Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of sterile alpha and TIR motif protein 1 (SARM1), or pharmaceutically acceptable salts, isotope enriched analogs, stereoisomers, stereoisomer mixtures, or prodrugs thereof; processes for their preparation and intermediates; and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application Serial No. 63 / 378,842, filed on October 7, 2022, and U.S. Provisional Application Serial No. 63 / 580,955, filed on September 6, 2023, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure generally relates to small molecule modulators of sterile alpha and TIR motif 1 (SARM1) protein and their use as therapeutic agents. Background Art

[0004] Neurodegenerative diseases are a class of progressive neurological disorders in which nerve cells malfunction and eventually die. Neuronal degeneration in patients with neurodegenerative diseases can manifest as a variety of symptoms, including changes in mood and behavior, irritability, sensory disturbances, movement and cognitive difficulties, and memory loss. These symptoms may progress to the inability to move or speak, dementia, and ultimately death.

[0005] Axonal degeneration has been identified as a key pathology in most neurodegenerative diseases. Axons are susceptible to mechanical injury (Wallerian degeneration) and disease (Wallerian degeneration).

[0006] In healthy axons, the N terminus of SARM1 interacts with the TIR domain, preventing TIR multimerization and subsequent NAD + However, under conditions of neuronal injury or disease, the N-terminal-TIR domain interaction of SARM1 is disrupted, allowing TIR multimerization to occur, followed by rapid loss of NAD+ and associated axonal degeneration. Summary of the Invention

[0007] Provided herein are compounds useful for treating and / or preventing diseases mediated at least in part by SARM1, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof.

[0008] In certain embodiments, compounds that inhibit SARM1 are provided.

[0009] In another embodiment, a pharmaceutical composition is provided, comprising a compound as described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0010] In another embodiment, provided is a method for treating a disease or condition mediated at least in part by SARM1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0011] The present disclosure also provides compositions, including pharmaceutical compositions; kits comprising the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof; methods of using (or administering) and preparing the compounds, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof; and intermediates thereof.

[0012] The present disclosure also provides a compound for use in a method of treating a disease, condition or disorder mediated at least in part by SARM1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, or a composition thereof.

[0013] In addition, the present disclosure provides the use of the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, or a composition thereof, in the manufacture of a medicament for treating a disease, condition or disorder mediated at least in part by SARM1.

[0014] The description herein sets forth exemplary embodiments of the present technology. However, it should be recognized that this description is not intended to limit the scope of the disclosure, but is provided as a description of exemplary embodiments.

[0015] 1. Definition

[0016] As used in this specification, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0017] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through a carbon atom. Dashes preceding or ending a chemical group are for convenience; a chemical group can be depicted with or without one or more dashes without losing its ordinary meaning. A wavy or dotted line drawn through a line in a structure indicates a designated point of attachment for a group. Unless chemically or structurally required, the order in which the chemical groups are written or named does not indicate or imply directionality or stereochemistry.

[0018] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6"Alkyl" means an alkyl group having 1 to 6 carbon atoms.

[0019] Mention herein of "about" a certain value or parameter includes (and describes) embodiments for the value or parameter itself. In certain embodiments, the term "about" includes an indicative amount ± 10%. In other embodiments, the term "about" includes an indicative amount ± 5%. In certain other embodiments, the term "about" includes an indicative amount ± 1%. In addition, the term "about X" includes a description of "X". In addition, unless the context clearly stipulates otherwise, the singular forms "a", "an" and "the" include plural references. Therefore, for example, mentioning "the compound" includes a plurality of such compounds, and mentioning "the assay" includes mentioning one or more assays and equivalents thereof known to those skilled in the art.

[0020] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 12 carbon atoms (i.e., C 1-12 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbon atoms is named by chemical name or identified by molecular formula, all positional isomers having that number of carbon atoms are encompassed; 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] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, and the like may also be referred to as "alkylene" groups or "alkylenyl" groups (e.g., methylene, ethylene, and propylene), "arylene" groups or "arylenyl" groups (e.g., phenylene or naphthylene, or for heteroarylene groups, such as quinolinyl), respectively. Furthermore, unless expressly indicated otherwise, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atoms that connect the moiety to the rest of the molecule.

[0022] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 12 carbon atoms (i.e., C 2-12 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 (ie, C 2-4 Examples of the alkenyl group include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0023] "Alkynyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 12 carbon atoms (i.e., C 2-12 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

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

[0025] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl."

[0026] “Alkylthio” refers to the group “alkyl-S—.” “Alkylsulfinyl” refers to the group “alkyl-S(O)—.” “Alkylsulfonyl” refers to the group “alkyl-S(O)2-.” “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyl.

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

[0028] "Acylamide" refers to both: a "C-acylamide" group, which means the group -C(O)NR y R z ; and an "N-amido" group, which means the group -NR yC(O)R z , where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein, or R y and R z Together they form a cycloalkyl or heterocyclyl; each of which may be optionally substituted as defined herein.

[0029] "Amino" refers to the group -NR y R z , where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0030] "Carbamimidoyl" refers to -C(NR y )(NR z 2), where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0031] "Aryl" refers to an aromatic carbocyclic radical having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group, regardless of the point of attachment. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group, regardless of the point of attachment. If one or more aryl groups are fused to a cycloalkyl group, the resulting ring system is a cycloalkyl group, regardless of the point of attachment.

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

[0033] "Carbamyl" refers to both: an "O-carbamyl" group, which means the group -OC(O)NR y R z ; and an "N-carbamyl" group, meaning the group -NR y C(O)OR z , where Ry and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0034] "Carboxyl ester" or "ester" refers to -OC(O)R x and -C(O)OR x , where R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0035] "Cyanoalkyl" refers to an alkyl group as defined above in which one or more (eg, 1 or 2) hydrogen atoms are replaced by a cyano (-CN) group.

[0036] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings (including fused, bridged, and spiro ring systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and cycloalkenyl groups having at least one sp 3 As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. In addition, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of how it is connected to the rest of the molecule. In addition, when two substitution positions are present on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]dodecyl, or spiro[5.5]undecyl.

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

[0038] "Imino" refers to the group -C(NR y )R z , where R y and R zEach is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

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

[0040] "Halogen" or "halo" refers to an atom occupying Group VIIA of the Periodic Table of the Elements, such as fluorine, chlorine, bromine, or iodine.

[0041] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen. For example, where the residue is substituted by more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("two") or three ("three") halo groups, which may be, but are not necessarily, identical halogens. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

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

[0043] "Haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.

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

[0045] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms), excluding any terminal carbon atom, are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the rest of the molecule is through a carbon atom. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl 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)2CH2CH2OCH3, etc.), and amines (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., where R y (i) alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. As used herein, heteroalkyl includes 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 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 single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (ie, C 3-12 heteroaryl) or 3 to 8 carbon ring atoms (ie, C 3-8In some embodiments, 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 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indole, oxazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidineyl, isoquinolinyl, thiazolyl, thiadiazolyl, thienyl (thiophenyl / thienyl), triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl group may be attached via any ring of the fused system. Any aromatic ring containing at least one heteroatom, whether single or multiple fused rings, is considered a heteroaryl group, regardless of how it is attached to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl groups do not contain or overlap with the aryl groups defined above.

[0047] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-."

[0048] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl radical in which one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl (i.e., a heterocyclyl radical having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiroheterocyclyl. The heterocyclyl radical can be a single ring or multiple rings, wherein the multiple rings can be fused rings, bridged rings or spiro rings, and can include one or more (e.g., 1 to 3) oxo (=O) moieties or N-oxide (-O-) moieties. Any non-aromatic ring or fused ring system containing at least one heteroatom and one non-aromatic ring is considered a heterocyclyl, regardless of the mode of attachment (i.e., it can be combined via carbon atoms or heteroatoms). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to a cycloalkyl, aryl or heteroaryl ring, regardless of the mode of attachment to the rest of the molecule. For example, fused ring systems such as decahydroquinazolinyl, 1,2,3,4-tetrahydroquinazolinyl, and 5,6,7,8-tetrahydroquinazolinyl are heterocyclyls, regardless of how they are attached to the rest of the molecule. As used herein, a heterocyclyl group has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl), 2 to 8 ring carbon atoms (ie, C 2-8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl), 3 to 8 ring carbon atoms (ie, C 3-8 heterocyclyl) or 3 to 6 ring carbon atoms (ie, C 3-6heterocyclic radical); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic radicals include, for example, azetidinyl, azepine, benzodioxolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolyl, isothiazolidinyl, isox ... oxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiomorpholinyl, thimorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. When two substitution positions are present on the same carbon atom, the term "heterocyclyl" also includes "spiroheterocyclyl". Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic systems such as oxabicyclo[2.2.2]octyl, 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, wherein the heterocyclyl group may be attached via either ring of the fused system.

[0049] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-."

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

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

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

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

[0054] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. Additionally, the term "optionally substituted" means that any one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms on a designated atom or group may or may not be replaced with a non-hydrogen moiety.

[0055] As used herein, the term "substituted" refers to any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5 or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom, such as, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamyl, thioalkyl, alkyl ... alkyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamide, thiol, thioxo, N-oxide, or -Si(R y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0056] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are independently replaced by deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -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 In certain embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by: -C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-CH2SO2R g or -CH2SO2NR g R h In the previous article, R gand R h R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl. In certain embodiments, "substituted" also means any of the above groups, wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms are replaced by a bond to amino, cyano, hydroxy, imino, nitro, oxo, sulfo, halo, alkyl, alkoxy, alkylamino, sulfanyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and / or heteroarylalkyl, or R is the same or different and is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy ... g With R h and R i The two together with the atoms to which they are attached form a heterocyclyl ring optionally substituted with oxo, halo, or an alkyl ring optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0057] Polymers or similar infinite structures obtained by infinitely defining substituents with other substituents connected (e.g., substituted aryl with substituted alkyl, which is itself substituted with substituted aryl, which is further substituted with substituted heteroalkyl, etc.) are not intended to be included in this article. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the continuous substitution of a substituted aryl with two other substituted aryl groups is limited to an aryl substituted with ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., a methyl group substituted with 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein.

[0058] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0059] Any compound or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically enriched analogs." An isotopically labeled compound has the structure depicted herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 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. Compounds of the present disclosure labeled with various isotopes, such as those incorporated 3 H and 14 Compounds containing radioactive isotopes such as C. Such isotope-labeled compounds can be used in metabolism studies, reaction kinetics studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or can be used in radiotherapy of patients.

[0060] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens are replaced by deuterium (e.g., hydrogen on a carbon atom). Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12): 524-527 (1984). Such compounds are synthesized using methods well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0061] The therapeutic compounds of the present disclosure that are labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improved therapeutic index. 18 F. 3 H or 11 C-labeled compounds can be used for PET or SPECT or other imaging studies. Isotopically labeled compounds and prodrugs thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. It should be understood that in this context, deuterium is considered a substituent in the compounds described herein.

[0062] The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0063] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

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

[0065] The term "pharmaceutically acceptable salt" with respect to a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and has no biologically or other undesirable effects. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. In addition, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Salts derived from inorganic acids include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, salts of acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. By way of example only, 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), tris(substituted alkyl)amines (i.e., N(substituted alkyl)3), Alkenylamine (i.e., N(alkenyl)3), substituted alkenylamine (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amine (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl)3), monocycloalkylamine, dicycloalkylamine, or tricycloalkylamine (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoarylamine, diarylamine, or triarylamine (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0066] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the equilibrium properties between the tautomers, those of ordinary skill in the art will understand that the compound contains both amide and imidic acid tautomers. Therefore, amide-containing compounds should be understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds should be understood to include their amide tautomers.

[0067] The compounds of the present disclosure, or their pharmaceutically acceptable salts, include asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomeric forms, which can be defined as (R)- or (S)-, or (D)- or (L)- for amino acids, in terms of absolute stereochemistry. The present disclosure is intended to include all of these possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and / or fractional crystallization). Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0068] "Stereoisomers" refer to compounds made up of the same atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers or mixtures thereof and includes "enantiomers," which are two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0069] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0070] The relative centers of compounds depicted herein are indicated graphically using a "fat bond" style (bold or parallel lines), and absolute stereochemistry is indicated using wedge-shaped bonds (bold or parallel lines).

[0071] "Prodrug" means any compound that releases an active parent drug in vivo according to the structure described herein when this prodrug is administered to a mammalian subject. Prodrugs of compounds described herein are prepared by modifying the functional groups present in the compounds described herein in such a way that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in the compounds in such a way that the modification can be conventionally operated or cleaved in vivo to release the parent compound. Prodrugs include compounds described herein, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups of the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of the hydroxyl functional groups of compounds described herein, amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) and the like. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Volume 14 of the ACS Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and Biologically Insusceptible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0072] 2. Compounds

[0073] Provided herein are SARM1 inhibitor compounds. In certain embodiments, a compound of Formula I is provided:

[0074]

[0075] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein R 1 、R 2 、R 4 、R 5 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、A 1 and A 2 Each is independently as defined herein.

[0076] In certain embodiments, a compound of Formula I is provided:

[0077]

[0078] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0079] A 1 is N, and A 2 is C; or

[0080] A 1 It is C, and A 2 It is N;

[0081] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0082] R 1 It is halogenated, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11)2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0083] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0084] R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11)2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0085] R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0086] Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0087] R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0088] R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0089] R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0090] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0091] Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0092] Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0093] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0094] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0095] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0096] Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and

[0097] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0098] where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

[0099] In certain embodiments, when R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express.

[0100] In certain embodiments, the compound is not N-[4-cyano-3-[3-(4-morpholinyl)imidazo[1,2-a]pyrimidin-7-yl]phenyl]-1-pyrrolidinecarboxamide, N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, (1S,2S)-N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, 4-[4-(acetylamino)-2-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]phenoxy]-1-piperidinylcarboxamide, 1,1-dimethyl- ethyl ester, N-[3-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]-4-[4-(trifluoromethyl)phenoxy]phenyl]-acetamide, N-[4-(4-chloro-2-fluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-2,2-dimethyl-propionamide, N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-cyclopropanecarboxamide or N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-propionamide.

[0101] In certain embodiments, a compound of Formula I is provided:

[0102]

[0103] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0104] A 1 is N, and A 2 is C; or

[0105] A 1 It is C, and A 2 It is N;

[0106] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0107] R 1 It is halogenated, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0108] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0109] R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0110] R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0111] Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0112] R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0113] R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0114] R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0115] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0116] Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0117] Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0118] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0119] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0120] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0121] Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and

[0122] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0123] where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0124] The conditions are:

[0125] a) When R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by indicates; and

[0126] b) The compound is not N-[4-cyano-3-[3-(4-morpholinyl)imidazo[1,2-a]pyrimidin-7-yl]phenyl]-1-pyrrolidinecarboxamide, N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, (1S,2S)-N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, 4-[4-(acetylamino)-2-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]phenoxy]-1-piperidinic acid 1,1-dimethylethyl ester, N-[4-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, -[3-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]-4-[4-(trifluoromethyl)phenoxy]phenyl]-acetamide, N-[4-(4-chloro-2-fluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-2,2-dimethyl-propionamide, N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-cyclopropanecarboxamide or N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-propionamide.

[0127] In certain embodiments, A 1 、X 3 and X 4 At least one of is not N.

[0128] In certain embodiments, when X 6 It is CN(R 11 )2, then A 2 、X 1 and X 5 At least one of is not N.

[0129] In certain embodiments, a compound of Formula IA is provided:

[0130]

[0131] Among them A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 4 、R 5 、R 8and R 9 Each is independently as defined herein.

[0132] In certain embodiments, R 8 and R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace.

[0133] In certain embodiments, R 2 or part yes:

[0134]

[0135] Each of which is independently optionally replaced by one to five Z 1 replace.

[0136] In certain embodiments, each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heteroaryl, -OR 12 or-C(O)OR 12 ; Each C 1-6 The alkyl and heteroaryl groups are independently optionally substituted with one to five hydroxy, methoxy or methyl groups.

[0137] In certain embodiments, R or a portion yes It may be optionally fused to a C6 aryl group; wherein q is 0, 1, 2 or 3; r is 0 or 1; s is 0, 1 or 2; t is 1 or 2; and X is CH2, CHZ 1 、C(Z 1 )2, NH, O or S.

[0138] In certain embodiments, Z 1 Yes-OR 12 In certain embodiments, Z 1 It is (2-methoxyethoxy)methyl.

[0139] In certain embodiments, R or a portion yes wherein q is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, or 3.

[0140] In certain embodiments, part yes in:

[0141] q is 0, 1, 2, 3, or 4;

[0142] p is 0, 1, 2, or 3;

[0143] Ring B is C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; and

[0144] L 1 Yes key, C 1-4 Alkyl, C 2-4 Alkenyl or C 2-4 Alkynyl.

[0145] In certain embodiments, L 1 is key or C 1-4 In certain embodiments, L 1 is key or C 1-2 In certain embodiments, L 1 is a bond or -CH2-. In certain embodiments, L 1 It is a key.

[0146] In certain embodiments, Ring B is optionally substituted with one to five Z 1a In certain embodiments, ring B is optionally substituted with one to five Z 1a substituted heteroaryl, and L 1 is key or C 1-2 In certain embodiments, ring B is optionally substituted with one to five Z 1a substituted heteroaryl, and L 1 is a bond or CH2. In certain embodiments, Ring B is heteroaryl, and L 1 In certain embodiments, Ring B is optionally substituted with one to five Z 1a Substituted heteroaryl, L 1 is a key, q is 1, and Z 1 It is C 1-6 alkyl.

[0147] In certain embodiments, L 1 is a bond, and Ring B is pyrimidinyl, oxadiazolyl or triazolyl, wherein the pyrimidinyl, oxadiazolyl or triazolyl is optionally substituted by one to five Z 1a replace.

[0148] In certain embodiments, L 1 is a bond, and Ring B is optionally substituted by one to five Z 1a In certain embodiments, L 1 is a bond, and Ring B is optionally substituted by one to five Z 1a In certain embodiments, L1 is a bond, and Ring B is optionally substituted by one to five Z 1a Substituted triazolyl.

[0149] In certain embodiments, L 1 is a bond, and ring B is:

[0150]

[0151] In certain embodiments, a compound of Formula IIA is provided:

[0152]

[0153] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0154] q is 0, 1, 2, 3, or 4;

[0155] p is 0, 1, 2, or 3;

[0156] A 1 is N, and A 2 is C; or

[0157] A 1 It is C, and A 2 It is N;

[0158] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0159] R 1 It is halogenated, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0160] R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0161] R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0162] Each R6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0163] Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0164] Each Z 1are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0165] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0166] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0167] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0168] Each Z 1bare independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and

[0169] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0170] where Z 1b and each C in L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

[0171] In certain embodiments, a compound of Formula IB is provided:

[0172]

[0173] Among them A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 4 、R 5 and R 7 Each is independently as defined herein.

[0174] In certain embodiments, R 7 is optionally replaced by one to five Z 1 Substituted C 1-6 alkyl.

[0175] In certain embodiments, R 7 It is cyclopropylmethyl, 2-phenylethyl or 2,2,2-trifluoroethyl.

[0176] In certain embodiments, R 2 is optionally replaced by one to five Z 1 Substituted C 1-6 alkyl.

[0177] In certain embodiments, Z 1 is optionally replaced by one to five Z 1a Substituted C 3-10 In certain embodiments, Z 1a is C optionally substituted by one to five halogen groups 1-6 In certain embodiments, Z 1 It is (3-trifluoromethyl)cyclobutyl.

[0178] In certain embodiments, R 2 It is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl or (3-(trifluoromethyl)cyclobutan-1-yl)methyl.

[0179] In certain embodiments, R 2 It is (3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl.

[0180] In certain embodiments, R 2is optionally replaced by one to five Z 1 Substituted C 3-10 Cycloalkyl.

[0181] In certain embodiments, a compound of formula IC is provided:

[0182]

[0183] Among them A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 4 、R 5 and Z 1 are each independently as defined herein; n is 1, 2, 3, 4, or 5; and m is 1, 2, 3, or 4.

[0184] In certain embodiments, R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[2.2.1]hept-7-yl, each of which is optionally substituted by one to five Z 1 replace.

[0185] In certain embodiments, each Z 1 are independently halogenated, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 cycloalkyl or heteroaryl.

[0186] In certain embodiments, R 2 is optionally replaced by one to five Z 1 substituted heterocyclic group.

[0187] In certain embodiments, R 2 is 2-azabicyclo[3.1.0]hexan-2-yl, pyrrolidinyl or tetrahydropyranyl, each of which is optionally substituted by one to five Z 1 replace.

[0188] In certain embodiments, R 2 is 2-azabicyclo[3.1.0]hex-2-yl or tetrahydropyranyl, each of which is optionally substituted by one to five Z 1 replace.

[0189] In certain embodiments, each Z 1 are independently halo, -C(O)OR 12 、C 1-6 Alkyl, C 1-6A haloalkyl or heteroaryl group, wherein each C 1-6 The alkyl group is optionally substituted with one to five methoxy groups.

[0190] In certain embodiments, each Z 1 is independently fluoro, -C(O)OCH3, 2-methoxyethyl, trifluoromethyl, pyridyl, pyrimidinyl or pyridazinyl.

[0191] In certain embodiments, each Z 1 Independently C 1-6 a haloalkyl or heteroaryl group.

[0192] In certain embodiments, R 4 It's hydrogen.

[0193] In certain embodiments, R 5 It is hydrogen or halogen.

[0194] In certain embodiments, R 5 It is hydrogen or fluorine.

[0195] In certain embodiments, R 1 Is halogenated, cyano, C 1-6 Alkyl or C 1-6 haloalkyl, wherein each C 1-6 The alkyl group is optionally substituted by one to five Z 1 In certain embodiments, R 1 is C substituted with one to five cyano groups 1-6 alkyl.

[0196] In certain embodiments, R 1 Is halogenated, cyano, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0197] In certain embodiments, R 1 is chloro, cyano, methyl, trifluoromethyl or cyanomethyl.

[0198] In certain embodiments, R 1 is chloro, cyano, methyl or trifluoromethyl.

[0199] In certain embodiments, A 1 is N, and A 2 It’s C.

[0200] In certain embodiments, part yes

[0201] In certain embodiments, part yes In certain embodiments, X1 、X 2 、X 3 、X 4 and X 5 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 3 、X 4 and X 5 Each is CH.

[0202] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 3 、X 5 and X 6 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 3 、X 5 and X 6 Each is CH.

[0203] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 4 and X 5 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 4 and X 5 Each is CH.

[0204] In certain embodiments, A 1 It is C, and A 2 It's N.

[0205] In certain embodiments, part yes

[0206] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 4 、X 5 and X 6 Each independently is CH or CR 6 In certain embodiments, X1 、X 2 、X 4 、X 5 and X 6 Each is CH.

[0207] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 3 、X 4 and X 6 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 3 、X 4 and X 6 Each is CH.

[0208] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 3 、X 4 and X 5 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 3 、X 4 and X 5 Each is CH.

[0209] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 4 and X 6 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 4 and X 6 Each is CH.

[0210] In certain embodiments, part yes In certain embodiments, X 2 、X 5 、X 4 and X 6 Each independently is CH or CR 6 In certain embodiments, X2 、X 3 、X 5 and X 6 Each is CH.

[0211] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 4 and X 5 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 4 and X 5 Each is CH.

[0212] In certain embodiments, part yes In certain embodiments, X 2 、X 3 、X 4 and X 5 Each independently is CH or CR 6 In certain embodiments, X 2 、X 3 、X 4 and X 5 Each is CH.

[0213] In certain embodiments, part yes In certain embodiments, X 2 、X 3 、X 4 and X 6 Each independently is CH or CR 6 In certain embodiments, X 2 、X 3 、X 4 and X 6 Each is CH.

[0214] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 5 and X 6 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 5 and X 6 Each is CH.

[0215] In certain embodiments, part yes In certain embodiments, X 2 、X 4 、X 5 and X 6 Each independently is CH or CR 6 In certain embodiments, X 2 、X 4 、X 5 and X 6 Each is CH.

[0216] In certain embodiments, part yes In certain embodiments, X 1 、X 2 、X 3 and X 6 Each independently is CH or CR 6 In certain embodiments, X 1 、X 2 、X 3 and X 6 Each is CH.

[0217] In certain embodiments, part yes In certain embodiments, X 2 、X 3 and X 6 Each independently is CH or CR 6 In certain embodiments, X 2 、X 3 and X 6 Each is CH.

[0218] In certain embodiments, X 1 It's N.

[0219] In certain embodiments, X 1 Is CH or CR 6 In certain embodiments, X 1 In certain embodiments, X 1 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0220] In certain embodiments, X 2 It's N.

[0221] In certain embodiments, X2 Is CH or CR 6 In certain embodiments, X 2 In certain embodiments, X 2 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0222] In certain embodiments, X 3 It's N.

[0223] In certain embodiments, X 3 Is CH or CR 6 In certain embodiments, X 3 In certain embodiments, X 3 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0224] In certain embodiments, X 4 It's N.

[0225] In certain embodiments, X 4 Is CH or CR 6 In certain embodiments, X 4 In certain embodiments, X 4 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0226] In certain embodiments, X 5 It's N.

[0227] In certain embodiments, X 5 Is CH or CR 6 In certain embodiments, X 5 In certain embodiments, X 5 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0228] In certain embodiments, X 6 It's N.

[0229] In certain embodiments, X 6 Is CH or CR 6 In certain embodiments, X 6 In certain embodiments, X 6 It's CR 6 In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0230] In certain embodiments, part yes:

[0231]

[0232]

[0233] Each of which is optionally replaced by R 6 replace.

[0234] In certain embodiments, part yes:

[0235]

[0236] Each of which is optionally replaced by R 6 replace.

[0237] In certain embodiments, R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

[0238] In certain embodiments, each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, heteroaryl, -OR 12 、-C(O)R 12 、-C(O)OR 12 or -C(O)N(R 12 )2; each C 1-6 Alkyl, C 1-6 The haloalkyl and heteroaryl groups are independently optionally substituted with one to five hydroxy, methoxy or methyl groups.

[0239] In certain embodiments, each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0240] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1b replace;

[0241] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0242] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1b replace;

[0243] Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl or -L-heterocyclyl; and

[0244] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6Alkyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 cycloalkyl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-.

[0245] In certain embodiments, each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0246] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0247] Each Z 1a are independently halo, -OR 13 or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0248] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace; and

[0249] Each Z 1b are independently halogenated or -OC 1-6 alkyl.

[0250] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided, wherein:

[0251] A 1 is N, and A 2 is C; or

[0252] A 1 It is C, and A 2 It is N;

[0253] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0254] R 1 Is halogenated, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 Cycloalkyl;

[0255] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0256] R 4 is hydrogen, halo, cyano, C 1-6 Alkyl or C 3-10 Cycloalkyl; wherein the C 1-6 Alkyl or C 3-10 Cycloalkyl is independently optionally substituted by one to five Z 1 replace;

[0257] R 5 is hydrogen, halo, cyano, C 1-6 Alkyl or C 3-10 Cycloalkyl; wherein the C 1-6 Alkyl or C 3-10 Cycloalkyl is independently optionally substituted by one to five Z 1 replace;

[0258] Each R 6 are independently halo, cyano, C 1-6 Alkyl or -OR 11 ; Each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1 replace;

[0259] R 7 It is C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0260] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0261] Each R 11 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclyl; wherein each hydrogen, C 1-6 Alkyl, C3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1a replace;

[0262] Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0263] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1b replace;

[0264] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0265] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein each C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1b replace;

[0266] Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6Alkyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl or -L-heterocyclyl; and

[0267] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 cycloalkyl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0268] The condition is that when R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express.

[0269] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided, wherein:

[0270] A 1 is N, and A 2 is C; or

[0271] A 1 It is C, and A 2 It is N;

[0272] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0273] R1 Is halogenated, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 Cycloalkyl;

[0274] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0275] R 4 It is hydrogen;

[0276] R 5 It is hydrogen;

[0277] Each R 6 are independently halo, cyano, C 1-6 Alkyl or -OR 11 ; Each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1 replace;

[0278] R 7 It is C 1-6 Alkyl or C 1-6 Haloalkyl; wherein the C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1 replace;

[0279] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0280] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1a replace;

[0281] Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12)2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0282] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0283] Each Z 1a are independently halo, -OR 13 or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0284] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace; and

[0285] Each Z1b are independently halogenated or -OC 1-6 alkyl;

[0286] The condition is that when R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express.

[0287] In certain embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided, wherein:

[0288] A 1 is N, and A 2 is C; or

[0289] A 1 It is C, and A 2 It is N;

[0290] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0291] R 1 Is halogenated, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-10 Cycloalkyl;

[0292] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace;

[0293] R4 It is hydrogen;

[0294] R 5 It is hydrogen;

[0295] Each R 6 are independently halo, cyano, C 1-6 Alkyl or -OR 11 ; Each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1 replace;

[0296] R 7 It is C 1-6 Alkyl or C 1-6 Haloalkyl; wherein the C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1 replace;

[0297] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0298] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1a replace;

[0299] Each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 12 or-C(O)OR 12 ; Each C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0300] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0301] Each Z 1a are independently halo, -OR 13 or C 1-6 Alkyl; each C 1-6The alkyl groups are independently optionally substituted with one to five Z 1b replace;

[0302] Each R 13 are independently hydrogen or C 1-6 Alkyl; each C 1-6 The alkyl groups are independently optionally substituted with one to five Z 1b replace; and

[0303] Each Z 1b are independently halogenated or -OC 1-6 alkyl;

[0304] The condition is that when R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express.

[0305] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer, or mixture of stereoisomers thereof is provided:

[0306] Table 1

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316] In certain embodiments, a compound selected from Table 2 or a pharmaceutically acceptable salt thereof is provided.

[0317] Table 2

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] 3. Methods

[0334] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Favorable or desired clinical results may include one or more of the following: a) inhibiting the disease or disorder (e.g., reducing one or more symptoms produced by the disease or disorder and / or reducing the extent of the disease or disorder); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and / or c) alleviating the disease, i.e., resolving clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or disorder, enhancing the effect of another drug therapy, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0335] "Prevention" or "preventing" refers to the treatment of any disease or disorder that results in the clinical symptoms of the disease or disorder not developing. In certain embodiments, the compound can be administered to a subject (including a human) who is at risk of developing the disease or disorder or has a family history of the disease or disorder.

[0336] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0337] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, means an amount sufficient to effect treatment to provide a therapeutic benefit (e.g., improvement in symptoms or slowing of disease progression) when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or disorder described herein. A therapeutically effective amount can vary depending on the subject and the disease or disorder being treated, the subject's weight and age, the severity of the disease or disorder, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0338] The methods described herein can be applied to cell populations in vivo or ex vivo. "In vivo" means within a living individual, such as an animal or human. In this context, the methods described herein can be used therapeutically for an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained using 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 ex vivo to determine the optimal administration schedule and / or dosage of the compounds of the present disclosure for a given indication, cell type, individual, and other parameters. The information collected from such uses can be used for experimental purposes or in the clinic to set an in vivo treatment plan. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will become apparent to those skilled in the art. The compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

[0339] In certain embodiments, compounds or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof that inhibit the activity of sterile alpha and TIR motif protein 1 (SARM1) are provided. In certain embodiments, compounds provided herein or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof inhibit SARM1.

[0340] In certain methods, uses, and compositions provided herein, the compound is a compound of Formula I:

[0341]

[0342] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0343] A 1 is N, and A 2 is C; or

[0344] A 1 It is C, and A 2 It is N;

[0345] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N;

[0346] R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0347] R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0348] R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0349] R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1replace;

[0350] Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0351] R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0352] R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0353] R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace;

[0354] or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0355] Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0356] Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace;

[0357] Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0358] Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0359] Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace;

[0360] Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and

[0361] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-;

[0362] where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

[0363] In certain embodiments, R 1 It is halogenated, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace.

[0364] In certain embodiments, R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, or heterocyclic group are independently optionally substituted by one to five Z 1 replace;

[0365] In certain embodiments, when R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express.

[0366] In certain embodiments, the compound is not N-[4-cyano-3-[3-(4-morpholinyl)imidazo[1,2-a]pyrimidin-7-yl]phenyl]-1-pyrrolidinecarboxamide (CAS No. 2080411-04-5), N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide (CAS No. 2479976-73-1), (1S,2S )-N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide (CAS No. 2479974-28-0), 4-[4-(acetylamino)-2-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]phenoxy]-1-piperidincarboxylic acid 1,1-dimethylethyl ester (CAS No. 2569003-03- 6), N-[3-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]-4-[4-(trifluoromethyl)phenoxy]phenyl]-acetamide (CAS No. 2569002-87-3), N-[4-(4-chloro-2-fluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-2,2-dimethyl-propionamide (CAS No. 2413 866-36-9), N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-cyclopropanecarboxamide (CAS No. 2413866-26-7) or N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-propionamide (CAS No. 2413866-25-6).

[0367] In certain embodiments, A 1 、X 3 and X 4 At least one of is not N.

[0368] In certain embodiments, when X 6 It is CN(R 11 )2, then A 2 、X 1 and X 5 At least one of is not N.

[0369] In certain embodiments, a method of inhibiting SARM1 activity is provided, comprising contacting a cell with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof. The inhibition can be in vitro or in vivo.

[0370] In certain embodiments, provided is a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0371] In certain embodiments, the present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting SARM1 activity (e.g., in vitro or in vivo).

[0372] In certain embodiments, compounds disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, are provided. They are used to inhibit the NADase activity of SARM1. In certain embodiments, a method of inhibiting SARM1 NADase activity and / or treating neurodegeneration or a neurological disease or condition in a subject in need thereof is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof.

[0373] In certain embodiments, a method for treating a disease or condition mediated at least in part by SARM1 is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0374] In certain embodiments, a method of treating axonal degeneration in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, inhibits axonal degeneration, including axonal degeneration caused by a decrease or depletion of NAD+. In certain embodiments, the compound, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, prevents axonal degeneration distal to axonal injury.

[0375] In certain embodiments, a method for treating degeneration of peripheral nervous system neurons or a portion thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0376] In certain embodiments, a method for treating degeneration of central nervous system neurons or a portion thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0377] In certain embodiments, the treating comprises reducing one or more symptoms or characteristics of neurodegeneration.

[0378] In certain embodiments, a method for inhibiting axonal degeneration is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0379] In certain embodiments, a method for treating a neurodegenerative or neurological disease or disorder is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0380] In certain embodiments, a method for treating a disease or condition associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, neurological injury, metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI) (see Ziogas et al., J. Neuroscience, 2018, 38(16):4031-4032 and WO2020191257), leukoencephalopathy or leukodystrophy is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0381] In certain embodiments, provided is a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in treating a disease or condition mediated at least in part by SARM1 in a subject in need thereof.

[0382] In certain embodiments, provided is a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting axonal degeneration in a subject in need thereof.

[0383] In certain embodiments, the present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for inhibiting axonal degeneration in a subject in need thereof.

[0384] In certain embodiments, the present disclosure provides the use of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in the manufacture of a medicament for treating neurodegeneration or a neurological disease or disorder, such as a disease or disorder associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

[0385] In certain embodiments, the disease or disorder is an acute disorder. In certain embodiments, the disease or disorder is a chronic disorder.

[0386] In certain embodiments, the disease or disorder is characterized by axonal degeneration in the central nervous system, the peripheral nervous system, the optic nerve, the cranial nerves, or a combination thereof.

[0387] In certain embodiments, the disease or disorder is or comprises acute damage to the central nervous system, such as, but not limited to, damage to the spinal cord and / or traumatic brain injury (TBI). In certain embodiments, the disease or disorder is or comprises chronic damage to the central nervous system, such as, but not limited to, damage to the spinal cord, traumatic brain injury (TBI) and / or traumatic axonal injury (TAI). In certain embodiments, the disease or disorder is or comprises chronic traumatic encephalopathy (CTE).

[0388] In certain embodiments, the disease or disorder is a chronic disorder affecting the central nervous system, such as, but not limited to, Parkinson's disease (see, e.g., Sajadi, A. et al., Curr. Biology. 2004, 14, 326-330; and Hasbani, DM et al., Exp. Neurology. 2006, 202, 93-99), amyotrophic lateral sclerosis (see, e.g., White, MA et al., Acta Neuropath. Comm. 2019, 7(1), 166), multiple sclerosis, Huntington's disease, or Alzheimer's disease.

[0389] In certain embodiments, the disease or disorder is acute peripheral neuropathy. In certain embodiments, the disease or disorder is chemotherapy-induced peripheral neuropathy (CIPN). See, for example, Geisler, S. et al., Brain. 2016, 139, 3092-3108; Turkiew, E. et al., J. Peripher. Nerv. Syst. 2017, 22, 162-171; Geisler, S. et al., JCI Insight. 2019, 4 (17), e129920; and Cetinkaya-Fisgin, A. et al., Sci. Rep. 2020, 21889. Chemotherapy-induced peripheral neuropathy (CIPN) is an example of an acute peripheral neuropathy that can be associated with various drugs, such as, but not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), or platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0390] In certain embodiments, the disease or condition is a chronic disease affecting the peripheral nervous system, such as, but not limited to, diabetic neuropathy, HIV neuropathy, Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis.

[0391] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, KW et al., J. Cell Bio. 2020, 219(8), e201912047).

[0392] In certain embodiments, the disease or condition is an acute condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, acute optic neuropathy (AON), or acute angle-closure glaucoma.

[0393] In certain embodiments, the disease or condition is a chronic condition affecting the optic nerve, such as, but not limited to, diabetic optic neuropathy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy (LHON), primary open-angle glaucoma, or autosomal dominant optic atrophy.

[0394] In certain embodiments, the disease or disorder is associated with retinal degeneration. In certain embodiments, the disease or disorder is Leber congenital amaurosis, such as Leber congenital amaurosis type 9 (LCA9) (see, e.g., Sasaki, Y. et al., eLife. 2020, 9, e62027).

[0395] In certain embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or conditions selected from the group consisting of neuropathy or axonopathy. In certain embodiments, one or more compounds and / or compositions described herein can be used, for example, to treat neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, the neuropathy associated with axonal degeneration is a hereditary or congenital neuropathy or axonopathy. In certain embodiments, the neuropathy associated with axonal degeneration is caused by de novo or somatic mutations. In certain embodiments, the neuropathy associated with axonal degeneration is selected from the list contained herein. In certain embodiments, neuropathy or axonopathy is associated with axonal degeneration, including but not limited to Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia, stroke, chemical injury, thermal injury or AIDS.

[0396] In certain embodiments, one or more compounds or compositions described herein are characterized by reducing one or more symptoms or characteristics of neurodegeneration when administered to a subject population. For example, in certain embodiments, the relevant symptoms or characteristics may be selected from the group consisting of: the degree, rate, and / or time of neuronal destruction. In certain embodiments, neuronal destruction may be or include axonal degeneration, synapse loss, dendrite loss, synapse density loss, dendritic arborization loss, axonal branching loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic potentiation loss, action potential potentiation loss, cytoskeletal stability loss, axonal transport loss, ion channel synthesis and conversion loss, neurotransmitter synthesis loss, neurotransmitter release and reuptake capacity loss, axonal potential propagation loss, neuronal hyperexcitability, and / or neuronal hypoexcitability. In certain embodiments, neuronal destruction is characterized by the inability to maintain an appropriate resting neuronal membrane potential. In certain embodiments, neuronal destruction is characterized by the appearance of inclusion bodies, plaques, and / or neurofibrillary tangles. In certain embodiments, neuronal destruction is characterized by the appearance of stress granules. In certain embodiments, the neuron destruction is characterized by intracellular activation of one or more members of the cysteine-aspartic acid protease (Caspase) family. In certain embodiments, the neuron destruction is characterized by programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis, and / or necrosis) and / or inflammation of the neurons.

[0397] In certain embodiments, the neurodegenerative or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a nerve injury disease or disorder, a metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal damage due to leukoencephalopathy, or a leukodystrophy. In certain embodiments, the neurodegenerative or neurological disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander's disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe's disease), Wallerian degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease, Alzheimer's disease, Parkinson's disease, Tay-Sacks disease, disease), Gaucher's disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurologic complications of chemotherapy (e.g., chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 deficiency, isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome, retinal degeneration, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis (e.g.,Leber congenital amaurosis type 9 (LCA9), neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomedullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia ataxia, hereditary ataxia, noise-induced hearing loss, congenital hearing loss, Lewy Body Dementia, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, spinocerebellar ataxia, preeclampsia, hereditary spastic paraplegia, spastic hemiplegia, familial spastic paraplegia, French settlement disease, Strumpell-Lorrain disease, or nonalcoholic steatohepatitis (NASH).

[0398] In certain embodiments, the present disclosure provides a SARM1 activity inhibitor for treating a neurodegeneration or neurological disease or condition involving axonal degeneration or axonopathy. The present disclosure also provides methods of using a SARM1 activity inhibitor to treat, prevent or improve axonal degeneration, axonopathy and a neurodegeneration or neurological disease or condition involving axonal degeneration. In certain embodiments, the present disclosure provides a method for inhibiting axonal degeneration, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof.

[0399] In certain embodiments, the present disclosure provides methods of treating neurodegeneration or a nervous system disease or disorder associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage due to leukoencephalopathy, or a leukodystrophy.

[0400] In certain embodiments, neuropathy and axonopathy comprise any disease or illness relating to neurons and / or supporting cells, such as glial cells, muscle cells or fibroblasts, and particularly relate to those diseases or illnesses of axonal damage. Axonal damage can be caused by traumatic injury or by disease, illness or exposure to non-mechanical damage caused by toxic molecules or drugs. The result of this damage can be degeneration or dysfunction of axons and loss of functional neuronal activity. The disease and illness that produce or are relevant to this axonal damage are one of a large number of neurological diseases and illnesses. This type of neuropathy can comprise peripheral neuropathy, central neuropathy or its combination. In addition, peripheral neurological manifestations can be produced by diseases that are mainly concentrated in the central nervous system, and central nervous system manifestations can be produced by basically surrounding or systemic diseases.

[0401] In certain embodiments, peripheral neuropathy may involve damage to peripheral nerves and / or may be caused by neurological diseases or as a result of systemic diseases. Some such diseases include infectious diseases such as diabetes, uremia, AIDS or leprosy, nutritional deficiencies, vascular or collagen disorders such as atherosclerosis, or autoimmune diseases such as systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis and polyarteritis nodosa. In certain embodiments, peripheral nerve degeneration is caused by traumatic (mechanical) damage to the nerves and chemical or thermal damage to the nerves. Such diseases that damage peripheral nerves include compression or entrapment injuries, such as glaucoma, carpal tunnel syndrome, direct trauma, penetrating injury, contusion, fracture or dislocation; pressure on superficial nerves (ulnar, radial or peroneal nerves), which may be caused by long-term use of crutches or prolonged stay in one position, or by tumors; intraneural bleeding; ischemia; exposure to cold or radiation or certain drugs or toxic substances such as herbicides or pesticides. In particular, nerve damage can be caused by chemical damage caused by cytotoxic anticancer agents such as paclitaxel, cisplatin, proteasome inhibitors or vinca alkaloids such as vincristine. Typical symptoms of such peripheral neuropathy include weakness, numbness, paresthesia (abnormal sensations such as burning, itching, tingling or tingling) and pain in the arms, hands, legs and / or feet. In certain embodiments, neuropathy is associated with mitochondrial dysfunction. Such neuropathy can show a decrease in energy levels, i.e., a decrease in NAD and ATP levels.

[0402] In certain embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy, which includes a broad spectrum of peripheral nerve disorders associated with metabolic systemic diseases. These diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutritional / vitamin deficiency, or mitochondrial disorders. The common hallmark of these diseases is that the structure or function of myelin and axons is altered due to metabolic pathway imbalance, thereby affecting the peripheral nerves.

[0403] In certain embodiments, neuropathy includes optic neuropathy, such as glaucoma; retinal ganglion degeneration, such as those associated with retinitis pigmentosa and outer retinal neuropathy; optic nerve neuritis and / or degeneration, including those associated with multiple sclerosis; traumatic injury to the optic nerve, which may include, for example, injury during tumor resection; hereditary optic neuropathies, such as Kjer disease and Leber's hereditary optic neuropathy (LHON); ischemic optic neuropathy, such as those secondary to giant cell arteritis; metabolic optic neuropathy, such as neurodegenerative diseases, including Leber's neuropathy; nutritional deficiencies, such as vitamin B12 or folic acid deficiency; and toxicity, such as caused by ethambutol or cyanide; neuropathy caused by adverse drug reactions; and neuropathy caused by vitamin deficiency. Ischemic optic neuropathy also includes non-arteritic anterior ischemic optic neuropathy.

[0404] In certain embodiments, the neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include various diseases. These diseases include those related to: progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease and Huntington's disease; central nervous system diseases that affect muscle function, such as Parkinson's disease; motor neuron disease and progressive ataxia, such as amyotrophic lateral sclerosis; demyelinating diseases, such as multiple sclerosis; viral encephalitis, such as those caused by enterovirus, arbovirus and herpes simplex virus; and prion disease. Mechanical damage, such as glaucoma or traumatic damage to the head and spine can also cause nerve damage and degeneration of the brain and spinal cord. In addition, ischemia and stroke and diseases such as nutritional deficiencies and chemical toxicity (such as chemotherapeutic agent related toxicity) can cause central nervous system neuropathy.

[0405] In certain embodiments, the present disclosure provides a method for treating a neuropathy or axonopathy associated with axonal degeneration. In certain embodiments, the neuropathy or axonopathy associated with axonal degeneration can be any of a variety of neuropathy or axonopathy, such as hereditary or congenital or those associated with Parkinson's disease, Alzheimer's disease, herpes infection, diabetes, amyotrophic lateral sclerosis, demyelinating disease, ischemia or stroke, chemical injury, thermal injury, and AIDS. In addition, neurodegenerative diseases not mentioned above and subsets of the above-mentioned diseases can also be treated with the methods of the present disclosure. Subsets of these diseases include Parkinson's disease or Alzheimer's disease.

[0406] In certain embodiments, the methods of the present invention include administering an effective amount of a compound and / or composition as described herein (e.g., a compound of Formula I) to a subject in need. In some such embodiments, the subject is at risk of a disease characterized by axonal degeneration. In certain embodiments, the subject suffers from a disease characterized by axonal degeneration. In certain embodiments, the subject is diagnosed with a disease characterized by axonal degeneration. In certain embodiments, the subject is at risk of a disease characterized by axonal degeneration. In certain embodiments, the subject is identified as having a risk of axonal degeneration, for example, based on the subject's genotype, diagnosis of a disease associated with axonal degeneration, and / or exposure to agents and / or conditions that induce axonal degeneration.

[0407] In certain embodiments, the subject is at risk for a neurodegenerative disorder. In certain embodiments, the subject is an elderly person. In certain embodiments, the subject is known to have a genetic risk factor for neurodegeneration. In certain embodiments, the subject has a family history of a neurodegenerative disease. In certain embodiments, the subject expresses one or more copies of a known genetic risk factor for neurodegeneration. In certain embodiments, the subject is from a population with a high incidence of neurodegeneration. In certain embodiments, the subject has a hexanucleotide repeat expansion in chromosome 9 open reading frame 72. In certain embodiments, the subject has one or more copies of the ApoE4 allele.

[0408] In certain embodiments, the neurodegenerative disease, disorder or condition can be or include traumatic neuronal injury. In certain embodiments, traumatic neuronal injury is blunt trauma, closed head injury, open head injury, exposure to concussion and / or explosive force, penetrating injury to the brain cavity or the innervated area of ​​the body. In certain embodiments, traumatic neuronal injury is a force that causes axonal deformation, stretching, squeezing or tearing. In certain embodiments, the disease or condition is traumatic brain injury (TBI).

[0409] In certain embodiments, the subject has engaged in or is engaged in an activity identified as a risk factor for neuronal degeneration, such as contact sports or an occupation with a higher chance of developing traumatic neuronal injury or TBI.

[0410] In certain embodiments, a method for treating a neurodegenerative disease, disorder or illness is provided, comprising administering a compound as described herein, and one or more of a DLK inhibitor or a NAMPT inhibitor to a patient in need thereof. In certain embodiments, a combination therapy is provided, which comprises a compound as described herein and a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, a combination therapy is provided, which comprises a compound as described herein, a DLK inhibitor and one or more additional therapeutic agents. In certain embodiments, a combination therapy is provided, which comprises a compound as described herein, a NAMPT inhibitor and one or more additional therapeutic agents. In certain embodiments, a combination therapy is provided, which comprises a compound as described herein, a DLK inhibitor, a NAMPT inhibitor and one or more additional therapeutic agents.

[0411] In certain embodiments, the DLK inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA, or an aptamer), an antibody, a dominant negative inhibitor, or a ribozyme. In certain embodiments, the DLK inhibitor is a small molecule. In certain embodiments, the DLK inhibitor is an siRNA. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide. In certain embodiments, the DLK inhibitor is a polypeptide. In certain embodiments, the DLK inhibitor is a peptide fragment. In certain embodiments, the DLK inhibitor is a nucleic acid. In certain embodiments, the DLK inhibitor is an antisense oligonucleotide.

[0412] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111, and CN104387391A, each of which is hereby incorporated by reference in its entirety.

[0413] In certain embodiments, the NAMPT inhibitor is a small molecule, a polypeptide, a peptide fragment, a nucleic acid (e.g., siRNA, antisense oligonucleotide, microRNA or aptamer), an antibody, a dominant negative inhibitor or a ribozyme. In certain embodiments, the NAMPT inhibitor is a small molecule. In some embodiments, the NAMPT inhibitor is an siRNA. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide. In certain embodiments, the NAMPT inhibitor is a polypeptide. In some embodiments, the NAMPT inhibitor is a peptide fragment. In certain embodiments, the NAMPT inhibitor is a nucleic acid. In some embodiments, the NAMPT inhibitor is an antisense oligonucleotide.

[0414] In certain embodiments, NAMPT inhibitors prevent the formation of nicotinamide mononucleotide (NMN). In certain embodiments, inhibition of NAMPT will inhibit the mammalian NAD+ salvage pathway.

[0415] In certain embodiments, provided is a composition comprising a compound described herein formulated for administration to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

[0416] In certain embodiments, a composition comprising a compound described herein is provided for use in combination with a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, such a composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0417] In certain embodiments, the subject may be a subject who has received, is receiving, or has been prescribed chemotherapy associated with peripheral neuropathy. Examples of chemotherapeutic agents include, but are not limited to, thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

[0418] In certain embodiments, the SARM1 inhibition described herein can be used in combination with one or more other therapies to treat related diseases, disorders or conditions. In certain embodiments, the dosage of the SARM1 inhibitor when used in combination therapy is changed compared to when administered as a monotherapy; alternatively or in addition, the therapy administered in combination with the SARM1 inhibition described herein is administered according to a different regimen or protocol than when administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, the composition comprising an additional therapeutic agent may act synergistically with the provided compound. In certain embodiments, one or both therapies used in the combination regimen are administered at a lower level or less frequently than when used as a monotherapy.

[0419] In certain embodiments, the compounds provided herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, or compositions thereof, are administered with NAD + or NAD + Precursors (e.g., nicotinamide riboside (NR), nicotinic acid (NA), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinic acid mononucleotide (NaMN), tryptophan (TRP), nicotinic acid adenine dinucleotide (NAAD), or vitamin B3) are administered in combination.

[0420] In certain embodiments, provided is a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, for use in inhibiting the activity of sterile alpha and TIR motif protein 1 (SARM1) (e.g., in vitro or in vivo).

[0421] In certain embodiments, the present disclosure provides compounds disclosed herein, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, for use in the manufacture of a method for inhibiting the activity of sterile alpha and TIR motif protein 1 (SARM1) (e.g., in vitro or in vivo) and supplementing axonal NAD + Use in pharmaceutical preparations of the level.

[0422] Axonal degeneration is associated with various types of neurodegenerative diseases and is considered an important indicator of disease progression and an interesting target for therapeutic treatment of these diseases. Similarly, axonal degeneration has also been observed in patients with traumatic brain injury and peripheral neuropathy.

[0423] In certain embodiments, a method for treating a disease or condition mediated at least in part by SARM1 is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0424] In certain embodiments, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and NAD + or NAD + Use of a combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3) in the manufacture of a medicament for treating or preventing a neurodegenerative disease in a subject in need thereof.

[0425] In certain embodiments, a method for treating any disease caused by SARM1 activity is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof and NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0426] In certain embodiments, the disease or disorder can be a disease or disorder of the central nervous system, and / or can be caused by or associated with a pathogen or traumatic injury. It should be understood that these general embodiments defined according to broad categories of diseases, disorders and illnesses are not mutually exclusive.

[0427] In certain embodiments, a method for treating a neurodegenerative disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof and NAD. + or NAD + A combination of precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B3).

[0428] Other embodiments include the use of the compounds disclosed herein in therapy.

[0429] 4. Medicine Box

[0430] Also provided herein are kits comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, and suitable packaging. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof and a label and / or instructions for use of the compound in a therapeutic indication (including a disease or disorder described herein).

[0431] Also provided herein are articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, in a suitable container, such as a vial, jar, ampoule, pre-loaded syringe, or intravenous bag.

[0432] 5. Pharmaceutical Composition and Mode of Administration

[0433] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein, comprising one or more compounds described herein or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by G.S. Banker & C.T. Rhodes).

[0434] The pharmaceutical composition can be administered in a single dose or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, oral, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or as an inhalant.

[0435] One mode of administration is parenteral administration, for example, by injection. Forms that can be incorporated into the pharmaceutical compositions described herein for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0436] Oral administration can be another route of administration for the compounds described herein. Administration can be carried out, for example, via capsules or enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug, the active ingredient is typically diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, a sachet, paper, or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid, or liquid substance that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, pouch, elixir, suspension, emulsion, solution, syrup, aerosol (in solid form or in a liquid medium), an ointment containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0437] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0438] Compositions including at least one compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug can be formulated using procedures as known in the art to provide rapid, continuous or delayed release of active ingredients after being applied to a subject. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing reservoirs or drug-polymer matrix formulations of coated polymers. Another formulation used in the methods disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of compounds described herein in controlled amounts. The structure and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be configured for continuous, pulsating or on-demand delivery of pharmaceutical agents.

[0439] To prepare solid compositions, such as tablets, the principal active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0440] The tablet or pill of compound described herein can be coated or otherwise mixed, to provide the dosage form that can provide the advantage of prolonged effect, or to protect it from the impact of acidic conditions in the stomach.For example, tablet or pill can include inner dose and outer dose component, the latter is the form of the envelope covering the former.These two components can be separated by enteric layer, and this enteric layer plays the effect of resisting the disintegration in the stomach and allowing inner component to enter the duodenum intact or delay release.Multiple materials can be used for this type of enteric layer or coating, and this type of material includes a mixture of multiple polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0441] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the compositions are administered via the oral or nasal respiratory route to achieve local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized using an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be connected to a face mask inhaler or intermittent positive pressure respirator. In one embodiment, the solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0442] The amount of the compound in a pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain about 0.01-99.99 wt % of the compound of the present disclosure, based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations are described below.

[0443] Formulation Example 1 - Tablet Formulation

[0444] The following ingredients are mixed thoroughly and compressed into single scored tablets.

[0445]

[0446] Formulation Example 2-Capsule Formulation

[0447] Mix the following ingredients thoroughly and fill into hard shell gelatin capsules.

[0448]

[0449] Formulation Example 3 - Suspension Formulation

[0450] The following ingredients are mixed to form a suspension for oral administration.

[0451]

[0452]

[0453] Formulation Example 4-Injection Formula

[0454] The following ingredients are mixed to form an injectable preparation.

[0455] Element quantity Compounds of the present disclosure 0.2mg-20mg Sodium acetate buffer solution, 0.4 M 2.0mL HCl (1N) or NaOH (1N) Add appropriate amount to the appropriate pH Water (distilled, sterile) Add appropriate amount to 20mL

[0456] Formulation Example 5 - Suppository Formulation

[0457] By combining the compounds of the present disclosure with Suppositories weighing 2.5 g were prepared by mixing H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) and having the following composition:

[0458]

[0459] 6. Medication

[0460] The specific dosage level of the compound of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, route of administration and excretion rate, drug combination and the severity of the specific disease of the subject receiving therapy. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). A dosage between about 0.1 and 150 mg / kg may be appropriate. In certain embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 and 60 mg / kg may be appropriate. In certain embodiments, a dosage of about 0.0001 to about 100 mg per kilogram of body weight per day, about 0.001 to about 50 mg of compound per kilogram of body weight, or about 0.01 to about 10 mg of compound per kilogram of body weight may be appropriate. When adjusting the dosage between subjects with very different body sizes, for example, when using the drug in children and adults, or when converting the effective dose of a non-human subject such as a dog to a dosage suitable for a human subject, it is particularly useful to normalize according to the subject's body weight.

[0461] 7. Synthesis of Compounds

[0462] Compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent from the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of representative compounds described herein can be achieved as described in the following examples. If available, reagents and starting materials can be purchased commercially from, for example, Sigma Aldrich or other chemical suppliers.

[0463] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

[0464] In addition, conventional protecting groups (" PG ") may be necessary for preventing some functional groups from experiencing undesired reactions. The protecting groups applicable to various functional groups and the conditions applicable to the protection and deprotection of specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006). Greene'sprotective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein. For example, the protecting group of alcohol, such as hydroxyl, including silyl ether (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM) and triisopropylsilyl (TIPS) ether), which can be removed by acid or fluorine ion such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py or HF-NEt3. Other protecting groups for alcohols include acetyl, which are removed by acid or base, benzoyl, which are removed by acid or base, benzyl, which are removed by hydrogenation, methoxyethoxymethyl ether, which are removed by acid, dimethoxytrityl, which are removed by acid, methoxymethyl ether, tetrahydropyranyl or tetrahydrofuranyl, which are removed by acid, and trityl, which are removed by acid. Examples of protecting groups for amines include benzyloxycarbonyl, which are removed by hydrogenolysis, p-methoxybenzylcarbonyl, which are removed by hydrogenolysis, tert-butoxycarbonyl, which are removed by concentrated strong acid (e.g., HCl or CF3COOH) or by heating to greater than about 80°C, 9-fluorenylmethoxycarbonyl, which are removed by bases such as piperidine, acetyl, which are removed by treatment with base, benzoyl, which are removed by treatment with base, benzyl, which are removed by hydrogenolysis, carbamate, which are removed by acid and mild heating, p-Anisyl removed by hydrogenolysis, 3,4-dimethoxybenzyl removed by hydrogenolysis, p-Anisyl removed by cerium(IV) ammonium nitrate, tosyl removed by concentrated acid (e.g. HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalene), troc (trichloroethyl chloroformate) removed by zinc insertion in the presence of acetic acid, and sulfonamides (nitrobenzenesulfonyl and o-nitrobenzenesulfonyl) removed by samarium iodide or tributyltin hydride.

[0465] In addition, the compounds of the present disclosure may contain one or more chiral centers. Therefore, if desired, such compounds can be prepared or separated into pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in stereoisomers. Unless otherwise indicated, all of these stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0466] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications thereof, for example, as described in the following standard reference texts: 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).

[0467] General synthesis

[0468] Scheme 1 shows a general method that can be used to synthesize the compounds described herein, wherein each A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X5 、X 6 、R 1 、R 2 、R 4 and R 5 are independently as defined herein; LG is a leaving group (eg, halo, alkoxy, etc.); and each R 50 are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic borate ester.

[0469] Plan I

[0470]

[0471] In Scheme 1, the compound of Formula I can be prepared by contacting compound I-1 with compound I-2 under suitable coupling reaction conditions, and then optionally functionalizing or deprotecting when needed. Alternatively, the compound of Formula I can be prepared by contacting compound I-3 with compound I-4 under suitable coupling reaction conditions, and then optionally functionalizing or deprotecting when needed. Alternatively, compound I-5 can be prepared by contacting compound I-6 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd (dppf) Cl ) and a base, and then optionally functionalizing or deprotecting when needed to prepare the compound of Formula I. After each reaction is completed, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, etc.

[0472] Further derivatization of the compounds or any intermediates provided by the steps outlined in Scheme I provides additional compounds of Formula I. It should be understood that any of the compounds or intermediates shown in Scheme I can be prepared using conventional methods or purchased from commercial sources. In addition, any intermediate or any product obtained by the methods outlined in Scheme I can be derivatized at any step to provide various compounds of Formula I. In certain embodiments, various substituents of the compounds or intermediates used in Scheme I are as defined in Formula I.

[0473] For example, compounds I-1 and I-5 can be prepared according to the following Scheme II by following a procedure similar to that described in Scheme I, wherein A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 4 and R 5are each independently as defined herein; X is a leaving group (eg, halo); LG is a leaving group (eg, halo, alkoxy, etc.); and each R 50 are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic borate ester.

[0474] Option II

[0475]

[0476] After completion of each reaction, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques, such as neutralization, extraction, precipitation, chromatography, filtration, and the like.

[0477] It should be understood that any compound or intermediate shown in Scheme II can be prepared using conventional methods or purchased from commercial sources. In addition, any intermediate or any product obtained by the method outlined in Scheme II can be derivatized at any step to provide various compounds of Formula I. In certain embodiments, various substituents of the compounds or intermediates used in Scheme II are as defined in Formula I.

[0478] In certain embodiments, a method for providing a compound of formula I is provided, the method comprising allowing a compound of formula I-1 to:

[0479]

[0480] With the compound of formula I-2:

[0481]

[0482] contacting under conditions sufficient to provide a compound of formula I; wherein A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 4 and R 5 Each is independently as defined herein, and LG is a leaving group.

[0483] In certain embodiments, a method for providing a compound of formula I is provided, the method comprising making a compound of formula I-5:

[0484]

[0485] With the compound of formula I-6

[0486]

[0487] contacting under conditions sufficient to provide a compound of formula I; wherein A 1 、A 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 1 、R 2 、R 4 and R 5 Each independently as defined herein, LG is a leaving group, and each R 50 are independently -OH, C 1-6 Alkoxy, or two R 50 Together with the boron atom to which they are attached, they form a cyclic boronate ester.

[0488] In certain embodiments, LG is halo, C 1-6 Alkoxy, benzyloxy or 4-OCH3-benzyloxy. Example

[0489] The following examples are included to demonstrate specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the technology disclosed in the following examples represents a technology that works well in the practice of the present disclosure and therefore can be considered as constituting a specific mode of its practice. However, based on the present disclosure, it will be appreciated by those skilled in the art that many changes can be made in the disclosed specific embodiments without departing from the spirit and scope of the present disclosure and still obtaining similar or similar results.

[0490] General experimental methods

[0491] All solvents used were commercially available and used without further purification.The reactions were generally carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0492] NMR spectroscopy: 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Avance III instrument operated at 300 MHz equipped with a BBFO 300 MHz probe or one of the following instruments operated at 400 MHz: a Bruker Avance 400 instrument equipped with a DUAL 400 MHz S1 probe, a Bruker Avance 600 instrument equipped with a 400 MHz 5 mm S1 probe, a Bruker Avance 600 instrument equipped with a 600 MHz 5 mm S1 probe, or a Bruker Avance 600 instrument equipped with a 600 MHz 5 mm S1 probe. 1 H- 13Bruker Avance 400 instrument for C ID, Bruker Avance III 400 instrument with nanobay equipped with direct probe Broadband BBF O 5 mm, Bruker Mercury Plus 400 NMR spectrometer equipped with Bruker 400 BBO probe. All deuterated solvents typically contained 0.03% to 0.05% v / v tetramethylsilane, which was used as a reference signal ( 1 H and 13 C is set to δδ0.00). In some cases, 1 H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker Advance 400 instrument operating at 400 MHz at approximately room temperature using the solvents described, unless otherwise stated. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are in parts per million, and conventional abbreviations are used to designate major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; br, broad.

[0493] Thin layer chromatography: In the case of thin layer chromatography (TLC), it refers to silica gel TLC using silica gel F254 (Merck) plates, with Rf being the distance traveled by the compound on the TLC plate divided by the distance traveled by the solvent. Column chromatography is performed on silica gel cartridges using an automated flash chromatography system, or on C18 cartridges in the case of reverse phase chromatography. Alternatively, thin layer chromatography (TLC) is performed on a HPLC system from Manchester-Nagel. (Silica gel 60F254), and UV was usually used to develop the spots. In some cases, additional development methods were also used. In these cases, the TLC plates were treated with iodine (generated by adding approximately 1 g of I2 to 10 g of silica gel and mixing thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (generated by thoroughly mixing 25 g of (NH4)6Mo7O in 450 mL of water and 50 mL of concentrated H2SO4). 24 .4H2O, 5g(NH4)2Ce(IV)(NO3)6) imaging to develop the compound.

[0494] Liquid chromatography-mass spectrometry and HPLC analysis: HPLC analysis was performed on a Shimadzu 20AB HPLC system with a photodiode array detector and a Luna-C18 (2) 2.0×50 mm, 5 μm column at a flow rate of 1.2 mL / min with a gradient solvent mobile phase A (MPA, H2O+0.037% (v / v) TFA): mobile phase B (MPB, ACN+0.018% (v / v) TFA) (0.01 min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5 min, 10% MPB). LCMS was detected at 220 and 254 nm or using evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC was performed under acidic or neutral conditions. Acidic: Luna C18 100×30 mm, 5 μm; MPA: HCl / H₂O = 0.04% or formic acid / H₂O = 0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25 mm, 5 μm; MPA: 10 mM NH₄HCO₃ in H₂O; MPB: ACN. Gradients under two conditions: 10% MPB to 80% MPB over 12 min at a flow rate of 20 mL / min, followed by 100% MPB over 2 min, and 10% MPB over 2 min. UV detection. SFC analysis was performed on a Thaler analytical SFC system using a UV / Vis detector and a series of chiral columns including AD, AS-H, OJ, OD, AY and IC, 4.6×100 mm, 3 μm columns, with a flow rate of 4 mL / min, where the gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.05% (v / v) IPA) (0.01 min, 10% MPB; 3 min, 40% MPB; 3.5 min, 40% MPB; 3.56-5 min, 10% MPB). Preparative SFC was performed on a ThaR 80 preparative SFC system using a UV / Vis detector and a series of chiral preparative columns, including AD-H, AS-H, OJ-H, OD-H, AY-H, and IC-H, 30×250 mm, 5 μm columns, with a flow rate of 65 mL / min, where the gradient solvent mobile phase A (MPA, CO2): mobile phase B (MPB, MeOH + 0.1% (v / v) NH3H2O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB).LC-MS data were also acquired using a UPLC-MS Acquit y equipped with a PDA detector and coupled to a Waters single quadrupole mass spectrometer. TM The system collected ions in alternating positive and negative electrospray ionization modes. The column used was a Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A linear gradient was applied, starting with 95% A (A: 0.1% formic acid in water) and ending with 95% B (B: MeCN containing 0.1% formic acid) over 2.0 min, for a total run time of 2.5 min. The column temperature was 40° C., and the flow rate was 0.8 mL / min.

[0495] Intermediate 1

[0496] Methyl-6-azabicyclo[3.1.1]heptane

[0497]

[0498] Methyl -6- azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone: At 25 ° C, under N2, to a mixture of N- (3- methylcyclohexyl) picolinamide (20 g, 91.62 mmol) in 1,1,2,2- tetrachloroethane (300 mL) was added AgOAc (45.88 g, 274.86 mmol), benzoquinone (4.95 g, 45.81 mmol), Na3PO4 (45 g, 274.86 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (269 g, 916.20 mmol) and Pd (OAc) 2 (2.06 g, 9.16 mmol). The mixture was stirred at 145 ° C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound. LCMS: m / z=217.10 [M+H] + .

[0499] 3-Methyl-6-azabicyclo[3.1.1]heptane: At 25 ° C, under N2, to a mixture of (3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (2.7 g, 12.48 mmol) in EtOH (50 mL) was added NaOH (4.99 g, 124.84 mmol). The mixture was stirred at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure (water pump, below 35 ° C) to obtain a mixture containing the product, NaOH and the sodium salt of the acid. The mixture was stirred in DCM (20 mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure (water pump, below 35 ° C). The post-treatment procedure was repeated 2-3 times or until the concentrated residue was free of solids to give the title compound as a mixture of approximately 10: 1 of cis and trans isomers. LCMS: m / z = 112.2 [M + H] + .

[0500] Intermediate 2

[0501] trans-3-methyl-6-azabicyclo[3.1.1]heptane

[0502]

[0503] N-(cis-3-methylcyclohexyl)picolinamide: A mixture of N-(trans-3-methylcyclohexyl)picolinamide and N-(cis-3-methylcyclohexyl)picolinamide was purified by preparative HPLC (column: Phenomenex luna C18 250×100 mm×15 μm; mobile phase: A: 10 mM TFA aqueous solution, B: MeCN; B in A: 40%-70% over 20 min) to give separated cis and trans isomers. The first eluting peak was concentrated under reduced pressure, adjusted to pH 7-8 with saturated aqueous NaHCO₃, and extracted with DCM (3×500 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound as a colorless oil. LCMS: m / z=219.2 [M+H] + .

[0504] (trans-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone was added to a mixture of N-(cis-3-methylcyclohexyl)picolinamide (10 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (300 mL) at 25 ° C under N2, AgOAc (22.94 g, 137.43 mmol), benzoquinone (2.48 g, 22.90 mmol), Na3PO4 (22.53 g, 137.43 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (134.66 g, 458.10 mmol) and Pd(OAc)2 (2.06 g, 9.16 mmol). The mixture was stirred at 145 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound as a brown oil. LCMS: m / z=217.0 [M+H] + .

[0505] Trans-3-methyl-6-azabicyclo[3.1.1]heptane: At 25 ° C, under N2, to a mixture of (trans-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (1.2 g, 5.55 mmol) in EtOH (15 mL) was added NaOH (2.22 g, 55.48 mmol). The mixture was stirred at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure (water pump, below 35 ° C) to obtain a mixture containing the sodium salt of the product, NaOH and acid. The mixture was stirred in DCM (20 mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure (water pump, below 35 ° C). The post-treatment procedure was repeated 2-3 times or until the concentrated residue did not contain solids to give the title compound in the form of a free base as a brown slurry. TFA was added and the mixture was stirred at 20 ° C for 0.5 hours, then concentrated under reduced pressure to give the TFA salt. LCMS: m / z = 112.2 [M+H] + .

[0506] Intermediate 3

[0507] cis-3-methyl-6-azabicyclo[3.1.1]heptane

[0508]

[0509] N-(trans-3-methylcyclohexyl)picolinamide: A mixture of N-(trans-3-methylcyclohexyl)picolinamide and N-(cis-3-methylcyclohexyl)picolinamide was purified by preparative HPLC (column: Phenomenex luna C18 250×100 mm×15 μm; mobile phase: A: 10 mM TFA aqueous solution, B: MeCN; B in A: 40%-70% over 20 min) to give separated cis and trans isomers. The second eluting peak was concentrated under reduced pressure, adjusted to pH 7-8 with saturated aqueous NaHCO₃, and extracted with DCM (3×300 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound as a colorless oil. LCMS: m / z=219.2 [M+H] + .

[0510] (cis-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone was added to a mixture of N-(trans-3-methylcyclohexyl)picolinamide (6 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (200 mL) at 25 ° C under N2, AgOAc (13.76 g, 82.46 mmol), benzoquinone (1.49 g, 13.74 mmol), Na3PO4 (13.52 g, 82.46 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (80.80 g, 274.86 mmol) and Pd(OAc)2 (1.23 g, 5.50 mmol). The mixture was stirred at 145 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound as a brown oil. LCMS: m / z=217.0 [M+H] + .

[0511] Cis-3-methyl-6-azabicyclo[3.1.1]heptane: At 25 ° C, under N2, to a mixture of (cis-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (2.4 g, 11.1 mmol) in EtOH (30 mL) was added NaOH (4.44 g, 111 mmol). The mixture was stirred at 90 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure (water pump, below 35 ° C) to obtain a mixture containing the product, NaOH and the sodium salt of the acid. The mixture was stirred in DCM (20 mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure (water pump, below 35 ° C). The post-treatment procedure was repeated 2-3 times or until the concentrated residue did not contain solids to give the title compound in the form of a free base. TFA was added and the mixture was stirred at 20 ° C for 0.5 hours, then concentrated under reduced pressure to give the TFA salt. LCMS: m / z = 112.2 [M+H] + .

[0512] Intermediate 4

[0513] cis-3-Fluoro-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0514]

[0515] tert-Butyl trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane (5.8 g, 28.53 mmol) in 1,4-dioxane (20 mL) was added aqueous NaOH (50 mL, 2 M) and Boc2O (12.45 g, 57.06 mmol) at 0°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with MTBE (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE=100:1 to 3:1) to give the title compound. LCMS: m / z=248.2 [M-tBu+H] + .

[0516] Trans-3-hydroxy-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester: Under argon, to a solution of trans-3- (benzyloxy) -6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (3.55 g, 11.70 mmol) in MeOH (50 mL) was added Pd / C (2 g, 10% on carbon) at 25 ° C. The suspension was degassed and purged with H2 three times. Under H2 (50 psi), the mixture was stirred at 30 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 158.2 [M-tBu + H] + .

[0517] Cis-3-fluoro-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: Under N2, DAST (166 mg, 0.19 mmol) was added to a solution of trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (110 mg, 0.09 mmol) in DCM (2 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction mixture was adjusted to pH = 7-8 with saturated aqueous NaHCO3 and extracted with DCM (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z = 160.2 [M-tBu+H] + .

[0518] Cis-3-fluoro-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a solution of cis-3-fluoro-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (30 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1.54 g, 14 mmol, 1 mL) at 20 ° C. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. The material was used directly in the next step.

[0519] Intermediate 5

[0520] cis-3-methoxy-6-azabicyclo[3.1.1]heptane

[0521]

[0522] N-(trans-3-methoxycyclohexyl)picolinamide: Under N2, to a mixture of trans-3-methoxycyclohexylamine hydrochloride (2 g, 12.07 mmol) and picolinic acid (1.78 g, 14.49 mmol) in DCM (50 mL) was added TEA (1.83 g, 18.11 mmol), DMAP (147.49 mg, 1.21 mmol) and EDCI (3.47 g, 18.11 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with H2O (20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give the title compound. LCMS: m / z = 235.1 [M+H] + .

[0523] (cis-3-methoxy-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a mixture of N-((1S,3S)-3-methoxycyclohexyl)picolinamide (1.6 g. 6.83 mmol) in 1,1,2,2-tetrachloroethane (50 mL) was added AgOAc (3.42 g, 20.49 mmol), benzoquinone (369 mg, 3.41 mmol), Na 3 PO 4 (3.36 g, 20.49 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (20.07 g, 68.29 mmol) and Pd(OAc) 2 (307 mg, 1.37 mmol) at 25° C. under N 2 . The mixture was stirred at 140° C. for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 1:1) to give the title compound. LCMS: m / z=232.9 [M+H] + .

[0524] Cis-3-methoxy-6-azabicyclo [3.1.1] heptane: At 25 ° C, to a mixture of (cis-3-methoxy-6-azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone (270 mg, 1.16 mmol) in EtOH (5 mL) was added NaOH (465 mg, 11.62 mmol). The mixture was stirred at 90 ° C for 4 hours and then concentrated under reduced pressure. The resulting residue was formed into a slurry in DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure. The post-treatment was repeated three times to obtain the title compound. The substance was used directly in the next step.

[0525] Intermediate 6

[0526] trans-6-azabicyclo[3.1.1]heptan-3-ol

[0527]

[0528] N-(cis-3-(benzyloxy)cyclohexyl)picolinamide: To a mixture of cis-3-(benzyloxy)cyclohexylamine hydrochloride (61.5 g, 254.39 mmol) and picolinic acid (37.58 g, 305.27 mmol) in EtOAc (400 mL) was added TEA (102.97 g, 1.02 mol, 141.63 mL) at 0°C under N2, followed by T3P (242.82 g, 381.58 mmol, 50% solution in EtOAc). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (1 L) and extracted with EtOAc (3×300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=311.0 [M+H] + .

[0529] (trans-3-(benzyloxy)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of N-(cis-3-(benzyloxy)cyclohexyl)picolinamide (39 g, 125.58 mmol) in 1,1,2,2-tetrachloroethane (500 mL) was added benzoquinone (6.79 g, 62.79 mmol), AgOAc (62.79 g, 376.74 mmol), Na 3 PO 4 (61.62 g, 376.74 mmol), 1,2,3,4,5-pentafluoro-6-iodobenzene (369.33 g, 1.26 mol) and Pd(OAc) 2 (2.81 g, 12.48 mmol) at 20° C. under N 2 . The mixture was stirred at 140° C. for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc) to afford the title compound. The material was used directly in the next step.

[0530] Trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane: To a mixture of (trans-3-(benzyloxy)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (13 g, 42.16 mmol) in EtOH (130 mL) was added NaOH (16.86 g, 421.57 mmol) under N2 at 20°C. The mixture was stirred at 90°C for 12 hours. The reaction mixture was concentrated under reduced pressure, slurried in DCM (100 mL), filtered through a pad of celite and the filtrate was concentrated under reduced pressure. This post-treatment was repeated 2-3 times to give the title compound. LCMS: m / z=204.3[M+H] + .

[0531] Trans-6-azabicyclo[3.1.1]heptan-3-ol: To a solution of trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane (200 mg, 0.98 mmol) in MeOH (20 mL) was added Pd / C (50 mg, 10% purity) at 25° C. under N2. The suspension was degassed and purged with H2 three times. Under H2 (50 psi), the mixture was stirred at 30° C. for 12 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z=114.2[M+H] + .

[0532] Intermediate 7

[0533] cis-3-Methyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0534]

[0535] Under N2, TEA (65 mg, 0.64 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (50 mg, 0.21 mmol) were added to a mixture of triphosgene (32 mg, 0.10 mmol) in THF (1.5 mL) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour. Then, cis-3-methyl-6-azabicyclo[3.1.1]heptane trifluoroacetate (56 mg, 0.25 mmol) and TEA (39 mg, 0.39 mmol) were added to the reaction solution. The reaction solution was stirred at 20 ° C for 1 hour. The reaction solution was diluted with H2O (2 mL) and extracted with EtOAc (3 × 2 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS: m / z=371.2 [M+H] + .

[0536] Intermediate 8

[0537] N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0538]

[0539] DCM (5mL) is added to a dry round-bottom flask containing triphosgene (636mg, 2.1mmol), and the resulting solution is cooled to 0 DEG C. A solution of 4- methyl -3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan -2- bases) aniline (500mg, 2.1mmol) and triethylamine (0.9mL, 6.4mmol) in DCM (5mL) is added dropwise. The reaction mixture is warmed to room temperature from 0 DEG C within 2 hours, and the reaction mixture is subsequently concentrated in a vacuum. The resulting residue is dissolved in DCM (10.8mL) and 6- azabicyclo [3.1.1] heptane hydrochloride (315mg, 2.4mmol) is added to the mixture, followed by triethylamine (0.9mL, 6.4mmol). The reaction mixture is stirred at room temperature for 4 hours. The reaction is cooled to 0 DEG C and quenched dropwise with saturated NaHCO3 aqueous solution (10mL). The reaction was extracted with DCM (3×20 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. Diethyl ether was added to the crude product and the solid was collected by filtration to give the title compound, which was used directly in the next step. LCMS: m / z=357.2 [M+H] + .

[0540] Intermediate 9

[0541] 3-Methyl-6-azabicyclo[3.1.1]heptane-3-carbonitrile trifluoroacetate

[0542]

[0543] 3-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: To a solution of cis-3-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (30 mg, 0.13 mmol) in THF (2 mL) was added LDA (0.081 mL, 2 M) under N2 at -78 ° C. The mixture was stirred at -78 ° C for 1 hour, followed by the addition of CH3I (23 mg, 0.16 mmol) in THF (2 mL) at -78 ° C and stirred for 1 hour. The reaction mixture was poured into saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=181.2 [Mt-Bu+H] + .

[0544] 3-Methyl-6-azabicyclo[3.1.1]heptane-3-carbonitrile trifluoroacetate: To a solution of tert-butyl 3-cyano-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (30 mg, 0.13 mmol) in DCM (2 mL) was added TFA (1.54 g, 0.014 mmol) under N2 at 25°C. The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 137.2 [M+H] + .

[0545] Intermediate 10

[0546] cis-6-Azabicyclo[3.1.1]heptane-3-carbonitrile trifluoroacetate

[0547]

[0548] tert-Butyl trans-3-((methylsulfonyl)oxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 0.94 mmol) in DCM (2 mL) was added TEA (285 mg, 2.81 mmol) and MsCl (161 mg, 1.41 mmol) at 0° C. under N2. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with H2O (2 mL) and extracted with DCM (3×3 mL). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=236.1 [Mt-Bu+H] + .

[0549] cis-3-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: To a solution of trans-3-((methylsulfonyl)oxy)-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (215 mg, 0.74 mmol) in DMF (5 mL) was added NaCN (109 mg, 2.21 mmol) at 20 ° C. The mixture was stirred at 65 ° C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=167.2 [Mt-Bu+H] + .

[0550] cis-6-Azabicyclo[3.1.1]heptane-3-carbonitrile trifluoroacetate: To a solution of cis-tert-butyl 3-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylate (130 mg, 0.59 mmol) in DCM (3 mL) was added TFA (7.95 g, 69.76 mmol) at 20°C. The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 123.2 [M+H] + .

[0551] Intermediate 11

[0552] 2-(6-Azabicyclo[3.1.1]hept-1-yl)-5-methyl-1,3,4-oxadiazole

[0553]

[0554] Tert-Butyl 1-(acetylaminocarbamoyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of N,N-diisopropylethylamine (0.43 mL, 2.49 mmol) in EtOAc (1.2 mL) was added acetohydrazide (67.55 mg, 0.91 mmol) at -20 ° C. Subsequently, 6-tert-butoxycarbonyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (200.0 mg, 0.83 mmol) was added, and the reaction was then warmed to -10 ° C. and stirred for 1 hour. T3P (791.23 mg, 1.24 mmol, 50% purity) was added dropwise and stirred for an additional 15 minutes. The reaction was concentrated and the residue was dissolved in EtOAc and H2O. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound.

[0555] 1- (5-methyl -1,3,4- oxadiazol-2-yl) -6- azabicyclo [3.1.1] heptane -6- carboxylic acid tert-butyl ester: at 0 ° C, to a solution of 1- (acetylaminocarbamoyl) -6- azabicyclo [3.1.1] heptane -6- carboxylic acid tert-butyl ester (166.0 mg, 0.56 mmol) in MeCN (1.9 mL) was added TEA (0.23 mL, 1.67 mmol) and then p-toluenesulfonyl chloride (117.08 mg, 0.61 mmol). The reaction was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. Ether was added to the resulting residue, followed by sonication. The mixture was concentrated to dryness and used directly in the next step.

[0556] 2-(6-Azabicyclo[3.1.1]hept-1-yl)-5-methyl-1,3,4-oxadiazole: To a solution of tert-butyl 1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (2080.0 mg, 7.45 mmol) in DCE (37.2 mL) was added trifluoroacetic acid (5.7 mL, 74.46 mmol). The reaction was stirred at room temperature for 2 hours. After 2 hours, the reactants were heated to 50 ° C and stirred overnight. After stirring overnight, the reactants were cooled and concentrated under reduced pressure. The residue was purified by HPLC to give the title compound. LCMS: m / z = 180.1 [M + H] + .

[0557] Intermediate 12

[0558] 6-Azabicyclo[3.1.1]heptane-1-carbonitrile trifluoroacetate

[0559]

[0560] tert-Butyl 1-carbamoyl-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 6-tert-butoxycarbonyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (333.51 mg, 1.38 mmol) in THF (2.3 mL) was added TEA (0.58 mL, 4.15 mmol) at -20 ° C. Subsequently, ethyl chloroformate (0.13 mL, 1.38 mmol) was added, the reaction was warmed to -10 ° C, and stirred for 1 hour. After 1 hour, NH (1.97 mL, 13.82 mmol, 7N in methanol) was added dropwise and stirred for another 15 minutes. The reactant was then concentrated and dissolved in EtOAc and H2O. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the desired compound.

[0561] 1-cyano-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester At 0 ° C, to a solution of 1-carbamoyl-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (285.0 mg, 1.19 mmol) in THF (11.8 mL) was added TEA (0.33 mL, 2.37 mmol), and then trifluoroacetic anhydride (0.16 mL, 1.19 mmol) was added dropwise. The reaction was stirred at 0 ° C and allowed to warm to room temperature overnight. The reactant was concentrated under reduced pressure and then dissolved in EtOAc and H2O. The organic layer was washed with saturated NaHCO3 aqueous solution and brine. The organic matter was dried over anhydrous Na2SO4 and concentrated to give the title compound.

[0562] 6-Azabicyclo[3.1.1]heptane-1-carbonitrile trifluoroacetate: To a solution of tert-butyl 1-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylate (250.0 mg, 1.12 mmol) in DCE (5.6 mL) was added trifluoroacetic acid (0.86 mL, 11.25 mmol). The reaction was heated to 50 ° C and stirred overnight. After stirring overnight, the reaction was cooled and concentrated to give the title compound. LCMS: m / z = 123.1 [M + H] + .

[0563] Intermediate 13

[0564] 6-Chloropyrazolo[1,5-a]pyrazine-4-carbonitrile

[0565]

[0566] To a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (300 mg, 1.60 mmol) in DMF (7 mL) was added Zn(CN)2 (187 mg, 1.60 mmol) and Pd(PPh3)4 (184 mg, 0.15 mmol) under N2 at 20 ° C. The mixture was stirred at 120 ° C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound.

[0567] Intermediate 14

[0568] cis-6-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxylic acid

[0569]

[0570] ((6-((Benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)oxy)trimethylsilane: To a solution of 6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-one (4 g, 18.16 mmol) and TMSCF (2.84 g, 19.98 mmol) in THF (24 mL) was added TBAF (0.18 mmol, 0.18 mL, 1 M in THF) at 0°C under N. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:0 to 10:1) to give the title compound.

[0571]

[0266] 6-((Benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-ol: To a solution of ((6-((benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)oxy)trimethylsilane (3.9 g, 10.76 mmol) in THF (40 mL) was added TBAF (21.52 mol, 21.52 mL, 1 M in THF) at 0°C under N2. The mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under reduced pressure to give the title compound.

[0572] Ethyl 6-((benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-yl oxalate: To a solution of 6-((benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-ol (3 g, 10.33 mmol) in DCM (30 mL) was added pyridine (2.45 g, 31 mmol) and ethyl 2-chloro-2-oxo-acetate (2.82 g, 20.67 mmol) at 0°C under N2. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 10:1) to give the title compound.

[0573] 2-((Benzyloxy)methyl)-6-(trifluoromethyl)tetrahydro-2H-pyran: To a solution of ethyl 6-((benzyloxy)methyl)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-yl oxalate (2.1 g, 5.38 mmol) in toluene (40 mL) was added AIBN (265 mg, 1.61 mmol) and tributyltinane (3.13 g, 10.76 mmol) under N2. The mixture was stirred at 130 ° C for 12 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 10:1) to give the title compound.

[0574] (6-(Trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol: To a solution of 2-((benzyloxy)methyl)-6-(trifluoromethyl)tetrahydro-2H-pyran (0.9 g, 3.28 mmol) in MeOH (18 mL) was added HCl / MeOH (4 M, 2.7 mL) and 10% Pd / C (0.3 g). The mixture was stirred at 20° C. under H (15 psi) for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound.

[0575] Cis-6-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxylic acid: To a solution of (6-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol (0.02 g, 0.11 mmol) in DCM (0.5 mL), MeCN (0.5 mL) and H2O (1 mL) was added NaIO4 (70 mg, 0.33 mmol) and RuCl3 (0.45 mg, 0.01 mmol) under N2. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with H2O (3 mL) and extracted with DCM (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound.

[0576] Intermediate 15

[0577] trans-5-(Trifluoromethyl)tetrahydro-2H-pyran-2-carboxylic acid

[0578]

[0579] To a solution of (trans-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol (50 mg, 0.27 mmol) in DCM (0.5 mL), H2O (1 mL) and MeCN (0.5 mL) was added NaIO4 (174 mg, 814.53 mmol) at 0°C, followed by the addition of RuCl3 (1 mg, 0.005 mmol) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound.

[0580] Intermediate 16

[0581] 3-(7-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylaniline

[0582]

[0583] Under N2, 3-(7-bromopyrrolo[2,1-f][1,2,4]triazine-2-yl)-4-methyl-aniline (300 mg, 1.0 mmol) and Cs2CO3 (645 mg, 1.98 mmol), CuI (19 mg, 0.1 mmol), 1,10-phenanthroline (36 mg, 0.2 mmol) were placed in 2-methoxyethanol (8 mL) in a microwave tube. The sealed tube was heated at 130 ° C for 3 hours under microwave irradiation. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=299.0[M+H] + .

[0584] Intermediate 17

[0585] trans-3-fluoro-6-azabicyclo[3.1.1]heptane

[0586]

[0587] tert-Butyl trans-3-((4-nitrobenzoyl)oxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate (400 mg, 1.88 mmol) and 4-nitrobenzoic acid (407 mg, 2.44 mmol) in THF (8 mL) was added PPh (738 mg, 2.81 mmol) and DIAD (569 mg, 2.81 mmol) at 0 ° C under N2. The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was slurried with DCM and filtered. The filter cake was dried under reduced pressure to give the title compound.

[0588] cis-tert-Butyl 3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl trans-3-((4-nitrobenzoyl)oxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate (320 mg, 0.88 mmol) in THF (4 mL) and HO (1 mL) was added LiOH·HO (185 mg, 4.42 mmol) at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound.

[0589] Trans-3-fluoro-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester: Under N2, a mixture of cis-3-hydroxy-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (200 mg, 0.93 mmol) in DAST (2 mL) was stirred at 0 ° C for 2 hours. The reaction mixture was quenched by adding saturated Na2CO3 aqueous solution until pH = 7 and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound.

[0590] trans-3-Fluoro-6-azabicyclo[3.1.1]heptane: A mixture of tert-butyl trans-3-fluoro-6-azabicyclo[3.1.1]heptane-6-carboxylate (240 mg, 1.11 mmol) in TFA (1.5 mL) and DCM (1 mL) was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 116.2 [M+H] + .

[0591] Intermediate 18

[0592] 2-Chloro-7-fluoropyrrolo[2,1-f][1,2,4]triazine

[0593]

[0594] Under N2, SelectFluor (3.46 g, 9.77 mmol) was added to a mixture of 2-chloropyrrolo[2,1-f][1,2,4]triazine (1 g, 6.51 mmol) and MeCN (20 mL) at 25 ° C. The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) to give the title compound. LCMS: m / z=172.1[M+H] + .

[0595] Intermediate 19

[0596] 4-Chloro-3-(pyrazolo[1,5-a]pyrazin-6-yl)aniline

[0597]

[0598] To a mixture of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.59 mmol) and 6-chloropyrazolo[1,5-a]pyrazine (91 mg, 0.59 mol) in 1,4-dioxane (1 mL) and H2O (0.1 mL) was added K3PO4 (377 mg, 1.77 mmol) and XPhos Pd G2 (47 mg, 0.06 mmol) under N2 at 25 ° C. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound. LCMS: m / z=245.1[M+H] + .

[0599] Intermediate 20

[0600] 6-Chloro-3-fluoropyrazolo[1,5-a]pyrazine

[0601]

[0602] Under N2, SelectFluor (692 mg, 1.95 mmol) was added to a mixture of 6-chloropyrazolo[1,5-a]pyrazine (150 mg, 0.98 mmol) in MeCN (5 mL) at 20 ° C. The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS: m / z=172.1[M+H] + .

[0603] Intermediate 21

[0604] 6-Bromopyrazolo[1,5-a]pyridine-4-carbonitrile and 4-Bromopyrazolo[1,5-a]pyridine-6-carbonitrile

[0605]

[0606] Under N2, CuCN (114 mg, 1.27 mmol) was added to a solution of 4,6-dibromopyrazolo[1,5-a]pyridine (350 mg, 1.27 mmol) in NMP (5 mL) at 20 ° C. The mixture was stirred at 180 ° C for 3 hours. The reaction mixture was filtered through a celite pad. The filtrate was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS=221.8,223.8[M+H] + .

[0607] Intermediate 22

[0608] 6-Chloropyrazolo[1,5-a]pyrazine-4-carbonitrile

[0609]

[0610] 6-Chloro-4-vinylpyrazolo[1,5-a]pyrazine: To a mixture of 4,6-dichloropyrazolo[1,5-a]pyrazine (500 mg, 2.66 mmol) and potassium vinyl trifluoroborate (356 mg, 2.66 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) was added K2CO3 (735 mg, 5.32 mmol) and Pd(dppf)Cl2 (195 mg, 0.27 mmol) at 20°C under N2. The mixture was stirred at 30°C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=180.1[M+H] + .

[0611] 6-Chloropyrazolo[1,5-a]pyrazine-4-carboxaldehyde: To a mixture of 6-chloro-4-vinyl-pyrazolo[1,5-a]pyrazine (900 mg, 5.01 mmol) in THF (40 mL) and H2O (20 mL) was added NaIO4 (3.22 g, 15.03 mmol) and potassium osmium(VI) dihydrate (184.63 mg, 0.50 mmol) under N2 at 0°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 3:1) to give the title compound. LCMS: m / z=182.1[M+H] + .

[0612] 6-Chloropyrazolo[1,5-a]pyrazine-4-carbaldehyde oxime: To a mixture of 6-chloropyrazolo[1,5-a]pyrazine-4-carbaldehyde (35 mg, 0.19 mmol) in EtOH (1 mL) was added NH2OH·HCl (20 mg, 0.29 mmol) and NaOAc (47 mg, 0.58 mmol) under N2 at 20°C. The mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=197.2[M+H] + .

[0613] 6-Chloropyrazolo[1,5-a]pyrazine-4-carbonitrile: Under N2, to a mixture of 6-chloropyrazolo[1,5-a]pyrazine-4-carbaldehyde oxime (20 mg, 0.10 mmol) in DCM (2 mL) was added Burgess reagent (73 mg, 0.31 mmol) at 20 ° C. The mixture was stirred at 20 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to give the title compound. LCMS: m / z=179.1[M+H] + .

[0614] Intermediate 23

[0615] trans-2-(pyridin-2-yl)cyclobutanecarboxylic acid

[0616]

[0617] cis-2-((Benzyloxy)carbonyl)cyclobutanecarboxylic acid: To a mixture of 3-oxabicyclo[3.2.0]heptane-2,4-dione (5 g, 39.65 mmol) and benzyl alcohol (8.57 g, 79.30 mmol, 8.25 mL) in THF (50 mL) was added DMAP (484.37 mg, 3.96 mmol) under N at 20°C. The mixture was stirred at 20°C for 12 hours. The mixture was poured into saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0618] cis-cyclobutane-1,2-dicarboxylic acid 1-benzyl 2-(1,3-dioxoisoindolin-2-yl) ester: Under N2, to a mixture of cis-2-((benzyloxy)carbonyl)cyclobutanecarboxylic acid (2 g, 8.54 mmol) and 2-hydroxyisoindolin-1,3-dione (1.80 g, 11.01 mmol) in DCM (100 mL) at 0 ° C. DMAP (104.31 mg, 0.85 mmol) was added. DCC (1.94 g, 9.39 mmol) was added dropwise to the mixture at 0 ° C., and then stirred at 25 ° C. for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:MTBE=7:1 to 5:1) to give the title compound.

[0619] trans-2-(pyridin-2-yl)cyclobutanecarboxylic acid benzyl ester: To a mixture of cis-cyclobutane-1,2-dicarboxylic acid 1-benzyl 2-(1,3-dioxoisoindolin-2-yl) ester (1.44 g, 3.80 mmol) and 2-bromopyridine (400 mg, 2.53 mmol) in DMA (8 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.28 g, 5.06 mmol), NiBr2·dtbbpy (247 mg, 0.51 mmol), and NaHCO3 (851 mg, 10.13 mmol) under N2 at 25°C. The reaction was irradiated under 390 nm violet light for 12 h. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound. LCMS: m / z = 268.1 [M+H] + .

[0620] Trans-2-(pyridin-2-yl)cyclobutanecarboxylic acid: To a solution of trans-2-(2-pyridinyl)cyclobutanecarboxylic acid benzyl ester (100 mg, 0.37 mmol) in MeOH (2 mL) was added 10% Pd / C (10 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. Under H2 (15 psi), the mixture was stirred at 20 ° C for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z=178.0 [M+H] + .

[0621] Intermediate 24

[0622] 3-Chloropyrrolo[1,2-a]pyrazine

[0623]

[0624] 1,3-Dichloropyrrolo[1,2-a]pyrazine: To a solution of pyrrolo[1,2-a]pyrazine-1,3-diol (2.5 g, 16.65 mmol) in POCl3 (33.00 g, 215.22 mmol) was added DIEA (2.15 g, 16.65 mmol) under N2 at 20°C. The mixture was stirred at 100°C for 12 hours. The mixture was stirred at 120°C for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was poured into H2O (40 mL) at 20°C. The aqueous phase was adjusted to pH = 7 with saturated aqueous Na2CO3 and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=100:1 to 5:1) to give the title compound. LCMS: m / z=187.1,189.1[M+H] + .

[0625] 3-Chloropyrrolo[1,2-a]pyrazine: To a solution of 1,3-dichloropyrrolo[1,2-a]pyrazine (370 mg, 1.98 mmol) in THF (2 mL) was added Zn (517 mg, 7.91 mmol) and AcOH (713 mg, 11.87 mmol) at 0 ° C under N2. The mixture was stirred at 70 ° C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was triturated with MTBE and collected by filtration. The solid was dried under reduced pressure to give the title compound. LCMS: m / z = 153.1 [M + H] + .

[0626] Intermediate 25

[0627] (4S,7S)4,5,6,7-Tetrahydro-4,7-methanopyrazolo[1,5-a]pyrazine hydrochloride

[0628]

[0629] Tert-butyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-((Z)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate: A solution of (2S,4R)-2-acetyl-4-[tert-butyl(dimethyl)silyl]oxy-pyrrolidine-1-carboxylate (3.6 g, 10.48 mmol) in DMF·DMA (40 mL) was stirred at 120°C for 16 hours. The mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 399.2 [M+H] + .

[0630] tert-Butyl (2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(1H-pyrazol-5-yl)pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-2-[(Z)-3-(dimethylamino)prop-2-enoyl]pyrrolidine-1-carboxylate (4.1 g, 10.29 mmol) in EtOH (40 mL) was added N2H4·H2O (566 mg, 11.31 mmol). The mixture was stirred at 80 °C for 3 hours. The mixture was concentrated under reduced pressure. The residue was diluted with H2O (30 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z = 268.2 [M–Boc+H] + .

[0631] tert-Butyl (2S, 4R) -4-hydroxy-2- (1H-pyrazol-5-yl) pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S, 4R) -4- [tert-butyl (dimethyl) silyl] oxy-2- (1H-pyrazol-5-yl) pyrrolidine-1-carboxylate (3.3 g, 8.98 mmol) in THF (50 mL) was added N, N-diethylethanamine 3HF (7.24 g, 44.89 mmol). The mixture was stirred at 50 ° C for 2 hours. The mixture was poured into a saturated aqueous NaHCO solution (100 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM: MeOH = 10: 1 to 5: 1) to give the title compound. LCMS: m / z = 254.2 [M+H] + .

[0632] (2S,4R)-tert-Butyl 4-((methylsulfonyl)oxy)-2-(1H-pyrazol-5-yl)pyrrolidine-1-carboxylate): To a solution of tert-butyl (2S,4R)-4-hydroxy-2-(1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (400 mg, 1.58 mmol) in DCM (10 mL) was added MsCl (217 mg, 1.90 mmol) and TEA (240 mg, 2.37 mmol). The mixture was stirred at 0 ° C for 1 hour. The mixture was diluted with H2O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) to give the title compound. LCMS: m / z = 232.1 [M–Boc+H] + .

[0633] tert-Butyl (4S,7S)-6,7-dihydro-4,7-methanopyrazolo[1,5-a]pyrazine-5(4H)-carboxylate: To a solution of tert-butyl (2S,4R)-4-((methylsulfonyl)oxy)-2-(1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (340 mg, 1.03 mmol) in DMF (1.5 mL) was added CsCO (670 mg, 2.05 mmol). The mixture was stirred at 80 ° C for 2 hours. The mixture was diluted with H O (10 mL) and extracted with EtOAc (3×10 mL), and the combined organic layers were washed with brine (5 mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:MTBE=3:1 to 0:1) to give the title compound. LCMS: m / z=236.2 [M+H] + .

[0634] (4S,7S)-4,5,6,7-tetrahydro-4,7-methanopyrazolo[1,5-a]pyrazine hydrochloride: (2S,4R)2,3,8-triazatricyclo[5.2.1.0 2,6 A solution of tert-butyl deca-3,5-diene-8-carboxylate (100 mg, 0.425 mmol) in HCl / EtOAc (4 N, 3 mL) was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 136.3 [M+H] + .

[0635] Intermediate 26

[0636] 4-Amino-5-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzonitrile

[0637]

[0638] To a solution of 4-chloro-2-fluoro-5-pyrrolo[2,1-f][1,2,4]triazine-2-yl-phenylamine (530 mg, 2.02 mmol) in DMF (5 mL) was added CuCN (542.15 mg, 6.05 mmol) and CuBr (28.94 mg, 0.202 mmol) under N2 at 20 ° C. The mixture was stirred at 80 ° C for 12 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) to give the title compound. LCMS: m / z=254.1[M+H] + .

[0639] Intermediate 27

[0640] trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0641]

[0642] Cis-1-amino-3-methylcyclohexanecarbonitrile: A mixture of 3-methylcyclohexanone (53 g, 0.47 mol), TMSCN (61 g, 0.61 mol) and diiodozinc (15 g, 47.25 mmol) was stirred at 20 ° C for 1 hour. Then, a MeOH solution of NH3 (7 M, 25.47 mL) was added to the above mixture, which was prepared by passing NH3 into MeOH (200 mL) at -78 ° C for 30 minutes. The mixture was stirred at 20 ° C for 16 hours and then concentrated under reduced pressure. The resulting residue was ground with DCM (500 mL) at 20 ° C for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 139.2 [M + H] + .

[0643] cis-1-Amino-3-methylcyclohexanecarboxylic acid hydrochloride: A solution of cis-1-amino-3-methylcyclohexanecarbonitrile (47 g, 0.70 mol) in HCl (10 N, 970 mL) was stirred at 100°C for 12 hours. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 158.2 [M+H] + .

[0644] Cis-1-amino-3-methylcyclohexanecarboxylic acid methyl ester hydrochloride: Under N2, SOCl2 (106 mL, 1.46 mol) was added dropwise to a mixture of cis-1-amino-3-methylcyclohexanecarboxylic acid hydrochloride (94 g, 0.49 mol) in MeOH (940 mL) at 0°C. The mixture was then stirred at 75°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with MTBE (1.5 L) at 20°C for 30 minutes, filtered, and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z=172.2 [M+H] + .

[0645] Cis-3-methyl-1-(pyridinecarboxamido)cyclohexanecarboxylic acid methyl ester: Under N2, to a mixture of cis-1-amino-3-methylcyclohexanecarboxylic acid methyl ester hydrochloride (79 g, 0.38 mol) and picolinic acid (61 g, 0.49 mol) in DCM (1.5 L) was added DIEA (147 g, 1.14 mol), DMAP (4.7 g, 0.038 mol) and EDCI (109 g, 0.57 mol) at 0 ° C. The mixture was stirred at 20 ° C for 12 hours, diluted with H2O (700 mL) and extracted with DCM (2×400 mL). The combined organic layers were washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 3: 1) to give the title compound. LCMS: m / z = 277.0 [M+H] + .

[0646] Trans-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester: Under N2, to a mixture of cis-3-methyl-1-(pyridinylcarboxamido)cyclohexanecarboxylic acid methyl ester (39 g, 141 mmol), AgOAc (70.68 g, 423 mmol), Na3PO4 (69.42 g, 423 mmol) and benzoquinone (7.62 g, 70.56 mmol) in 1,1,2,2-tetrachloroethane (720 mL) at 20 ° C., Pd(OAc)2 (6.33 g, 28.23 mmol) and 1,2,3,4,5-pentafluoro-6-iodo-benzene (414.87 g, 1411.35 mmol) were added. The mixture was stirred at 140 ° C. for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=100:1 to 1:1) to give the title compound. LCMS: m / z=275.0 [M+H] + .

[0647] Trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of trans-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester (7.4 g, 26.98 mmol) in EtOH (100 mL) was added NaOH (10.79 g, 270 mmol) under N2 at 25 ° C. The mixture was stirred at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (15 mL) and the pH was adjusted to 6-7 with HCl (6N), and then lyophilized to give the title compound. LCMS: m / z=156.2 [M+H] + .

[0648] Intermediate 28

[0649] 2-Fluoro-5-(imidazo[1,2-a]pyrazin-6-yl)-4-methylaniline

[0650]

[0651] To a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg, 0.79 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) was added 6-chloroimidazo[1,2-a]pyrazine (146 mg, 0.95 mmol), K2CO3 (330 mg, 2.39 mmol) and Pd(dppf)Cl2 (58 mg, 0.07 mmol) at 20°C under N2. The mixture was stirred at 100°C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) to give the title compound. LCMS: m / z=243.2 [M+H] + .

[0652] Intermediate 29

[0653] cis-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxylic acid

[0654]

[0655] Cis-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol: To a mixture of cis-2-(benzyloxymethyl)-5-(trifluoromethyl)tetrahydropyran (100 mg, 0.36 mmol) in MeOH (2 mL) was added HCl / MeOH (0.5 mL, 4 M) and 10% Pd / C (25 mg). The reaction mixture was degassed and purged with H2 (15 psi) 3 times, then stirred at 20 ° C under H2 (15 psi) for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound.

[0656] Cis-5-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxylic acid: To a solution of (cis-5-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methanol (60 mg, 0.33 mmol) in DCM (0.5 mL), H2O (1 mL) and MeCN (0.5 mL) was added NaIO4 (209 mg, 0.98 mmol) and RuCl3 (1 mg, 0.006 mmol) at 0°C under N2. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound.

[0657] Intermediate 30

[0658] 3-(7-Bromopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylaniline

[0659]

[0660] 2-(2-Methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine: To a solution of 2-chloropyrrolo[2,1-f][1,2,4]triazine (2 g, 13.02 mmol) in 1,4-dioxane (30 mL) and H2O (3 mL) was added 4,4,5,5-tetramethyl-2-(2-methyl-5-nitrophenyl)-1,3,2-dioxaborolane (5.14 g, 19.54 mmol), K2CO3 (4.50 g, 32.56 mmol) and Pd(dppf)Cl2 (952 mg, 1.30 mmol) at 20°C under N2. The mixture was stirred at 100°C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 9:1) to give the title compound. LCMS: m / z=255.0 [M+H] + .

[0661] 7-Bromo-2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine: To a solution of 2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine (1.25 g, 4.92 mmol) in MeCN (25 mL) was added NBS (700 mg, 3.93 mmol) at 0 ° C under N2. The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was filtered. The filter cake was triturated with EtOAc (20 mL), the solid was collected by filtration and dried under reduced pressure to give the title compound. LCMS: m / z=333.1, 335.0 [M+H] + .

[0662] 3-(7-Bromopyrrolo[2,1-f][1,2,4]triazine-2-yl)-4-methylaniline: To a solution of 7-bromo-2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine (400 mg, 1.20 mmol) in EtOH (8 mL) and H2O (2 mL) was added Fe (335 mg, 6.00 mmol) and NHCl (321 mg, 6.00 mmol) at 20°C under N2. The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 3:1) to give the title compound. LCMS: m / z=302.9, 304.9 [M+H] + .

[0663] Intermediate 31

[0664] 2-(5-amino-2-methylphenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile

[0665]

[0666] 2-(2-Methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile: To a solution of 7-bromo-2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine (500 mg, 1.50 mmol) in NMP (8 mL) was added CuCN (403 mg, 4.50 mmol) at 20 ° C under N2. The mixture was stirred at 140 ° C for 12 hours, diluted with H2O (50 mL) and filtered. The filter cake was dissolved in EtOAc (20 mL), filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=280.1[M+H] + .

[0667] 2-(5-Amino-2-methylphenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile: To a solution of 2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile (60 mg, 0.21 mmol) in EtOH (2 mL) and H2O (0.5 mL) at 20°C was added Fe (60 mg, 1.07 mmol) and NHCl (57 mg, 1.07 mmol). The mixture was stirred at 80°C for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 250.1 [M+H] + .

[0668] Intermediate 32

[0669] 3-(7-(Difluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylaniline

[0670]

[0671] 2-(2-Methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde: DMF (10 mL) was added to a solution of POCl3 (3.32 g, 21.63 mmol) at 0°C, and the mixture was stirred at 0°C for 0.5 hours. The reaction mixture was warmed to 20°C. 2-(2-Methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine (550 mg, 2.16 mmol) was added, and the reaction mixture was heated at 95°C for 5 hours. The reaction mixture was poured into H2O, adjusted to pH = 7 by adding saturated aqueous NaHCO3 solution, and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 10:1 to 1:1) to give the title compound. LCMS: m / z = 283.2 [M+H] + .

[0672] 7-(Difluoromethyl)-2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine: To a solution of 2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (500 mg, 1.77 mmol) in DCM (10 mL) was added DAST (856 mg, 5.31 mmol) under N2 at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into H2O, adjusted to pH = 7 by adding saturated aqueous NaHCO3 solution and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=5:1) to give the title compound. LCMS: m / z=305.1[M+H] + .

[0673] 3-(7-(Difluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-2-yl)-4-methylaniline: To a solution of 7-(difluoromethyl)-2-(2-methyl-5-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine (100 mg, 0.32 mmol) in EtOH (4 mL) and H2O (1 mL) was added Fe (91 mg, 1.64 mmol) and NHCl (87 mg, 1.64 mmol) at 25 °C. The mixture was stirred at 70 °C for 2 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS: m / z=274.9 [M+H] + .

[0674] Intermediate 33

[0675] cis-3-cyclopropyl-6-azabicyclo[3.1.1]heptane

[0676]

[0677] N-(3-cyclopropylcyclohexyl)picolinamide: To a mixture of 3-cyclopropylcyclohexylamine hydrochloride and picolinic acid (3.01 g, 24.42 mmol) in DCM (40 mL) was added DMAP (229 mg, 1.88 mmol), TEA (5.70 g, 56.35 mmol) and EDCI (5.40 g, 28.17 mmol) at 0°C under N2. The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch Xtimate C18 250×70 mm×10 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 45%-75%, 20 minutes) to give the title compound. LCMS: m / z = 245.0 [M+H] + .

[0678] Cis-3-cyclopropyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: Under N2, to a mixture of N-(3-cyclopropylcyclohexyl)picolinamide (1.6 g, 6.55 mmol) in 1,1,2,2-tetrachloroethane (60 mL) was added Na3PO4 (3.22 g, 19.65 mmol), benzoquinone (354 mg, 3.27 mmol), AgOAc (3.28 g, 19.65 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (19.25 g, 65.48 mmol) and Pd(OAc)2 (294 mg, 1.31 mmol) at 25 ° C. The mixture was stirred at 145 ° C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:2) to give the title compound. LCMS: m / z=243.0 [M+H] + .

[0679] Cis-3-cyclopropyl-6-azabicyclo[3.1.1]heptane: Under N2, to a mixture of cis-3-cyclopropyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (250 mg, 1.03 mmol) in EtOH (3 mL) was added NaOH (413 mg, 10.32 mmol) at 20 ° C. The mixture was stirred at 90 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure (water bath, less than 35 ° C) to obtain a mixture containing the sodium salt of the product, NaOH and acid. The mixture was stirred in DCM (20 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure (water bath, less than 35 ° C) to give the title compound. LCMS: m / z = 138.2 [M + H] + .

[0680] Intermediate 33

[0681] 1-(Pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0682]

[0683] 6- azabicyclo [3.1.1] heptane -1,6- dicarboxylic acid 6- tert-butyl ester 1-methyl ester: Under N2, to a mixture of 6- azabicyclo [3.1.1] heptane -1- carboxylic acid methyl ester (5 g, 32.22 mmol) in DCM (50 mL) and MeOH (10 mL) was added TEA (6.52 g, 64.44 mmol), Boc2O (14.06 g, 64.44 mmol) and DMAP (393 mg, 3.22 mmol) at 0 ° C. Then, the mixture was stirred at 25 ° C for 3 hours. The reaction mixture was diluted with saturated NH4Cl aqueous solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give the title compound.

[0684] 1-Carbamoyl-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: A mixture of 6-tert-butyl 1-methyl 6-azabicyclo[3.1.1]heptane-1,6-dicarboxylate (5 g, 19.58 mmol) in 25% NH3·H2O (30 mL) was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (15 mL), and the solid was collected by filtration and dried under reduced pressure to give the title compound. LCMS: m / z = 185.2 [Mt-Bu+H] + .

[0685] 1-cyano-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester: Under N2, to a mixture of 1-carbamoyl-6-azabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (1.3 g, 5.41 mmol) in THF (10 mL) was added methoxycarbonyl-(triethylammonium) sulfonyl-nitrene (3.87 g, 16.23 mmol) at 25 ° C. The mixture was stirred at 65 ° C for 3 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give the title compound.

[0686] tert-Butyl 1-(Imino(methoxy)methyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl 1-cyano-6-azabicyclo[3.1.1]heptane-6-carboxylate (500 mg, 2.25 mmol) in MeOH (8 mL) was added NaOMe (405 mg, 2.25 mmol, 30% purity in methanol) at 0° C. under N2. The mixture was stirred at 25° C. for 12 h and the solution was used directly in the next step.

[0687] 1-Carbamimidoyl-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: To a mixture of 1-(imino(methoxy)methyl)-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (500 mg, 1.97 mmol) in MeOH (8 mL) was added NH4Cl (126.20 mg, 2.36 mmol) at 25°C under N2. The mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 240.3 [M+H] + .

[0688] 1-(Pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester: Under N2, to a mixture of 1-carbamimidoyl-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (500 mg, 2.09 mmol) and (Z)-3-(dimethylamino)acrolein (311 mg, 3.13 mmol) in EtOH (10 mL) was added K2CO3 (578 mg, 4.18 mmol) at 25 ° C. The mixture was stirred at 90 ° C. for 12 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 1: 1 to 0: 1) to give the title compound. LCMS: m / z = 276.3 [M + H] + .

[0689] 1-(Pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate: A mixture of tert-butyl 1-pyrimidin-2-yl-6-azabicyclo[3.1.1]heptane-6-carboxylate (200 mg, 0.73 mmol) in DCM (3 mL) and TFA (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 176.2 [M+H] + .

[0690] Intermediate 34

[0691] N-(2-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0692]

[0693] To a mixture of triphosgene (142 mg, 0.48 mmol) in THF (35 mL) was added TEA (363 mg, 3.58 mmol) and 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.19 mmol) at 0 ° C. Under N2, the mixture was stirred at 25 ° C. for 1 hour, followed by the addition of 6-azabicyclo[3.1.1]heptane (173.17 mg, 1.30 mmol) and TEA (218 mg, 2.16 mmol). The mixture was stirred at 25 ° C. for 16 hours, diluted with H2O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=5:1 to 3:1) to give the title compound. LCMS: m / z=375.3 [M+H] + .

[0694] Intermediate 35

[0695] N 6 -(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo[3.1.1]

[0696] Heptane-1,6-dicarboxamide

[0697]

[0698] 6-((4-Methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a mixture of CDI (1.74 g, 10 mmol) in DCM (70 mL) was added a solution of 4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline (2 g, 8.92 mmol) in DCM (70 mL) at -20 °C under N2. The mixture was stirred at 20 °C for 12 hours. Then, a solution of DIPEA (3.17 g, 24.50 mmol) and 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (1.98 g, 9.80 mmol) in DCM (20 mL) was added to the above solution at 20 °C. The mixture was stirred at 20°C for 4 hours and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 250×70 mm×10 μm; mobile phase: A: 10 mM aqueous NH4HCO3, B: MeCN; % B in A: 15%-40%, 18 minutes) to yield the title compound. LCMS: m / z = 392.2 [M+H] + .

[0699] N 6 -(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-1,6-dicarboxamide: To a mixture of 6-((4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (1 g, 2.55 mmol) in DMF (15 mL) was added DIPEA (660 mg, 5.11 mmol), NHCl (1.37 g, 25.55 mmol) and HATU (1.94 g, 5.11 mmol) at 20° C. under N2. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with H2O (40 mL) and extracted with DCM:i-PrOH (v:v = 3:1) (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:(EtOAc:EtOH = 3:1) = 1:0 to 1:1) to give the title compound. LCMS: m / z = 391.2 [M+H] + .

[0700] Intermediate 36

[0701] 3-(7-Methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylaniline

[0702]

[0703] Under N2, to a solution of 3-(7-bromopyrrolo[2,1-f][1,2,4]triazine-2-yl)-4-methylaniline (200 mg, 0.66 mmol) in MeOH (5 mL) was added Cs2CO3 (430 mg, 1.32 mmol), 1,10-phenanthroline (24 mg, 0.131 mmol) and CuI (13 mg, 0.07 mmol) at 20 ° C. The mixture was stirred at 100 ° C for 3 hours under microwave irradiation. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) to give the title compound. LCMS: m / z=255.1[M+H] + .

[0704] Intermediate 37

[0705] trans-6-((2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0706]

[0707] Under N2, 2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazine-2-yl)aniline (400 mg, 1.65 mmol) and TEA (501 mg, 0.69 mmol) were added to a solution of triphosgene (245 mg, 0.83 mmol) in THF (20 mL) at 0 ° C. The mixture was stirred at 0 ° C for 3 hours. Then, trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (305 mg, 1.97 mmol) and TEA (498 mg, 4.92 mmol) were added to the above mixture at 25 ° C. The mixture was stirred at 25 ° C for 12 hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 250×70 mm×10 μm; mobile phase: A: 10 mM aqueous NH4HCO3, B: MeCN; % B in A: 15%-45%, 20 min) to give the title compound. LCMS: m / z=424.2 [M+H] + .

[0708] Intermediate 38

[0709] 2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline

[0710]

[0711] To a solution of 2-chloropyrrolo[2,1-f][1,2,4]triazine (2 g, 13.02 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was added 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.60 g, 14.33 mmol), K2CO3 (5.40 g, 39.07 mmol) and Pd(dppf)Cl2 (953 mg, 1.30 mmol) under N2 at 20° C. The reaction mixture was stirred at 100° C. for 2 h under N2, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc) and subsequently by preparative HPLC (Xtimate C18 250×80 mm×10 μm; mobile phase: A: 10 mM aqueous NH4HCO3, B: MeCN; % B in A: 25%-60%, 27 minutes) to give the title compound. LCMS: m / z=243.2 [M+H] + .

[0712] Intermediate 39

[0713] 1-(Methoxymethyl)-6-azabicyclo[3.1.1]heptane

[0714]

[0715] (1-(Hydroxymethyl)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a mixture of methyl 6-pyridoyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (600 mg, 2 mmol) and CaCl (1.02 g, 9 mmol) in MeOH (25 mL) was added portionwise NaBH (523 mg, 14 mmol) at 0°C under N2. The mixture was stirred at 20°C for 3 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (15 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LCMS: m / z=233.2 [M+H] + .

[0716] (1-(Methoxymethyl)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: Under N2, to a mixture of (1-(hydroxymethyl)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (450 mg, 2 mmol) in THF (8 mL) was added NaH (116 mg, 3 mmol, purity 60%) at 0°C. The mixture was stirred at 0°C for 30 minutes, and then a solution of MeI (330 mg, 2 mmol) in THF (2 mL) was added at 0°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 1:1) to give the title compound. LCMS: m / z=247.2 [M+H] + .

[0717] 1-(Methoxymethyl)-6-azabicyclo[3.1.1]heptane: To a mixture of (1-(methoxymethyl)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (400 mg, 1 mmol) in EtOH (8 mL) was added NaOH (650 mg, 16 mmol) at 20°C. The mixture was stirred at 90°C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z=142.3 [M+H] + .

[0718] Intermediate 40

[0719] 6-((4-methyl-3-(pyrrolo[1,2-a]pyrimidin-3-yl)phenyl)carbamoyl)-6-azabicyclo

[0720] [3.1.1] Heptane-1-carboxylic acid

[0721]

[0722] Under N2, to a solution of CDI (697 mg, 4.30 mmol) in DCM (20 mL) was added a solution of 4-methyl-3-(pyrrolo[1,2-a]pyrimidin-3-yl)aniline (800 mg, 3.58 mmol) in DCM (20 mL) at -20 ° C. The mixture was stirred at -20 ° C for 3 hours. Then, 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (2.94 g, 4.16 mmol) and DIPEA (1.34 g, 10.40 mmol) were added to the above mixture at 25 ° C. The mixture was stirred at 25 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C18 80×40 mm×3 μm; mobile phase: A: 10 mM aqueous NH4HCO3, B: MeCN; % B in A: 10%-30%, 8 minutes) to give the title compound. LCMS: m / z=391.2 [M+H] + .

[0723] Intermediate 41

[0724] 4-Methyl-3-(pyrrolo[1,2-a]pyrazin-3-yl)aniline

[0725]

[0726] Under N2, 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (164 mg, 0.71 mmol), K3PO4 (499 mg, 2.35 mmol) and XPhos Pd G2 (37 mg, 0.05 mmol) were added to a solution of 3-chloropyrrolo[1,2-a]pyrazineacetic acid ester (100 mg, 0.47 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) at 20 ° C. The mixture was stirred at 90 ° C for 6 hours. The reaction mixture was filtered through a celite pad, and the filtrate was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 5:1) to give the title compound. LCMS: m / z=223.9 [M+H] + .

[0727] Intermediate 42

[0728] 4-Methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)aniline

[0729]

[0730] 2-(5-amino-2-methylphenyl)pyrrolo[1,2-a]pyrimidine-8-carboxylic acid ethyl ester: Under N2, to a solution of 2-chloropyrrolo[1,2-a]pyrimidine-8-carboxylic acid ethyl ester (770 mg, 3.43 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (959 mg, 4.11 mmol) in 1,4-dioxane (14 mL) and H2O (1.4 mL) was added K2CO3 (1.18 g, 8.57 mmol) and Pd(dppf)Cl2 (250.8 mg, 0.34 mmol) at 20°C. The reaction mixture was stirred at 100°C for 12 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) to give the title compound. LCMS: m / z=296.0[M+H] + .

[0731] 2-(5-amino-2-methylphenyl)pyrrolo[1,2-a]pyrimidine-8-carboxylic acid: To a solution of ethyl 2-(5-amino-2-methylphenyl)pyrrolo[1,2-a]pyrimidine-8-carboxylate (250 mg, 0.85 mmol) in EtOH (7.5 mL) and H2O (2.5 mL) was added NaOH (169 mg, 4.23 mmol) at 20°C. The mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH and the resulting residue was diluted with H2O (5 mL), adjusted to pH 7-8 with aqueous HCl solution, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound. LCMS: m / z=268.0 [M+H] + .

[0732] 4-Methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)aniline: To a solution of 2-(5-amino-2-methylphenyl)pyrrolo[1,2-a]pyrimidine-8-carboxylic acid (170 mg, 0.64 mmol) in DMF (3 mL) was added CuO (25 mg, 0.32 mmol) under N2 at 20 ° C. The mixture was stirred at 160 ° C for 6 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) to give the title compound. LCMS: m / z=224.0[M+H] + .

[0733] Intermediate 43

[0734] (1R,3R,5R)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

[0735]

[0736]

[0266] tert-Butyl (1R,3R,5R)-3-((4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate: To a mixture of 4-methyl-3-pyrrolo[2,1-f][1,2,4]triazin-2-yl-phenylamine (300 mg, 1.34 mmol) and (1R,3R,5R)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (253 mg, 1.11 mmol) in DCM (3 mL) was added HATU (508 mg, 1.34 mmol) and TEA (564 mg, 5.57 mmol). The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 1:1) to give the title compound. LCMS: m / z=434.3 [M+H] + .

[0737] (1R,3R,5R)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide: A solution of tert-butyl (1R,3R,5R)-3-((4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.46 mmol) in HCl / EtOAc (2 mL, 4 M) was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 334.2 [M+H] + .

[0738] Intermediate 44

[0739] (1S,3S,5S)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide

[0740]

[0741]

[00145] tert-Butyl (1S,3S,5S)-3-((4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate: To a solution of 4-methyl-3-pyrrolo[2,1-f][1,2,4]triazin-2-yl-phenylamine (300 mg, 1.34 mmol) and (1S,3S,5S)-2-tert-butoxycarbonyl-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (253 mg, 1.11 mmol) in DCM (3 mL) was added HATU (635 mg, 1.67 mmol) and TEA (564 mg, 5.57 mmol) under N at 20°C. The mixture was stirred at 20°C for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) to give the title compound. LCMS: m / z=434.2 [M+H] + .

[0742] (1S,3S,5S)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide: A solution of tert-butyl (1S,3S,5S)-3-((4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.46 mmol) in HCl / EtOAc (2 mL, 4 M) was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 334.1 [M+H] + .

[0743] Intermediate 45

[0744] 3-(Imidazolo[1,2-a]pyrazin-6-yl)-4-methylaniline

[0745]

[0746] Under N2, to a solution of 6-chloroimidazo[1,2-a]pyrazine (2 g, 13.02 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.64 g, 15.63 mmol) in 1,4-dioxane (30 mL) and H2O (3 mL) was added K2CO3 (4.50 g, 32.56 mmol) and Pd(dppf)Cl2 (953 mg, 1.30 mmol) at 25 ° C. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 1: 1 to 0: 1) to give the title compound. LCMS: m / z = 225.2 [M + H] + .

[0747] Intermediate 46

[0748] trans-6-((4-chloro-2-fluoro-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-

[0749] 3-Methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0750]

[0751] 4-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: Under N2, to a solution of 5-bromo-4-chloro-2-fluoroaniline (3 g, 13.37 mmol) in 1,4-dioxane (60 mL) was added bis(pinacolato)diboron (5.09 g, 20.05 mmol), KOAc (3.94 g, 40.10 mmol) and Pd(dppf)Cl2 (978 mg, 1.34 mmol) at 25 ° C. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 15: 1 to 10: 1) to give the title compound. LCMS: m / z = 272.3 [M + H] + .

[0752] 4-Chloro-2-fluoro-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline: To a solution of 4-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.06 g, 3.91 mmol) in 1,4-dioxane (16 mL) and H2O (1.6 mL) was added 2-chloropyrrolo[2,1-f][1,2,4]triazine (400 mg, 2.60 mmol), K2CO3 (1.08 g, 7.81 mmol) and Pd(dppf)Cl2 (191 mg, 0.26 mmol) at 20°C under N2. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=263.1 [M+H] + .

[0753] trans-6-((4-chloro-2-fluoro-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of triphosgene (282 mg, 0.95 mmol) in THF (8 mL) under N2 at 0 °C were added TEA (578 mg, 5.72 mmol) and 4-chloro-2-fluoro-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline (500 mg, 1.90 mmol). The mixture was stirred at 20°C for 1 hour, then trans-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (2.37 g, 2.29 mmol, 15% purity) was added, followed by TEA (578 mg, 5.72 mmol). The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250×70 mm×10 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 5%-50%, 18 minutes) to give the title compound. LCMS: m / z=444.1 [M+H] + .

[0754] Intermediate 47

[0755] 2-Fluoro-4-methyl-5-(pyrazolo[1,5-b]pyridazin-6-yl)aniline

[0756]

[0757] 2-(4-Fluoro-2-methyl-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a solution of bis(pinacolato)diboron (2.17 g, 8.55 mmol) and 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (1 g, 4.27 mmol) in 1,4-dioxane (10 mL) was added KOAc (1.26 g, 12.82 mmol) and Pd(dppf)Cl2.CHCl2 (348 mg, 0.43 mmol) at 20°C under N2. The mixture was stirred at 100°C for 3 hours and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 3:1) to give the title compound. LCMS: m / z=282.1 [M+H] + .

[0758] 3-(4-Fluoro-2-methyl-5-nitrophenyl)pyridazine: A mixture of 2-(4-fluoro-2-methyl-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 3.56 mmol), 3-bromopyridazine (679 mg, 4.27 mmol), Pd(dppf)Cl (260 mg, 0.36 mmol) and KCO (1.23 g, 8.89 mmol) in 1,4-dioxane (10 mL) and H0 (1 mL) was stirred at 100° C. under N for 6 h. The reaction mixture was diluted with H0 (10 mL) and extracted with EtOAc (3×10 mL) at 20° C. The combined organic layers were washed with brine (3×10 mL), dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 0:1) to give the title compound. LCMS: m / z=234.1 [M+H] + .

[0759] 3-(4-Fluoro-2-methyl-5-nitrophenyl)pyridazin-1-amine mesitylenesulfonate: To a solution of amino 2,4,6-trimethylbenzenesulfonate trifluoroacetate (1 g, 3.04 mmol) in DCM (3 mL) was added 3-(4-fluoro-2-methyl-5-nitrophenyl)pyridazine (320 mg, 1.37 mmol) under N at 0° C. The reaction mixture was stirred at 20° C. for 16 hours and then concentrated under reduced pressure to give the title compound.

[0760] 6-(4-Fluoro-2-methyl-5-nitrophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylic acid ethyl ester: To a solution of ethyl prop-2-ynoate (809 mg, 8.25 mmol) in MeCN (20 mL) was added DBU (2.51 g, 16.50 mmol) and 3-(4-fluoro-2-methyl-5-nitrophenyl)pyridazin-1-amine mesitylenesulfonate (3.7 g, 8.25 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 16 hours. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 3:1) to give the title compound. LCMS: m / z=345.0[M+H] + .

[0761] 6-(4-Fluoro-2-methyl-5-nitrophenyl)pyrazolo[1,5-b]pyridazine: A solution of ethyl 6-(4-fluoro-2-methyl-5-nitrophenyl)pyrazolo[1,5-b]pyridazine-3-carboxylate (290 mg, 0.84 mmol) in H2O (3 mL) and H2SO4 (5.52 g, 56.28 mmol) was stirred at 120 ° C for 16 hours. The reaction mixture was poured into ice water (5 mL) and the pH was adjusted to 7-8 with saturated aqueous Na2CO3. The mixture was extracted with EtOAc (3×30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=1:0 to 1:1) to give the title compound. LCMS: m / z=273.1[M+H] +

[0762] 2-Fluoro-4-methyl-5-(pyrazolo[1,5-b]pyridazin-6-yl)aniline: To a solution of 6-(4-fluoro-2-methyl-5-nitrophenyl)pyrazolo[1,5-b]pyridazine (60 mg, 0.22 mmol) in EtOH (3 mL) and H2O (1 mL) was added NH4Cl (58 mg, 1.10 mmol) and Fe (61 mg, 1.10 mmol) at 20 ° C. The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 1: 0 to 1: 1) to give the title compound. LCMS: m / z = 243.1 [M + H] + .

[0763] Intermediate 48

[0764] 2-Fluoro-5-(imidazo[1,2-a]pyrazin-6-yl)-4-methylaniline

[0765]

[0766] Under N2, to a solution of 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg, 0.80 mmol) and 6-chloroimidazo[1,2-a]pyrazine (147 mg, 0.96 mmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL) was added K2CO3 (331 mg, 2.39 mmol) and Pd(dppf)Cl2 (59 mg, 0.08 mmol) at 20 ° C. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give the title compound.

[0767] Intermediate 49

[0768] 3-Fluoro-4-methyl-5-pyrrolo[2,1-f][1,2,4]triazin-2-yl-aniline

[0769]

[0770] To a mixture of 3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1 mmol) in 1,4-dioxane (3 mL) and H2O (0.3 mL) was added 2-chloropyrrolo[2,1-f][1,2,4]triazine (139 mg, 0.91 mmol), K2CO3 (375 mg, 2.72 mmol), and Pd(dppf)Cl2 (66 mg, 0.09 mmol) at 20°C under N2. The mixture was stirred at 100°C for 4 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS: m / z=243.1 [M+H] + .

[0771] Intermediate 50

[0772] 4-Methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)aniline

[0773]

[0774] 6-Chloropyrazolo[1,5-a]pyrazine: To a mixture of 4,6-dichloropyrazolo[1,5-a]pyrazine (500 mg, 2.66 mmol) in THF (5 mL) was added Zn (348 mg, 5.32 mmol) and HOAc (5 mL) at 0 ° C under N2. The mixture was stirred at 80 ° C for 4 hours. The mixture was adjusted to pH = 7-8 with saturated aqueous Na2CO3 solution and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 5:1) to give the title compound. LCMS: m / z=154.0[M+H] + .

[0775] 4-Methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)aniline: To a mixture of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (90 mg, 0.39 mmol) and 6-chloropyrazolo[1,5-a]pyrazine (71 mg, 0.46 mmol) in 1,4-dioxane (6 mL) and H2O (0.6 mL) was added K2CO3 (160 mg, 1.16 mmol) and Pd(dppf)Cl2 (28 mg, 0.038 mmol) at 20°C under N2. The mixture was stirred at 100°C for 16 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound. LCMS: m / z = 225.1 [M+H] + .

[0776] Intermediate 51

[0777] 3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylaniline

[0778]

[0779] Under N2, to a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (680 mg, 2.92 mmol) and 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (693 mg, 3.50 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was added K2CO3 (1.21 g, 8.75 mmol) and Pd(dppf)Cl2 (213 mg, 0.29 mmol) at 20 ° C. The mixture was stirred at 100 ° C for 12 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 224.1 [M + H] + .

[0780] Intermediate 52

[0781] 1-(1-Methyl-1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate and 1-(1-methyl-1H-1,2,4-triazol-5-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0782]

[0783] (E)-tert-Butyl 1-(((dimethylamino)methylene)carbamoyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: A solution of tert-butyl 1-carbamoyl-6-azabicyclo[3.1.1]heptane-6-carboxylate (3.2 g, 13.32 mmol) in DMF-DMA (60 mL) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 296.3 [M+H] + .

[0784] tert-Butyl 1-(1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of (E)-1-(((dimethylamino)methylene)carbamoyl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (3.48 g, 11.78 mmol) in 1,4-dioxane (60 mL) was added HOAc (1.41 g, 23.56 mmol) and N2H4·H2O (662 mg, 12.96 mmol, 98% purity) in one portion at 20°C under N2. The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 1:2) to give the title compound. LCMS: m / z=265.2 [M+H] + .

[0785] tert-Butyl 1-(1-methyl-1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a mixture of tert-butyl 1-(1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 1.13 mmol) in DMF (5 mL) under N2 was added NaH (54 mg, 1.36 mmol, 60% in mineral oil) in one portion at 0°C and the reaction mixture was stirred at 0°C for 30 min. At 0 ° C, MeI (242 mg, 1.70 mmol) in DMF (1 mL) was added dropwise to the above solution, and the reaction mixture was warmed to 20 ° C and stirred for 1 hour. The reaction mixture was quenched by adding H2O (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=279.2 [M+H] + .

[0786] 1-(1-Methyl-1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate and 1-(1-methyl-1H-1,2,4-triazol-5-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a mixture of tert-butyl 1-(1-methyl-1H-1,2,4-triazol-3-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl 1-(1-methyl-1H-1,2,4-triazol-5-yl)-6-azabicyclo[3.1.1]heptane-6-carboxylate (330 mg, 1.19 mmol) in DCM (12 mL) was added TFA (4 mL) dropwise under N at 0° C. The mixture was warmed to 20° C. and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 179.2 [M+H] + .

[0787] Intermediate 53

[0788] trans-1-((2-methoxyethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane

[0789]

[0790] (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of methyl trans-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylate (1 g, 3.65 mmol) and CaCl (1.62 g, 14.58 mmol) in MeOH (30 mL) was added NaBH (828 mg, 21.87 mmol) at 0°C under N. The reaction mixture was warmed to 20°C for 1 hour. The reaction mixture was diluted with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=247.2 [M+H] + .

[0791] (trans-1-((2-methoxyethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (500 mg, 2.03 mmol) in DMF (10 mL) was added NaH (122 mg, 3.05 mmol, 60% in mineral oil) at 0°C under N2, and the reaction mixture was stirred at 0°C for 0.5 hours. To the above mixture was added 1-bromo-2-methoxyethane (1.41 g, 10.15 mmol) at 0°C, and the reaction mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution (30 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=2:1 to 0:1) to give the title compound. LCMS: m / z=305.2 [M+H] + .

[0792] trans-1-((2-methoxyethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane: To a solution of (trans-1-((2-methoxyethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (160 mg, 0.53 mmol) in EtOH (3 mL) was added NaOH (210 mg, 5.26 mmol) at 25° C. The reaction mixture was heated to 90° C. and stirred for 16 hours, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with DCM (5 mL) and filtered through Celite. Filter through a pad of 4% paraffin wax and concentrate under reduced pressure. This subsequent treatment was repeated three times to obtain the title compound. LCMS: m / z = 200.2 [M+H] + .

[0793] Intermediate 54

[0794] trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]heptane

[0795]

[0796] (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (1.00 g, 3.65 mmol) and CaCl (1.62 g, 14.58 mmol) in MeOH (30 mL) was added NaBH (828 mg, 21.87 mmol) at 0°C under N. The reaction mixture was warmed to 20°C and stirred for 1 hour. The reaction mixture was diluted with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=247.2 [M+H] + .

[0797] (trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (300 mg, 1.22 mmol) in DMF (12 mL) was added NaH (73 mg, 1.83 mmol, 60% in mineral oil) at 0°C under N2, and the reaction mixture was stirred for 0.5 hours. MeI (346 mg, 2.44 mmol) was added dropwise to the above mixture at 0°C, and the reaction mixture was warmed to 20°C and stirred for 2 hours. The reaction mixture was diluted with saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. LCMS: m / z=261.2 [M+H] + .

[0798] Trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]heptane: To a solution of (trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (100 mg, 0.38 mmol) in EtOH (2 mL) was added NaOH (154 mg, 3.84 mmol) at 25 ° C. The reaction mixture was heated to 90 ° C and stirred for 16 hours. The mixture was filtered through Celite. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The resulting residue was slurried with DCM (5 mL), filtered, and the filtrate was concentrated under reduced pressure to afford the title compound. LCMS: m / z = 156.3 [M+H] + .

[0799] Intermediate 55

[0800] 2-(4-amino-5-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)acetonitrile

[0801]

[0802] Dimethyl 2-(2-bromo-5-fluoro-4-nitrophenyl)malonate and dimethyl 2-(4-bromo-5-fluoro-2-nitrophenyl)malonate: A suspension of NaH (8.07 g, 202 mmol, 60% in mineral oil) in 1,4-dioxane (200 mL) was cooled to 0 ° C under N2. A solution of 1-bromo-2,4-difluoro-5-nitro-benzene (20 g, 84.04 mmol) and dimethyl malonate (13.32 g, 101 mmol) in 1,4-dioxane (200 mL) was added dropwise to the NaH suspension at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, then warmed to 25 ° C and stirred for 15 hours. The reaction mixture was poured into saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) to give the title compound.

[0803] 2-(2-Bromo-5-fluoro-4-nitrophenyl)acetic acid and 2-(4-Bromo-5-fluoro-2-nitrophenyl)acetic acid: A solution of dimethyl 2-(2-bromo-5-fluoro-4-nitrophenyl)malonate and dimethyl 2-(4-bromo-5-fluoro-2-nitrophenyl)malonate (23.7 g, 67.70 mmol) in 8M HCl (337 mL) was heated to 100° C. and stirred for 12 hours. The solid was collected by filtration and dried under reduced pressure to give the title compound.

[0804] 2-(4-Bromo-5-fluoro-2-nitrophenyl)acetamide and 2-(2-Bromo-5-fluoro-4-nitrophenyl)acetamide: To a solution of 2-(2-bromo-5-fluoro-4-nitrophenyl)acetic acid and 2-(4-bromo-5-fluoro-2-nitrophenyl)acetic acid (4.56 g, 16.40 mmol) (1:2) in DCM (60 mL) was added DMF (59.94 mg, 0.82 mmol) at 0 ° C under N2, followed by dropwise addition of (COCl)2 (2.50 g, 19.68 mmol). The reaction mixture was stirred at 0 ° C for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was added to a separate flask at 0 ° C, in which the product was dried by stirring NH 3(g) (6 g, 371 mmol) was bubbled into DCM (300 mL) for 20 minutes. A solution of ammonia in DCM was prepared in advance. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 0:1) to give the title compound. LCMS: m / z=277.0, 279.0 [M+H] + .

[0805] 2-(4-amino-2-bromo-5-fluorophenyl)acetamide and 2-(2-amino-4-bromo-5-fluorophenyl)acetamide: To a mixture of 2-(2-bromo-5-fluoro-4-nitrophenyl)acetamide and 2-(4-bromo-5-fluoro-2-nitrophenyl)acetamide (1:2) (1 g, 3.61 mmol) in EtOH (20 mL) and H2O (5 mL) at 20 ° C., Fe (1.01 g, 18.05 mmol) and NHCl (966 mg, 18.05 mmol) were added. The reaction mixture was heated to 80 ° C. and stirred for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (10 mL), washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LCMS: m / z=247.1, 249.1 [M+H] + .

[0806] N-(5-Bromo-4-(cyanomethyl)-2-fluorophenyl)-2,2,2-trifluoroacetamide and N-(5-Bromo-2-(cyanomethyl)-4-fluorophenyl)-2,2,2-trifluoroacetamide: To a mixture of 2-(4-amino-2-bromo-5-fluorophenyl)acetamide and 2-(2-amino-4-bromo-5-fluorophenyl)acetamide (510 mg, 2.06 mmol) in 1,4-dioxane (10 mL) at 0°C was added pyridine (1.14 g, 14.45 mmol) and TFAA (2.17 g, 10.32 mmol). The reaction mixture was warmed to 25°C and stirred for 2 hours. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 3:1) to give the title compound. LCMS: m / z=325.0, 327.0 [M+H] + .

[0807] N-(4-(Cyanomethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroacetamide and N-(2-(Cyanomethyl)-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroacetamide: 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2,2-trifluoroacetamide A mixture of heterocyclopentane (572 mg, 2.25 mmol), N-[5-bromo-4-(cyanomethyl)-2-fluorophenyl]-2,2,2-trifluoroacetamide and N-[5-bromo-2-(cyanomethyl)-4-fluoro-phenyl]-2,2,2-trifluoro-acetamide (610 mg, 1.88 mmol), KOAc (553 mg, 5.63 mmol) and Pd(dppf)Cl2 (138 mg, 0.19 mmol) in 1,4-dioxane (10 mL) was degassed and purged with N2 three times. The reaction mixture was heated to 100 ° C and stirred for 6 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=20:1 to 3:1) to give the title compound. LCMS: m / z=373.1 [M+H] + .

[0808] 2-(4-amino-5-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)acetonitrile: N-[4-(cyanomethyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,2,2-trifluoroacetamide (260 mg, 0.70 mmol) and N-[2-(cyanomethyl)-4-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-2,2,2-trifluoroacetamide, 2-chloropyrrolo[2,1-f][1,2,4]triazine (118 mg, 0.77 mmol), K2CO3 (241 mg, 1.75 mmol) and Pd(dppf)Cl2 (51 mg, 0.70 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) were degassed and purged with N2 three times. The mixture was heated to 100°C and stirred for 5 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to give the title compound.

[0809] Example 1

[0810] N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo

[0811] [3.1.1] Heptane-6-carboxamide (1)

[0812]

[0813] To a solution of N-[2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6-azabicyclo[3.1.1]heptane-6-carboxamide (50 mg, 0.13 mmol) and 2-chloropyrrolo[2,1-f][1,2,4]triazine (31 mg, 0.2 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was added K2CO3 (55 mg, 0.4 mmol) and Pd(dppf)Cl2 (10 mg, 0.01 mol) at 25°C under N2. The mixture was stirred at 100°C for 12 hours. The reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound. 1H NMR (400MHz, CDCl3): δ9.01 (s, 1H), 8.63 (d, J = 8.8Hz, 1H), 7.84 (s, 1H), 7.01 (d, J = 12Hz, 1H), 6.97-6.94 (m, 1H), 6.88 (d, J = 4.4Hz, 1H), 6.19 (br s,1H),4.29-4.24(m,2H),2.60-2.52(m,1H),2.49(s,3H),2.45-2.34(m,2H),2.05-1.90(m,1H),1.82-1.70(m,3H),1.52(d,J=8.8Hz,1H). LCMS:m / z=366.2[M+H] + .

[0814] Example 2

[0815] cis-N-(5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-2-fluoro-4-methylphenyl)-3-methyl-6-

[0816] Azabicyclo[3.1.1]heptane-6-carboxamide (2)

[0817]

[0818] To a solution of cis-N-(2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and H O (0.2 mL) was added 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (31 mg, 0.15 mmol), K CO (54 mg, 0.39 mmol) and Pd(dppf)Cl (9 mg, 0.01 mmol) at 20° C. under N2. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC followed by preparative TLC (SiO 2 , PE:EtOAc=2:1) ​​to give the title compound. 1H NMR (400MHz, CDCl3): δ8.55(s,1H),8.37(s,1H),8.16(d,J=8.4Hz,1H),7.77( d,J=9.2Hz,1H),7.51(dd,J=1.6,9.2Hz,1H),7.03(d,J=12.0Hz,1H),6.30(br s,1H),4.31-4.21(m,2H),2.71-2.54(m,3H),2.23(s,3H),2.11-1.96(m,1H),1.44-1.31(m,2H),1.10(d,J=8.4Hz,1H),1.05(d,J=6.8Hz,3H). LCMS: m / z=380.2[M+H] + .

[0819] Example 3

[0820] cis-3-Methyl-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (3)

[0821]

[0822] To a solution of cis-3-methyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (50 mg, 0.14 mmol) and 2-chloropyrrolo[2,1-f][1,2,4]triazine (31 mg, 0.20 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was added K2CO3 (56 mg, 0.41 mmol) and Pd(dppf)Cl2 (10 mg, 0.01 mmol) at 20°C under N2. The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound. 1H NMR (400MHz, CDCl3): δ9.04(s,1H),7.87(s,1H),7.69-7.67(m,1H),7.67- 7.63(m,1H),7.24(s,1H),6.99-6.97(m,1H),6.91-6.89(m,1H),6.12(s,1 H),4.23-4.19(m,2H),2.65-2.55(m,3H),2.52(s,3H),2.12-2.05(m,1H), 1.35(dd,J=9.2,13.6Hz,2H), 1.08(d,J=8.4Hz,1H), 1.04(d,J=6.8Hz,3H). LCMS:m / z=362.3[M+H] + .

[0823] Example 4

[0824] N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo[3.1.1]

[0825] Heptane-6-carboxamide (4)

[0826]

[0827] To a mixture of N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (30 mg, 0.08 mmol) and 2-chloropyrrolo[2,1-f][1,2,4]triazine (19 mg, 0.13 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL) was added K2CO3 (35 mg, 0.25 mmol) and Pd(dppf)Cl2 (6 mg, 0.01 mmol) under N2 at 20°C. The mixture was stirred at 100°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: A: aqueous NH 4 HCO 3 solution, B: MeCN; % B in A: 35%-65%, 8 min) to give the title compound. 1H NMR (400MHz, CDCl3): δ9.03 (s, 1H), 7.86 (d, J = 0.8Hz, 1H), 7.69 (d, J = 2.0Hz, 1H), 7.65 (dd, J = 2. 4,8.4Hz,1H),7.24(d,J=8.4Hz,1H),6.99-6.96(m,1H),6.91-6.87(m,1H),6.08(s,1H),4.23(br d,J=6.0Hz,2H),2.59-2.53(m,1H),2.52(s,3H),2.45-2.34(m,2H),2.02-1.88(m,1H),1.82-1.69(m,3H),1.50(d,J=8.8Hz,1H). LCMS: m / z=348.2[M+H] + .

[0828] The following compounds were prepared by methods analogous to those described herein.

[0829]

[0830]

[0831]

[0832]

[0833]

[0834] Example 19

[0835] 6-((4-Methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (19)

[0836]

[0837] Under N2, to a mixture of CDI (1.74 g, 10 mmol) in DCM (70 mL) was added a solution of 4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazine-2-yl)aniline (2 g, 8.92 mmol) in DCM (70 mL) at -20 ° C. The mixture was stirred at 20 ° C for 12 hours. Then, under N2, a solution of DIPEA (3.17 g, 24.50 mmol) and 6-azabicyclo[3.1.1]heptane-1-carboxylic acid (1.98 g, 9.80 mmol) in DCM (20 mL) was added to the above solution at 20 ° C. The mixture was stirred at 20 ° C for 4 hours. The reaction was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 250×70 mm×10 μm; mobile phase: A: 10 mM NH 4 HCO 3 aqueous solution, B: MeCN; % B in A: 15%-40%, 18 min) to give the title compound. 1 HNMR (400MHz, CD3OD): δ9.08(s,1H),7.98(s,1H),7.81(d,J=2.0Hz,1H),7.48(dd,J=2.0,8.0Hz,1H),7.24(d,J=8.0Hz,1H),7.11-7.01(m,2H),4.11(br s,1H),2.55(br t,J=8.4Hz,1H),2.49-2.36(m,5H),2.13-1.95(m,2H),1.78(d,J=8.8Hz,1H),1.76-1.63(m,2H). LCMS: m / z=392.2[M+H] + .

[0838] Example 20

[0839] N-(4-methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-

[0840] Formamide (20)

[0841]

[0842] To a solution of CDI (26 mg, 0.16 mmol) in DCM (1 mL) was added a solution of 4-methyl-3-(pyrrolo[1,2-a]pyrimidin-2-yl)aniline (30 mg, 0.13 mmol) in DCM (1 mL) under N2 at -20 ° C. The mixture was stirred at -20 ° C for 3 hours, and then TEA (38 mg, 0.38 mmol) and 6-azabicyclo[3.1.1]heptane (37 mg, 0.38 mmol) were added to the reaction mixture at 20 ° C. The mixture was stirred at 50 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 25%-55%, 10 minutes) to give the title compound. 1 H NMR (400MHz, CDCl3): δ8.20 (d, J=7.6Hz, 1H), 7.51 (dd, J=2.0, 8.0Hz, 1H), 7.45 (d,J=2.4Hz,1H),7.24-7.19(m,2H),7.00(t,J=3.6Hz,1H),6.72(d,J=7.2Hz,1 H),6.65(d,J=4.0Hz,1H),6.06(s,1H),4.27-4.21(m,2H),2.58-2.51(m,1H),2 .44-2.33(m,5H),2.01-1.89(m,1H),1.78-1.70(m,3H),1.50(d,J=8.4Hz,1H). LCMS: m / z=347.2[M+H] + .

[0843] Example 21

[0844] N-(3-(7-methoxypyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (21)

[0845]

[0846] To a mixture of triphosgene (58 mg, 0.20 mmol) in THF (2 mL) was added TEA (80 mg, 0.79 mmol) and 3-(7-methoxypyrrolo[2,1-f][1,2,4]triazine-2-yl)-4-methylaniline (100 mg, 0.39 mmol) under N2 at 0 ° C. The mixture was stirred at 20 ° C for 1 hour, and then 6-azabicyclo[3.1.1]heptane hydrochloride (63 mg, 0.47 mol) and TEA (80 mg, 0.79 mmol) were added to the above mixture. The mixture was stirred at 20 ° C for another 1 hour. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge Prep OBDC18 150×40 mm×10 μm; mobile phase: A: 10 mM aqueous NH 4 HCO 3 solution, B: MeCN, B in A: 30%-70%, 8 min) to give the title compound. 1 H NMR (400MHz, CDCl3): δ8.83(s,1H),7.70(dd,J=2.4,8.0Hz,1H),7.54(d,J=2.8Hz,1H),7 .21(d,J=8.4Hz,1H),6.81(d,J=4.8Hz,1H),6.39(d,J=4.8Hz,1H),6.06(s,1H),4.21(br d,J=6.0Hz,2H),4.14(s,3H),2.57-2.52(m,1H),2.50(s,3H),2.45-2.34(m,2H),1.99-1.87(m,1H),1.81-1.68(m,3H),1.49(d,J=8.4Hz,1H). LCMS: m / z=378.2[M+H] + .

[0847] Example 22

[0848] N-(3-(7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl)-4-methylphenyl)-6-azabicyclo

[0849] [3.1.1] Heptane-6-carboxamide (22)

[0850]

[0851] Under N2, to a solution of CDI (193 mg, 1.19 mmol) in DCM (10 mL) was added dropwise a solution of 3- (7- bromopyrrolo [2, 1-f] [1, 2, 4] triazine -2- base) -4- methylaniline (300 mg, 0.99 mmol) in DCM (10 mL) at -20 ° C. The mixture was stirred at 20 ° C for 2 hours, followed by the addition of 6- azabicyclo [3.1.1] heptane (143 mg, 1.47 mmol) and TEA (298 mg, 2.59 mmol). The reaction mixture was stirred at 20 ° C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (PE:EtOAc=3:1 to 1:1) to give the title compound. 1 HNMR (400MHz, CDCl3): δ8.97(s,1H),7.83(d,J=2.0Hz,1H),7.72(dd,J=2.0,8.0 Hz,1H),7.31-7.28(m,1H),7.03(d,J=4.8Hz,1H),6.96(d,J=4.8Hz,1H),6.13(br s,1H),4.27-4.22(m,2H),2.64(s,3H),2.61-2.52(m,1H),2.47-2.37(m,2H),2.04-1.91(m,1H),1.84-1.74(m,3H),1.52(d,J=8.8Hz,1H). LCMS: m / z = 426.1, 428.1 [M+H] + .

[0852] Example 23

[0853] cis-N-(2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3-methoxy-6-azabicyclo[3.1.1]heptane-6-carboxamide (23)

[0854]

[0855] To a solution of triphosgene (25 mg, 0.08 mmol) in THF (3 mL) was added 2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazine-2-yl)aniline (40 mg, 0.17 mmol) and TEA (50 mg, 0.50 mmol) at 0 ° C. Under N2, 2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazine-2-yl)aniline (40 mg, 0.17 mmol) and TEA (50 mg, 0.50 mmol) were added at 0 ° C. The mixture was stirred for 3 hours, followed by the addition of cis-3-methoxy-6-azabicyclo[3.1.1]heptane (26 mg, 0.20 mmol) and TEA (50 mg, 0.50 mmol). The mixture was stirred at 20 ° C. for 12 hours. The reaction mixture was diluted with H2O (0.5 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: A: 10 mM aqueous NH 4 HCO 3 solution, B: MeCN; % B in A: 20%-50%, 8 min) to give the title compound. 1 H NMR (400MHz, CDCl3): δ9.01 (s, 1H), 8.59 (d, J = 8.8Hz, 1H), 7.86-7.82 (m, 1H), 7.01 ( d,J=12.0Hz,1H),6.96(dd,J=2.8,4.8Hz,1H),6.88(dd,J=1.2,4.4Hz,1H),6.19(br s,1H),4.25(br d,J=6.0Hz,2H),3.79-3.63(m,1H),3.33(s,3H),2.79(br dd,J=7.2,14.8Hz,2H),2.58-2.51(m,1H),2.50(s,3H),1.84(br dd,J=1.2,14.9Hz,2H), 1.76(d,J=8.8Hz,1H). LCMS: m / z=396.2[M+H] + .

[0856] Example 24

[0857] 1-(Methoxymethyl)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-

[0858] Azabicyclo[3.1.1]heptane-6-carboxamide (24)

[0859]

[0860] Under N2, to a mixture of CDI (43 mg, 0.27 mmol) in DCM (2 mL) was added dropwise a solution of 4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazine-2-yl)aniline (50 mg, 0.22 mmol) in DCM (2 mL) at -20 ° C. The mixture was stirred at 20 ° C for 2 hours, followed by addition of a solution of TEA (45 mg, 0.45 mmol) and 1-(methoxymethyl)-6-azabicyclo[3.1.1]heptane (58 mg, 0.25 mmol) in DCM (1 mL). The reaction mixture was stirred at 20 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 75 x 30 mm x 3 μm; mobile phase: A: 10 mM FA in water, B: MeCN; % B in A: 30%-80%, 8 min) to give the title compound. 1 HNMR (400MHz, CD Cl3): δ9.02 (s, 1H), 8.78 (br s,1H),7.84(s,1H),7.77(d,J=2.4Hz,1H),7.58(dd,J=2.4,8.4Hz,1H),7.20(d,J= 8.4Hz,1H),6.96-6.94(m,1H),6.89-6.84(m,1H),4.26-4.14(m,1H),3.67(d,J=10. 0Hz,1H),3.52(s,3H),3.47(d,J=9.6Hz,1H),2.56-2.44(m,5H),2.08(t,J=7.6Hz,1 H), 1.97-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.67-1.56 (m, 2H), 1.42 (d, J = 8.4Hz, 1H). LCMS: m / z=392.2[M+H] + .

[0861] Example 25

[0862] cis-N-(3-(imidazo[1,2-a]pyrazin-6-yl)-4-methylphenyl)-3-methyl-6-azabicyclo

[0863] [3.1.1] Heptane-6-carboxamide (25)

[0864]

[0865] Under N2, to a solution of CDI (521 mg, 3.21 mmol) in DCM (21 mL) was added a solution of 3-(imidazo[1,2-a]pyrazin-6-yl)-4-methylaniline (600 mg, 2.67 mmol) in DCM (21 mL) at –20 ° C. The mixture was stirred at –20 ° C for 3 hours, followed by the addition of cis-3-methyl-6-azabicyclo[3.1.1]heptane (411 mg, 3.69 mmol) and TEA (801 mg, 7.92 mmol). The mixture was stirred at 30 ° C for 12 hours. The reaction mixture was diluted with H2O (120 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) and further slurried with EtOAc to give the title compound. 1 H NMR (400MHz, CDCl3): δ9.16 (s, 1H), 8.20 (d, J = 1.6Hz, 1H), 7.84 (d, J = 2Hz, 1 H),7.72(s,1H),7.62(d,J=2.4Hz,1H),7.30-7.28(m,1H),7.24-7.20(m,1H ),6.18(s,1H),4.23-4.20(m,2H),2.65-2.55(m,3H),2.36(s,3H),2.11-2. 01(m,1H),1.38-1.32(m,2H),1.08(d,J=8.4Hz,1H),1.03(d,J=8.8Hz,3H). LCMS:m / z=362.2[M+H] + .

[0866] Example 26

[0867] N-(2-Fluoro-4-methyl-5-(pyrazolo[1,5-b]pyridazin-6-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (26)

[0868]

[0869] At 0 ° C, to a solution of triphosgene (21 mg, 0.072 mmol) in THF (0.5 mL), TEA (29 mg, 0.29 mmol) and 2-fluoro-4-methyl-5-(pyrazolo[1,5-b]pyridazine-6-yl)aniline (35 mg, 0.15 mmol) in THF (0.5 mL) were added. The mixture was stirred at 20 ° C for 1 hour, followed by addition of a solution of 6-azabicyclo[3.1.1]heptane hydrochloride (28 mg, 0.22 mmol). The mixture was stirred at 20 ° C for 16 hours. The reaction mixture was quenched by adding H2O (1 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex C18 75×30 mm×3 μm; mobile phase: Mobile phase: A: 10 mM NH 4 HCO 3 aqueous solution, B: MeCN; % B in A: 25%-65%, 8 min) to give the title compound. 1 HNMR (400MHz, CDCl3): δ8.34(d,J=8.4Hz,1H),8.05(d,J=2.4Hz,1H),7.97(d,J=9.2H z,1H),7.19(d,J=9.2Hz,1H),7.03(d,J=11.6Hz,1H),6.66(d,J=2.4Hz,1H),6.21(br d,J=2.0Hz,1H),4.35-4.23(m,2H),2.61-2.53(m,1H),2.44(s,3H),2.42- 2.33(m,2H),2.04-1.93(m,1H),1.82-1.74(m,3H),1.53(d,J=8.8Hz,1H). LCMS: m / z=366.2[M+H] + .

[0870] Example 27

[0871] N-(2-Fluoro-5-(imidazo[1,2-a]pyrazin-6-yl)-4-methylphenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (27)

[0872]

[0873] To a mixture of triphosgene (31 mg, 0.10 mmol) in THF (2 mL) under N2 was added TEA (63 mg, 0.62 mmol) and 2-fluoro-5-imidazo[1,2-a]pyrazin-6-yl-4-methyl-aniline (50 mg, 0.21 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour, followed by the addition of 6-azabicyclo[3.1.1]heptane (60.62 mg, 0.29 mmol) and TEA (62.24 mg, 0.62 mmol). The reaction mixture was stirred at 20 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: A: 10 mM NH4HCO3 aqueous solution, B: MeCN; B% in A: 25%-45%, 8 minutes) to give the title compound. 1 HNMR (400MHz, CDCl3) δ9.13(d,J=0.8Hz,1H),8.25(d,J=8.4Hz,1H),8.21(d,J= 1.6Hz,1H),7.84(d,J=0.8Hz,1H),7.71(s,1H),7.02(d,J=12.0Hz,1H),6.22(br d,J=2.4Hz,1H),4.27(br d,J=6.2Hz,2H),2.62-2.53(m,1H),2.44-2.33(m,5H),2.03-1.91(m,1H),1.83-1.71(m,3H),1.53(d,J=8.8Hz,1H). LCMS=366.2[M+H] + .

[0874] Example 28

[0875] N-(3-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo

[0876] [3.1.1] Heptane-6-carboxamide (28)

[0877]

[0878] To a solution of CDI (37 mg, 0.23 mmol) in DCM (1 mL) was added a solution of 3-fluoro-4-methyl-5-pyrrolo[2,1-f][1,2,4]triazine-2-yl-phenylamine (50 mg, 0.21 mmol) in DCM (1 mL) at –20 ° C. The mixture was stirred at 20 ° C for 16 hours, followed by the addition of a solution of 6-azabicyclo[3.1.1]heptane (30 mg, 0.31 mmol) in DCM (1 mL) and TEA (42 mg, 0.41 mmol). The mixture was stirred at 20 ° C for another 16 hours. The reaction mixture was diluted with H2O (3 mL) and extracted with DCM (3 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: A: 10 mM aqueous NH 4 HCO 3 solution, B: MeCN; % B in A: 35%-65%, 8 min) to give the title compound. 1 HNMR (400MHz, CDCl3): δ9.03(s,1H),7.87(s,1H),7.70-7.66(m,1H),7.37(s,1H),7.01-6.99(m,1H),6.99-6.91(m,1H),6.08 (s,1H),4.25-4.23(m,2H),2.58-2.54(m,1H),2.41-2.36(m,5H),2.05-1.95(m,1H),1.78-1.72(m,3H),1.52(d,J=8.8Hz,1H). LCMS:m / z=366.2[M+H] + .

[0879] Example 29

[0880] Phenethyl (4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamate (29)

[0881]

[0882] Under N2, 4-methyl-3-pyrrolo[2,1-f][1,2,4]triazine-2-yl-phenylamine (200 mg, 0.9 mmol) and TEA (180 mg, 1.78 mmol) were added to a solution of triphosgene (132 mg, 0.4 mmol) in THF (4 mL) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour, followed by the addition of 2-phenylethanol (109 mg, 0.9 mmol). The mixture was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: 10 mM aqueous NH 4 HCO 3 solution, B: MeCN; % B in A: 52%-82%, 8 min) to give the title compound. 1 H NMR (400MHz, CDCl3): δ9.03(s,1H),7.87(s,1H),7.75(s,1H),7.47(br s,1H),7.32-7.28(m,2H),7.27-7.23(m,4H),6.99-6.98(m,1H),6.91-6.90(m,1H),6.77(br s, 1H), 4.41 (t, J = 7.2Hz, 2H), 3.01 (t, J = 7.2Hz, 2H), 2.53 (s, 3H). LCMS:m / z=373.2[M+H] + .

[0883] The following compounds were prepared by methods analogous to those described herein.

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] Examples 52 and 53

[0893] (1S,5R)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (52) and (1R,5S)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (53)

[0894]

[0895] N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a mixture of 4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline (100 mg, 0.40 mmol) and triphosgene (66 mg, 0.22 mmol) in THF (2 mL) was added TEA (122 mg, 0.12 mmol) at 0°C under N2. The reaction mixture was stirred at 0°C for 1 hour. Then, 1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane trifluoroacetate (138 mg, 0.48 mmol) and TEA (122 mg, 0.12 mmol) were added to the mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, EtOAc) to afford the title compound. LCMS: m / z = 426.3 [M+H] + .

[0896] (1S,5R)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (52) and (1R,5S)-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide (53): N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-1-(pyrimidin-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide was separated by SFC (Chiralcel OZ-3, 250mm×30mm, 5μm; mobile phase: A: CO2, B: MeOH containing 0.1% NH3H2O; B% in A: 50%-50%, 15 minutes; flow rate: 80g / min; wavelength: 220nm; column temperature: 35°C; system back pressure: 120 bar), Example 52 was obtained as the first eluting peak and separated as a single enantiomer. 1 H NMR(400MHz, CDCl3): δ10.87(br s,1H),9.05(s,1H),8.83(d,J=5.2Hz,2H),7.93-7.82(m,2H),7.73(dd,J=2.4,8 .4Hz,1H),7.32(t,J=4.8Hz,1H),7.25(d,J=8.4Hz,1H),6.98(dd,J=2.4,4.4Hz, 1H),6.90(dd,J=1.2,4.4Hz,1H),4.32-4.23(m,1H),2.86-2.67(m,2H),2.62-2. 52(m,1H),2.50(s,3H),2.11-1.95(m,3H),1.94-1.83(m,1H),1.78-1.68(m,1H). Further elution gave Example 53 as the second eluting peak, isolated as a single enantiomer. 1H NMR(400MHz, CDCl3): δ10.87(br s,1H),9.05(s,1H),8.83(d,J=5.2Hz,2H),7.92-7.81(m,2H),7.73(dd,J=2.0,8 .0Hz,1H),7.32(t,J=5.2Hz,1H),7.25(d,J=8.4Hz,1H),6.98(dd,J=2.8,4.8Hz, 1H), 6.90 (dd, J=1.2, 4.4Hz, 1H), 4.40-4.17 (m, 1H), 2.85-2.66 (m, 2H), 2.61-2. 52(m,1H),2.50(s,3H),2.12-1.96(m,3H),1.94-1.81(m,1H),1.77-1.69(m,1H).

[0897] Examples 54 and 55

[0898] (1S,4R)-N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-carboxamide (54)

[0899] (1R,4S)-N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-carboxamide (55)

[0900]

[0901] N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-carboxamide: To a solution of triphosgene (61.25 mg, 0.21 mmol) in THF (2 mL) at 0°C were added 2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)aniline (100 mg, 0.41 mmol) and TEA (83.54 mg, 0.83 mmol). The mixture was stirred at 20°C for 1 hour. Then, 1,2,3,4-tetrahydro-1,4-methanoisoquinoline (72 mg, 0.49 mmol) and TEA (83.54 mg, 0.83 mmol) were added to the reaction solution. The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc = 1:1) to give the title compound. LCMS: m / z = 414.2 [M+H] + .

[0902] (1S,4R)-N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-carboxamide (54) and (1R,4S)-N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-carboxamide )-formamide (55): N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3,4-dihydro-1,4-methanoisoquinoline-2(1H)-formamide (130 mg, 0.314 mmol) was purified by SFC (REGIS(s,s)WHELK-O1, 250 mm×30 mm, 5 μm; mobile phase: A: CO2, B: EtOH containing 0.1% NH3H2O; % B in A: 50%, 15 min; flow rate: 70 mL / min; wavelength: 220 nm; column temperature: 35°C; system back pressure: 120 bar) to give Example 54, which was the first eluting single enantiomer separated. 1H NMR (400 MHz, CDCl3): δ 8.99 (s, 1H), 8.57 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.35 (dd, J = 6.8, 15.2 Hz, 2H), 7.24-7.10 (m, 2H), 7.01-6.93 (m, 2H), 6.87 (d, J = 4.8 Hz, 1H), 6.32 (br s, 1H), 5.26 (br s, 1H), 3.84-3.68 (m, 2H), 2.91 (d, J = 7.6 Hz, 1H), 2.47 (s, 3H), 2.12-1.94 (m, 2H). Further elution gave Example 55 as the second eluting peak, which was isolated as a single enantiomer. 1 H NMR (400MHz, CDCl3): δ8.99 (s, 1H), 8.57 (d, J = 8.4Hz, 1H), 7.83 (s, 1H), 7.35 (dd, J = 6 .8,15.2Hz,2H),7.24-7.10(m,2H),7.01-6.93(m,2H),6.87(d,J=4.8Hz,1H),6.32(br s,1H),5.26(br s,1H),3.84-3.68(m,2H),2.91(d,J=7.6Hz,1H),2.47(s,3H),2.12-1.94(m,2H).

[0903] Example 56

[0904] N-(4-Methyl-3-(pyrrolo[1,2-a]pyrazin-3-yl)phenyl)bicyclo[2.2.1]heptane-7-carboxamide (56)

[0906]

[0907] To a solution of 4-methyl-3-(pyrrolo[1,2-a]pyrazin-3-yl)aniline (30 mg, 0.13 mmol) in pyridine (1 mL) was added bicyclo[2.2.1]heptane-7-carboxylic acid (23 mg, 0.16 mmol) and EDCI (52 mg, 0.27 mmol) at 0° C. under N2. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound. 1H NMR (400MHz, CDCl3): δ8.87(s,1H),7.94(s,1H),7.61(s,1H),7.48-7.43(m,2H),7.27-7.19( m,2H),6.94-6.91(m,1H),6.84-6.81(m,1H),2.53(brd,J=12.0Hz,3H),2.39(s,3H),1.88(br d,J=7.6Hz,2H), 1.69(br d,J=7.2Hz,2H), 1.33(br d,J=6.8Hz,4H). LCMS:m / z=346.2[M+H] + .

[0908] Example 57

[0909] cis-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-4-(trifluoromethyl)cyclohexanecarboxamide (57)

[0910]

[0911] Under N2, EDCI (128 mg, 0.67 mmol) was added to a solution of 4-methyl-3-pyrrolo[2,1-f][1,2,4]triazine-2-yl-aniline (100 mg, 0.4 mmol) and cis-4-(trifluoromethyl)cyclohexanecarboxylic acid (105 mg, 0.5 mmol) in pyridine (2 mL) at 0 ° C. The mixture was stirred at 20 ° C for 16 hours. The reaction mixture was diluted with H2O (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) and then purified by preparative HPLC to give the title compound. 1 H NMR (400MHz, DMSO-d6): δ9.89(s,1H),9.27(s,1H),8.15-8.12(m,1H),8.07(d,J=2.0Hz,1H),7.61(dd,J=2.0,8.0Hz,1H),7.25(d,J= 8.4Hz,1H),7.09-7.06(m,1H),7.05-7.02(m,1H),2.65(m,1H),2.44(s,3H),2.39-2.24(m,1H),2.04-1.94(m,2H),1.79-1.56(m,6H). LCMS: m / z=403.1[M+H] + .

[0912] Examples 58 and 59

[0913] cis-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide (58) and trans-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide (59)

[0914]

[0915] 3-Cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide: Under N2, EDCI (34 mg, 0.179 mmol) was added to a mixture of 4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)aniline (20 mg, 0.089 mmol) and 3-cyclopropylcyclobutanecarboxylic acid (15 mg, 0.11 mmol) in pyridine (1 mL) at 0°C. The mixture was stirred at 20°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative TLC (SiO2, PE:EtOAc=1:1) to give the title compound. LCMS: m / z=347.2[M+H] + .

[0916] cis-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide (58) and trans-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide (59): 3-Cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide was separated by the following method: DAICEL CHIRALCEL OD 250 mm × 30 mm, 10 μm; mobile phase: A: CO2, B: containing 0.1% NH3H2O ​​in MeOH; B% in A%: 33%-33%, flow rate: 70 g / min; wavelength: 220 nm; column temperature: 35°C; system back pressure: 120 bar, 5 minutes), gave two peaks: cis-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide Example 58 (peak 1 in SFC) 1H NMR (400MHz, CDCl3): δ9.13 (s, 1H), 8.51 (s, 1H), 8.08 (d, J = 2.4Hz, 1H), 7.65 (s, 1H), 7.57-7.54 (m, 1H), 7.27-7.25 (m, 1H), 7.10 (br s,1H),6.84(d,J=2.4Hz,1H),2.94-2.86(m,1H),2.39(s,3H),2.27-2.23(m,2H),2.06-2.03(m,2H) ,2.01-1.89(m,1H),0.83-0.78(m,1H),0.42-0.36(m,2H),0.13-0.08(m,2H)LCMS:m / z=347.2[M+H] + and trans-3-cyclopropyl-N-(4-methyl-3-(pyrazolo[1,5-a]pyrazin-6-yl)phenyl)cyclobutanecarboxamide Example 59 (peak 2 in SFC) 1 H NMR (400MHz, CDCl3): δ9.13 (s, 1H), 8.51 (s, 1H), 8.08 (d, J = 2.4Hz, 1H), 7.66 (s, 1H), 7.57-7.54 (m, 1H), 7.28-7.25 (m, 1H), 7.12 (br s,1H),6.84(d,J=2.4Hz,1H),3.11-3.05(m,2H),2.46-2.41(m,2H),2.39(s,3H ),2.06-2.03(m,3H),0.91-0.87(m,1H),0.45-0.41(m,2H),0.12-0.08(m,2H). LCMS:m / z=347.2[M+H] + .

[0917] Examples 60 and 61

[0918] cis-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide (60) and trans-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide (61)

[0919] Cyclopropylcyclobutanecarboxamide (61)

[0920]

[0921] N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide: To a mixture of 4-methyl-3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)aniline (95 mg, 0.42 mmol) in pyridine (2 mL) was added 3-cyclopropylcyclobutanecarboxylic acid (50 mg, 0.35 mmol) and EDCI (136 mg, 0.71 mmol) at 20 ° C under N2. The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EtOAc=3:1) to give the title compound. LCMS: m / z=347.2[M+H] + .

[0922] cis-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide (60) and trans-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide (61): The isomer mixture was subjected to SFC (REGIS(S,S)WHELK-O1 250 mm×30 mm, 10 μm; mobile phase: A: CO2, B: containing 0.1% IPA of NH3H2O; B% at 28%-28% in 9 minutes; flow rate: 70 g / min; wavelength: 220 nm; column temperature: 35°C; system back pressure: 120 bar) to give cis-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide Example 60 (peak 1 in SFC). 1 H NMR (400MHz, CDCl3): δ8.54(s,1H),8.38(s,1H),7.78(br d,J=9.2Hz,1H),7.59(br s,1H),7.51(br d,J=8.8Hz,1H),7.42(br d,J=8.0Hz,1H),7.33(br s,1H),7.25(br d,J=5.6Hz,1H),2.97-2.81(m,1H),2.25(s,3H),2.30-2.20(m,2H),2.10-1.98(m,2H),1.97 -1.85(m,1H),0.88-0.70(m,1H),0.43-0.32(m,2H),0.12-0.6(m,2H)LCMS:m / z=347.2[M+H]+ ; and trans-N-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-methylphenyl)-3-cyclopropylcyclobutanecarboxamide Example 61 (peak 2 in SFC). 1 HNMR (400MHz, CDCl3): δ8.53(s,1H),8.38(br s,1H),7.76(br d,J=9.2Hz,1H),7.58(br d,J=13.2Hz,2H),7.50(br d,J=8.8Hz,1H),7.42(br d,J=8.0Hz,1H),7.23(br d,J=8.0Hz,1H),3.13-3.04(m,1H),2.46-2.37(m,2H),2.24(s,3H),2.11-1.97(m,3H),0.90-0.79(m,1H),0.43-0.35(m,2H),0.07(br d,J=2.0Hz,2H). LCMS: m / z=347.2[M+H] + .

[0923] The following compounds were or can be prepared by methods analogous to those described herein.

[0924]

[0925]

[0926]

[0927]

[0928] Example 72

[0929] 1-Cyano-N-(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo

[0930] [3.1.1] Heptane-6-carboxamide

[0931]

[0932] Under N2, at 0 °C 6To a mixture of -(4-methyl-3-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-1,6-dicarboxamide (900 mg, 2.31 mmol) in DCM (20 mL) was added TFAA (2.42 g, 11.53 mmol) and TEA (1.17 g, 11.53 mmol). The mixture was stirred at 20 ° C for 12 hours. The reaction mixture was diluted with H2O (15 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:(EtOAc:EtOH=3:1)=1:0 to 1:1) and further purified by preparative HPLC to give the title compound. 1 H NMR (400MHz, CD3OD): δ9.10(s,1H),7.98(s,1H),7.82(d,J=2.0Hz,1H),7.51(dd,J=2.4,8.4Hz,1H),7.26(d,J=8.4Hz,1H),7. 08-7.03(m,2H),4.47-4.42(m,1H),2.84-2.73(m,2H),2.45(s,3H),2.31-2.18(m,1H),2.11-1.96(m,3H),1.83-1.71(m,2H). LCMS:m / z=373.1[M+H] + .

[0933] Examples 73 and 74

[0934] (1S,3S,5R)-N-(2-Fluoro-4-methyl-5-pyrrolo[2,1-f][1,2,4]triazin-2-ylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide and (1R,3R,5S)-N-(2-Fluoro-4-methyl-5-pyrrolo[2,1-f][1,2,4]triazin-2-ylphenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0935]

[0936] 1-(2-Acetylhydrazidecarbonyl)-N-(2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3-methyl-6-azabicyclo[3.1.1]heptane-6-carboxamide: To a solution of 6-((2-fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)carbamoyl)-3-methyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (330 mg, 0.78 mmol) in DMF (5 mL) was added acetohydrazide (87 mg, 1.17 mmol), DIEA (201 mg, 1.56 mmol) and HATU (593 mg, 1.56 mmol) under N at 20° C. The mixture was stirred at 20° C. for 12 h. The reaction mixture was quenched by adding H2O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:(EtOAc:EtOH=3:1)=3:1 to 1:1) to give the title compound. LCMS: m / z=480.3 [M+H] + .

[0937] N-(2-Fluoro-4-methyl-5-(pyrrolo[2,1-f][1,2,4]triazin-2-yl)phenyl)-3-methyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)-6-azabicyclo[3.1.1]heptane-6-c...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is halogenated, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl or heterocyclic groups are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution; The conditions are: a) When R 1 is fluorine, R 4 is hydrogen, and R 2 is benzyloxy, in When optionally substituted with one or two fluorine or one or two methyl groups; then part Not by express; as well as b) The compound is not N-[4-cyano-3-[3-(4-morpholinyl)imidazo[1,2-a]pyrimidin-7-yl]phenyl]-1-pyrrolidinecarboxamide, N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, (1S,2S)-N-[6-[5-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, 4-[4-(acetylamino)-2-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]phenoxy]-1-piperidinic acid 1,1-dimethylethyl ester, N-[4-(acetylamino)-2-methylphenyl]imidazo[1,2-a]pyridin-2-yl]-2-fluoro-cyclopropanecarboxamide, -[3-[3-methyl-8-(methylamino)-1,2,4-triazolo[4,3-a]pyridin-6-yl]-4-[4-(trifluoromethyl)phenoxy]phenyl]-acetamide, N-[4-(4-chloro-2-fluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-2,2-dimethyl-propionamide, N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-cyclopropanecarboxamide or N-[4-(2,4-difluorophenoxy)-3-(3-methyl-1,2,4-triazolo[4,3-a]pyridin-6-yl)phenyl]-propionamide.

2. The compound of claim 1, wherein A 1 、X 3 and X 4 At least one of them is not N.

3. The compound of claim 1, wherein X 6 It is CN(R 11 )2, then A 2 、X 1 and X 5 At least one of them is not N.

4. A compound according to any one of the preceding claims, which is represented by Formula IA:

5. The compound of claim 4, wherein R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace.

6. The compound of claim 5, wherein R 2 or part yes: Each of which is independently optionally replaced by one to five Z 1 replace.

7. The compound of claim 5 or 6, wherein each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heteroaryl, -OR 12 or-C(O)OR 12 ; Each C 1-6 The alkyl and heteroaryl groups are independently optionally substituted with one to five hydroxy, methoxy or methyl groups.

8. The compound of any one of claims 1 to 3, which is represented by Formula IB:

9. The compound of any one of claims 1 to 3 or 8, wherein R 7 Is to be selected by one to five Z 1 Substituted C 1-6 alkyl.

10. The compound of claim 9, wherein R 7 It is cyclopropylmethyl, 2-phenylethyl or 2,2,2-trifluoroethyl.

11. The compound of claim 1, wherein R 2 Is to be selected by one to five Z 1 Substituted C 1-6 alkyl.

12. The compound of claim 11, wherein R 2 It is (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl or (3-(trifluoromethyl)cyclobutan-1-yl)methyl.

13. The compound of claim 1, wherein R 2 Is to be selected by one to five Z 1 Substituted C 3-10 Cycloalkyl.

14. The compound of claim 13, wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[2.2.1]hept-7-yl, each of which is optionally substituted by one to five Z 1 replace.

15. The compound of claim 13 or 14, wherein each Z 1 are independently halogenated, C 1-6 Haloalkyl, -OC 1-6 Alkyl, C 3-10 cycloalkyl or heteroaryl.

16. The compound of claim 1, wherein R 2 Is to be selected by one to five Z 1 substituted heterocyclic group.

17. The compound of claim 1, wherein R 2 is 2-azabicyclo[3.1.0]hex-2-yl, pyrrolidinyl or tetrahydropyranyl, each of which is optionally substituted by one to five Z 1 replace.

18. The compound of claim 16 or 17, wherein each Z 1 are independently halo, -C(O)OR 12 、C 1-6 Alkyl, C 1-6 A haloalkyl or heteroaryl group, wherein each C 1-6 The alkyl group is optionally substituted with one to five methoxy groups.

19. A compound as claimed in any one of the preceding claims, wherein R 4 It's hydrogen.

20. A compound as claimed in any one of the preceding claims, wherein R 5 It is hydrogen or halogen.

21. A compound as claimed in any one of the preceding claims, wherein R 5 It is hydrogen or fluorine.

22. A compound as claimed in any one of the preceding claims, wherein R 1 Is halogenated, cyano, C 1-6 Alkyl or C 1-6 haloalkyl, wherein each C 1-6 The alkyl group is optionally substituted by one to five Z 1 replace.

23. A compound as claimed in any one of the preceding claims, wherein R 1 is chloro, cyano, methyl, trifluoromethyl or cyanomethyl.

24. The compound of any one of claims 1 to 23, wherein A 1 is N, and A 2 It’s C.

25. The compound of any one of claims 1 to 23, wherein A 1 It is C, and A 2 It's N.

26. A compound as described in any one of claims 1 to 23, wherein part yes: Each of which is optionally replaced by R 6 replace.

27. The compound of claim 26, wherein R 6 Is halogenated, cyano, -OR 11 or C optionally substituted by one to five halogenated 1-6 alkyl.

28. A compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof.

29. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier.

30. A method for inhibiting SARM1 activity, the method comprising contacting a cell with an effective amount of: a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof; a pharmaceutical composition according to claim 29; or a compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

31. The method of claim 30, wherein the contacting is performed in vivo.

32. A method for treating a disease or condition mediated at least in part by SARM1, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof; a pharmaceutical composition according to claim 29; or a compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

33. A method for inhibiting axonal degeneration, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or the pharmaceutical composition of claim 29.

34. A method for treating neurodegeneration or a nervous system disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, or a pharmaceutical composition of claim 29.

35. The method of claim 34, wherein the neurodegeneration or nervous system disease or condition is associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a nerve injury disease or condition, a metabolic disease, a mitochondrial disease, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

36. The method of claim 35, wherein the disease or condition is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Waller degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Louger's disease), Huntington disease, Alzheimer disease, Parkinson disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12 Vitamin E deficiency, isolated vitamin E deficiency syndrome, Basen-Kenzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, retinitis pigmentosa, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, La Crosse virus encephalitis, bunyavirus encephalitis, pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomedullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

37. A method for treating chemotherapy-induced peripheral neuropathy (CIPN), comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof; a pharmaceutical composition according to claim 29; or a compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 The alkyl radicals are substituted with cycloalkyl, heterocyclyl, aryl or heteroaryl radicals.

38. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, a pharmaceutical composition according to claim 29, or a compound of formula I as follows: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution; They are useful for treating diseases or conditions mediated at least in part by SARM1.

39. The method of claim 38, wherein the disease or disorder is spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Waller degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Louger's disease), Huntington disease, Alzheimer disease, Parkinson disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kenzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, Pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomedullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

40. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 29, for use in therapy.

41. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 29, for use in the treatment of spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Waller degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Louger's disease), Huntington disease, Alzheimer disease, Parkinson disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kenzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, Pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomedullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

42. Use of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer or mixture of stereoisomers thereof, or a pharmaceutical composition according to claim 29, for the manufacture of a medicament for treating spinal cord injury, stroke, multiple sclerosis, progressive multifocal leukoencephalopathy, congenital myelin deficiency, encephalomyelitis, acute disseminated encephalomyelitis, central pontine myelinolysis, osmotic hyponatremia, anoxic demyelination, ischemic demyelination, adrenoleukodystrophy, Alexander disease, Niemann-Pick disease, Pelizaeus Merzbacher disease, periventricular leukomalacia, globoid cell leukodystrophy (Krabbe disease), Waller degeneration, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS, Louger's disease), Huntington disease, Alzheimer disease, Parkinson disease, Tay-Sachs disease, Gaucher disease, Hurler syndrome, traumatic brain injury (TBI), traumatic axonal injury (TAI), post-radiation injury, neurologic complications of chemotherapy (chemotherapy-induced peripheral neuropathy, CIPN), neuropathy, acute ischemic optic neuropathy, vitamin B12 12 deficiency, isolated vitamin E deficiency syndrome, Basen-Kenzweig syndrome, retinal degeneration, retinitis pigmentosa, glaucoma, traumatic optic nerve injury, Leber hereditary optic atrophy (neuropathy), Leber congenital amaurosis, neuromyelitis optica, metachromatic leukodystrophy, acute hemorrhagic leukoencephalitis, trigeminal neuralgia, Bell's palsy, cerebral ischemia, multiple system atrophy, traumatic glaucoma, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy with tropical spastic paresis, West Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis, Pediatric viral encephalitis, essential tremor, Charcot-Marie-Tooth disease, motor neuron disease, spinal muscular atrophy (SMA), hereditary sensory and autonomic neuropathy (HSAN), adrenomedullary neuropathy, progressive supranuclear palsy (PSP), Friedreich's ataxia, hereditary ataxias, noise-induced hearing loss, congenital hearing loss, dementia with Lewy bodies, frontotemporal dementia, amyloidosis, diabetic neuropathy, HIV neuropathy, enteric neuropathy and axonopathy, Guillain-Barré syndrome, or severe acute motor axonal neuropathy (AMAN).

43. A method for providing a compound of formula I or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, the method comprising reacting a compound of formula I-1: With the compound of formula I-2: contacting under conditions sufficient to provide a compound of formula I; wherein: A 1 is N, and A 2 is C; or A 1 It is C, and A 2 It is N; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are each independently N, CH or CR 6 ; The condition is, X 1 、X 2 、X 3 、X 4 、X 5 and X 6 At least one of them is N; R 1 It is hydrogen, halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 2 Yes-OR 7 、-NR 8 R 9 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; Each R 6 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 11 )2、-OR 11 、-SR 11 、-C(O)R 11 、-C(O)OR 11 、-S(O)R 11 、-S(O)2R 11 、-C(O)N(R 11 )2、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2R 11 、-S(O)N(R 11 )2、-S(O)2N(R 11 )2、-NR 11 C(O)N(R 11 )2、-NR 11 S(O)N(R 11 )2、-NR 11 S(O)2N(R 11 )2、-OC(O)N(R 11 )2 or -NR 11 C(O)OR 11 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 7 It is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 8 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; R 9 It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1 replace; or R 8 With R 9 Together they form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; Each R 11 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 12 )2、-OR 12 、-SR 12 、-C(O)R 12 、-C(O)OR 12 、-S(O)R 12 、-S(O)2R 12 、-C(O)N(R 12 )2、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O)2R 12 、-S(O)N(R 12 )2、-S(O)2N(R 12 )2、-NR 12 C(O)N(R 12 )2、-NR 12 S(O)N(R 12 )2、-NR 12 S(O)2N(R 12 )2、-OC(O)N(R 12 )2 or -NR 12 C(O)OR 12 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1a replace; Each R 12 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halo, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -N(R 13 )2、-OR 13 、-SR 13 、-C(O)R 13 、-C(O)OR 13 、-S(O)R 13 、-S(O)2R 13 、-C(O)N(R 13 )2、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O)2R 13 、-S(O)N(R 13 )2、-S(O)2N(R 13 )2、-NR 13 C(O)N(R 13 )2、-NR 13 S(O)N(R 13 )2、-NR 13 S(O)2N(R 13 )2、-OC(O)N(R 13 )2 or -NR 13 C(O)OR 13 ; Each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each R 13 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl are independently optionally substituted by one to five Z 1b replace; Each Z 1b are independently halo, cyano, -OH, -SH, -NH2, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -LC 1-6 Alkyl, -LC 2-6 Alkenyl, -LC 2-6 Alkynyl, -LC 1-6 Haloalkyl, -LC 3-10 cycloalkyl, -L-heterocyclyl, -L-aryl, or -L-heteroaryl; and Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)2-, -N(C 1-6 Alkyl)-, -N(C 2-6 alkenyl)-, -N(C 2-6 Alkynyl)-, -N(C 1-6 Haloalkyl)-, -N(C 3-10 Cycloalkyl)-, -N(heterocyclyl)-, -N(aryl)-, -N(heteroaryl)-, -C(O)-, -C(O)O-, -C(O)NH-, -C(O)N(C 1-6 alkyl)-, -C(O)N(C 2-6 alkenyl)-, -C(O)N(C 2-6 Alkynyl)-, -C(O)N(C 1-6 Haloalkyl)-, -C(O)N(C 3-10 -cycloalkyl)-, -C(O)N(heterocyclyl)-, -C(O)N(aryl)-, -C(O)N(heteroaryl)-, -NHC(O)-, -NHC(O)O-, -NHC(O)NH-, -NHS(O)-, or -S(O)2NH-; where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2, -NO2, -SF5, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substituted; and LG is a leaving group.

44. The method of claim 43, wherein LG is halogenated, C 1-6 Alkoxy, benzyloxy or 4-OCH3-benzyloxy.

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