1-carboxylate, 0.67 mL (7.78 mmol) of isopropylamine, 10 mL of dichloromethane, and 3.15 g (14.85 mmol) of sodium triacetoxyborohydride were combined and stirred at room temperature for 3 days. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3, extracted with dichloromethane, dried (MgSO4), and evaporated to dryness to give tert-butyl 3-(isopropylamino)pyrrolidine-1-carboxylate, the crude product of which was used in the next step.

[0457] 1.53 g (6.7 mmol) of 3-(isopropylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, 5 mL of MeOH, and 4 N HCl in dioxane (20 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound, the crude product of which was used for the next step.

[0458] Intermediate 6: N-(3,3-difluorocyclobutyl)pyrrolidine-3-amine·2HCl

[0459]

[0460] 3-O-pyrrolidine-1-carboxylic acid tert-butyl ester (1310 mg, 7.07 mmol, 1 equivalent) was dissolved in DCM (80 mL), and 3,3-difluorocyclobutan-1-amine (1120 mg, 7.78 mmol, 1.10 equivalent) and sodium triacetoxyborohydride (4650 mg, 21.9 mmol, 3.10 equivalent) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aqueous solution) and extracted three times with DCM. The combined organic matter was dried (MgSO4) and concentrated under vacuum to give crude 3-((3,3-difluorocyclobutanyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification.

[0461] Crude 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 was added to dioxane (20 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum to give the crude title compound, which was used without further purification. Intermediate 7: N-(oxetane-3-yl)pyrrolidine-3-amine·2TFA

[0462]

[0463] 3-Oxopyrrolidine-1-carboxylic acid tert-butyl ester (1310 mg, 7.70 mmol, 1 equivalent) was dissolved in DCM (10 mL), and oxetane-3-amine (568 mg, 7.78 mmol, 1.10 equivalent) and sodium triacetoxyborohydride (3140 mg, 14.84 mmol, 2.10 equivalent) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aqueous solution) and washed three times with DCM. The combined organic matter was washed with saturated salt solution, dried (using phase separation filter paper), and concentrated under vacuum to give crude 3-(oxetane-3-ylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification.

[0464] 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 h. The solvent was removed under vacuum to obtain the crude title compound, which was used without further purification.

[0465] Intermediate 8: (3R*,4S*)-N-cyclopropyl-4-fluoro-N-methylpyrrolidine-3-amine·2HCl

[0466]

[0467] (1R*,5S*)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (896 mg, 4.69 mmol), N-methylcyclopropylamine (1 g, 14.08 mmol), and water (1 mL) were combined in a sealed tube and heated to 50 °C for 2 days. The reaction was cooled to room temperature, quenched with a saturated aqueous solution of NaHCO3, extracted with dichloromethane (2x), dried (MgSO4), and evaporated to dryness to give (3R*,4R*)-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, the crude product of which was used in the next step.

[0468] Combine (3R*,4R*)-3-(cyclopropyl(methyl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) and dichloromethane (10 mL). 50% of the solution will be in THF (0.32 mL, 0.86 mmol). The solution was added dropwise at room temperature, and the reaction was stirred overnight. The reaction was quenched by adding saturated sodium bicarbonate and extracted with DCM (x2). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give tert-butyl (3R*,4S*)-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine-1-carboxylate, the crude product of which was used for the next step.

[0469] (3R*,4S*)-3-(cyclopropyl(methyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, MeOH (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a brown oil, the crude product of which was used for the next step.

[0470] Intermediate 9: (3aR*,6aS*)-3-cyclopropylhexahydro-2H-pyrrolo[3,4-d]oxazol-2-one hydrochloride

[0471]

[0472] (1R*,5S*)-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.25 g, 6.75 mmol), cyclopropylamine (8.0 mL, 95.84 mmol), and water (12 mL) were added to a reaction tube. The reaction tube was sealed and heated to 50 °C for 48 h. The reaction was cooled to room temperature and quenched by adding saturated sodium bicarbonate. The aqueous layer was extracted with DCM (x2), and the organic layer was dried (MgSO4). The solvent was removed under vacuum to give crude (3R*,4R*)-3-(cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, which was used in the next step without further purification.

[0473] The crude material (3R*,4R*)-3-(cyclopropylamino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester from the previous step was dissolved in DCM (40 mL) and di-tert-butyl dicarbonate (1.62 g, 7.43 mmol) was added, followed by triethylamine (2 mL, 14.35 mmol). The reaction was stirred overnight at room temperature. The solvent was removed under vacuum to give crude (3R*,4R*)-3-((tert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester, which was used in the next step without further purification.

[0474] Crude (3R*,4R*)-3-((tert-butoxycarbonyl)(cyclopropyl)amino)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (342 mg, 1.00 mmol) was dissolved in DCM (10 mL). 50% Deoxo- The solution was added dropwise at room temperature, and the reaction was stirred overnight. The reaction was quenched by adding saturated sodium bicarbonate and extracted with DCM (x2). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give (3aR*,6aS*)-3-cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-carboxylic acid tert-butyl ester. The material was used without further purification.

[0475] Crude (3aR*,6aS*)-3-cyclopropyl-2-oxohexahydro-5H-pyrrolo[3,4-d]oxazol-5-carboxylic acid tert-butyl ester (239 mg, 0.69 mmol) was dissolved in methanol (3 mL) and added dropwise to dioxane (3 mL) with 4N HCl. The reaction was stirred overnight at room temperature, and the solvent was removed under vacuum to give the title compound. The material was used in the next step without further purification.

[0476] Intermediate 10: 8-Methoxy-2-methylimidazo[1,2-a]pyrazine-6-amine·2HCl

[0477]

[0478] 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 (using a phase separator). The solvent was removed under reduced pressure, and the crude material was purified by silica gel column chromatography (gradient elution, 0-100% ethyl acetate in cyclohexane) to give the title compound. 1 ¹H NMR (400MHz, CDCl₃) δ 7.82 (d, J = 1.6Hz, 1H), 6.49 (d, J = 1.5Hz, 1H), 3.99 (s, 3H), 2.43 (s, 3H). LCMS (ES⁺) 244 (M + H)⁺, RT 3.07 min (analytical method AcHSSC18).

[0479] 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 bubbling nitrogen for 5 min, then heated to 100 °C for 42 h with a hot block. After cooling to room temperature, LCMS analysis showed partial conversion. The reaction mixture was evaporated to dryness on silica and purified by rapid chromatography, eluting with 1%–9% MeOH in EtOAc to give N-(8-methoxy-2-methylimidazo[1,2-a]pyrazine-6-yl)acetamide. MS(ES+)₂₂₁(M+H). 1 H NMR (400MHz, d6-DMSO) δ10.20(s,1H),8.79(s,1H),7.88(s,1H),4.04(s,3H),2.32(s,3H),2.10(s,3H).

[0480] HCl (4 M in dioxane, 4.3 mL, 17.25 mmol) was added to N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)acetamide (380 mg, 1.73 mmol) in methanol (11 mL) at room temperature with stirring. After 18 hours, the reaction mixture was concentrated under reduced pressure to give the title compound.

[0481] Intermediate 11: N-(tert-butyl)pyrrolidine-3-amine·2HCl

[0482]

[0483] 1000 mg, 5.40 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in DCM (10 mL), and tert-butylamine (0.62 mL, 5.94 mmol, 1.10 equivalent) and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equivalent) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aqueous solution) and washed three times with DCM. The combined organic matter was washed with saturated salt solution, dried (using phase separation filter paper), and concentrated under vacuum to give crude tert-butyl 3-(tert-butylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0484] Crude tert-butyl 3-(tert-butylamino)pyrrolidine-1-carboxylate (1310 mg, 5.41 mmol, 1 equivalent) was dissolved in methanol (10 mL), and 4M HCl (13.5 mL, 54.05 mmol, 10 equivalent) in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum to give crude N-(tert-butyl)pyrrolidine-3-amine·2HCl, which was used without further purification.

[0485] Intermediate 12: N-cyclopropylpyrrolidine-3-amine·2HCl

[0486]

[0487] 1000 mg, 5.40 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in DCM (10 mL), and cyclopropylamine (0.41 mL, 5.94 mmol, 1.10 equivalent) and sodium triacetoxyborohydride (2400 g, 11.34 mmol, 2.10 equivalent) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aqueous solution) and washed three times with DCM. The combined organic matter was washed with saturated salt solution, dried (using phase separation filter paper), and concentrated under vacuum to give crude tert-butyl 3-(cyclopropylamino)pyrrolidine-1-carboxylate, which was used without further purification.

[0488] 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 (13.5 mL, 53.91 mmol, 10 equivalent) in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum to give crude N-cyclopropylpyrrolidine-3-amine·2HCl, which was used without further purification.

[0489] Intermediate 13: N-(cyclopropylmethyl)pyrrolidine-3-amine

[0490]

[0491] 1000 mg, 5.40 mmol, 1 equivalent of tert-butyl 3-oxopyrrolidine-1-carboxylate was dissolved in DCM (10 mL), and cyclopropane methylamine (0.42 mL, 5.94 mmol, 1.10 equivalent) and sodium triacetoxyborohydride (2400 mg, 11.34 mmol, 2.10 equivalent) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with NaHCO3 (aqueous solution) and extracted three times with DCM. The combined organic matter was washed with saturated brine, dried (using phase separation filter paper), and concentrated under vacuum to give crude 3-((cyclopropylmethyl)amino)pyrrolidine-1-carboxylate tert-butyl ester, which was used without further purification.

[0492] 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 equivalent) in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum, and the residue was loaded into MeOH and placed on a 10 g SCX box (pre-conditioned with MeOH). Elution was performed with MeOH (2 CV) followed by 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated under vacuum to give crude N-(cyclopropylmethyl)pyrrolidine-3-amine, which was used without further purification.

[0493] Intermediate 14: 4-(pyrrolidone-3-yl)morpholine

[0494]

[0495] 3-O-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 5.4 mmol) and morpholine (0.52 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at room temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM and washed with water and brine, and the layers were separated using a phase separator. The solvent was removed under vacuum to obtain crude 3-morpholinopyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification.

[0496] 1.38 g (5.40 mmol) of tert-butyl 3-morpholinopyrrolidine-1-carboxylate was dissolved in methanol (10 mL) and 4 M HCl (13.5 mL, 53.99 mL) in dioxane was added at room temperature. The reaction was stirred for 18 h, and the solvent was removed under vacuum to give the crude product, which was purified by an SCX 10 g box (pre-conditioned with MeOH), eluted with MeOH (2 CV), and then eluted with 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated under vacuum to give crude 4-(pyrrolidine-3-yl)morpholine, which was used without further purification.

[0497] Intermediate 15: n-Butylpyrrolidine-3-amine·2HCl

[0498]

[0499] tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.4 mmol) and butylamine (0.59 mL, 5.94 mmol) were dissolved in DCM (10 mL). Sodium triacetoxyborohydride (2.4 g, 11.34 mmol) was added at room temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM and 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-(butylamine)pyrrolidine-1-carboxylate, which was used without further purification.

[0500] 1.31 g (5.41 mmol) of tert-butyl 3-(butylamine)pyrrolidine-1-carboxylate was dissolved in methanol (10 mL), and 4 M HCl (13.5 mL, 13.5 mL) in dioxane was added at room temperature. The reaction was stirred for 18 h, and the solvent was removed under vacuum to obtain crude N-butylpyrrolidine-3-amine, which was used without further purification.

[0501] Intermediate 16: N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-amine·2HCl

[0502]

[0503] 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 DCM (50 mL). Sodium triacetoxyborohydride (3.14 g, 14.84 mmol) was added at room temperature, and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM and washed with water and brine, and the layers were separated using a phase separator. The solvent was removed under vacuum to give crude tert-butyl 3-((tetrahydro-2H-pyran-4-yl)amino)pyrrolidine-1-carboxylate, which was used without further purification.

[0504] 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 was stirred for 18 h, and the solvent was removed under vacuum to give crude N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-amine·2HCl, which was used without further purification.

[0505] Intermediate 17: 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine

[0506]

[0507] Sodium hydride (60% dispersion in mineral oil, 256 mg, 6.4 mmol) was added in portions to a mixture of 6,8-dibromo-2-methylimidazo[1,2-a]pyrazine (1.69 g, 5.8 mmol) in methanol (30 mL), and the reaction was stirred for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was placed in EtOAc and washed with water and brine. The organic matter was concentrated under vacuum to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyrazine, which was used without further purification.

[0508] Intermediate 18: N-(pyrrolidone-3-ylmethyl)cyclopropylamine.2HCl

[0509]

[0510] 3-Formylpyrrolidine-1-carboxylic acid tert-butyl ester (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 a saturated aqueous solution of NaHCO3, extracted with dichloromethane, dried (MgSO4), and evaporated to dryness to give 2.29 g of 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil, the crude product of which was used in the next step.

[0511] 3-((cyclopropylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.29 g, 9.54 mmol), MeOH (20 ml), and 4N HCl in dioxane (10 ml) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a clear oil, the crude product of which was used for the next step.

[0512] Intermediate 19: N-methyl-N-(pyrrolidone-3-ylmethyl)prop-2-amine.2HCl

[0513]

[0514] 3-((isopropylamino)methyl)pyrrolidine-1-carboxylate tert-butyl ester (200 mg, 0.83 mmol) was dissolved in DMF (3 mL), and then sodium hydride (60%, 50 mg, 1.24 mmol) and methyl iodide (51 μL, 0.83 mmol) were added at room temperature and stirred for 65 h. The reaction mixture was then quenched with LiCl aqueous solution (4%), extracted with ethyl acetate (x2), dried on phase separator paper, and evaporated to dryness to give 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate tert-butyl ester (190 mg) as a clear oil, the crude product of which was used for the next step.

[0515] The tert-butyl 3-((isopropyl(methyl)amino)methyl)pyrrolidine-1-carboxylate (190 mg, 0.74 mmol), MeOH (3 ml), and 4N HCl in dioxane (1.9 ml) were combined and stirred at room temperature for 19 hours. The reaction mixture was then evaporated to dryness to give the title compound as an oil, the crude product of which was used for the next step.

[0516] Intermediate 20: N-(pyrrolidone-3-ylmethyl)prop-2-amine.2HCl

[0517]

[0518] 3-((isopropylamino)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 1.24 mmol), MeOH (5 mL), and 4N HCl in dioxane (4 mL) were combined and stirred at room temperature for 16 hours. The reaction mixture was then evaporated to dryness to give the title compound as a white solid, the crude product of which was used for the next step.

[0519] Intermediate 21: 6-Methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine. 2HBr

[0520]

[0521] According to method L Boc protection, 3-methoxypyridin-4-amine (370 mg, 2.98 mmol, 1 equivalent) was extracted. The crude product was purified by silica chromatography with an elution gradient of 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent was removed under vacuum to give tert-butyl (3-methoxypyridin-4-yl)carbamate (590 mg, 88%) as a white solid LCMS(ES+)225(M+H)+.

[0522] According to the method, the aminopyridinium salt was formed from tert-butyl (3-methoxypyridin-4-yl)carbamate (590 mg, 2.63 mmol, 1 equivalent). LCMS showed the consumption of the starting material and a new peak with the correct target mass ion (240). The reaction mixture was used for the next step without any treatment (assuming 100% yield).

[0523] According to method N 1,3-dipolar addition, from 1-amino-4-((tert-butoxycarbonyl)amino)-3-methoxypyridine-1-onium 2,4-dinitrophenolate (1114 mg, 2.63 mmol, 1 equivalent). The reaction mixture was concentrated onto silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-75% EtOAc in cyclohexane. The fractions containing the desired material 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 a grayish-white solid. LCMS (ES+) 350 (M+H) + 1H 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).

[0524] Decarboxylation was performed according to method OHBr from ethyl 5-((tert-butoxycarbonyl)amino)-6-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (169 mg, 0.484 mmol, 1 equivalent). The reaction mixture was concentrated under vacuum to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine as a brown oil. This was used for the next step without further purification.

[0525] 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

[0526]

[0527] According to method L Boc protection, from 3-fluoropyridin-4-amine (925 mg, 8.25 mmol, 1 equivalent). The crude product was purified by silica chromatography with an elution gradient of 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent was removed under vacuum to give tert-butyl (3-fluoropyridin-4-yl)carbamate (1453 mg, 83%) as a white solid LCMS(ES+)213(M+H)+.

[0528] According to the method, the aminopyridinium salt was formed from tert-butyl (3-fluoropyridin-4-yl)carbamate (503 mg, 2.37 mmol, 1 equivalent). LCMS showed the consumption of the starting material and a new peak with the correct target mass ion (228). The reaction mixture was used for the next step without any treatment (assuming 100% yield).

[0529] According to method N 1,3-dipolar addition, from 1-amino-4-((tert-butoxycarbonyl)amino)-3-fluoropyridine-1-onium 2,4-dinitrophenolate (1278 mg, 3.11 mmol, 1 equivalent), the reaction mixture was concentrated onto silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-20% EtOAc in cyclohexane. Fractions containing the target mass were combined and the solvent was removed under vacuum to give 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 further purified by silica chromatography with an elution gradient of 0-18% EtOAc in cyclohexane to give the title compound.

[0530] Ethyl 5-((tert-butoxycarbonyl)amino)-6-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (product 1) (127 mg, 12%) LCMS (ES+) 338 (M+H)+

[0531] Ethyl 5-((tert-butoxycarbonyl)amino)-4-fluoro-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (product 2) (265 mg, 25%) LCMS (ES+) 338 (M+H)+ 1 H NMR (400MHz, CDCl3) δ8.20-8.18(m,1H),7.90(dd,J=7.0,7.0Hz,1H),6.90(d,J=1 .9Hz, 1H), 4.35 (q, J = 7.2Hz, 2H), 2.63 (s, 3H), 1.55 (s, 9H), 1.40 (t, J = 7.3Hz, 3H).

[0532] Intermediate 24: 6-Fluoro-2-methylpyrazolo[1,5-a]pyridine-5-amine. 2HBr

[0533]

[0534] Decarboxylation was performed according to method OHBr 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 give crude 6-fluoro-2-methylpyrazolo[1,5-a]pyridine-5-amine as a brown solid. This was used for the next step without further purification. 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.

[0535]

[0536] According to method L Boc protection, 3-methylpyridin-4-amine (600 mg, 5.55 mmol, 1 equivalent) was purified by silica chromatography with an elution gradient of 0-100% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent was removed under vacuum to give tert-butyl (3-methylpyridin-4-yl)carbamate (939 mg, 81%) as a white solid. LCMS(ES+)209(M+H)+.

[0537] According to the method, the aminopyridinium salt was formed from tert-butyl (3-fluoropyridin-4-yl)carbamate (939 mg, 4.51 mmol, 1 equivalent). LCMS showed the consumption of the starting material and a new peak with the correct target mass ion (224). The reaction mixture was used for the next step without any treatment (assuming 100% yield).

[0538] According to method N1,3-dipolar addition, from 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-onium 2,4-dinitrophenolate (1835 mg, 4.51 mmol, 1 equivalent). The reaction mixture was concentrated onto silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-50% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent was removed under vacuum to give the title compound.

[0539] Ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (product 1) (516 mg, 34%) LCMS (ES+) 334 (M+H)+ 1 H NMR (400MHz, CDCl3) δ8.67(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, 7.2Hz, 3H).

[0540] Ethyl 5-((tert-Butoxycarbonyl)amino)-2,4-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (product 2) (253 mg, 18%) LCMS (ES+) 334(M+H)+ 1 H NMR (400MHz, CDCl3) δ8.23(d,J=7.4Hz,1H),7.67(d,J=7.3Hz,1H),6.54(s,1H),4. 35(q,J=7.2Hz,2H),2.58(s,3H),2.57(s,3H),1.54(s,9H),1.40(t,J=7.1Hz,3H).

[0541] Intermediate 27: 2,6-Dimethylpyrazolo[1,5-a]pyridine-5-amine. 2HBr

[0542]

[0543] Decarboxylation was performed according to method OHBr from ethyl 5-((tert-butoxycarbonyl)amino)-2,6-dimethylpyrazolo[1,5-a]pyridine-3-carboxylate (250 mg, 0.750 mmol, 1 equivalent). The reaction mixture was concentrated under vacuum to give crude 2,6-dimethylpyrazolo[1,5-a]pyridine-5-amine as a brown oil in 2HBr. This was used for the next step without further purification. Intermediate 28: 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine

[0544]

[0545] According to method L Boc protection, tert-butyl (3-ethoxypyridin-4-amine) (2200 mg, 15.9 mmol, 1 equivalent) was obtained as a yellow solid. It was used in the next step without further purification.

[0546] According to method M, aminopyridinium salt was formed from tert-butyl (3-ethoxypyridin-4-yl)carbamate (4200 mg, 17.6 mmol, 1 equivalent). LC-MS showed the consumption of the starting material and a new peak with the correct target mass ion (254). The reaction mixture was used for the next step without further treatment (assuming 100% yield).

[0547] According to method N1,3 dipole addition, from 1-amino-4-((tert-butoxycarbonyl)amino)-3-ethoxypyridine-1-onium 2,4-dinitrophenolate (7702 mg, 17.626 mmol, 1 equivalent). The reaction mixture was concentrated onto silica under vacuum, and the crude product was purified by silica chromatography with an elution gradient of 0-60% EtOAc in cyclohexane. The fractions containing the desired material were combined and the solvent was removed under vacuum to give ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 5%) as a yellow solid. LCMS (ES+) 364 (M+H) + 1H 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).

[0548] Decarboxylation was performed according to method OHBr from ethyl 5-((tert-butoxycarbonyl)amino)-6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (380 mg, 0.941 mmol, 1 equivalent). The reaction mixture was concentrated under vacuum to give crude 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine as a brown oil. The crude product was loaded onto a 5 g SCX box (pre-conditioned with MeOH). The residue was eluted with MeOH, followed by elution with 7 M NH3 in MeOH. The ammonia fraction was concentrated under vacuum to give 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-amine as a brown oil. This was used for the next step without further purification.

[0549] Intermediate 29: 6-(difluoromethoxy)-2-methyl-2H-indazole-5-amine

[0550]

[0551] 5-Bromo-1H-indazole-6-ol (900 mg, 4.22 mmol, 1 equivalent), sodium dichlorofluoroacetate (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 h. EtOAc and H₂O were added, and the layers were separated. The aqueous layer was washed with EtOAc (x²), and the combined organic matter was washed with brine, dried (using phase separation filter paper), and concentrated under vacuum. The crude product was purified by silica chromatography with an elution gradient of 5–100% EtOAc in cyclohexane. The fractions containing the desired material 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)

[0552] 5-Bromo-6-(difluoromethoxy)-1H-indazole (490 mg, 1.86 mmol, 1 equivalent) was dissolved in EtOAc (50 mL), and trimethyloxonium tetrafluoroborate (413 mg, 2.79 mmol, 1.5 equivalent) was added. The reaction mixture was stirred at room temperature for 16 h. EtOAc and H2O were added, and the layers were separated. The aqueous layer was washed with EtOAc (x2), the combined organic matter was washed with brine, dried (using phase separation filter paper), and concentrated under vacuum to give 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 77%) LCMS (ES+) 277,279(M+H)+(Br) 1H NMR (400MHz, DMSO) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.50 (s, 1H), 7.34 (t, J = 74.6Hz, 1H), 4.18 (s, 3H).

[0553] 5-Bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (400 mg, 1.44 mmol, 1 equivalent), diphenylmethyleneimine (0.24 mL, 1.44 mmol, 1 equivalent), Cs₂CO₃ (706 mg, 2.16 mmol, 1.5 equivalent), 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 min. The reaction mixture was stirred in a sealed tube at 80 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous phase was extracted with EtOAc (x³). The combined organic phases were washed with brine, dried (using phase separation filter paper), and the solvent was removed under vacuum. The crude product was purified by silica chromatography with an elution gradient of 0–75% EtOAc in cyclohexane. The fractions containing the desired material were combined, and the solvent was removed under vacuum to obtain N-(6-(difluoromethoxy)-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethyleneimine. Although impurities were still present, it was used in the next step without further purification.

[0554] N-(6-(difluoromethoxy)-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethylimine (220 mg, 0.48 mmol, 1 equivalent) was dissolved in MeOH (10 mL) and 4M HCl (0.48 mL, 1.91 mmol, 4 equivalent) in dioxane was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under vacuum to give 6-(difluoromethoxy)-2-methyl-2H-indazole-5-amine·2HCl as a red solid. This was used for the next step without further purification. Intermediate 30: 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazin-2-carboxamide

[0555]

[0556] According to method H TCFH coupling, 5-chloropyrazine-2-carboxylic acid (321 mg, 2.02 mmol, 1 equivalent) and 6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-amine·2HBr (858 mg, 2.02 mmol, 1 equivalent) were used. The reaction mixture was diluted with H2O and the solid was filtered off. The solid was washed with MeCN:H2O (1:2)(x3) to give 5-chloro-N-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazine-2-carboxamide (327 mg, 80% pure, 40%) LCMS(ES+)318(M+H)+ as a yellow solid.

[0557] Intermediate 31: (6-bromo-8-fluoroimidazolo[1,2-a]pyridin-2-yl)methanol

[0558]

[0559] 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 refluxed for 18 h. The reaction was cooled to room temperature and the solvent was removed under vacuum to give the residue. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate. The EtOAc layer was dried (MgSO4) and the solvent was removed under vacuum to give the residue, which was purified by silica chromatography with an elution gradient of 0–50% EtOAc / cyclohexane to give the title compound (1.76 g, 59%) as a grayish-white solid.

[0560] Methyl 6-bromo-8-fluoroimidazole[1,2-a]pyridine-2-carboxylate (1.76 g, 6.13 mmol) was dissolved in THF (50 mL) and cooled to -78 °C. 1 M DIBAL (12.88 mL, 12.88 mmol) was added dropwise to toluene, and the reaction was allowed to warm to room temperature for 18 h. The reaction was cooled to 0 °C in an ice bath and quenched by adding water. The aqueous layer was extracted with EtOAc x3, and the organic layer was dried (MgSO4). The solvent was removed under vacuum to obtain the residue, which was purified by silica chromatography with an elution gradient of 0–100% EtOAc / cyclohexane to give the title compound (1.1 g, 73%) as a clear oil.

[0561] Intermediate 32: (S)-5-(3-(((tert-butoxycarbonyl)(cyclopropyl)amino)methyl)pyrrolidone-1-yl)pyrazine-2-carboxylate lithium

[0562]

[0563] (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 methanol (50.00 mL) were combined. Sodium cyanoborohydride (345 mg, 5.49 mmol, 1.10 equivalent) was added, followed by acetic acid (0.20 mL). The reaction was then heated to 55 °C with a hot block for 2 days. The reaction was then cooled to room temperature. The mixture was diluted with dichloromethane, washed with 10% NaOH solution, dried (MgSO4), and concentrated under vacuum to give a mixture (1.29 g) of (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1-carboxylate tert-butyl ester and (R)-3-((dicyclopropylamino)methyl)pyrrolidine-1-carboxylate tert-butyl ester as a clear oil. The crude product was used for the next step.

[0564] A mixture of (3R)-3-[(cyclopropylamino)methyl]pyrrolidine-1-carboxylate tert-butyl ester and (R)-3-((dicyclopropylamino)methyl)pyrrolidine-1-carboxylate tert-butyl ester (1.20 g, 4.99 mmol, 1.00 equivalent), methanol (10 mL), and 4M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.01 equivalent) were combined and stirred at room temperature for 23 hours. The reaction was then concentrated under vacuum and partitioned between dichloromethane and 15% NaOH aqueous solution. The organic layer was concentrated under vacuum to give a mixture (718 mg) of N-[[(3S)-pyrrolidine-3-yl]methyl]cyclopropylamine dihydrochloride and (S)-N-cyclopropyl-N-(pyrrolidine-3-ylmethyl)cyclopropylamine dihydrochloride as a clear gel, which was used directly for the next step.

[0565] A mixture of N-[[(3S)-pyrrolidine-3-yl]methyl]cyclopropylamine and (S)-N-cyclopropyl-N-(pyrrolidine-3-ylmethyl)cyclopropylamine dihydrochloride (700 mg, 4.99 mmol, 1.00 equivalent), methyl 5-chloro-2-pyrazincarboxylate (861 mg, 4.99 mmol, 1.00 equivalent), N,N-diisopropylethylamine (2.0 mL, 11.5 mmol, 2.30 equivalent), and 1,4-dioxane (100.00 mL) was combined and heated to 100 °C for 16 hours using a hot block. The reaction mixture was cooled to room temperature and used directly in the next step.

[0566] Di-tert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.00 equivalent) was added to the reaction mixture from the previous step, and the mixture was stirred at room temperature for 2 hours. The crude reaction was concentrated onto silica under vacuum and purified by rapid chromatography to give methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidine-1-yl]pyrazine-2-carboxylate (682 mg) as a clear gel. This was used directly in the next step. LCMS(ES+)377(M+H)+.

[0567] Methyl 5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidine-1-yl]pyrazin-2-carboxylate (682 mg, 1.81 mmol, 1.00 equivalent), lithium hydroxide monohydrate (76 mg, 1.81 mmol, 1.00 equivalent), methanol (30.00 mL), and water (3.00 mL) were combined and heated to 50 °C for 16 hours using a hot block. The mixture was concentrated under vacuum to give [5-[(3S)-3-[[tert-butoxycarbonyl(cyclopropyl)amino]methyl]pyrrolidine-1-yl]pyrazin-2-carbonyl]oxylithium (672 mg) as a white solid. LCMS(ES+)363(M+H)+, acidic.

[0568] Intermediate 33: N-[[(3R)-pyrrolidone-3-yl]methyl]cyclopropylamine dihydrochloride

[0569]

[0570] N-[[(3R)-pyrrolidine-3-yl]methyl]cyclopropylamine dihydrochloride was prepared using the same chemical reaction as its enantiomer N-[[(3S)-pyrrolidine-3-yl]methyl]cyclopropylamine dihydrochloride and was used directly in the next step.

[0571] Intermediate 34: (R)-5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate lithium

[0572]

[0573] (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 methanol (50.00 mL) were combined. Sodium cyanoborohydride (371 mg, 5.91 mmol, 1.10 equivalent) was added, followed by acetic acid (0.20 mL). The reaction was then heated to 55 °C with a hot block for 20 hours. The reaction was cooled to room temperature and diluted with dichloromethane, washed with 10% NaOH solution, dried over (MgSO4), and concentrated under vacuum to give (3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.11 g) as a clear oil, which was used directly in the next step.

[0574] (3R)-3-(cyclopropylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (1.11 g, 4.91 mmol, 1.00 equivalent), methanol (10.00 mL), and 4M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol, 4.07 equivalent) were combined and stirred at room temperature for 20 hours. The reaction was concentrated under vacuum to give (3R)-N-cyclopropylpyrrolidine-3-amine dihydrochloride (985 mg) as a white semi-solid, which was used directly in the next step.

[0575] (3R)-N-cyclopropylpyrrolidine-3-amine dihydrochloride (985 mg, 4.95 mmol, 1.00 equivalent), methyl 5-chloro-2-pyrazincarboxylate (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 equivalent) were combined and heated to 100 °C for 3 days using a hot block. The reaction was cooled to room temperature, and the crude product was used in the next step.

[0576] Di-tert-butyl dicarbonate (1.1 mL, 5.00 mmol, 1.01 equivalents) was added to the reaction mixture from the previous step and stirred for 3 days. The reaction was concentrated onto silica under vacuum and purified by rapid chromatography to give methyl 5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidine-1-yl]pyrazine-2-carboxylate (436 mg) as a pale yellow gel, which was used directly in the next step. LCMS(ES+)363(M+H)+.

[0577] 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), methanol (30.00 mL), and water (3.00 mL) were combined and heated to 55 °C for 20 hours using a hot block. The reaction was concentrated under vacuum to give [5-[(3R)-3-[tert-butoxycarbonyl(cyclopropyl)amino]pyrrolidine-1-yl]pyrazine-2-carbonyl]oxylithium (349 mg) as a brownish-red glass. LCMS (ES+) 349(M+H)+, acidic.

[0578] Intermediate 35: N-(azacyclobutane-3-ylmethyl)cyclopropylamine

[0579]

[0580] Cyclopropylamine (2.1 mL, 29.7 mmol), tert-butyl 3-formylazetane-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 h. A saturated aqueous solution of sodium bicarbonate (200 mL) was added to the reaction mixture and stirred vigorously for 10 min. The organic matter was collected and washed with water and brine, then passed through a phase separator and concentrated to dryness to give the title compound (5.1 g, 83%) as a clear oil, which was used directly in the next step.

[0581] 3-[(cyclopropylamino)methyl]azacyclobutane-1-carboxylic acid tert-butyl ester (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 h. The reaction mixture was concentrated under vacuum and loaded onto an SCX container, and washed with DCM / MeOH (1:1). The compound was released using DCM / MeOH / 7M ammonia in MeOH (5:5:1) and concentrated to dryness to give N-(azacyclobutane-3-ylmethyl)cyclopropylamine (1.19 g, 71%) as a colorless oil. Special note: Multiple elutions are required to release the product from the SCX container. 1 HNMR(400MHz, CDCl3)δ,3.74(dd,J=7.8,7.8Hz,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).

[0582] Intermediate 36: 3-(azacyclobutane-3-yl)-1-methylpiperidine hydrochloride

[0583]

[0584] A mixture of tert-butyl 3-(piperidin-3-yl)azacyclobutane-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 matter was extracted with DCM. The combined organic matter was passed through a phase separator and concentrated under reduced pressure to give a crude material as a grayish-white gel, which was used without further purification (tert-butyl 3-(1-methylpiperidin-3-yl)azacyclobutane-1-carboxylate; 330 mg).

[0585] A solution of tert-butyl 3-(1-methylpiperidin-3-yl)azacyclobutane-1-carboxylate (265 mg, 1.04 mmol) in dioxane was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give a crude material as a colorless oil, which was used without further purification (3-(azacyclobutane-3-yl)-1-methylpiperidin hydrochloride; 310 mg). MS (ES+) 155.1 [M-HCl+H] + .

[0586] Intermediate 37: 3-(azacyclobutane-3-yl)-1-cyclopropylpiperidine hydrochloride

[0587]

[0588] A mixture of tert-butyl 3-(piperidin-3-yl)azacyclobutane-1-carboxylate (250 mg, 1.04 mmol), 1-(ethoxycyclopropoxy)trimethylsilane (0.23 mL, 1.14 mmol), and sodium cyanoborohydride in methanol (10 mL) and acetic acid (0.1 mL) was heated to 50 °C for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic matter was separated and washed with brine, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give a crude material as an orange gel, which was used without further purification (tert-butyl 3-(1-cyclopropylpiperidin-3-yl)azacyclobutane-1-carboxylate; 224 mg). MS (ES+) 281.2 [M+H + .

[0589] A solution of tert-butyl 3-(1-cyclopropylpiperidin-3-yl)azacyclobutane-1-carboxylate (224 mg, 0.799 mmol) in dioxane and 4 M HCl (6.7 mL, 26.6 mmol) in methanol (6.7 mL) was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give a crude material as a colorless oil, which was used without further purification (3-(azacyclobutane-3-yl)-1-cyclopropylpiperidin hydrochloride; 144 mg). MS (ES+) 181.1 [M-HCl+H + .

[0590] Intermediate 38: 5-chloro-N-(6-ethoxy-2-methyl-indazol-5-yl)pyrazine-2-carboxamide

[0591]

[0592] Iodomethane (0.76 mL, 12.2 mmol) was added dropwise 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), and the reaction was stirred overnight. The reaction mixture was diluted with EtOAc and water, the organic compounds were separated, and further extracted with EtOAc. The combined organic compounds were washed with brine, dried over sodium sulfate, decanted, and concentrated under reduced pressure. The crude material was purified by rapid column chromatography (0 to 100% EtOAc in cyclohexane; 80 g column). The fraction containing the product was concentrated under reduced pressure to give the title compound (586 mg; 23% yield) as a brown solid. MS (ES+) 222.2 [M+H] + . 1HNMR (400MHz, CDCl3) δ8.16 (s, 1H), 8.00 (s, 1H), 7.08 (s, 1H), 4.21-4.15 (m, 5H), 1.49 (t, J = 7.0Hz, 3H).

[0593] 10% palladium on carbon (279 mg, 2.62 mmol) was added to a completely 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), and the reaction was heated to 70 °C overnight. After 24 hours, the reaction was cooled to room temperature, filtered through a diatomaceous earth pad, and washed with MeOH. The filtrate was concentrated under reduced pressure to produce a brown gel, and the crude material was used directly for the next step without further purification (460 mg; 92% yield). MS (ES+) 192.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.54 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 4.09 (s, 3H), 3.72 (q, J = 7.0Hz, 2H), 1.49 (t, J = 7.0Hz, 3H).

[0594] A suspension of 6-ethoxy-2-methyl-indazole-5-amine (460 mg, 2.41 mmol), 5-chloro-2-pyrazinic acid (381 mg, 2.41 mmol), chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate (810 mg, 2.89 mmol), and 1-methylimidazole (0.58 mL, 7.22 mmol) in acetonitrile (12 mL) was stirred under nitrogen for over a 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 give 5-chloro-N-(6-ethoxy-2-methyl-indazole-5-yl)pyrazin-2-carboxamide (410 mg; 51% yield) as a yellow powder. MS (ES+) 332.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.39(s,1H),9.27(d,J=1.4Hz,1H),8.81(s,1H),8.62(d,J=1.4Hz, 1H), 7.82 (s, 1H), 7.02 (s, 1H), 4.22 (q, J = 7.0Hz, 2H), 4.16 (s, 3H), 1.57 (t, J = 7.0Hz, 3H).

[0595] Intermediate 39: N-(azacyclobutane-3-ylmethyl)cyclopropylamine dihydrochloride

[0596]

[0597] A suspension of tert-butyl 3-fluoro-3-(hydroxymethyl)azacyclobutane-1-carboxylate (500 mg, 2.44 mmol) and Des Martin periodane (1.24 g, 2.92 mmol) in dichloromethane (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with an aqueous solution of sodium thiosulfate (10% w / v) and a saturated aqueous solution of sodium bicarbonate and stirred for 20 minutes. The mixture was passed through a phase separator, and the organic matter was concentrated under reduced pressure to give a colorless oil, which was used without further purification (480 mg; 97% yield).

[0598] A mixture of tert-butyl 3-fluoro-3-formyl-azacyclobutane-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 matter was concentrated under reduced pressure to give a crude material (250 mg; 87% yield) as a pale yellow gel.

[0599] A solution of tert-butyl 3-[(cyclopropylamino)methyl]-3-fluoro-azacyclobutane-1-carboxylate (250 mg, 1.02 mmol) in dioxane and 4M hydrogen chloride (5.0 mL, 20.0 mmol) in methanol (5 mL) was stirred for three days at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude material as a brown solid, which was used without further purification (210 mg; 95% yield).

[0600] Intermediate 40: 1-(azacyclobutane-3-ylmethyl)-3-methoxy-azacyclobutane

[0601]

[0602] 3-Formylpyrrolidine-1-carboxylate tert-butyl ester (0.50 g, 2.70 mmol), sodium triacetoxyborohydride (1.26 g, 5.94 mmol), and 3-methoxyaziridine hydrochloride (334 mg, 2.70 mmol) were combined in dichloromethane (50 mL) and stirred at room temperature for 17 hours. A saturated aqueous solution of sodium bicarbonate (15 mL) was added to the reaction mixture, and the mixture was stirred vigorously for 10 min. The organic matter was collected and washed with water and brine, then passed through a phase separator and concentrated to dryness to give 3-[(3-methoxyaziridine-1-yl)methyl]aziridine-1-carboxylate tert-butyl ester (700 mg), which was used without further purification.

[0603] 3-[(3-methoxyaziridine-1-yl)methyl]aziridine-1-carboxylic acid tert-butyl ester (700 mg, 2.73 mmol) and trifluoroacetic acid (1.0 mL, 13.7 mmol) were combined in dichloromethane (30 mL) and stirred at room temperature for 21 hours. The reaction mixture was concentrated under vacuum and then dissolved in DCM:MeOH (1:1, 20 mL) and passed through an SCX cartridge. The column was eluted with DCM:MeOH (1:1) to remove TFA, and the product was released using DCM:MeOH:7M NH3 in MeOH (5:5:1). The fraction containing the product was concentrated to dryness to give 1-(aziridine-3-ylmethyl)-3-methoxy-aziridine (400 mg) as a colorless oil.

[0604] Intermediate 41: 1-Cyclopropyl-3,3'-Diazacyclobutane

[0605]

[0606] The tert-butyl 1-[3,3'-diazacyclobutane]-1-carboxylate (80 mg, 0.38 mmol), (1-ethoxycyclopropoxy)trimethylsilane (0.15 mL, 0.75 mmol), methanol (2.5 mL), acetic acid (0.01 mL), and sodium cyanoborohydride (47 mg, 0.75 mmol) were combined and stirred at 50 °C for 18 hours. The mixture was partitioned between DCM and saturated sodium bicarbonate, dried, and evaporated to give 1'-cyclopropyl-[3,3'-diazacyclobutane]-1-carboxylate tert-butyl ester (103 mg) as a colorless oil, the crude product of which was used in the next step.

[0607] 1'-Cyclopropyl-[3,3'-diazacyclobutane]-1-carboxylic acid tert-butyl ester (100 mg, 0.38 mmol), DCM (1 ml), and TFA (1 ml) were combined and stirred at room temperature for 65 hours. The reaction mixture was purified by SCX to give 1-cyclopropyl-3,3'-diazacyclobutane (56 mg) as a crude yellow oil, which was used in the next step.

[0608] Intermediate 41a: 2,8-Dimethylimidazo[1,2-a]pyrazine-6-amine

[0609]

[0610] 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% ammonia solution (8 mL) was heated to 90 °C for 3 h under microwave irradiation. After cooling to room temperature, the material was filtered through diatomaceous earth and washed with water and methanol. The filtrate was acidified to pH 4 with 2 M HCl and then concentrated. The residue was applied to a 70 g SCX box and eluted with 100 mL MeOH, followed by 150 mL 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 give 2,8-dimethylimidazo[1,2-a]pyrazine-6-amine (450 mg, 2.77 mmol, 63%) as a brown powder.

[0611] Intermediate H1: 5-chloro-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0612]

[0613] 3-Chloro-5-nitro-pyridin-2-amine (0.0010 g, 5.76 μmol), 1-bromo-2,2-dimethoxypropane (0.0012 mL, 9.22 μmol), pyridinium p-toluenesulfonate (0.00014 g, 0.576 μmol), and IPA (10.00 mL) were combined, and the reaction mixture was stirred at 95 °C for 4.5 h. The reaction mixture was filtered and washed with IPA to give the desired product (91% purity, 1.5 g, quantitative). LCMS (ES) + )212(M+H) + , RT 1.35min.

[0614] 8-Chloro-2-methyl-6-nitro-imidazo[1,2-a]pyridine (300 mg, 1.42 mmol) and iron (396 mg, 7.09 mmol) in acetic acid (1 mL) were stirred at 60 °C for 1 h. The reaction mixture was loaded into an SCX container and passed through 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 give the desired product (211 mg, 82%). LCMS (ES) + )181(M+H) + , RT 1.05min.

[0615] 8-Chloro-2-methylimidazo[1,2-a]pyridin-6-amine (211 mg, 1.16 mmol), 5-chloro-2-pyrazinic acid (184 mg, 1.16 mmol), chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate (489 mg, 1.74 mmol), and 1-methylimidazolium (0.28 mL, 3.49 mmol) were stirred in acetonitrile (8.00 mL) under nitrogen at room temperature for 16 h. The reaction mixture was concentrated, diluted with DCM, and washed with aqueous sodium bicarbonate solution. The organic layer was concentrated onto silica and purified by column chromatography, eluting with cyclohexane / EtOAc (0-100% gradient). Appropriate fractions were combined and concentrated under vacuum to give the desired product (211 mg, 75%). LCMS (ES) + )322(M+H) + ,RT 1.23min. 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 9.26 (s, 1H), 9.21 (d, J = 1.6Hz, 1H), 8.60 (s, 1H), 7.47 (s, 1H), 7.19 (d, J = 1.6Hz, 1H), 2.51 (s, 3H).

[0616] Intermediate H2 (5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide)

[0617]

[0618] 5-Bromo-3-methoxy-pyridin-2-amine (3.57 g, 17.6 mmol), 1-bromo-2,2-dimethoxypropane (3.8 mL, 28.1 mmol), pyridinium p-toluenesulfonate (0.44 g, 1.76 mmol), and IPA (10.00 mL) were combined. The reaction mixture was stirred at 95 °C for 5 h. The reaction mixture was diluted with 3:1 DCM / IPA and washed with brine. The organic layer was concentrated under vacuum to give 6-bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (4.2 g, 96%). LCMS (ES) + )242(M+H) + ,RT 1.02min. 1 H NMR (400MHz, DMSO) δ8.44(1H,d,J=1.6Hz), 7.66(1H,s), 6.81(1H,d,J=1.5Hz), 3.95(3H,s), 2.32(3H,s).

[0619] 6-Bromo-8-methoxy-2-methylimidazo[1,2-a]pyridine (1.01 g, 4.19 mmol), copper iodide (I) (0.16 g, 0.838 mmol), potassium carbonate (0.87 g, 6.28 mmol), ammonium hydroxide solution (0.26 mL, 6.28 mmol), L-proline (0.19 g, 1.68 mmol), and DMSO (10.00 mL) were added to a reaction flask. The reaction vessel was sealed and heated at 90 °C for 16 h. The reaction mixture was passed through an SCX box containing MeOH and NH3 (7 M) in MeOH, and the appropriate fractions were concentrated under vacuum to give the desired product (1.19 g, 99%). LCMS(ES) + 179 (M+H) + .

[0620] 8-Methoxy-2-methylimidazo[1,2-a]pyridin-6-amine (326 mg, 1.84 mmol), 5-chloro-2-pyrazincarboxylic acid (292 mg, 1.84 mmol), chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate (774 mg, 2.76 mmol), and 1-methylimidazolium (0.44 mL, 5.52 mmol) were stirred under nitrogen at room temperature for 16 h. The reaction mixture was concentrated, diluted with 3:1 DCM:IPA, and washed with brine. The crude product was purified by column chromatography, eluting with cyclohexane / EtOAc (0-100% gradient) to give 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (909 mg, 87%). LCMS (ES) + )317(M+H) + .

[0621] Intermediate H3: 5-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrazin-2-carboxamide

[0622]

[0623] HBTU (1.88 g, 4.96 mmol, 1.00 equivalent), triethylamine (3.5 mL, 24.8 mmol, 5.00 equivalent), 5-chloro-2-pyrazinic 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 h. LC-MS showed no expected chlorination material present, but rather the formation of HOBt adducts. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was washed several times with EtOAc. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum. Note: A significant amount of the HOBt adduct was retained in the aqueous layer. The material was purified by rapid silica chromatography (gradient elution from c-hex to EtOAc) to obtain 5-(benzotriazol-1-yloxy)-N-(7-fluoro-2-methyl-indazole-5-yl)pyrazin-2-carboxamide (586 mg, 28%) as a pale yellow solid. LCMS (ES+) 405 (M+H) + . 1 H NMR (400MHz, DMSO) δ10.81 (s, 1H), 9.16 (s, 1H), 8.82 (s, 1H), 8.48 (d, J = 2.7Hz, 1H), 8.25-8.2 0(m,2H),7.87(d,J=8.3Hz,1H),7.71(dd,J=7.6,7.6Hz,1H),7.62-7.57(m,2H),4.20(s,3H).

[0624] Intermediate 42: 7-Fluoro-2-methyl-2H-indazole-5-amine hydrochloride

[0625]

[0626] 5-Bromo-2,3-difluorobenzaldehyde (5 g, 22.6 mmol), methoxyamine hydrochloride (2.27 g, 27.1 mmol), and potassium carbonate (6.88 g, 49.8 mmol) were added to ethylene glycol dimethyl ether (100 mL). The reaction was heated to 45 °C for 18 h. The reaction was cooled to room temperature and filtered through a glass sintered filter. The collected solid was washed with EtOAc. The collected liquid was concentrated under vacuum to give 5-bromo-2,3-difluorobenzaldehyde O-methyl oxime (6.82 g, 100%) as a pale yellow solid.

[0627] 5-Bromo-2,3-difluorobenzaldehyde O-methyl oxime (5.66 g, 22.6 mmol) was dissolved in 1,4-dioxane (150 mL), and hydrazine (3.6 mL, 0.113 mol) was added. The reaction was heated at 90 °C for 5 days. The reaction was cooled to room temperature and concentrated under vacuum. The residue was purified by silica chromatography (EtOAc / cyclohexane 0-40%) to give 5-bromo-7-fluoro-2H-indazole (3.83 g, 71%) as a grayish-white solid.

[0628] 5-Bromo-7-fluoro-1H-indazole (3.83 g, 17.8 mmol) was dissolved in ethyl acetate (100 mL) and cooled to 0 °C in an ice bath. Trimethyloxonium tetrafluoroborate (3.95 g, 26.7 mmol) was added in portions, and the reaction was warmed to room temperature after the addition was complete. The reaction was stirred at room temperature for 18 h. The reaction was quenched with water, extracted with EtOAc, and the layers were separated. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel, eluting with 0–50% EtOAc in cyclohexane to give 5-bromo-7-fluoro-2-methyl-2H-indazole (2.42 g, 55%) as a grayish-white solid.

[0629] 5-Bromo-7-fluoro-2-methyl-indazole (2.42 g, 10.6 mmol) was dissolved in degassed tetrahydrofuran (100 mL), and cesium carbonate (5.16 g, 15.8 mmol), palladium(II) acetate (0.24 g, 1.06 mmol), (rac)-2,2'-bis(diphenylphosphino)-1,1'-bidinaphthalene (0.66 g, 1.06 mmol), and benzophenone imine (1.8 mL, 10.6 mmol) were added. The reaction tube was purged with nitrogen and sealed. The reaction was heated at 80 °C for 18 h. The reaction was cooled to room temperature, the solid was filtered and washed with EtOAc. The filtrate was concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel, eluting with EtOAc / cyclohexane 0-100% to give oil (3 g). 1 1H NMR analysis showed that the main component was 5-bromo-7-fluoro-2-methyl-indazole, of which 35% was converted to N-(7-fluoro-2-methyl-2H-indazole-5-yl)-1,1-diphenylmethylene.

[0630] Impure material (3.00 g, 4.58 mmol, assumed 35% purity) was dissolved in degassed tetrahydrofuran (80 mL), and cesium carbonate (2.24 g, 6.88 mmol), palladium(II) acetate (0.21 g, 0.917 mmol), (rac)-(+)-2,2'-bis(diphenylphosphino)-1,1'-bidinaphthalene (0.57 g, 0.917 mmol), and benzophenone imine (0.92 mL, 5.50 mmol) were added. The reaction tube was purged with nitrogen and sealed. The reaction was heated at 80 °C for 24 h. The reaction was cooled to room temperature, the solid was filtered, and washed with EtOAc. The filtrate was concentrated under vacuum to obtain the residual oil. The residue was purified by column chromatography on silica gel and eluted with EtOAc / cyclohexane 0-100% to give N-(7-fluoro-2-methyl-2H-indazol-5-yl)-1,1-diphenylmethyleneimine (2.56 g, >100%) as a grayish-white solid.

[0631] N-(7-fluoro-2-methyl-indazol-5-yl)-1,1-diphenyl-methylimine (2.56 g, 7.77 mmol) was suspended in methanol (10 mL), and 4N hydrogen chloride (19 mL, 77.7 mmol) in dioxane was added at room temperature. The reaction was stirred at room temperature for 18 h. The solvent was removed under vacuum to give a pale yellow solid. EtOAc was added, and the resulting slurry was stirred for about 10 min. The solid was filtered and washed with additional EtOAc to give the title compound (1.66 g, 95%) as a grayish-white solid. LCMS(ES+)166(M+H)+.

[0632] Intermediate 43: Cyclopropyl ((2-oxopyrrolidone-3-yl)methyl)tert-butyl carbamate

[0633]

[0634] Methanesulfonyl chloride (0.58 mL, 7.45 mmol) was added dropwise to a stirred solution of 3-(hydroxymethyl)pyrrolidone-2-one (780 mg, 6.77 mmol) in dichloromethane (50 mL) and triethylamine (1.9 mL, 13.5 mmol). The reaction was stirred at room temperature for 18 h. The reaction was quenched by adding water, and the layers were separated using a phase separator. DCM was removed under vacuum to give (2-oxopyrrolidone-3-yl)methylmethanesulfonate (800 mg, 61%) as a white solid.

[0635] Methyl (2-oxopyrrolidone-3-yl)methanesulfonate (800 mg, 4.14 mmol) was dissolved in acetonitrile (15 mL), and triethylamine (1.7 mL, 12.4 mmol) was added, followed by cyclopropylamine (1.7 mL, 24.8 mmol). The reaction tube was sealed and heated in a microwave oven at 120 °C for 2 h. 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 10% 7N NH3 / MeOH in MeOH). The ammonia fraction was combined and the solvent was removed under vacuum to give 3-((cyclopropylamino)methyl)pyrrolidone-2-one (438 mg, 69%) as a yellow oil.

[0636] 3-[(cyclopropylamino)methyl]pyrrolidone-2-one (438 mg, 2.84 mmol) was dissolved in dichloromethane (30 mL). Di-tert-butyl dicarbonate (0.72 mL, 3.12 mmol) and 4-(dimethylamino)pyridine (17 mg, 0.142 mmol) were added. The reaction was stirred at room temperature for 18 h. The solvent was removed under vacuum to obtain a residue, which was purified by silica chromatography (10 g, eluted with EtOAc) to give the title compound (420 mg, 58%) as a clear oil. Intermediate 44: 5-chloro-N-(7-fluoro-2-methyl-2H-indazol-5-yl)pyrazin-2-carboxamide

[0637]

[0638] 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 was stirred at room temperature for 3 h. The reaction was quenched by adding water, and the aqueous layer was extracted with DCM. The layers were separated using a phase separator, and DCM was removed under vacuum to give the title compound (280 mg, 65%) as a light brown solid. This was used in the next step without further purification.

[0639] Intermediate 45: 5-chloro-N-(1H-indazol-5-yl)pyrazin-2-carboxamide

[0640]

[0641] 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 was stirred at room temperature for 3 h.

[0642] The reaction was quenched with water, and the aqueous phase was extracted with DCM x3. The layers were separated using a phase separator, and the solvent was removed under vacuum to give the title compound (305 mg, 79%) as a brown solid. It was used for the next step without further purification.

[0643] Intermediate 46: 5-chloro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-carboxamide

[0644]

[0645] 4-Fluoro-2-methyl-1,3-benzoxazol-6-amine (200 mg, 1.20 mmol), 5-chloro-2-pyrazinic 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'-tetramethylformamidin hexafluorophosphate (400 mg, 1.43 mmol) was added, and the suspension was stirred at room temperature for 18 h.

[0646] The solid formed was collected by filtration and washed with acetonitrile and water. The solid was dried overnight in a vacuum oven to give the title compound (250 mg, 67%) as a grayish-white solid. It was used for the next step without further purification.

[0647] Intermediate 47: 5-(3-(((tert-butoxycarbonyl)(methyl)amino)methyl)azacyclobutane-1-yl)pyrazine-2-carboxylic acid

[0648]

[0649] N-(azacyclobutane-3-ylmethyl)carbamate tert-butyl ester (675 mg, 3.62 mmol), methyl 5-chloro-2-pyrazinate (625 mg, 3.62 mmol), cesium carbonate (2373 mg, 7.28 mmol), and 1,4-dioxane (25 mL) were combined and heated under reflux overnight. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The residue was absorbed in DCM and 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 (25 g, eluted with EtOAc 0-100% in cyclohexane) to give a yellow oil (870 mg, 74%).

[0650] Methyl 5-[3-[(tert-butoxycarbonylamino)methyl]azacyclobutan-1-yl]pyrazine-2-carboxylate (250 mg, 0.776 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (60%, 34 mg, 0.853 mmol) was added. The reaction was stirred at room temperature for 1 h. Iodomethane (0.048 mL, 0.776 mmol) was added, and the reaction was stirred at room temperature for 18 h. The reaction was quenched with MeOH (to avoid ester hydrolysis), and the solvent was removed under vacuum to give the residual oil. This was used for the next step without further purification.

[0651] Methyl 5-[3-[[tert-butoxycarbonyl(methyl)amino]methyl]azacyclobutane-1-yl]pyrazine-2-carboxylate (261 mg, 0.776 mmol) was dissolved in methanol (2 mL) and water (1 mL), and lithium hydroxide monohydrate (33 mg, 0.776 mmol) was added. The reaction was stirred at room temperature for 18 h. 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 EtOAc x4. The organic layer was separated and dried over a hydrophobic glass feedstock. The solvent was removed under vacuum to give the title compound (155 mg, 61%) as a clear oil. It was used for the next step without further purification.

[0652] Intermediate 48: 7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine-6-amine.HCl

[0653]

[0654] 4-Fluoro-3-methylpyridin-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 h. The reaction mixture was then evaporated to dryness to give a brown solid, the crude of which was used for the next step. LCMS(ES+)205 / 207(M+H)+.

[0655] 5-Bromo-4-fluoro-3-methylpyridin-2-amine (813 mg, 3.96 mmol) (from the crude product of the previous step), 1-bromo-2,2-dimethoxypropane (0.80 mL, 5.95 mmol), p-toluenesulfonic acid pyridinium (100 mg, 0.396 mmol), and 2-propanol (15 mL) were combined in a sealed tube and heated to 85 °C overnight. A grayish-white precipitate was observed. The reaction mixture was cooled to room temperature, concentrated under vacuum, and partitioned between about 10% aqueous NaOH and dichloromethane. The organic phase was dried (MgSO4) and concentrated under vacuum to give 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 (400MHz, CDCl3) δ8.09 (d, J = 6.3 Hz, 1H), 7.25 (s, 1H), 2.53 (d, J = 2.5 Hz, 3H), 2.44 (s, 3H).

[0656] Cesium carbonate (1721 mg, 5.28 mmol), palladium(II) acetate (79 mg, 0.352 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-bidinaphthalene (219 mg, 0.352 mmol), 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine (856 mg, 3.52 mmol), and tetrahydrofuran (20 mL) were combined, and the reaction mixture was degassed by bubbling under nitrogen for 5 min. The reaction tube was sealed and heated to 85 °C with a hot block over the weekend. The reaction mixture was filtered through a diatomaceous earth layer to remove the cesium salt and washed with EtOAc. The organic phase was concentrated onto silica under vacuum and purified by rapid chromatography. The starting material and target appear as a co-extruded gel. 622 mg, brownish solid. LCMS alkaline, RT = 1.42 min, 243 / 245 M+H starting material, RT = 1.70 min, 344 M+H target. Used as is for the next step.

[0657] A mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine and N-(7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-yl)-1,1-diphenyl-methylimino (622 mg, from a previous step), methanol (5 mL), and 4M hydrogen chloride in dioxane (5.0 mL, 20.0 mmol) was combined and stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness to give 767 mg of amber solid. LCMS analysis showed a mixture of 6-bromo-7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridine and 7-fluoro-2,8-dimethyl-imidazo[1,2-a]pyridin-6-amine in HCl. LCMS basic, RT = 1.04 min, 180 M + H target, RT = 1.42 min, 243 / 245 bromide in the starting material. Use it as is for the next step.

[0658] Example 1: (R)-5-(2-ethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0659]

[0660] (R)-3-ethylpiperazin-1-carboxylic acid tert-butyl ester (263 mg, 1.23 mmol) was added to a solution of intermediate 1 (150 mg, 0.49 mmol) in dioxane (1 mL). Triethylamine (0.1 mL, 0.74 mmol) was added, and the reaction was heated in a microwave oven at 140 °C for 30 min. The solvent was removed under vacuum, and the residue was purified by silica chromatography (elution gradient 0-10% ethyl acetate / cyclohexane) to give (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperazin-1-carboxylic acid tert-butyl ester. MS (ES+) 484 (M+H).

[0661] 4M hydrochloric acid in dioxane (10 mL) was added to a solution of (R)-3-ethyl-4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.29 mmol) in methanol (2 mL). The reaction was stirred at room temperature for 1 h. The solvent was removed under vacuum, and the crude product was purified by reversed-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 h. 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 (400MHz, DMSO) δ10.44 (s, 1H), 9.22 (d, J = 1.3Hz, 1H), 8.77 (s, 1H), 8.31 (s,1H),7.93(d,J=2.0Hz,1H),7.60(dd,J=1.1,12.7Hz,1H),4.47-4.44(m, 1H),4.32(d,J=12.9Hz,1H),3.14-2.98(m,3H),2.81(dd,J=2.9,12.5Hz,1H ), 2.70-2.64 (m, 1H), 2.39 (s, 3H), 1.92-1.74 (m, 2H), 0.89 (t, J = 7.5Hz, 3H).

[0662] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0663]

[0664]

[0665]

[0666] Example 12: 5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0667]

[0668] The following materials were prepared using general method D in the following quantities: intermediate 1 (127 mg, 0.41 mmol), N-(pyrrolidone-3-ylmethyl)cyclopropylamine dihydrochloride (87 mg, 0.41 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (3 mL). The crude material was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 410.2(M+H)+, RT 3.59 min (analytical method Bicarb BEHC18). 1 H NMR (400MHz, DMSO) δ10.17(s,1H),8.95(d,J=1.7Hz,1H),8.50(d,J=1.4Hz,1H),7 .72(d,J=1.1Hz,1H),7.65(dd,J=0.8,3.1Hz,1H),7.33(dd,J=1.6,13.1Hz,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).

[0669] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0670]

[0671]

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684] Example 52: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(pyrrolidine-1-ylmethyl)pyrrolidine-1-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0685]

[0686] Intermediate 2 (100 mg, 0.3 mmol), 1-(pyrrolidone-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 heated to 100 °C for 16 hours using a hot block. 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. LCMS (ES⁺) 421.2(M⁺H)⁺, RT 2.04 min (Analytical method AcHSSC18); 1 H NMR (400MHz, DMSO) δ9.66 (s, 1H), 9.15 (s, 1H), 8.75 (d, J = 1.3Hz, 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=1.9Hz,6H),2.50-2.42(m,6H),2.40(s,3H),2.15-2.13(m,1H),1.71(s,6H).

[0687] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0688]

[0689]

[0690]

[0691]

[0692] Example 65: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(piperazin-1-yl)pyrazin-2-carboxamide

[0693]

[0694] 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 heated to 100 °C for 4 hours using a hot block. The reaction mixture was diluted with EtOAc, washed with water (x2), brine, and evaporated to dryness to give methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazine-2-carboxylate, the crude product of which was used in the next step. MS (ES+) 323 (M+H).

[0695] Methyl 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazin-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 give lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazin-2-carboxylate, the crude product of which was used for the next step. MS (ES+) 309 (M+H).

[0696] Lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazin-2-carboxylate (157 mg, 0.5 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (81 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL), and DMF (2 mL) were combined and stirred at room temperature for 3 days. The reaction mixture was then purified by preparative HPLC to give tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazin-1-carboxylate. MS (ES+) 453 (M+H).

[0697] 10.6 mg of 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazin-1-carboxylic acid tert-butyl ester, 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 absorbed in MeOH. Na₂CO₃ was added and stirred for 5 min. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 353(M+H)⁺, RT 1.86 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ9.68(s,1H),9.15(s,1H),8.75(d,J=1.1Hz,1H),8.37(d,J=1.1Hz,1H ), 8.01 (s, 1H), 3.71-3.67 (m, 4H), 2.82 (dd, J = 5.1, 5.1Hz, 4H), 2.71 (s, 3H), 2.40 (s, 3H).

[0698] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0699]

[0700]

[0701] Other analogues are prepared from commercially available or synthetic amines using the same chemical reaction, but with 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine instead of 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0702]

[0703]

[0704]

[0705]

[0706] Example 83(R)-5-(3-(ethylamino)pyrrolidone-1-yl)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazin-2-carboxamide

[0707]

[0708] 5-Chloropyrazin-2-carboxylic acid (246 mg, 1.55 mmol) and dichloromethane (10 mL) were combined at room temperature under a nitrogen atmosphere. Oxaloyl chloride (0.27 mL, 3.1 mmol) was added, followed by 1 drop of DMF. The reaction mixture was stirred for 21 hours and then evaporated to dryness. Intermediate 10 (276 mg, 1.55 mmol), dichloromethane (30 mL), and triethylamine (2 mL) were added, and the reaction was stirred for 1 hour. The reaction mixture was evaporated to dryness to give 5-chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazin-2-carboxamide, the crude product of which was used for the next step.

[0709] 5-Chloro-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)pyrazin-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 to 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 give the title compound. LCMS (ES+) 397 (M+H)+, RT 1.9 min (Analytical method AcHSSC18).1 H NMR (400MHz, DMSO) δ9.48-9.46(m,1H),8.89(s,1H),8.74(d,J=1.1Hz,1H),8.02(d,J=1.3Hz,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=7.2,7.2Hz,3H).

[0710] Other analogs are prepared using the same chemical reaction and suitable amines. Some enantiomers are separated by chiral SFC, in which case the chirality is arbitrarily assigned.

[0711]

[0712]

[0713] Example 86: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperazin-1-yl)pyrazin-2-carboxamide

[0714]

[0715] Lithium 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrazin-2-carboxylate (157 mg, 0.5 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (83 mg, 0.5 mmol), HBTU (190 mg, 0.5 mmol), triethylamine (0.75 mL), and DMF (2 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to give tert-butyl 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazin-1-carboxylate. MS (ES+) 456 (M+H).

[0716] 80 mg of 4-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 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 absorbed in MeOH. Na₂CO₃ was added and stirred for 5 min. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 356(M+H)⁺, RT 1.67 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.45(s,1H),9.19(d,J=1.6Hz,1H),8.74(d,J=1.0Hz,1H),8.32(s,1H),7.89(d,J=2.6 Hz, 1H), 7.57 (dd, J=1.5, 13.0Hz, 1H), 3.65 (dd, J=5.1, 5.1Hz, 4H), 3.41 (dd, J=5.1, 5.1Hz, 4H), 2.35 (s, 3H).

[0717] Example 87: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0718] And Example 88: N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0719]

[0720] Methyl 5-chloropyrazine-2-carboxylate (665 mg, 3.85 mmol), ((3R*,4S*)-4-fluoropyrrolidine-3-yl)carbamate tert-butyl ester (786 mg, 3.85 mmol), cesium carbonate (1.25 g, 3.85 mmol), and DMF (10 mL) were combined in a sealed tube and heated to 100 °C for 18 hours. The reaction mixture was then diluted with EtOAc, washed with water (3x) and brine (1x), and evaporated to dryness to give methyl 5-((3R*,4S*)-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate, the crude product of which was used without further purification.

[0721] Methyl 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-2-carboxylate (630 mg, 1.85 mmol) and DMF (15 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 89 mg, 2.22 mmol) was added to the stirred reaction mixture, followed by MeI (0.14 mL, 2.22 mmol). The reaction mixture was stirred for 22 hours, then diluted with EtOAc and washed with water (3x) and brine (1x). The organic layer was evaporated to dryness to give methyl 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-2-carboxylate solid, the crude product of which was used without further purification.

[0722] Methyl 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-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. The reaction mixture was then evaporated to dryness to give lithium 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-2-carboxylate, the crude product of which was used without further purification.

[0723] Lithium 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-2-carboxylate, 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (162 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (5 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was then purified by preparative HPLC to give tert-butyl ((3R*,4S*)-4-fluoro-1-(5-(((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamoyl ester, which was used without further purification.

[0724] ((3R*,4S*)-4-fluoro-1-(5-(((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl, methanol (3 mL), and 4NHCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, dissolved in MeOH, stirred with Na2CO3 for 5 min, filtered through an Isolute NH2 resin box, and the filtrate was evaporated to dryness. The crude solid was purified by preparative HPLC, followed by chiral preparative HPLC to obtain the desired product.

[0725] cis isomer, enantiomer 1

[0726] N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (analytical method AcHSSC18); 1 H NMR (400MHz, DMSO) δ9.69(s,1H),9.15(s,1H),8.78(s,1H),8.10(s,1H),8.01(s,1H),5.39(d,J=52.3Hz,1H),4.05-3.92(m, 2H), 3.81 (dd, J = 12.7, 39.6Hz, 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).

[0727] cis isomer, enantiomer 2

[0728] N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-5-((3S,4R)-3-fluoro-4-(methylamino)pyrrolidone-1-yl)pyrazin-2-carboxamide. LCMS (ES+) 385 (M+H)+, RT 1.77 min (analytical method AcHSSC18); 1H NMR (400MHz, DMSO) δ9.69(s,1H),9.15(s,1H),8.78(s,1H),8.10(s,1H),8.01(s,1H),5.39(d,J=52.3Hz,1H),4.05-3.92(m, 2H), 3.81 (dd, J = 12.7, 39.6Hz, 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).

[0729] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0730]

[0731] Other analogues were prepared using the same chemical reactions with lithium 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazine-2-carboxylate or lithium 5-((3R*,4R*)-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, Boc-protected amines were used, in which case the Boc group at the end of the synthetic sequence was removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product was separated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case chirality was arbitrary.

[0732]

[0733]

[0734] Example 92: (S)-5-([1,3'-dipyrrolidine]-1'-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0735]

[0736] Methyl 5-chloropyrazine-2-carboxylate (473 mg, 2.74 mmol), (S)-1,3'-dipyrrolidine (384 mg, 2.74 mmol), cesium carbonate (1.14 g, 3.5 mmol), and DMF (10 mL) were combined in a sealed tube and heated to 100 °C for 16 hours. The reaction mixture was filtered to remove the cesium salt and washed with EtOAc. The combined organic filtrate was evaporated to dryness to give methyl (S)-5-([1,3'-dipyrrolidine]-1'-yl)pyrazine-2-carboxylate, the crude product of which was used without further purification.

[0737] Methyl (S)-5-([1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxylate, LiOH·H₂O (126 mg, 3 mmol), MeOH (50 mL), and water (5 mL) were combined and heated to 45 °C for 16 hours. The reaction mixture was then evaporated to dryness to give lithium (S)-5-([1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxylate, the crude product of which was used without further purification.

[0738] Lithium (S)-5-([1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxylate (161 mg, 0.6 mmol), intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL), and DMF (2 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+)422(M+H)+, RT 2.45 min (Analytical method AcHSSC18). 1 H NMR(400MHz,DMSO)δ10.06(s,1H),8.76(d,J=1.1Hz,1H),8.69(s,1H),8.23(s,1 H),8.07(d,J=1.0Hz,1H),7.11(s,1H),4.10(s,3H),3.99(s,3H),3.83-3.69(m,2 H),3.56-3.48(m,1H),3.39(dd,J=6.9,11.8Hz,1H),2.89-2.89(m,1H),2.56(d, J=3.6Hz, 4H), 2.20-2.19 (m, 1H), 2.01-1.97 (m, 1H), 1.73 (dd, J=5.0, 5.0Hz, 4H).

[0739] Example 93: (S)-5-([1,3'-dipyrrolidine]-1'-yl)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0740]

[0741] Lithium (S)-5-([1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxylate (95 mg, 0.36 mmol), intermediate 3 (69 mg, 0.36 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL), and DMF (2.5 mL) were combined and stirred overnight at room temperature. The reaction mixture was purified by preparative HPLC to give the title compound. LCMS (ES+) 436.5 (M+H)+, RT 2.6 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.14 (s, 1H), 8.75 (d, J = 1.3Hz, 1H), 8.68 (s, 1H), 8.21 (s,1H),8.04(s,1H),7.09(s,1H),4.22(q,J=6.9Hz,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),2.19-2.1 3(m,2H),1.96(dd,J=3.6,8.2Hz,2H),1.75-1.69(m,4H),1.51-1.46(m,3H).

[0742] Example 94: 5-((3S*,4R*)-3-fluoro-4-(methylamino)pyrrolidine-1-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazin-2-carboxamide

[0743]

[0744] Lithium 5-((3R*,4S*)-3-((tert-butoxycarbonyl)(methyl)amino)-4-fluoropyrrolidine-1-yl)pyrazin-2-carboxylate (187 mg, 0.54 mmol), intermediate 4 (106 mg, 0.6 mmol), HBTU (228 mg, 0.6 mmol), triethylamine (0.5 mL), and DMF (3 mL) were combined and stirred at room temperature for 3 hours. The reaction mixture was then purified by preparative HPLC to give tert-butyl ((3R*,4S*)-4-fluoro-1-(5-(((6-methoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate, which was used without further purification.

[0745] ((3R*,4S*)-4-fluoro-1-(5-(((6-methoxy-2-methyl-2H-indazol-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester was deprotected using the universal method C(HCl Boc deprotection) to give the title compound. LCMS (ES+) 400 (M+H)+, RT 2.3 min (Analytical method AcHSSC18). 1 H NMR (400MHz, 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=55.2Hz,1H),4.10(s,3H),3.99(s,3H),4.04-3.70(m,4H),3.20(dd,J=10.2,10.2Hz,1H),2.42(s,3H).

[0746] Example 95: (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(pyrrolidine-3-yloxy)pyrazin-2-carboxamide

[0747]

[0748] (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.53 mmol) in DMF (2 mL) was added to a suspension of NaH (32 mg, 0.801 mmol) in DMF (1 mL), and the reaction was stirred at room temperature for 30 min. Intermediate 1 (163 mg, 0.534 mmol) was added, and the reaction was heated to 90 °C for 5.5 h. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (x2), and the combined organic solutions were dried over MgSO4 and evaporated to dryness. The crude mixture was purified by rapid chromatography to give (S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester. MS (ES+) 457 (M+H).

[0749] (S)-3-((5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (63 mg, 0.14 mmol), methanol (1 mL), and 4N HCl in dioxane (0.35 mL, 1.38 mmol) were combined and stirred at room temperature for 17 hours. The reaction mixture was evaporated to dryness, and the crude material was purified by preparative HPLC to give the title compound. LCMS (ES+) 357(M+H)+, RT 1.62 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.74 (s, 1H), 9.21 (d, J = 1.6Hz, 1H), 8.90 (s, 1H), 8.38 (s,1H),7.92(d,J=2.8Hz,1H),7.57(dd,J=1.5,13.0Hz,1H),5.50(dd,J=5.8 ,5.8Hz,1H),3.68-3.52(m,1H),3.15(dd,J=5.2,12.5Hz,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).

[0750] Other analogues are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by preparative HPLC.

[0751]

[0752] Example 97 N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3R,4R)-3-methyl-4-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0753]

[0754] ((3R,4R)-4-methylpyrrolidone-3-yl)carbamate tert-butyl ester (251 mg, 1.25 mmol) and methyl 5-chloropyrazine-2-carboxylate (216 mg, 1.25 mmol) were dissolved in DMF (4 mL) and the reaction was heated to 100 °C for 18 h. The reaction was cooled to room temperature, diluted with EtOAc, and filtered through diatomaceous earth. The solvent was removed under vacuum to give the crude product. The crude product was purified by silica chromatography (elution gradient 0-100% EtOAc / cyclohexane) to give methyl 5-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-methylpyrrolidone-1-yl)pyrazine-2-carboxylate. MS (ES+) 337 (M+H).

[0755] Methyl 5-((3R,4R)-3-((tert-butoxycarbonyl)amino)-4-methylpyrrolidine-1-yl)pyrazin-2-carboxylate (344 mg, 1.02 mmol) was dissolved in DMF (2 mL) and cooled in an ice bath. Sodium hydride / in mineral oil 60% (45 mg, 1.12 mmol) was added, and the reaction was stirred for 15 min. Iodimethane (145 mg, 1.02 mmol) was added, and the reaction was allowed to warm to room temperature for 3 h. LCMS indicated the starting material. Sodium hydride / in mineral oil 60% (45 mg, 1.12 mmol) was added again, followed by methyl iodine (145 mg, 1.02 mmol), and the reaction was stirred again for 18 h. Water (1 mL) was added, followed by sodium hydroxide (82 mg, 1.04 mmol), and the reaction was stirred for 18 h. The reaction was acidified to pH 5 with 1 M HCl, and the aqueous layer was extracted with EtOAc x3. The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidone-1-yl)pyrazin-2-carboxylic acid. MS(ES+)337(M+H).

[0756] 5-((3R,4R)-3-((tert-butoxycarbonyl)(methyl)amino)-4-methylpyrrolidin-1-yl)pyrazin-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 was stirred overnight at room temperature. The solvent was removed under vacuum to give the crude product. ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidone-3-yl)(methyl)carbamate tert-butyl carbamate was purified by silica chromatography (elution gradient 0-100% EtOAc / cyclohexane). MS(ES+) 484(M+H).

[0757] ((3R,4R)-1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-4-methylpyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (610 mg, 1.02 mmol) was dissolved in methanol (2 mL) and added to dioxane (10 mL) with 4 M HCl. The reaction was stirred overnight at room temperature. The solvent was removed under vacuum to give the crude product. The crude product was purified by an SCX 5 g SCX box (pre-conditioned with MeOH), eluted with 1:1 MeOH / DCM (2 cv) and then with 2.3 M NH3 / MeOH (3 CV). The ammonia fraction was concentrated under vacuum to give the residue. The title compound was further purified by reversed-phase HPLC. LCMS (ES+) 384.2 (M+H)+, RT 1.72 min (Analytical method AcHSSC18); 1 NH NMR (400MHz, DMSO) δ 10.45 (s, 1H), 9.20 (d, J = 1.5Hz, 1H), 8.74 (d, J = 1.1Hz, 1H), 7.96 (s, 1H), 7.90 (d, J = 2.6Hz, 1H), 7.57 (dd, J = 1.6, 13.1Hz, 1H), 3.70–3.63 (m, 2H), 3.26–3.08 (m, 3H), 2.32 (m, 6H), 1.02 (d, J = 5.9Hz, 3H) NH is masked by the DMSO peak.

[0758] The following examples are prepared using a similar procedure starting with methyl 5-chloropyrazine-2-carboxylate and the amine. The final product was separated by SCX and / or preparative HPLC. Some enantiomers were separated by chiral SFC, in which case the chirality was arbitrarily assigned.

[0759]

[0760]

[0761]

[0762] Example 106: (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidine-1-yl)pyrazin-2-carboxamide and Example 107: (R)-5-(3-(1-aminocyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0763]

[0764] Methyl 5-chloropyrazine-2-carboxylate (191 mg, 1.1 mmol), (R)-(1-(pyrrolidine-3-yl)cyclopropyl)carbamate tert-butyl ester (250 mg, 1.1 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (4 mL) were combined in a sealed tube and heated to 100 °C for 23 hours using a hot block. The reaction mixture was then diluted with EtOAc, washed with water (3x) and brine (1x), and evaporated to dryness to give methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate, the crude product of which was used without further purification.

[0765] Methyl (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazin-2-carboxylate (341 mg, 0.91 mmol) and DMF (10 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 45 mg, 1.13 mmol) was added, followed by MeI (0.07 mL, 1.13 mmol), and stirring was continued for 10 days. The reaction mixture was then diluted with EtOAc, washed with water (3x) and brine (1x), dried (MgSO4) and evaporated to dryness to give a mixture of (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate and (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate, the crude product of which was used without further purification.

[0766] 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) were combined and heated to 45 °C for 18 hours using a hot block. The reaction mixture was then evaporated to dryness to give a mixture of lithium (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate and lithium (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazine-2-carboxylate, the crude product of which was used without further purification.

[0767] A mixture of lithium (R)-5-(3-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazin-2-carboxylate and lithium (R)-5-(3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)pyrrolidine-1-yl)pyrazin-2-carboxylate, 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) was combined and stirred at room temperature for 2 hours. The reaction mixture was then purified by preparative HPLC to obtain the desired product.

[0768] (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)cyclopropyl)(methyl)tert-butyl carbamate, used without further purification.

[0769] (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)cyclopropyl)tert-butyl carbamate, used without further purification.

[0770] (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)cyclopropyl)(methyl)carbamate tert-butyl ester (65.1 mg), methanol (3 mL), and 4 NHCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(1-(methylamino)cyclopropyl)pyrrolidine-1-yl)pyrazin-2-carboxamide. LCMS (ES+) 410(M+H)+, RT 1.93 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.42(s,1H),9.19(d,J=1.5Hz,1H),8.74(d,J=1.1Hz,1 H),7.97(d,J=1.3Hz,1H),7.89(d,J=2.8Hz,1H),7.57(dd,J=1.7,13.0Hz,1H) ,3.81-3.73(m,2H),3.46-3.42(m,1H),3.13(dd,J=10.2,10.2Hz,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).

[0771] (R)-(1-(1-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)cyclopropyl)tert-butyl carbamate (41.9 mg), methanol (3 mL), and 4 NHCl in dioxane (3 mL) were combined and stirred at room temperature for 7 hours. The reaction mixture was then evaporated to dryness and purified by preparative HPLC to give (R)-5-(3-(1-aminocyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 396 (M+H)+, RT 1.9 min (Analytical method AcHSSC18). 1H NMR (400MHz, DMSO) δ10.42(s,1H),9.19(d,J=1.6Hz,1H),8.74(d,J=1.1Hz,1H),7.97(d,J=1.3Hz,1H),7.89(d,J=2.8Hz,1H),7.57(dd,J=1.7,1 3.1Hz,1H),3.82-3.69(m,2H),3.50-3.41(m,2H),2.35(s,3H),2.09(d, J=8.3Hz, 1H), 2.00 (s, 1H), 1.93 (d, J=9.8Hz, 1H), 0.49 (d, J= 6.4Hz, 4H).

[0772] Example 108: (R)-N-(6-ethoxy-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0773]

[0774] Intermediate 3 (0.32 mmol), lithium (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate (100 mg, 0.32 mmol), HBTU (137 mg, 0.36 mmol), triethylamine (0.5 mL), and DMF (2.5 mL) were combined and stirred at room temperature for 18 hours. The reaction mixture was then purified by preparative HPLC to give (R)-(1-(5-((6-ethoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate as a grayish-white solid, which was used without further purification.

[0775] (R)-(1-(5-((6-ethoxy-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl, methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred at room temperature for 2 hours. The reaction mixture was then evaporated to dryness, absorbed in MeOH, and stirred over sodium carbonate for 5 min, followed by filtration through an Isolute NH2 resin box. The filtrate was evaporated to dryness to give the title compound. LCMS (ES+) 396(M+H)+, RT 2.5 min (Analytical method AcHSSC18). 1H NMR (400MHz, DMSO) δ10.18 (s, 1H), 8.79 (d, J = 1.3Hz, 1H), 8.72 (s, 1H), 8.2 5(s,1H),8.07(d,J=1.3Hz,1H),7.13(s,1H),4.27(q,J=7.0Hz,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=6.9,6.9Hz,3H).

[0776] Other analogs are prepared from (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylic acid and the amine using method H (TCFH coupling). In some cases, a Boc-protected amine is used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC.

[0777]

[0778]

[0779] Example 110: (R)-5-(3-(ethylamino)pyrrolidone-1-yl)-N-(6-methoxy-2-methyl-2H-indazol-5-yl)pyrazine-2-carboxamide

[0780]

[0781] 5-Chloropyrazin-2-carboxylic acid (159 mg, 1 mmol) and dichloromethane (10 mL) were combined under a nitrogen atmosphere. Oxaloyl 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 give 5-chloro-N-(6-methoxy-2-methyl-2H-indazole-5-yl)pyrazin-2-carboxamide, the crude product of which was used without further purification. MS (ES+) 318 / 320 (M+H).

[0782] 5-Chloro-N-(6-methoxy-2-methyl-2H-indazole-5-yl)pyrazin-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 heated to 100 °C for 1 hour using a hot block. 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 give the title compound. LCMS (ES+) 396(M+H)+, RT 2.36 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.05(s,1H),8.75(d,J=1.3Hz,1H),8.69(s,1H),8.23(s,1H),8.04(d,J=1.3Hz,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=7.1,7.1Hz,3H).

[0783] Other analogues are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC.

[0784]

[0785]

[0786] Example 112: (R)-5-(3-(cyclopropylamino)pyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0787]

[0788] (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 to 55 °C for 16 hours. The reaction mixture was then diluted with dichloromethane, washed with a saturated aqueous solution of NaHCO3, dried over (MgSO4), and evaporated to dryness to give (R)-3-(cyclopropylamino)pyrrolidine-1-carboxylic acid tert-butyl ester, the crude product of which was used in the next step.

[0789] (R)-3-(cyclopropylamino)pyrrolidine-1-carboxylic acid tert-butyl ester (455 mg, 2 mmol), MeOH (15 mL), and 4N HCl in dioxane (15 mL) were combined and stirred at room temperature for 24 hours. The reaction mixture was then evaporated to dryness to give (R)-N-cyclopropylpyrrolidine-3-amine·2HCl, the crude product of which was used for the next step.

[0790] (R)-N-cyclopropylpyrrolidine-3-amine in 2HCl (500 mg), intermediate 1 (400 mg, 1.3 mmol), cesium carbonate (1.63 g, 5 mmol), and DMF (7 mL) were combined and heated to 100 °C for 20 hours. The cesium salt was then filtered off, and the filtrate was purified by preparative HPLC to obtain the title compound. LCMS (ES+) 396(M+H)+, RT 1.75 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.44(s,1H),9.23(d,J=1.8Hz,1H),8.78(d,J=1.3Hz,1 H),8.00(d,J=1.3Hz,1H),7.93(d,J=2.5Hz,1H),7.60(dd,J=1.5,13.0Hz,1H ),3.78-3.53(m,4H),3.51-3.42(m,1H),2.61-2.58(m,1H),2.39(s,3H),2.2 1-2.12(m,2H),1.99-1.99(m,1H),0.45(d,J=6.6Hz,2H),0.33-0.25(m,2H).

[0791] Other analogues are prepared from commercially available or synthetic amines using the same chemical reaction. The final products are separated by preparative HPLC.

[0792]

[0793]

[0794] Example 114 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(5-fluoro-2-methyl-1,3-benzoxazol-6-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0795]

[0796] According to Method H, 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylic acid (126 mg, 0.361 mmol, 1 equivalent) and 5-fluoro-2-methylbenzo[d]oxazol-6-amine (60 mg, 0.361 mmol, 1 equivalent) were extracted from 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 by silica chromatography with an elution gradient of 0-10% EtOAc in cyclohexane. Fractions containing the desired material were combined and the solvent was removed under vacuum to give cyclopropyl(1-(5-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamate tert-butyl ester. LCMS(ES+) 497(M+H)+.

[0797] Deprotection was performed according to method E TFA Boc from 26 mg (0.0511 mmol) of tert-butyl carbamate (1-(5-((5-fluoro-2-methylbenzo[d]oxazol-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamate. The reaction mixture was concentrated under vacuum and the residue was applied to a 2 g SCX cartridge, eluted with 2 column volumes of methanol followed by 3 column volumes of 2 M methanolic ammonia. The ammonia fraction was concentrated under vacuum to give 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(5-fluoro-2-methyl-1,3-benzooxazol-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 397 (M+H)+, RT 4.57 min (analytical method Bicarb BEHC18) 1 H NMR (400MHz, DMSO) δ9.91(d,J=2.4Hz,1H),8.75(s,1H),8.47(d,J=6.5Hz,1H),8.04(s,1H),7.71(d,J=10.9Hz,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=6.7Hz,2H),0.32-0.23(m,2H).

[0798] Example 115 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2,6-dimethylindazole-5-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0799]

[0800] According to Method H, 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazin-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) were used. The reaction mixture was diluted with water, the solid was filtered and washed with 1:1 MeCN / H2O to give crude cyclopropyl(1-(5-(((2,6-dimethyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamate tert-butyl ester, which was used without further purification.

[0801] Deprotection was performed according to method E TFA Boc from tert-butyl carbamate (36 mg, 0.0732 mmol). The reaction mixture was concentrated under vacuum and the residue was applied to a 2 g SCX cartridge, eluted with 2 column volumes of methanol followed by 3 column volumes of 2 M methanolic ammonia. The ammonia fraction was concentrated under vacuum and the residue was purified by reversed-phase HPLC to give 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2,6-dimethylindazole-5-yl)pyrrazine-2-carboxamide. LCMS (ES+) 392(M+H)+, RT 2.38 min (Analytical method AcHSSC18) 1 H NMR(400MHz,DMSO)δ9.74(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=6.6Hz,2H),0.36-0.28(m,2H).

[0802] Example 116 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0803]

[0804] According to method H, lithium 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate (97 mg, 0.273 mmol) was reacted with 2,7-dimethylimidazo[1,2-a]pyridin-6-amine (44 mg, 0.273 mmol) in DMF (2.0 mL). The reaction mixture was diluted with water, the solid was filtered, washed with 1:1 MeCN / H2O, and purified by reversed-phase HPLC to give cyclopropyl(1-(5-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamoyl tert-butyl carbamate. LCMS(ES+)492(M+H)+.

[0805] According to Method E, cyclopropyl (1-(5-((2,7-dimethylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)tert-butyl carbamate (9.4 mg, 0.020 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum and the residue was applied to a 2 g SCX cartridge, eluted with 2 column volumes of methanol followed by 3 column volumes of 2M methanolic ammonia. The ammonia fraction was concentrated under vacuum to give the title compound. LCMS (ES+) 392(M+H)+, RT 3.95 min (Analytical method Bicarb BEHC18) 1 H NMR (400MHz, MeOD) δ8.78(s,1H),8.65(d,J=1.3Hz,1H),7.87(d,J=1.3Hz,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=0.8Hz,3H),2.29(d,J=0.7Hz,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).

[0806] Example 117(R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0807]

[0808] (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.37 mmol) and ethyl trifluoroacetate (2.29 g, 16.1 mmol) were stirred in ethanol (20 mL) at 60 °C for 17 h. The reaction mixture was concentrated to dryness and crude (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylic acid tert-butyl ester was used in the next step. LCMS(ES+)283(M+H) + .

[0809] Borane·THF (21.5 mL, 1 M, 21.5 mmol) was added dropwise to a stirred solution of (R)-3-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylic acid tert-butyl ester (5.37 mmol) in THF (10 mL). The mixture was refluxed for 17 h after the addition. The reaction mixture was cooled to room temperature and saturated NH4Cl aqueous solution (20 mL) was added, followed by heating to 60 °C for 2 h. The mixture was concentrated and the resulting aqueous solution was extracted with EtOAc (2 x 30 mL). The organic layer was collected, dried (MgSO4), filtered, and concentrated. (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester was purified by rapid silica column chromatography (gradient, DCM to DCM / MeOH / 7 MNH3 in MeOH [89:10:1]). LCMS(ES+)213(M+H) + .

[0810] (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 3.29 mmol) and HCl in dioxane (4 M, 4 mL, 16 mmol) were stirred in MeOH (10 mL) for 17 h. The mixture was concentrated to dryness and crude (R)-N-(2,2,2-trifluoroethyl)pyrrolidine-3-amine·HCl was used for the next step.

[0811] (R)-N-(2,2,2-trifluoroethyl)pyrrolidine-3-amine·HCl (87 mg, 0.36 mmol) and Cs₂CO₃ (533 mg, 1.64 mmol) were added to a stirred solution of intermediate 1 (100 mg, 0.33 mmol) in DMF (4 mL). The mixture was stirred at 100 °C for 17 h and then cooled to room temperature. The reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated from the aqueous layer and then extracted with another EtOAc (10 mL). The combined organic layers were washed with water (3 × 30 mL), dried (MgSO₄), filtered, and concentrated to dryness. The title compound was purified by preparative HPLC. LCMS (ES+) 438 (M+H)+, RT 2.64 min (Analytical method AcHSSC18); 1 ¹H NMR (400MHz, 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), 1 proton was masked by a water peak.

[0812] Example 118N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxamide

[0813] And Example 119N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxamide

[0814]

[0815] 1.25 g (6.75 mmol) of 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester, pyrrolidine (6.816 g (95.84 mmol)), and water (12 mL) were combined in a sealed tube and heated to 50 °C for 5 days. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane (2x). The combined organic layer was dried (MgSO4) and evaporated to dryness on silica. It was purified by rapid chromatography, eluting with 1% NH4OH / 10% MeOH / CH2Cl2 to give (3'R*,4'R*)-4'-hydroxy-[1,3'-dipyrrolidine]-1'-carboxylic acid tert-butyl ester, the crude product of which was used in the next step.

[0816] (3'R*,4'R*)-4'-hydroxy-[1,3'-dipyrrolidine]-1'-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol), dichloromethane (10 mL) and (50% in THF) (0.32 mL, 0.86 mmol) were combined and stirred for 2 days at room temperature under a nitrogen atmosphere. The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane (2x). The combined organic layers were dried (MgSO4) and evaporated to dryness to give tert-butyl (3'R*,4'S*)-4'-fluoro-[1,3'-dipyrrolidine]-1'-carboxylate, the crude product of which was used for the next step.

[0817] (3'R*,4'S*)-4'-fluoro-[1,3'-dipyrrolidine]-1'-carboxylic acid tert-butyl ester, methanol (3 mL), and 4N HCl in dioxane (3 mL) were combined and stirred for 16 hours. The reaction mixture was evaporated to dryness to give (3'R*,4'S*)-4'-fluoro-1,3'-dipyrrolidine·2HCl, the crude product of which was used for the next step without further purification.

[0818] (3'R*,4'S*)-4'-fluoro-1,3'-dipyrrolidine·2HCl, intermediate 1 (200 mg, 0.65 mmol), cesium carbonate (800 mg, 2.45 mmol), and DMF (4 mL) were combined in a sealed tube and heated to 100 °C for 6 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...

[0819] Example 118, cis isomer, enantiomer 1

[0820] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'S,4'R)-4'-fluoro-[1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxamide. LCMS (ES+) 428(M+H)+, RT 1.82 min (analytical method AcHSSC18). 1 HNMR (400MHz, DMSO) δ10.47(s,1H),9.20(d,J=1.5Hz,1H),8.78(d,J=1.3Hz,1H),8.08(s,1H),7.90(d,J=2.8Hz,1H),7.58(dd,J=1.6,13. 0Hz,1H),5.47(td,J=1.9,51.0Hz,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=4.5,4.5Hz,4H).

[0821] Example 119, cis isomer, enantiomer 2

[0822] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((3'R,4'S)-4'-fluoro-[1,3'-dipyrrolidine]-1'-yl)pyrazin-2-carboxamide. LCMS (ES+) 428(M+H)+, RT 1.82 min (analytical method AcHSSC18). 1 HNMR (400MHz, DMSO) δ10.47(s,1H),9.20(d,J=1.5Hz,1H),8.78(d,J=1.3Hz,1H),8.08(s,1H),7.90(d,J=2.8Hz,1H),7.58(dd,J=1.6,13. 0Hz,1H),5.47(td,J=1.9,51.0Hz,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=4.5,4.5Hz,4H).

[0823] Other analogs are prepared using the same chemical reaction and suitable amines. Some enantiomers are separated by chiral SFC, in which case the chirality is arbitrarily assigned.

[0824]

[0825] Example 121(R)-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-5-(3-(methylamino)pyrrolidone-1-yl)pyrazin-2-carboxamide

[0826]

[0827] A mixture of (R)-methyl(pyrrolidine-3-yl)carbamate tert-butyl ester (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 to 110 °C for 17 hours in a sealed tube. The reaction was cooled to room temperature and diluted with EtOAc, washed with water and brine, and the organic matter was concentrated under vacuum to give (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylate methyl ester.

[0828] A mixture of (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate (671 mg) and ammonia in methanol (4 N, 20 mL) was heated to 90 °C for 19 hours. The reaction was cooled to room temperature and concentrated under vacuum to give (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl.

[0829] According to method F, (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (308 mg, 0.96 mmol) and 5-bromo-6-fluoro-2-methyl-2H-indazole (229 mg, 1.0 mmol) were coupled. The crude material was purified by preparative HPLC to obtain (R)-(1-(5-((6-fluoro-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester.

[0830] According to Method E, (R)-(1-(5-((6-fluoro-2-methyl-2H-indazole-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (78 mg, 0.17 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum, the residue was absorbed in MeOH and stirred with Na2CO3 for 5 min, filtered, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 370(M+H)+, RT 2.37 min (Analytical Method AcHSSC18). 1HNMR (400MHz, DMSO) δ9.82(d,J=2.8Hz,1H),8.75(d,J=1.0Hz,1H),8.49(d,J=7.9Hz,1H),8.39(s,1H),8.04(s, 1H), 7.51 (d, J = 12.1Hz, 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).

[0831] Example 122(R)-N-(8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0832]

[0833] According to method F, (R)-(1-(5-carbamoylpyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (150 mg, 0.47 mmol) and intermediate 17 (119 mg, 0.49 mmol) were coupled. The crude material was purified by preparative HPLC to obtain (R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester.

[0834] According to method E, (R)-(1-(5-((8-methoxy-2-methylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (24 mg, 0.050 mmol) was treated with TFA. The reaction mixture was concentrated under vacuum, the residue was absorbed in MeOH and stirred with Na2CO3 for 5 min, filtered, and the filtrate was purified by preparative HPLC to give the title compound. LCMS (ES+) 383(M+H)+, RT 1.9 min (Analytical method AcHSSC18). 1 H NMR(400MHz,DMSO)δ9.47(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).

[0835] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0836]

[0837] Example 125: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperidin-4-yl)pyrazin-2-carboxamide

[0838]

[0839] Sodium carbonate (500 mg, 4.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (202 mg, 0.65 mmol) were added to a solution of intermediate 1 (200 mg, 0.65 mmol) in dioxane (15 mL) and water (2 mL). 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 h. The reaction was cooled to room temperature and the solvent was removed under vacuum to obtain the residue, which was purified by silica chromatography to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate. MS(ES+)453(M+H).

[0840] A solution of tert-butyl 4-(5-(((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in ethyl acetate (15 mL) was hydrogenated in recirculation mode for 6 h at 1 mL / min, 40 °C, and 40 bar using an H-cube and a 20% Pd(OH)2 / C box. Subsequent LCMS analysis showed almost complete conversion. The solvent was removed under vacuum to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperidine-1-carboxylate, which was used in the next step without further purification.

[0841] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)piperidin-1-carboxylic acid tert-butyl ester, DCM (3 mL), and TFA (1 mL) were prepared using general method E and in the following amounts: 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperidin-4-yl)pyrazin-2-carboxamide. The reaction mixture was evaporated to dryness, absorbed in MeOH, treated with Na2CO3, and then filtered. The ester was purified by reversed-phase HPLC followed by achiral SFC to give N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(piperidin-4-yl)pyrazin-2-carboxamide. LCMS (ES+) 355.2 (M+H)+, RT 1.61 min (Analytical method AcHSSC18) 1 H NMR (400MHz, DMSO) δ10.92-10.90(m,1H),9.23(d,J=1.6Hz,2H),8.76(s,1H),7.94(d,J=2.8Hz,1H),7.57(dd,J=2.0,12. 9Hz,1H),3.10-3.00(m,3H),2.63(dd,J=10.5,12.0Hz,2H),2.36(s,3H),1.84-1.81(m,2H),1.70(dq,J=3.9,12.2Hz,2H).

[0842] Example 126: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(piperazin-1-yl)pyrimidin-5-carboxamide

[0843]

[0844] 2-Chloropremine-5-carboxylic acid (159 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-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 give 2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-5-carboxamide. MS (ES+) 405 (M+H).

[0845] 2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-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 heated to 100 °C for 3 days using a hot block. The reaction mixture was purified by preparative HPLC to give tert-butyl 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate. MS (ES+) 456 (M+H).

[0846] 27.5 mg of 4-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 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 absorbed in MeOH. Na₂CO₃ was added and stirred for 5 min. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 356(M+H)+, RT 1.61 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.22-10.21(m,1H),9.05(d,J=1.6Hz,1H),8.89(s,2H),7.91(d,J=2.8Hz,1H),7 .28(dd,J=1.4,12.7Hz,1H),3.81-3.77(m,4H),2.76(dd,J=5.0,5.0Hz,4H),2.45(s,1H),2.35(s,3H).

[0847] Example 127: (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(3-(methylamino)pyrrolidine-1-yl)pyrimidin-5-carboxamide

[0848]

[0849] 345 mg, 2 mmol of tert-butyl 2-chloropyrimidin-5-carboxylate, (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 heated to 100 °C for 1 hour using a hot block. The reaction mixture was diluted with EtOAc, washed with water (x⁴) and brine (x⁻¹), and evaporated to dryness to give methyl (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidin-5-carboxylate. MS RT(ES+) 337(M+H).

[0850] 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 to 50 °C for 3 days using a hot block. The reaction mixture was then evaporated to dryness to give lithium (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-5-carboxylate, the crude product of which was used for subsequent reactions. MS(ES+) 323(M+H).

[0851] Lithium (R)-2-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidin-5-carboxylate (200 mg, 0.62 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (100 mg, 0.62 mmol), HBTU (235 mg, 0.62 mmol), triethylamine (0.5 mL), and DMF (3 mL) were combined and stirred at room temperature for 1.5 hours. The reaction mixture was then purified by preparative HPLC to give (R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-2-yl)pyrrolidine-3-yl)(methyl)carbamoyl tert-butyl carbamate. MS(ES+) 467(M+H).

[0852] (R)-(1-(5-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (49 mg), dichloromethane (3 mL), and TFA (1 mL) were combined and stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness and then absorbed in MeOH. Na2CO3 was added and stirred for 5 min. The reaction mixture was then filtered, the filtrate was evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 367(M+H)+, RT 1.73 min (Analytical method AcHSSC18). 1H NMR (400MHz, DMSO) δ10.69(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, 11.7Hz,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).

[0853] Other analogues can be prepared using the same chemical reaction from commercially available or synthetic amines.

[0854]

[0855]

[0856] Example 129: (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-(3-(methylamino)pyrrolidone-1-yl)pyrimidin-5-carboxamide

[0857]

[0858] 2-Chloroprene-5-carboxylic acid (500 mg, 3.15 mmol) and dichloromethane (10 mL) were combined under a nitrogen atmosphere. Oxaloyl chloride (0.55 mL, 6.3 mmol) was added, followed by DMF (1 drop). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness. 8-Fluoro-2-methylimidazo[1,2-a]pyridin-6-amine (750 mg, 3.15 mmol), dichloromethane (30 mL), and triethylamine (3 mL) were added, and the reaction mixture was stirred for 1.5 hours. The reaction mixture was then evaporated to dryness to give 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-5-carboxamide, the crude product of which was used for subsequent reactions. MS (ES+) 306 / 308 (M+H).

[0859] 2-Chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidin-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 heated to 100 °C for 16 hours using a hot block. 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 give the title compound. LCMS (ES+) 370 (M+H)+, RT 1.61 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ9.95(s,1H),8.94(d,J=1.6Hz,1H),8.89(s,2H),7.84(d,J=2.8Hz,1H),7.28(dd,J=1.5,12.7Hz,1H),3.76-3.5 9(m,3H),3.42(dd,J=4.6,11.7Hz,1H),3.35-3.28(m,1H),2.37(d,J=0.7Hz,3H),2.36(s,3H),2.24-2.08(m,1H),1.90-1.81(m,1H).

[0860] Other analogs are prepared from commercially available or synthetic amines using the same chemical reactions. In some cases, Boc-protected amines are used, in which case the Boc group at the end of the synthetic sequence is removed using 4N HCl in dioxane (General Method C) or TFA / DCM (General Method E). The final product is separated by SCX and / or preparative HPLC. Some enantiomers are separated by chiral SFC, in which case chirality is arbitrary.

[0861]

[0862]

[0863]

[0864] Example 136(R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-(3-(ethylamino)pyrrolidine-1-yl)pyrimidine-5-carboxamide

[0865]

[0866] 2-Chloroprene-5-carboxylic acid (317 mg, 2 mmol) and dichloromethane (5 mL) were combined at room temperature under a nitrogen atmosphere. Oxaloyl chloride (0.35 mL, 4 mmol) was added, followed by 1 drop of DMF. The reaction mixture was stirred for 21 hours and then evaporated to dryness. 2,8-Dimethylimidazo[1,2-a]pyrazin-6-amine (324 mg, 2 mmol), dichloromethane (30 mL), and triethylamine (2 mL) were added, and the reaction was stirred for 2 hours. The reaction mixture was then evaporated to dryness to give 2-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrimidine-5-carboxamide, the crude product of which was used for the next step.

[0867] 2-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)pyrimidin-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 heated to 100 °C for 2 hours using a hot block. 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 give the title compound. LCMS (ES+) 381(M+H)+, RT 1.79 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.69(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=7.1,7.1Hz,3H).

[0868] Example 137 2-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide and

[0869] Example 138 2-((3R,4S)-3-(ethylamino)-4-fluoropyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide

[0870]

[0871] 2.17 g (10.64 mmol) of cis-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, dichloromethane (40 mL), triethylamine (2 mL), and di-tert-butyl dicarbonate (2.55 g, 11.7 mmol) were combined and stirred at room temperature for 18 hours. The reaction mixture was then evaporated to dryness to give (3R*,4S*)-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, the crude product of which was used in the next step without further purification.

[0872] (3R*,4S*)-3-((tert-butoxycarbonyl)amino)-4-fluoropyrrolidine-1-carboxylate tert-butyl ester and DMF (20 mL) were combined at room temperature under a nitrogen atmosphere. NaH (60% in oil, 511 mg, 12.77 mmol) was added, followed by EtI (1 mL, 12.77 mmol). The reaction mixture was stirred for 3 days, then diluted with EtOAc, washed with water (4x), brine (1x), and evaporated to dryness to give (3R*,4S*)-3-((tert-butoxycarbonyl)(ethyl)amino)-4-fluoropyrrolidine-1-carboxylate tert-butyl ester, the crude product of which was used for the next step without further purification.

[0873] (3R*,4S*)-3-((tert-butoxycarbonyl)(ethyl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester, methanol (15 mL), and 4N HCl in dioxane (15 mL) were combined and stirred for 16 hours. The reaction mixture was then evaporated to dryness to give (3R*,4S*)-N-ethyl-4-fluoropyrrolidine-3-amine·2HCl, the crude product of which was used for the next step without further purification.

[0874] (3R*,4S*)-N-ethyl-4-fluoropyrrolidine-3-amine·2HCl (133 mg, 0.65 mmol), 2-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide (200 mg, 0.65 mmol), cesium carbonate (487 mg, 1.5 mmol), and DMF (3 mL) were combined in a sealed tube and heated to 100 °C for 20 hours using a hot block. 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 desired product.

[0875] cis isomer, enantiomer 1

[0876] 2-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide. LCMS (ES+) 402.3 (M+H)+, RT 1.62 min (Analytical method AcHSSC18). 1 HNMR (400MHz, DMSO) δ10.25(s,1H),9.06(d,J=1.6Hz,1H),8.92(d,J=4.0Hz,2H),7.92( d,J=2.8Hz,1H),7.29(dd,J=1.7,12.6Hz,1H),5.30(td,J=3.1,54.4Hz,1H),4.05-3.89 (m,2H),3.78(ddt,J=3.0,18.3,20.3Hz,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, 7.1Hz, 3H).

[0877] cis isomer, enantiomer 2

[0878] 2-((3R,4S)-3-(ethylamino)-4-fluoropyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrimidine-5-carboxamide. LCMS (ES+) 402(M+H)+, RT 1.62 min (Analytical method AcHSSC18). 1 HNMR (400MHz, DMSO) δ10.25(s,1H),9.06(d,J=1.6Hz,1H),8.92(d,J=4.0Hz,2H),7.92( d,J=2.8Hz,1H),7.29(dd,J=1.7,12.6Hz,1H),5.30(td,J=3.1,54.4Hz,1H),4.05-3.89 (m,2H),3.78(ddt,J=3.0,18.3,20.3Hz,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, 7.1Hz, 3H).

[0879] Other analogues are prepared using the same chemical reaction.

[0880]

[0881] Examples 140-141

[0882] Examples 140-141 were carried out according to the following method:

[0883] Unless otherwise specified, reagents and solvents were used as received from commercial suppliers. All non-aqueous reactions were performed under a dry nitrogen atmosphere (unless otherwise specified). Proton NMR spectra were obtained on a Bruker AVANCE 300 spectrometer at 300 MHz, a Bruker AVANCE 500 spectrometer at 500 MHz, or a Bruker ASCEND 500 spectrometer at 500 MHz. Spectra are given in ppm (δ), and the coupling constant J value is reported in Hertz (Hz). Tetramethylsilane was used as an internal standard for proton NMR. Mass spectrometry and LCMS analyses were obtained using a Waters Acquity SQD (ESI, UP-LCMS) or Shimadzu 2020 UP-LCMS instrument. UPLC analysis was obtained using an Acquity UPLCBEH C18 column (1.7 μm, 2.1 × 75 mm) eluted with a solvent gradient according to Method 1. HPLC analysis was performed using a Phenomenex C18 Kinetex column (5 μm, 4.6 x 150 mm) eluted with a solvent gradient according to Method 2. Detection was performed by UV at 254 and 215 nm. UPLC-MS data were obtained using standard methods: (a) low pH, Waters CSHC18 column (1.7 μm, 2.1 x 50 mm), column temperature 55 °C, sample concentration 0.5 mM in DMSO, ESI mass detection, UV DAD detection wavelength range 210–400 nm, and elution according to the solvent gradient of Method 3; or (b) high pH, ​​Waters UPLC Xbridge BEH C18 column (2.5 μm, 2.1 x 50 mm), column temperature 45 °C, sample concentration 0.5 mM in DMSO, ESI mass detection, UV DAD detection wavelength range 210–400 nm, and elution according to the solvent gradient of Method 4.

[0884] Method 1

[0885]

[0886] A = water containing 0.1% v / v trifluoroacetic acid

[0887] B = Acetonitrile with 0.1% v / v trifluoroacetic acid

[0888] Method 2

[0889]

[0890] A = water containing 0.1% v / v trifluoroacetic acid

[0891] B = Acetonitrile with 0.1% v / v trifluoroacetic acid

[0892] Method 3

[0893]

[0894] A = Water containing 0.02% v / v formic acid

[0895] B = Acetonitrile with 0.02% v / v formic acid

[0896] Method 4

[0897]

[0898] A = 1mM ammonium formate in water

[0899] Adjust the pH to 10 with NH4OH.

[0900] B = 95:5 acetonitrile / water

[0901] Example 140(R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-(methyl-amino)pyrrolidone-1-yl)pyridazin-3-carboxamide

[0902]

[0903] N,N-diisopropylethylamine (0.13 mL, 0.78 mmol) was added to a solution of (R)-6-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyridazin-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), 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 h. Water (30 mL) was then added, followed by a saturated aqueous solution of sodium bicarbonate (30 mL). The resulting suspension was extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give (R)-(1-(6-((8-fluoro-2-methylimid-azo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl. 1 H NMR (500MHz, CDCl3) δ9.71 (s, 1H), 9.04 (d, J = 1.5Hz, 1H), 8.06 (d, J = 9.5Hz, 1H), 7.43 (d, J = 2.5Hz, 1H), 6.83 (dd, J = 11.0Hz, 1.5Hz, 1H), 6.77 (d ,J=9.5Hz,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] + .

[0904] Trifluoroacetic acid (0.50 mL, 6.5 mmol) was added to a solution of (R)-(1-(6-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)pyrrolidine-3-yl)(methyl)carbamate (0.061 g, 0.13 mmol) in dichloromethane (4.5 mL), and the mixture was stirred at room temperature for 90 min. Subsequently, volatiles were removed under reduced pressure, and the resulting residue was absorbed and concentrated again in 80:18:2 dichloromethane / methanol / ammonium hydroxide (2 x 25 mL). The crude product was purified by chromatography (silica gel; dichloromethane to 80:18:2 dichloromethane / methanol / ammonium hydroxide; gradient elution). The obtained product was combined with another batch and ground together with 90:10 heptane / dichloromethane to give (R)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-(methylamino)pyrrolidine-1-yl)pyridazin-3-carboxamide. mp 198–200℃,dec; 1 H NMR (500MHz, DMSO–d6) δ10.89(s,1H),9.21(d,J=1.5Hz,1H),7.92(d,J=9.4Hz,1H),7.90(d,J=2.5Hz,1H),7.60(dd,J=13.0,1. 5Hz,1H),7.02(d,J=9.4Hz,1H),3.87–3.33(m,5H),2.34(s,3H),2.32(s,3H),2.17–2.08(m,1H),1.94–1.85(m,1H); MS(ESI)m / z 370[M+H] + HPLC: Method 2, t R =3.00 min, >99% (AUC) at 254 and 215 nm.

[0905] Example 141(R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)-pyrrolidine-1-yl)pyrimidin-2-carboxamide

[0906]

[0907] Pyridine (0.031 mL, 0.39 mmol) and (R)-methyl(pyrrolidine-3-yl)carbamate tert-butyl ester (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 h and then at 80 °C for 18 h. The mixture was then cooled, water (8 mL) was added, and the mixture was added to a saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The obtained residue was purified by chromatography (silica gel; dichloromethane to 95:5 dichloromethane / methanol; gradient elution) to give (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidine-2-carboxylic acid methyl ester. 1 H NMR(500MHz,CDCl3)δ8.14(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] + .

[0908] 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-carboxylic acid (0.107 g, 0.318 mmol) in tetrahydrofuran (6.9 mL), and the mixture was stirred at room temperature for 16 h. Afterward, volatiles 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, and the resulting solid was collected by filtration, washed with water, and dried under vacuum to give (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 x 20 mL), the combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain a second batch of (R)-5-(3-((tert-butoxycarbonyl)(methyl)-amino)pyrrolidine-1-yl)pyrimidine-2-carboxylic acid. 1H NMR(500MHz,DMSO–d6)δ12.63(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] + .

[0909] N,N-diisopropylethylamine (0.203 mL, 1.17 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HBTU, 0.166 g, 0.437 mmol) were added to a solution of (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrimidin-2-carboxylic acid (0.094 g, 0.29 mmol) and 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (0.047 g, 0.29 mmol) in N,N-dimethylformamide (2.4 mL), and the mixture was stirred at room temperature for 16 h. Afterward, water (20 mL) was added. The solid formed was collected by filtration, washed with water (10 mL) and dried under vacuum to give (R)-(1-(2-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-5-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester. 1 H NMR(500MHz,DMSO–d6)δ9.98(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,2H),2.77(s,3H),2.70(s,3H),2.39(s,3H),2.19–2.11(m,2H),1.43(s,9H); MS(ESI)m / z 467[M+H] + .

[0910] Trifluoroacetic acid (0.348 mL, 4.54 mmol) was added to a solution of (R)-(1-(2-((2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)carbamoyl)pyrimidin-5-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (0.106 g, 0.227 mmol) in dichloromethane (4.7 mL), and the mixture was stirred at room temperature for 2 h. Subsequently, the solvent was removed under vacuum, dichloromethane (40 mL) was added, and the mixture was concentrated to dryness again. The resulting residue was dissolved in dichloromethane (40 mL) and washed with a saturated aqueous sodium bicarbonate 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 (silica gel; dichloromethane to 85:14:1 dichloromethane / methanol / ammonium hydroxide; gradient elution) to give (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)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 give (R)-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrimidine-2-carboxamide. mp 266–268 °C; 1 H NMR(500MHz,DMSO–d6)δ9.96(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,3H),2.39(s,3H),2.32(s,3H),2.14–1.84(m,3H); 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 =0.83min, >99%(AUC), MS(ESI)m / z 367[M+H] + .

[0911] Example 142: (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(piperidin-2-yl)azacyclobutane-1-yl)pyrazin-2-carboxamide

[0912] 2-(azacyclobutane-3-yl)-1-benzylpiperidine

[0913]

[0914] Benzyl bromide (0.37 mL, 3.12 mmol) was added to a solution of tert-butyl 3-(piperidin-2-yl)azacyclobutane-1-carboxylate (500 mg, 2.08 mmol) in DCM (7 mL), followed by the addition of a saturated sodium carbonate solution (7 mL), and the resulting mixture was stirred at room temperature for 19 h. The mixture was then partitioned between DCM and water. The aqueous phase was extracted again (x1), the combined organic phases were passed through phase separation paper, and evaporated to dryness. The crude product was purified by silica chromatography (elution gradient 0-100% [EtOAc+ in MeOH 5% NH3] / cyclohexane) to give tert-butyl 3-(1-benzylpiperidin-2-yl)azacyclobutane-1-carboxylate.

[0915] 3-(1-benzylpiperidin-2-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (540 mg, 1.63 mmol) was dissolved in a mixture of DCM (5 mL) and TFA (5 mL), and the resulting mixture was stirred at room temperature for 18 h. The mixture was evaporated to dryness to obtain an oil, which was partitioned between DCM and an aqueous sodium carbonate solution. The aqueous phase was extracted with DCM (x1), and the combined organic phases were passed through phase separation paper and evaporated to dryness to give 2-(azacyclobutane-3-yl)-1-benzylpiperidin.

[0916]

[0917] Method D was followed for 22 h with the following amounts: 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (119 mg, 0.39 mmol), 2-(azacyclobutane-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, which was extracted with DCM (x2). The organic phase was then dried over phase separation paper and evaporated to dryness. The crude product was purified by silica chromatography with an elution gradient of 25–100% EtOAc / cyclohexane followed by 0–1% NH3(7N) / EtOAc in MeOH. The material was then purified by chiral SFC to obtain 5-(3-(1-benzylpiperidin-2-yl)azacyclobutane-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (enantiomer 1).

[0918] Enantiomer 1, namely 5-(3-(1-benzylpiperidin-2-yl)azacyclobutan-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (34 mg, 0.068 mmol), was dissolved in MeOH (1 mL) and degassed by jet N2 for 20 min. Pd / C (10%, 5 mg) was then added, followed by 1-methyl-1,4-cyclohexadiene (76 μL, 0.68 mmol), and the resulting mixture was heated to 60 °C for 3 h. Further 1-methyl-1,4-cyclohexadiene (76 μL, 0.68 mmol) was added and the mixture was incubated 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 again incubated at 60 °C overnight, after which complete conversion was achieved. The mixture was filtered through diatomaceous earth, washed with a large amount of MeOH, and evaporated to obtain a crude residue, which was purified by reversed-phase HPLC to obtain (S)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-(piperidin-2-yl)azacyclobutan-1-yl)pyrazin-2-carboxamide. LCMS (ES+) 410(M+H)+, RT 1.81 min (Analytical method AcHSSC18); 1 H NMR (400MHz, DMSO) δ10.44(s,1H),9.19(d,J=1.5Hz,1H),8.73(d,J=1.3Hz,1H),7.90(d,J=2.8Hz,1H),7. 86(d,J=1.3Hz,1H),7.56(dd,J=1.6,13.1Hz,1H),4.26-4.17(m,2H),4.10(dd,J=5.6,9.1Hz,1H),4.00(d d,J=5.7,9.0Hz,1H),3.06(d,J=11.0Hz,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).

[0919] Example 143 5-[3-(cyclopropylamino)pyrrolidine-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2)

[0920] 2-Methylpyrazolo[1,5-a]pyridine-5-amine

[0921]

[0922] 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 equivalent) were suspended in THF, and the reaction mixture was purged with N₂ for 15 min. The tube was sealed, and the reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature, diluted with water, and washed with EtOAc (x³). The combined organics were washed with brine, dried, and the solvent was removed under vacuum. The crude product was purified by silica chromatography with an elution gradient of 5-60% EtOAc in cyclohexane. The fractions containing the desired compound were combined and the solvent was removed under vacuum to give N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)-1,1-diphenylimine. LCMS(ES+)312(M+H)+

[0923] 2-Methylpyrazolo[1,5-a]pyridine-5-amine (185 mg, 0.529 mmol, 1 equivalent) was dissolved in MeOH (2.0 mL) and 4M HCl (1.3 mL, 5.29 mmol, 10 equivalent) 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 applied to a 2 g SCX cartridge, eluted with 2 column volumes of methanol, followed by 3 column volumes of 2M methanolic ammonia. The ammonia fraction was concentrated under vacuum to give 2-methylpyrazolo[1,5-a]pyridine-5-amine. LCMS(ES+)148(M+H)+.

[0924]

[0925] According to Method H, 5-(3-((tert-butoxycarbonyl)(cyclopropyl)amino)pyrrolidine-1-yl)pyrazin-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) were diluted with water, the solid was filtered and washed with 1:2 MeCN / H2O to give cyclopropyl(1-(5-(((2-methylpyrazolo[1,5-a]pyridine-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamate tert-butyl ester, which was used without further purification.

[0926] According to Method E, tert-butyl cyclopropyl (1-(5-((2-methylpyrazolo[1,5-a]pyridin-5-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)carbamate (71 mg, 0.149 mmol) was extracted. The reaction mixture was concentrated under vacuum and the residue was applied to a 2 g SCX box, eluted with 2 column volumes of methanol, and then eluted with 3 column volumes of 2M methanolic ammonia. The ammonia fraction was concentrated under vacuum to obtain crude 5-[3-(cyclopropylamino)pyrrolidone-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazin-2-carboxamide, which was purified by HPLC to obtain 5-[3-(cyclopropylamino)pyrrolidone-1-yl]-N-(2-methylpyrazolo[1,5-a]pyridin-5-yl)pyrazin-2-carboxamide (enantiomer 1 + enantiomer 2). LCMS (ES+) 378(M+H)+, RT 4.32 min (analytical method Bicarb BEHC18) 1 HNMR (400MHz, DMSO) δ10.22(s,1H),8.56(s,1H),8.29(d,J=7.6Hz,1H),8.03(s,1H),7.78(s,1H),7.07(dd,J=2.0,7.6Hz,1 H),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=6.6Hz,2H),0.15-0.06(m,2H).

[0927] Example 144 3-(6-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0928]

[0929] 6-Chloropyridazin-3-carboxylic acid (270 mg, 1.7 mmol), 2-methylimidazo[1,2-a]pyridin-6-amine (250 mg, 1.7 mmol), HBTU (683 mg, 1.8 mmol), and triethylamine (1 mL, 7.2 mmol) were dissolved in DMF (6 mL) and stirred at room temperature for 24 h. The solution containing crude 6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3-carboxamide was used without further purification.

[0930] 6-Chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)pyridazin-3-carboxamide (approximately 0.24 mmol from a 1 mL solution of the previous step), 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 h. After cooling to room temperature, the solids were removed by filtration, and the filtrate was purified by preparative HPLC to give 3-(6-((2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyridazin-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tert-butyl ester. LCMS(ES+)464(M+H)+, RT2.75min (analysis method 10cm_Formic_AQ). 1 H NMR (400MHz, DMSO) δ10.91(s,1H),9.32(s,1H),8.04-8.00(m,1H),7.80(s,1H),7.63(dd,J=1.8,9.6Hz,1H),7.47(d,J=9.6Hz,1H),7.41(d,J =9.6Hz,1H),4.36(s,2H),4.28(d,J=12.4Hz,2H),3.21(d,J=12.0Hz,2H),2.37(s,3H),1.99-1.94(m,2H),1.72(d,J=4.6Hz,2H),1.50(s,9H).

[0931] Comparative Examples

[0932] Comparative Example 145: N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide

[0933]

[0934] 6-Chloro-2-methoxynicotinic acid (188 mg, 1 mmol), 2,8-dimethylimidazo[1,2-a]pyrazin-6-amine (162 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (4 mL) were combined and stirred for 17 hours. The reaction mixture was diluted with EtOAc, washed with water (2x), and evaporated to dryness to give 6-chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxynicotinamide, the crude product of which was used in the next step.

[0935] 6-Chloro-N-(2,8-dimethylimidazo[1,2-a]pyrazin-6-yl)-2-methoxynicotinamide (70 mg, 0.21 mmol), piperazine (45 mg, 0.52 mmol), triethylamine (1 mL), and dioxane (6 mL) were combined in a sealed tube and heated to 100 °C for 17 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 382(M+H)+, RT 2.07 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ9.86 (s, 1H), 9.19 (s, 1H), 8.13 (d, J = 8.8Hz, 1H), 7.97 (s, 1H), 6.56 (d, J = 8.8Hz, 1H), 4.08 (s, 3H), 3.59 (dd, J = 5.0, 5.0Hz, 4H), 2.80 (dd, J = 5.0, 5.0Hz, 4H), 2.70 (s, 3H), 2.39 (s, 3H).

[0936] Comparative Example 146N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1-yl)nicotinamide

[0937]

[0938] 6-Chloro-2-methoxynicotinic acid (188 mg, 1 mmol), 8-fluoro-2-methylimidazo[1,2-a]pyridin-6-amine·2HCl (238 mg, 1 mmol), HBTU (379 mg, 1 mmol), triethylamine (1 mL), and DMF (4 mL) were combined and stirred for 17 hours. The reaction mixture was diluted with EtOAc, washed with water (2x), and evaporated to dryness to give 6-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxynicotinamide, the crude product of which was used in the next step.

[0939] The crude product from the previous step, piperazine (86 mg, 1 mmol), triethylamine (1 mL), and dioxane (10 mL) were combined in a sealed tube and heated to 100 °C for 17 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by preparative HPLC to give the title compound. LCMS (ES+) 385 (M+H)+, RT 1.89 min (Analytical method AcHSSC18). 1HNMR (400MHz, DMSO) δ9.68(s,1H),9.11(d,J=1.6Hz,1H),8.03(d,J=8.7Hz,1H),7.88(d,J=2.8Hz,1H),7.37(dd,J=1.6, 12.9Hz, 1H), 6.50 (d, J = 8.8Hz, 1H), 4.03 (s, 3H), 3.57 (dd, J = 5.0, 5.0Hz, 4H), 2.79 (dd, J = 5.0, 5.0Hz, 4H), 2.35 (s, 3H).

[0940] Comparative Example 147: N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl)nicotinamide

[0941]

[0942] 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 give the title compound. LCMS (ES+) 351(M+H)+, RT 2.89 min (analytical method Bicarb BEHC18). 1 H NMR (400MHz, DMSO) δ10.04(s,1H),9.19(s,1H),8.76(d,J=2.3Hz,1H),8.10(dd,J=2.6,9.1Hz,1H),7.74(s,1H),7.44(d,J=9.5Hz,1H), 7.35(dd,J=2.0,9.5Hz,1H), 6.94(d,J=9.0Hz,1H), 3.65(dd,J=5.0,5.0Hz,4H), 2.41(dd,J=5.1,5.1Hz,4H), 2.33(s,3H), 2.23(s,3H).

[0943] Examples 148 and 149: (R)-5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide;

[0944] (S)-5-(3-((cyclopropylamino)methyl)pyrrolidin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0945]

[0946] N-(pyrrolidone-3-ylmethyl)cyclopropylamine·2HCl (488 mg, 2.29 mmol), 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (700 mg, 2.29 mmol), cesium carbonate (2.98 g, 9.16 mmol), and DMF (8 mL) were combined and heated to 100 °C for 4 hours. The cesium salt was then filtered off, and the filtrate was purified by preparative HPLC, followed by chiral preparative HPLC to obtain:

[0947] Example 148

[0948] Enantiomer 1

[0949] 5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 410(M+H)+, RT 1.83 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.44(s,1H),9.22(d,J=1.6Hz,1H),8.77(d,J=1.3Hz,1H),7.99 (d,J=1.3Hz,1H),7.92(d,J=2.8Hz,1H),7.59(dd,J=1.8,13.0Hz,1H),3.78-3.67(m,2 H),3.58-3.45(m,1H),3.28(dd,J=7.3,11.0Hz,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=1.6,6.6Hz,2H),0.27-0.23(m,2H).

[0950] Example 149

[0951] Enantiomer 2

[0952] 5-(3-((cyclopropylamino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 410(M+H)+, RT 1.83 min (Analytical method AcHSSC18). 1H NMR (400MHz, DMSO) δ10.44(s,1H),9.22(d,J=1.6Hz,1H),8.77(d,J=1.3Hz,1H),7.99 (d,J=1.3Hz,1H),7.92(d,J=2.8Hz,1H),7.59(dd,J=1.8,13.0Hz,1H),3.78-3.67(m,2 H),3.58-3.45(m,1H),3.28(dd,J=7.3,11.0Hz,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=1.6,6.6Hz,2H),0.27-0.23(m,2H).

[0953] Other analogues are prepared from commercially available or synthetic amines using the same chemical reaction. The final products are separated by preparative HPLC.

[0954]

[0955] Examples 151 and 152: (R)-5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide;

[0956] (S)-5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolid-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0957]

[0958] 5-(3-((cyclopropylamino)methyl)pyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide was reacted with formaldehyde (37 wt.%, 10%-15% methanol, 1.5 mL in H2O) and sodium triacetoxyborohydride (168 mg, 0.794 mmol) and stirred at room temperature for 18 h. The mixture was then partitioned between DCM and an aqueous solution of sodium bicarbonate. The aqueous phase was then re-extracted with DCM (x1), and the combined organic phases were passed through phase separation paper and evaporated to dryness to give a crude residue. The crude product was purified by silica chromatography with an elution gradient of 0-4% NH3(7N) / EtOAc in MeOH. The material was then purified by chiral SFC followed by HPLC to provide:

[0959] Example 151

[0960] Enantiomer 1

[0961] 5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 424(M+H)+, RT 1.92 min (analytical method AcHSSC18); 1 HNMR(400MHz,DMSO)δ10.42(s,1H),9.19(d,J=1.5Hz,1H),8.75(d,J=1.3Hz,1H), 7.98(d,J=1.4Hz,1H),7.90(d,J=2.8Hz,1H),7.57(dd,J=1.6,13.2Hz,1H),3.73-3 .64(m,2H),3.57-3.49(m,1H),3.23(dd,J=6.8,11.1Hz,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).

[0962] Example 152

[0963] Enantiomer 2

[0964] 5-(3-((cyclopropyl(methyl)amino)methyl)pyrrolidone-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 424(M+H)+, RT 1.92 min (analytical method AcHSSC18); 1 HNMR (400MHz, DMSO) δ10.42(s,1H),9.19(d,J=1.6Hz,1H),8.75(d,J=1.3Hz,1H),7.98(d,J=1 .4Hz,1H),7.90(dd,J=0.8,3.2Hz,1H),7.57(dd,J=1.7,13.1Hz,1H),3.73-3.64(m,2H),3.57- 3.50(m,1H),3.22(dd,J=6.7,11.0Hz,1H),2.65-2.59(m,1H),2.52(t,J=1.8Hz,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).

[0965] Other analogues are prepared using the same chemical reaction and the amine (commercial or intermediate as described in the intermediate section). When a Boc-protected amine is used, the Boc group is subsequently removed with TFA or HCl using method C or D.

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973] Example 170: (R)-5-(3-(1-(cyclopropylamino)cyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0974]

[0975] (R)-5-(3-(1-aminocyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (60 mg, 0.15 mmol) was dissolved in methanol (2 mL) and (1-ethoxycyclopropoxy)trimethylsilane (29 mg, 0.21 mmol) and sodium cyanoborohydride (11 mg, 0.18 mmol) were added. Acetic acid (20 μL) was added and the reaction was heated at 50 °C overnight. The reaction was cooled to room temperature and the solvent was removed under vacuum to obtain the residue, which was purified by preparative HPLC to give (R)-5-(3-(1-(cyclopropylamino)cyclopropyl)pyrrolidine-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 436 (M+H)+, RT 1.98 min (analytical method AcHSSC18); 1H NMR (400MHz, DMSO) δ10.44(s,1H),9.23(d,J=1.5Hz,1H),8.78(d,J=1.3Hz,1H),8.00(d,J =1.5Hz,1H),7.93(d,J=2.3Hz,1H),7.61(dd,J=1.5,13.1Hz,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).

[0976] Example 171: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(6-methyl-2,6-diazaspiro[3,5]nonane-2-yl)pyrazin-2-carboxamide

[0977]

[0978] A mixture of 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (55 mg, 0.18 mmol), 6-methyl-2,6-diazaspiro[3.5]nonane dihydrochloride (50 mg, 0.24 mmol) and cesium carbonate (235 mg, 0.722 mmol) in DMF (1.5 mL) was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, filtered, and purified by achiral reversed-phase HPLC (Xbridge Phenyl 19x150mm, 10μm, 40%-100% MeOH / H2O (10mMNH4CO3), 20mL / min, room temperature) to give N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(6-methyl-2,6-diazaspiro[3,5]nonane-2-yl)pyrazin-2-carboxamide. LCMS (ES+) 410.3 [M+H + RT 1.83 minutes (analysis method AcHSSC18). 1H NMR (400MHz, DMSO) δ10.44(s,1H),9.19(d,J=1.6Hz,1H),8.72(d,J=1.3Hz,1H),7.90-7.87(m,2H),7.56(dd,J=1.6,13.1Hz,1H),3.90(d,J =9.0Hz,2H),3.86(d,J=9.0Hz,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).

[0979] Example 172: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(2,6-diazaspiro[3,5]nonane-2-yl)pyrazin-2-carboxamide

[0980]

[0981] A mixture of 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (89 mg, 0.29 mmol), tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate hydrochloride (100 mg, 0.38 mmol), and cesium carbonate (382 mg, 1.17 mmol) in DMF (3 mL) was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature, filtered, and the solid was washed with EtOAc. The combined filtrates were concentrated under reduced pressure to give crude material, which was used without further purification, assuming a quantitative yield. MS (ES+) 496.3 [M+H] + .

[0982] Hydrogen chloride (in dioxane, 4 M, 2.4 mL, 9.75 mmol) was added to a solution of tert-butyl 2-(5-((8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)carbamoyl)pyrazin-2-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (145 mg, 0.293 mmol) in methanol (2.5 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reversed-phase HPLC (Xbridge Phenyl 19x150mm, 10μm, 20%-80% MeOH / H2O (10mM NH4CO3), 20mL / min, room temperature) to obtain N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(2,6-diazaspiro[3,5]nonane-2-yl)pyrazin-2-carboxamide. LCMS (ES+) 396.0 [M+H]+ RT 1.80 minutes (analysis method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.44(s,1H),9.19(d,J=1.5Hz,1H),8.72(d,J=1.3Hz, 1H),7.90-7.86(m,2H),7.58(d,J=1.5Hz,1H),7.56(dd,J=1.6,13.1Hz,1H), 7.55(d,J=1.6Hz,1H),3.90(d,J=8.9Hz,2H),3.83(d,J=8.9Hz,2H),2.84(s ,2H),2.67-2.61(m,2H),2.35(s,3H),1.80-1.71(m,2H),1.50-1.41(m,2H).

[0983] Example 173: N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyrazine-2-carboxamide

[0984]

[0985] 2,2,6,6-Tetramethyl-4-piperidinol (116 mg, 0.974 mmol) was added to a suspension of NaH (60% in oil) (55 mg, 1.38 mmol) in DMF (3 mL) and the reaction was stirred at room temperature for 30 min. 5-Chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide (100 mg, 0.33 mmol) was added and the reaction was heated to 95 °C for 1 h. The reaction mixture was evaporated to dryness. The crude mixture was purified by rapid chromatography using a KP-NH column, followed by preparative HPLC purification to obtain the title compound. LCMS (ES+) 427(M+H)+, RT 2.02 min (Analytical method AcHSSC18). 1 H NMR (400MHz, DMSO) δ10.74(s,1H),9.24(d,J=1.6Hz,1H),8.90(d,J=1.3Hz,1H),8.37(d,J=1.3Hz,1H),7.92(d,J=2.8Hz,1H),7.57(dd,J= 1.6,13.1Hz,1H),5.61-5.53(m,1H),2.35(s,3H),2.03(dd,J=4.0,12.0Hz,2H),1.29(dd,J=11.5,11.5Hz,2H),1.23(s,6H),1.12(s,6H).

[0986] Example 174: 5-(5-cyclopropylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide

[0987]

[0988] N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)pyrazin-2-carboxamide (100 mg, 0.262 mmol) was dissolved in methanol (8 mL) and (1-ethoxycyclopropyloxy)trimethylsilane (48 mg, 0.275 mmol), NaBH3CN (18 mg, 0.29 mmol), and acetic acid (0.2 mL), and the reaction was heated to 55 °C for 18 hours. (1-ethoxycyclopropyloxy)trimethylsilane (48 mg, 0.275 mmol) and NaBH3CN (18 mg, 0.29 mmol) were added, and heating continued for another 18 hours. The reaction was cooled to room temperature, and potassium carbonate (500 mg, 3.6 mmol) was added. The solvent was removed under vacuum, and the crude mixture was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic layer was separated, dried (MgSO4), and evaporated to dryness. The crude material was purified by preparative HPLC to obtain 5-(5-cyclopropylhexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazin-2-carboxamide. LCMS (ES+) 422(M+H)+, RT 1.82 min (Analytical method AcHSSC18); 1 H NMR (400MHz, DMSO) δ10.44(s,1H),9.19(d,J=1.6Hz,1H),8.75(d,J=1.1Hz,1H),8.00(d,J =1.3Hz,1H),7.90(d,J=2.8Hz,1H),7.57(dd,J=1.6,13.1Hz,1H),3.83(dd,J=8.3,11.5Hz, 2H), 3.42 (dd, J=3.3, 11.5Hz, 2H), 2.96 (dd, J=7.5, 7.5Hz, 2H), 2.77 (dd, J=6.9, 9.2Hz, 2H) ,2.69-2.62(m,2H),2.35(s,3H),1.67-1.61(m,1H),0.43-0.37(m,2H),0.33-0.27(m,2H).

[0989] Example 175: (R)-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-(methylamino)pyrrolidine-1-yl)pyrazin-2-carboxamide

[0990]

[0991] To a solution of methyl 5-chloropyrazine-2-carboxylate (500 mg, 2.9 mmol) in dioxane (10 mL), tert-butyl (R)-methyl(pyrrolidine-3-yl)carbamate (696 mg, 3.48 mmol) was added. Triethylamine (0.61 mL, 4.35 mmol) was added, and the reaction was heated in a microwave oven at 140 °C for 30 min. The solvent was removed under vacuum, and a portion of the residue was purified by rapid chromatography using an elution gradient of 20%–100% EtOAc in cyclohexane to give lithium (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazine-2-carboxylate. LCMS (AQ6 general-purpose acid gel electrophoresis) RT 1.54 min, (ES+) 337 (M+H). 1 H NMR(400MHz, CDCl3)δ8.79(s,1H),7.89(s,1H),4.89-4.80(m,1H),3.93(s,3H),3 .83-3.76(m,2H),3.58-3.45(m,2H),2.82(s,3H),2.27-2.13(m,2H),1.48(s,9H).

[0992] Methyl (R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate (194 mg, 0.577 mmol, 1 equivalent) was dissolved in MeOH (5 mL) and H₂O (0.5 mL), and lithium hydroxide monohydrate (36 mg, 0.865 mmol, 1.50 equivalent) was added. The reaction mixture was stirred for 16 hours. An additional portion of lithium hydroxide monohydrate (45 mg, 1.1 mmol) was added, and the reaction mixture was stirred at 45 °C for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The resulting material was used for the next step without further purification. LCMS (AQ6 general-purpose acid gel electrophoresis) RT 1.4 min, (ES+) 323 (M+H).

[0993] 6,8-Dimethylimidazo[1,2-a]pyrazin-2-amine (50 mg, 0.31 mmol), lithium methyl(R)-5-(3-((tert-butoxycarbonyl)(methyl)amino)pyrrolidine-1-yl)pyrazin-2-carboxylate (99 mg, 0.31 mmol), HBTU (129 mg, 0.339 mmol), triethylamine (0.064 mL, 0.46 mmol), and DMF (1 mL) were combined and stirred at room temperature for 18 hours. A further portion of HBTU (160 mg, 0.422 mmol) was added, and the reaction was heated to 50 °C for 2.5 hours. The solvent was removed under vacuum, and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined extracts were dried (MgSO4), evaporated, and the crude product was purified by rapid chromatography (elution gradient of 20-100% EtOAc in cyclohexane followed by 10% ethanol / ethyl acetate), and then purified by rapid chromatography on KP-NH (elution gradient of 20-100% EtOAc) to give (R)-(1-(5-((6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl carbamate. LCMS (AQ6 general acid gel electrophoresis) RT 1.53 min, (ES+) 467 (M+H).

[0994] (R)-(1-(5-((6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)carbamoyl)pyrazin-2-yl)pyrrolidine-3-yl)(methyl)carbamate tert-butyl ester (35 mg, 0.07 mmol), methanol (1 mL), dioxane (1 mL), and 4N HCl in dioxane (0.5 mL, 2.0 mmol) were combined and stirred at room temperature for 3 hours. The mixture was evaporated to dryness, the crude material was dissolved in methanol (2 mL) and stirred with potassium carbonate, re-evaporated, and purified by preparative HPLC to obtain the title product. LCMS (ES+) 367(M+H)+, RT 1.88 min (Analytical method AcHSSC18); 1 H NMR (400MHz, DMSO) δ10.25(s,1H),8.76(d,J=1.3Hz,1H),8.34(s,1H),8.29(s,1H),8.03(d,J=1.4Hz,1H),3 .69-3.59(m,3H...

Claims

1. A compound of formula I: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: X 1 X 2 X 3 and X 4 It is CR 4 Or N, where X 1 X 2 X 3 and X 4 The two in it are N; Each R 4 It is hydrogen on its own; Y 1 It is CR 5 ; R 5 It is hydrogen or a halogen group; Y 2 It is CR 6 ; R 6 It is hydrogen; and Y 3 It is CR 3 ; R 3 It is hydrogen or a halogen group; Z 1 and Z 2 Each of them is C; Ring A and ring B together form a 9-membered bicyclic heteroaryl group containing one nitrogen atom; Ring B is R 8 It is C 1-6 alkyl; R 1 Yes -L 1 -R 11 L 1 It does not exist, and R 11 It is arbitrarily divided by 1 to 4 R 13 Heterocyclic groups substituted with functional groups; Each R 13 Independently selected by optional R 16 Replacement C 1-6 Alkyl, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, -NH2 or -NHR 14 ; Each R 14 Selected independently from C 1-6 Alkyl or C 3-10 cycloalkyl; Each R 16 Independently a halogenated group or -NHR 21 ; Each R 21 Selected independently from C 1-6 Alkyl or C 3-10 cycloalkyl; and R 2 It is hydrogen; "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure and containing 3 to 12 cyclic carbon atoms and 1 to 5 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur atom is optionally oxidized to form an N-oxide, sulfinyl (-S(O)-) or sulfoxide (-S(O)2-), and may contain 1 to 3 oxo or N-oxide (-O) groups. - )part.

2. The compound according to claim 1, wherein the compound has formula Ia: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

3. A compound of formula IIa: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: R 8 It is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; X 1 X 2 X 3 and X 4 It is CR 4 Or N, where X 1 X 2 X 3 and X 4 At least two but no more than three of them are N; Each R 4 It is hydrogen on its own; Y 1 It is CR 5 Or N; R 5 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy; R 3 It is hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; R 1 Yes -L 1 -R 11 L 1 It is -O-, -N(R) 12 )-、-N(R 12 )-C 1-3 Alkylene - or not present, and R 11 It is arbitrarily divided by 1 to 4 R 13 Heterocyclic groups substituted with functional groups; R 12 Is it hydrogen or C? 1-6 alkyl; Each R 13 Independently selected from halogen groups, C 1-6 Alkyl, optionally R 16 Replacement C 3-10 cycloalkyl, heteroaryl, optionally R 16 Substituted heterocyclic groups, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2 and -C(O)OR 15 ; Each R 14 Selected independently from C 1-6 Alkyl, C 3-10 Cycloalkyl and heterocyclic groups; and each R 14 Optionally, it is divided into one to six halogen groups, C 1-3 Alkoxy or C 3-10 Cycloalkyl substitution; Each R 15 C is independent 1-6 alkyl; Each R 16 Independently, it is a halogen group, -NH2, or -NHR. 21 C 1-6 Alkyl, OR 21 Or C 3-10 cycloalkyl; Each R 21 Selected independently from C 1-6 Alkyl and C 3-10 cycloalkyl; and R 2 It is hydrogen; "Heteroaryl" refers to an aromatic group having a monocyclic or multiple fused rings, containing 3 to 12 cyclic carbon atoms and 1 to 5 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur; and "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure and containing 3 to 12 cyclic carbon atoms and 1 to 5 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur atom is optionally oxidized to form an N-oxide, sulfinyl (-S(O)-) or sulfoxide (-S(O)2-), and may contain 1 to 3 oxo or N-oxide (-O) groups. - )part.

4. A compound of formula IIb: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein: R 10 It is C 1-6 alkyl; X 1 It is N; X 2 It is CH; X 3 It is N; and X 4 It is CH; R 3 It is hydrogen or a halogen group; Y 1 It is CR 5 ; R 5 It is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R 1 Yes -L 1 -R 11 L 1 It does not exist, and R 11 It is arbitrarily divided by 1 to 4 R 13 Heterocyclic groups substituted with functional groups; Each R 13 Independently selected from halogen groups, C 1-6 Alkyl, heterocyclic, optionally R 16 Substituted heterocyclic group -C 1-6 Alkyl, -NHR 14 -C 1-6 Alkylene-NHR 14 or -C 1-6 Alkylene-N(R) 14 )2; Each R 14 Selected independently from C 1-6 Alkyl or C 3-10 cycloalkyl; and each R 14 Optionally, it is coated with one to six halogen groups or C 1-3 Alkyl substitution; Each R 16 Independently, it is a halogen or OR 21 ; Each R 21 Selected independently from C 1-6 Alkyl groups, and each R 21 Choose one to six Cs 1-3 Alkoxy substitution; and R 2 It is hydrogen; "Heterocyclic group" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure and containing 3 to 12 cyclic carbon atoms and 1 to 5 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur atom is optionally oxidized to form an N-oxide, sulfinyl (-S(O)-) or sulfoxide (-S(O)2-), and may contain 1 to 3 oxo or N-oxide (-O) groups. - )part.

5. The compound according to claim 3, wherein the compound has formula IIIa: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

6. The compound according to claim 3, wherein the compound has formula IIIb: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

7. The compound according to claim 3, wherein the compound has formula IIIc: Or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.

8. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 11 It is optionally composed of 1 to 4 independently selected halogen groups, C 1-6 Alkyl, C 3-10 Cycloalkyl, heteroaryl, heterocyclic, heterocyclic-C 1-6 Alkyl, -NH2, -NHR 14 -N(R) 14 )2、-C 1-6 Alkylene -NH2, -C 1-6 Alkylene-NHR 14 -C 1-6 Alkylene-N(R) 14 )2 and -C(O)OR 15 The heterocyclic group substituted with the group; wherein each R 14 It may be optionally replaced by one to three halogen groups.

9. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 11 yes Where ring C is arbitrarily divided by 1 to 4 Rs 13 A 4- to 10-membered heterocyclic group containing 0, 1, or 2 additional cyclic nitrogen atoms.

10. The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein the ring C is optionally surrounded by 1 to 4 R... 13 A 5- to 10-membered bicyclic heterocyclic group containing an additional cyclic nitrogen atom.

11. The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein the ring C is optionally surrounded by 1 to 4 R... 13 A 5- to 10-membered spirobicyclic heterocyclic group containing an additional cyclic nitrogen atom.

12. The compound of claim 9 or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein the ring C is optionally surrounded by 1 to 4 R... 13 A 5- to 10-membered fused bicyclic heterocyclic group containing an additional cyclic nitrogen atom.

13. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 11 Selected from Each of these is arbitrarily divided by 1 to 4 Rs. 13 Group substitution.

14. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 11 Optionally, it is composed of 1 to 4 elements independently selected from fluorine, methyl, ethyl, 2,2-difluoroethylaminomethyl, N-methyl-2,2-difluoroethylaminomethyl, (3,3,3-trifluoropropyl-1-ylamino)methyl, cyclopropyl, 1-(cyclopropylamino)-1-cyclopropyl, 1-pyrrolidinyl, N-morpholinyl, N-pyrrolidinyl, N-pyrrolidinylmethyl, 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 1-methyl-2-piperidinyl, 1-cyclopropyl-2-piperidinyl, cyclopropylamino, N-cyclopropylaminomethyl, (1-methyl-1-cyclopropylamino)methyl, 1-(N-cyclopropylamino)ethyl, N,N-dicyclopropylaminomethyl, N-methoxyethyl-N -Substitution of cyclopropylaminomethyl, N-cyclopropyl-N-methylamino, N-cyclopropyl-N-methylaminomethyl, amino, aminomethyl, methylamino, ethylamino, isopropylamino, isopropylamino, N-isopropyl-N-aminomethyl, tert-butylamino, n-butylamino, N-methylaminomethyl, N,N-dimethylaminomethyl, 3,3-difluorocyclobutylamino, tetrahydropyranylamino, oxetanebutylamino, (3-methoxy-1-azacyclobutyl)methyl, (3-methoxy-1-pyrrolidinyl)methyl, (3-fluoro-1-pyrrolidinyl)methyl, (3-fluoro-3-methyl-1-pyrrolidinyl)methyl, 4-morpholinylmethyl and tert-butoxycarbonyl groups.

15. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 3 It is a halogen group.

16. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 3 It's fluorine.

17. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 3 It is a methyl group.

18. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 3 It is a methoxy group.

19. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 5 It is hydrogen.

20. The compound according to any one of claims 3-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 5 It is C 1-6 Alkyl group.

21. The compound according to any one of claims 3-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 5 It is a methoxy group.

22. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein R 8 It is a methyl group.

23. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein L 1 It does not exist.

24. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein Y 1 It is CR 5 .

25. The compound according to any one of claims 3 and 5-7, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, wherein Y 1 It is N.

26. A compound or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, said compound being 27. A pharmaceutical composition comprising the compound of any one of claims 1-26 or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable excipient.

28. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 27, in the preparation of a medicament for the treatment of Huntington's disease.

29. Use of the compound of any one of claims 1-26, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 27, in the preparation of a medicament for treating Huntington's disease, wherein the medicament is combined with a second active agent.

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