Compounds, compositions and methods

Abstract

The present disclosure relates generally to small molecule inhibitors of the 1 (SARM1) protein containing sterile alpha and TIR motifs, or pharmaceutically acceptable salts, isotopically enriched analogs, stereoisomers, stereoisomer mixtures or prodrugs thereof, methods of making and intermediates thereof, and methods of use thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 315,944, filed on March 2, 2022, and U.S. Provisional Application No. 63 / 345,869, filed on May 25, 2022, under 35 U.S.C. §119(e), the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates generally to small molecule modulators of sterile alpha and TIR motif-containing 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, which can progress to inability to move or speak, dementia, and ultimately death.

[0005] Axonal degeneration has been identified as an important 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 dimerization 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 a 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, 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.

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

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

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

[0015] 1. Definition

[0016] 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)NH 2 The term "a" or "b" refers to a group that is connected via a carbon atom. A dash at the front or end of a chemical group is for convenience; a chemical group may 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.

[0017] The prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0018] Mention herein that "about" a certain value or parameter includes (and describes) embodiments for the value or parameter itself. In certain embodiments, the term "about" includes an indication of ±10%. In other embodiments, the term "about" includes an indication of ±5%. In certain other embodiments, the term "about" includes an indication of ±1%. In addition, the term "about X" includes a description of "X". In addition, unless the context clearly specifies otherwise, the singular forms "one" and "the" include plural references. Therefore, for example, mentioning "compound" includes a plurality of such compounds, and mentioning "determination" includes mentioning one or more determinations known to those skilled in the art and their equivalents.

[0019] "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 carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons are contemplated; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 ), sec-butyl (i.e. -CH(CH 3 )CH 2 CH 3 ), isobutyl (i.e. -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e. -C(CH 3 ) 3 ); and "propyl" includes n-propyl (i.e. -(CH 2 ) 2 CH 3 ) and isopropyl (i.e. -CH(CH 3 ) 2 ).

[0020] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, divalent heteroaryl groups, etc. may also be referred to as "al kylene" groups or "alkylenyl" groups (e.g., methylene, ethylene, and propylene), "arylene" groups or "arylenyl" groups (e.g., phenylene or naphthylene or quinolyl for heteroarylene), respectively. In addition, unless otherwise expressly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last mentioned group contains the atoms with which the moiety is attached to the rest of the molecule.

[0021] "Alkenyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon double bond and having 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 (i.e. C 2-4 Examples of the alkenyl group include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0022] "Alkynyl" refers to a group containing at least one (e.g., 1-3 or 1) carbon-carbon triple bond and having 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.

[0023] “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.

[0024] "Alkoxyalkyl" refers to the group "alkyl-O-alkyl".

[0025] "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.

[0026] "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 include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0027] "Acylamino" refers to both: -C(O)NR y R z The "C-amido" group and the group -NR y C(O)R z An "N-amido" group, wherein 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.

[0028] "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.

[0029] "Carbamimidyl" 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.

[0030] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, 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 6-10The term "aryl" refers to a group consisting of a cycloalkyl, ...

[0031] "Arylalkyl" or "aralkyl" refers to the radical "aryl-alkyl-".

[0032] "Carbamyl" refers to both: -OC(O)NR y R z The "O-carbamyl" group and the group -NR y C(O)OR z An "N-carbamyl" group, wherein 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.

[0033] "Carboxyl ester" or "ester" refers to -OC(O)R x and -C(O)OR x Both, of which R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0034] "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.

[0035] "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 3-6Cycloalkyl). 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 the connection to the rest of the molecule. In addition, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, such as spiral [2.5] octyl, spiral [4.5] dodecyl or spiral [5.5] undecyl.

[0036] "Cycloalkylalkyl" refers to the radical "cycloalkyl-alkyl-".

[0037] "Imino" refers to the group -C(NR y )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.

[0038] "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.

[0039] "Halogen" or "halo" refers to an atom occupying Group VIIA of the Periodic Table of the Elements, such as fluorine, chlorine, bromine or iodine.

[0040] "Haloalkyl" refers to an unbranched or branched alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogen. For example, in the case where the residue is replaced by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl refer to alkyl substituted by two ("two") or three ("three") halogens, which may be, but not necessarily, the same halogen. 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.

[0041] "Haloalkoxy" refers to an alkoxy group as defined above wherein one or more (eg, 1 to 6 or 1 to 3) of the hydrogen atoms are replaced by a halogen.

[0042] "Haloalkoxyalkyl" refers to an alkoxyalkyl group as defined above wherein one or more (eg, 1 to 6 or 1 to 3) of the hydrogen atoms are replaced by a halogen.

[0043] "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.

[0044] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) (excluding any terminal carbon atoms) 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 y is 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., -CH 2 OCH 3 、-CH(CH 3 )OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 etc.), thioethers (e.g., -CH 2 SCH 3 、-CH(CH 3 )SCH 3 、-CH 2 CH 2 SCH 3 、-CH 2 CH 2 SCH 2 CH 2 SCH 3 etc.), sulfones (e.g., -CH 2 S(O) 2 CH 3 、-CH(CH 3 )S(O) 2 CH 3 、-CH 2 CH 2 S(O) 2CH 3 、-CH 2 CH 2 S(O) 2 CH 2 CH 2 OCH 3 etc.) and amines (e.g., -CH 2 NR y CH 3 、-CH(CH 3 )NR y CH 3 、-CH 2 CH 2 NR y CH 3 、-CH 2 CH 2 NR y CH 2 CH 2 NR y CH 3 etc., where R y is hydrogen, 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.

[0045] "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 (i.e., C 3-12 heteroaryl) or 3 to 8 carbon ring atoms (i.e. C 3-8The term "heteroaryl" refers to a 5-10 ring system, a 5-7 ring system, or a 5-6 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 include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl / benzothiophene 1-a]pyridinyl, 1-oxopyridyl, 1-oxopyridyl, 1-oxopyridyl, 1-oxopyridin ... Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolyl, isoquinolyl, benzo[b]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl may be attached via any one of the rings of the fused system. Any aromatic ring with single or multiple fused rings containing at least one heteroatom is considered a heteroaryl, regardless of how it is attached to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0046] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

[0047] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl (i.e., a heterocyclyl having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiro heterocyclyl. The heterocyclyl group may be monocyclic or polycyclic (wherein the polycyclic may be fused rings, bridged rings or spiro rings), and may contain one or more (e.g., 1 to 3) oxo (=O) moieties or N-oxides (-O -) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., attachment may be via a carbon atom or a heteroatom). In addition, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to a cycloalkyl, aryl, or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein, a heterocyclyl group has from 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic group) or 3 to 6 ring carbon atoms (i.e. C 3-6 heterocyclic 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 independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclic radicals include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepanyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolyl, indolizinyl, isoindolyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydro 1-dioxo-1-thiomorpholinyl, 1- ... 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 may be attached via either ring of the fused system.

[0048] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0049] "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.

[0050] "Sulfonyl" refers to the group -S(O) 2 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 sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0051] "Sulfinyl" refers to the group -S(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 sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0052] "Sulfonamide" refers to the group -SO 2 NR y R z and-NR y SO 2 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.

[0053] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, 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 by a moiety other than hydrogen.

[0054] 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) of the hydrogen atoms are 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, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH 2 , =NN H 2 , imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O) 2 OH, sulfonamide, thiol, thio, N-oxide or -Si(R y ) 3 , where each R y and R is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0055] 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)Rg 、-S(O) 2 R g 、-OS(O) 1-2 R g 、-S(O) 1-2 OR g 、-NR g S(O) 1-2 NR g R h , =NSO 2 R g , =NOR g 、-S(O) 1-2 NR g R h 、-SF 5 、-SCF 3 or -OCF 3 In certain embodiments, "substituted" also means any of the above groups, wherein one or more (eg, 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 、-CH 2 SO 2 R g or -CH 2 SO 2 NR g R h In the previous text, R g and 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 the following groups: 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 g and 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 optionally substituted with oxo, halo, amino, hydroxy or alkoxy.

[0056] Polymers or similar infinite structures that are achieved by infinitely defining substituents with other substituents attached (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 herein. Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of substituted aryl with two other substituted aryl groups is limited to aryl substituted with (aryl substituted with (substituted aryl)). Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein.

[0057] 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.

[0058] 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." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced by atoms 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, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure, such as 3 H and 14 Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques (e.g., positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or in radiotherapy of patients.

[0059] 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, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized using means well known in the art, for example, by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0060] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may 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 deuterium is considered a substituent in the compounds described herein in this context.

[0061] 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 in 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.

[0062] 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.

[0063] Pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, stereoisomers, stereoisomer mixtures, and prodrugs of the compounds described herein are also provided. "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.

[0064] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "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 in the form of 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, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic bases or organic bases. By way of example only, salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, 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., NH 2 (alkyl)), dialkylamine (i.e. HN(alkyl) 2 ), trialkylamine (ie N (alkyl) 3 ), substituted alkylamines (i.e. NH 2 (substituted alkyl)), di(substituted alkyl)amine (i.e. HN(substituted alkyl) 2 ), tri(substituted alkyl)amine (i.e. N(substituted alkyl) 3 ), alkenylamine (i.e. NH 2 (alkenyl)), dienylamine (i.e. HN(alkenyl) 2 ), trienylamine (i.e. N(enyl) 3 ), substituted alkenylamines (i.e. NH 2 (substituted alkenyl)), di(substituted alkenyl)amine (i.e. HN(substituted alkenyl) 2), tri(substituted alkenyl)amine (i.e. N(substituted alkenyl) 3 , monocyclic alkylamine, dicyclic alkylamine or tricyclic alkylamine (i.e. NH 2 (cycloalkyl), HN(cycloalkyl) 2 、N(cycloalkyl) 3 ), monoarylamine, diarylamine or triarylamine (i.e. NH 2 (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, and the like.

[0065] Some of the compounds exist in the form of 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 tautomers, it will be understood by those of ordinary skill in the art that compounds contain both amide and imidic acid tautomers. Therefore, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0066] The compounds of the present disclosure or their pharmaceutically acceptable salts include asymmetric centers and thus may produce enantiomers, diastereomers and other stereoisomeric forms, which may be defined as (R)- or (S)- or as (D)- or (L)- for amino acids in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may 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 / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0067] "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 refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0068] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0069] 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).

[0070] "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 manipulated 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), etc. 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 ACSSymposium Series; "Design of Prodrugs," H. Bundgaard, ed., Elsevier, 1985; and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated by reference in its entirety.

[0071] 2. Compounds

[0072] Provided herein are compounds that are inhibitors of SARM1. In certain embodiments, a compound of formula I is provided:

[0073]

[0074] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0075] X 1 , X 2 , X 3and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0076] R is tert-butyl, substituted by one to five R 8 Substituted C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C 3-10 Cycloalkyl or heterocyclic group; wherein the C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace;

[0077] R 1 Halogen, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(R11 ) 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 is independently optionally substituted by one to five Z 1 replace;

[0078] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0079] R 3 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 is independently optionally substituted by one to five Z 1 replace;

[0080] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0081] R 4 is hydrogen, halogen, 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)OR11 、-S(O)R 11 、-S(O) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0082] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0083] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0084] R 7 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 is independently optionally substituted by one to five Z 1 replace;

[0085] Each R 8 are independently halo, cyano, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(R 11 ) 2 、-OC(O)N(R 11 ) 2 or -NR 11 C(O)OR 11 wherein said C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0086] 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 is independently optionally substituted by one to five Z 1a replace;

[0087] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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)2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0088] 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 is independently optionally substituted by one to five Z 1b replace;

[0089] Each Z 1a are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0090] 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 is independently optionally substituted by one to five Z1b replace;

[0091] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0092] 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) 2 NH-;

[0093] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

[0094] In certain embodiments, the compound is not N-[3-[6-ethoxy-5-(tetrahydro-2H-pyran-4-yl)-3-pyridazinyl]-4-methylphenyl]-2,3-dihydro-1H-isoindole-5-carboxamide (CAS No. 1887220-28-1), (3R)-1-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl]-N-[4-hydroxy-3-(2-pyridyl)phenyl]-3-pyrrolidinecarboxamide (CAS No. 947607-02-5), 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide (CAS No. 134920 7-35-7), N-[3-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-methoxyphenyl]hexahydro-1,3-dimethyl-4,6-dioxo-2-thioxo-5-pyrimidinecarboxamide (CAS No. 102767-13-5), 1-(1,3-benzodioxol-5-yl)-N-[4-methyl-3-(2-pyridinyl)phenyl]-cyclopropanecarboxamide (CAS No. 945235-04-1), N-[4-[(4-propyl-1-piperazinyl)carbonyl]-3-(2-pyridinyl)phenyl]cyclopropanecarboxamide (CAS No. 2736488-37-0), 4,4'-(((2-(pyridin-2-yl)-1,4-phenylene)bis(azanediol) 1-hydroxycyclobutanecarboxamide (CAS No. 1443361-68-9), N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide (CAS No. 2080411-18-1), N-[3-(3-amino-1,2,4-triazine-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide (CAS No. 2080411-25-0), rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-hydroxycyclobutanecarboxamide (CAS No. 2080411-25-0), S No. 2850202-28-5), rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-3,3-difluorocyclobutanecarboxamide (CAS No. 2850202-29-6), rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-fluorocyclopropanecarboxamide (CAS No. 2850202-27-4) or rel-N-[3,4-Difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-(trifluoromethyl)cyclopropanecarboxamide (CAS No. 2850202-26-3). ,

[0095] In certain embodiments, when X 2 N, R 1 is methyl, R 4 is hydrogen or fluorine, and R 5 When X is hydrogen, 1 and X 3 In other words, in certain embodiments, when X 2 N, R 1 is methyl, R 4 is hydrogen or fluorine, and R 5 When X is hydrogen, 1 and X 3 None of them are CR 6 , where R 6 It is a morpholinyl group.

[0096] In certain embodiments, when R is -OR 7 When R 1 It is methyl.

[0097] In certain embodiments, when R is substituted C 1-6 When it is an alkyl group, R 1 is substituted or unsubstituted C 1-6 alkyl.

[0098] In certain embodiments, when R is substituted or unsubstituted heterocyclyl, the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted pyridin-2(1H)-onyl.

[0099] In certain embodiments, part Not 4,5-diethyl-6-hydroxypyrimidin-2-yl or 4,5-diethyl-1,6-dihydro-6-oxo-2-pyrimidinyl.

[0100] In certain embodiments, a compound of Formula I is provided:

[0101]

[0102] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0103] X 1 , X 2 , X3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0104] R is tert-butyl, substituted by one to five R 8 Substituted C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C 3-10 Cycloalkyl or heterocyclic group; and said C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace;

[0105] R 1 Halogen, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0106] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0107] R 3 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 is independently optionally substituted by one to five Z 1 replace;

[0108] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0109] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0110] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0111] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0112] R 7 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 is independently optionally substituted by one to five Z 1 replace;

[0113] Each R 8 are independently halo, cyano, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(R 11 ) 2 、-OC(O)N(R 11 ) 2 or -NR 11 C(O)OR 11 wherein said C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0114] 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 is independently optionally substituted by one to five Z 1a replace;

[0115] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0116] 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 is independently optionally substituted by one to five Z 1b replace;

[0117] Each Z 1a are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0118] 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 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace;

[0119] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0120] 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) 2 NH-;

[0121] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0122] The conditions are:

[0123] i) the compound is not N-[3-[6-ethoxy-5-(tetrahydro-2H-pyran-4-yl)-3-pyridazinyl]-4-methylphenyl]-2,3-dihydro-1H-isoindole-5-carboxamide, (3R)-1-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl]-N-[4-hydroxy-3-(2-pyridyl)phenyl]-3-pyrrolidinecarboxamide, 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide, N-[3-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-4-methoxyphenyl]hexahydro-1,3-dimethyl -4,6-dioxo-2-thioxo-5-pyrimidinecarboxamide, (3R,5aS,6R,8aS,9S,11R,11aR)-N-[4-chloro-3-(2-pyridyl)phenyl]octahydro-3,6,9-trimethyl-3,11-epoxy-3H,11H-furo[3,4-j]-1,2-benzodioxepane-9-carboxamide, 1-(1,3-benzodioxol-5-yl)-N-[4-methyl-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, N-[4-[(4-propyl-1-piperazinyl)carbonyl]-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, 4,4'-(((2-(pyridin-2-yl)-1,4 -phenylene)bis(azanediyl))bis(carbonyl))bis(cyclohexane-1-carboxylic acid) dibutyl ester, N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, N-[3-(3-amino-1,2,4-triazin-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, 2-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-[(4-morpholinylcarbonyl)amino]benzenesulfonic acid, N-[4-fluoro-3-[2-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-4-pyrimidinyl]phenyl]-1-piperazinecarboxamide, 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridinyl)- 1H-indole-1-carboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-hydroxycyclobutanecarboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-3,3-difluorocyclobutanecarboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-fluorocyclopropanecarboxamide or rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-(trifluoromethyl)cyclopropanecarboxamide;

[0124] ii) When X 2 N, R 1 is methyl, R 4 is hydrogen or fluorine, and R 5 When X is hydrogen, 1 and X 3 None of them are C-morpholinyl;

[0125] iii) When R is -OR 7 When R 1 is methyl;

[0126] iv) When R is a substituted C 1-6 When it is an alkyl group, R 1 is substituted or unsubstituted C 1-6 Alkyl; and

[0127] v) When R is a substituted or unsubstituted heterocyclic group, the substituted or unsubstituted heterocyclic group is not a substituted or unsubstituted pyridin-2(1H)-onyl group.

[0128] In certain embodiments, a compound of Formula I is provided:

[0129]

[0130] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0131] X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0132] R is tert-butyl, C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C3-10 Cycloalkyl or heterocyclic group; wherein the C 1-6 The alkyl group is replaced by one to five R 8 Replaced, and the C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace;

[0133] R 1 Halogen, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z1 replace;

[0134] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0135] R 3 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 is independently optionally substituted by one to five Z 1 replace;

[0136] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0137] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O)2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0138] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0139] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0140] R 7 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 is independently optionally substituted by one to five Z 1 replace;

[0141] Each R 8 are independently halo, cyano, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 )2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(R 11 ) 2 、-OC(O)N(R 11 ) 2 or -NR 11 C(O)OR 11 wherein said C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0142] 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 is independently optionally substituted by one to five Z 1a replace;

[0143] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0144] 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 is independently optionally substituted by one to five Z 1b replace;

[0145] Each Z 1a are independently halo, cyano, -NO 2 , 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) 2 R 13 、-C(O)N(R 13) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0146] 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 is independently optionally substituted by one to five Z 1b replace;

[0147] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 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

[0148] 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) 2 NH-;

[0149] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0150] The conditions are:

[0151] i) the compound is not N-[3-[6-ethoxy-5-(tetrahydro-2H-pyran-4-yl)-3-pyridazinyl]-4-methylphenyl]-2,3-dihydro-1H-isoindole-5-carboxamide, (3R)-1-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl]-N-[4-hydroxy-3-(2-pyridyl)phenyl]-3-pyrrolidinecarboxamide, 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridyl)phenyl]-6-(trifluoromethyl)-1H- Indole-1-carboxamide, N-[3-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-4-methoxyphenyl]hexahydro-1,3-dimethyl-4,6-dioxo-2-thioxo-5-pyrimidinecarboxamide, (3R,5aS,6R,8aS,9S,11R,11aR)-N-[4-chloro-3-(2-pyridinyl)phenyl]octahydro-3,6,9-trimethyl-3,11-epoxy-3H,11H-furo[3,4-j]-1,2-benzodioxepane-9-carboxamide, 1-(1,3 -benzodioxol-5-yl)-N-[4-methyl-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, N-[4-[(4-propyl-1-piperazinyl)carbonyl]-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, 4,4'-(((2-(pyridin-2-yl)-1,4-phenylene)bis(azanediyl))bis(carbonyl))bis(cyclohexane-1-carboxylic acid) dibutyl ester, N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, N-[3-(3-amino-1 , 2,4-triazine-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, 2-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-[(4-morpholinylcarbonyl)amino]benzenesulfonic acid, N-[4-fluoro-3-[2-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-4-pyrimidinyl]phenyl]-1-piperazinecarboxamide or 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide;

[0152] ii) When X 2 N, R 1 is methyl, R 4 is hydrogen or fluorine, and R 5 When X is hydrogen, 1 and X 3 None of them are C-morpholinyl;

[0153] iii) When R is -OR 7 When R 1 is methyl;

[0154] iv) When R is a substituted C 1-6 When it is an alkyl group, R 1 is substituted or unsubstituted C 1-6 Alkyl; and

[0155] v) When R is a substituted or unsubstituted heterocyclic group, the substituted or unsubstituted heterocyclic group is not a substituted or unsubstituted pyridin-2(1H)-onyl group.

[0156] In certain embodiments, R is tert-butyl, substituted by one to five R 8 Substituted C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace.

[0157] In certain embodiments, R is tert-butyl or is replaced by one to five R 8 Substituted C 1-6 alkyl.

[0158] In certain embodiments, R is tert-butyl.

[0159] In certain embodiments, R is replaced by one to five R 8 Substituted C 1-6 alkyl.

[0160] In certain embodiments, each R 8 are independently halogen, C 3-10 Cycloalkyl, heterocyclyl or -OR 11 In certain embodiments, each R 8 are independently halogen, C 3-10 Cycloalkyl, heterocyclyl or -OH.

[0161] In certain embodiments, R is C 3-10 Cycloalkyl or heterocyclic group; wherein the C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace.

[0162] In certain embodiments, R is optionally substituted with one to five Z 1 Substituted C 3-10 Cycloalkyl.

[0163] In certain embodiments, R is optionally substituted with one to five Z 1 Substituted heterocyclic group.

[0164] In certain embodiments, the compound is represented by Formula II:

[0165]

[0166] Where X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 and R 5 Each of is independently as defined herein.

[0167] In certain embodiments, a compound of formula II is provided:

[0168]

[0169] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0170] X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0171] R 1 Halogen, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0172] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0173] R 3 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 is independently optionally substituted by one to five Z 1 replace;

[0174] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0175] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0176] R 5 is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Cycloalkyl, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0177] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0178] 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 is independently optionally substituted by one to five Z 1a replace;

[0179] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0180] 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, C3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1b replace;

[0181] Each Z 1a are independently halo, cyano, -NO 2 , 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0182] Each R 13are 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 is independently optionally substituted by one to five Z 1b replace;

[0183] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0184] 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) 2 NH-;

[0185] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0186] Provided that the compound is not N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, N-[3-(3-amino-1,2,4-triazin-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, 2-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-[(4-morpholinylcarbonyl)amino]benzenesulfonic acid, N-[4-fluoro-3-[2-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-4-pyrimidinyl]phenyl]-1-piperazinecarboxamide or 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridinyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide, and when X 2 N, R 1 is methyl, R 4 is hydrogen and R 5 When X is hydrogen, 1 and X 3 It is C-morpholinyl.

[0187] In certain embodiments, the compound is represented by Formula III:

[0188]

[0189] Where X 1 , X 2 , X 3 , X 4 , R 1 , R 4 , R 5 and R 7 Each of is independently as defined herein.

[0190] In certain embodiments, R 7 C 1-6 alkyl.

[0191] In certain embodiments, X 1 is N.

[0192] In certain embodiments, X 2 , X 3 and X 4 CR 6 .

[0193] In certain embodiments, X 2 is N.

[0194] In certain embodiments, X 1 , X 3 and X 4 CR 6 .

[0195] In certain embodiments, X 3 is N.

[0196] In certain embodiments, X 1 , X 2 and X 4 CR 6 .

[0197] In certain embodiments, X 4 is N.

[0198] In certain embodiments, X 1 , X 2 and X 3 CR 6 .

[0199] In certain embodiments, X 1 and X 3 is N.

[0200] In certain embodiments, X 2 and X 4 CR 6 .

[0201] In certain embodiments, X 1 and X 4 is N.

[0202] In certain embodiments, X 2 and X 3 CR 6 .

[0203] In certain embodiments, X 2 and X 4 is N.

[0204] In certain embodiments, X 1 and X 3 CR 6 .

[0205] In certain embodiments, X 3 and X 4 is N.

[0206] In certain embodiments, X 1 and X 2 CR 6 .

[0207] In certain embodiments, R 4 It is hydrogen, fluorine, chlorine, bromine, cyano or methyl.

[0208] In certain embodiments, R 4 For hydrogen.

[0209] In certain embodiments, R 5 is hydrogen or fluorine.

[0210] In certain embodiments, R 5 is hydrogen, fluorine or chlorine.

[0211] In certain embodiments, R 4 and R 5 In certain embodiments, the compound is represented by Formula IA:

[0212]

[0213] Each of R, R 1 and R 6 Independently as defined herein.

[0214] In certain embodiments, the compound is represented by Formula IIA:

[0215]

[0216] Each R 1 , R 2 , R 3 and R 6 Independently as defined herein.

[0217] In certain embodiments, the compound is represented by Formula IIIA:

[0218]

[0219] Each R 1 , R 6 and R 7Independently as defined herein.

[0220] In certain embodiments, the compound is represented by Formula IIB:

[0221]

[0222] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0223] In certain embodiments, the compound is represented by Formula IIB-1:

[0224]

[0225] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0226] In certain embodiments, the compound is represented by Formula IIB-2:

[0227]

[0228] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0229] In certain embodiments, the compound is represented by Formula IIC:

[0230]

[0231] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0232] In certain embodiments, the compound is represented by Formula IID:

[0233]

[0234] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0235] In certain embodiments, the compound is represented by Formula IIE:

[0236]

[0237] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0238] In certain embodiments, the compound is represented by Formula IIE:

[0239]

[0240] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0241] In certain embodiments, the compound is represented by Formula IIE:

[0242]

[0243] Where R 1 , R 2 , R 3 and R 6 Each of is independently as defined herein.

[0244] In certain embodiments, a compound of formula IV is provided:

[0245]

[0246] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0247] R 1 Hydrogen, halogen, cyano, -NO 2 , 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) 2 R 11、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0248] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0249] R 3 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, C3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0250] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0251] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0252] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0253] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , C1-6 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0254] 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, C2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0255] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1areplace;

[0256] 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 is independently optionally substituted by one to five Z 1b replace;

[0257] Each Z 1a are independently halo, cyano, -NO 2 , 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0258] 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 is independently optionally substituted by one to five Z 1b replace;

[0259] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0260] 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(C2-6 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) 2 NH-;

[0261] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0262] The conditions are:

[0263] Part a) Not for and

[0264] b) the compound is not N-[3-[4-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-2-pyrimidinyl]phenyl]-1-piperazinecarboxamide, N-[3-[4-(1H-indazol-5-ylamino)-2-pyrimidinyl]phenyl]-4-morpholinecarboxamide, N-[3-ethyl-5-(2-pyrimidinyl)phenyl]-7,8-dihydro-4-(2-methylphenyl)-2-(3-pyridinyl)pyrido[4,3-d]pyrimidine-6(5H)-carboxamide or 5-[[(1,1-dimethylethoxy)carbonyl][2-[3-[(4-morpholinylcarbonyl)amino]phenyl]-4-pyrimidinyl]amino]-1H-indazole-1-carboxylic acid 1,1-dimethylethyl ester.

[0265] In certain embodiments, each R 6 are independently hydrogen, halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10Cycloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl.

[0266] In certain embodiments, each R 6 are independently hydrogen, halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl or -OC 1-6 alkyl.

[0267] In certain embodiments, each R 6 and R is independently hydrogen, fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl, methoxy, 2-methoxyethoxymethyl, fluoromethoxy or difluoromethoxy.

[0268] In certain embodiments, each R 6 are independently hydrogen, fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, cyclopropyl or methoxy.

[0269] In certain embodiments, each R 6 are independently hydrogen, fluorine, cyano, methyl, trifluoromethyl, cyclopropyl or methoxy.

[0270] In certain embodiments, R 6 Not hydroxyl.

[0271] In certain embodiments, R 1 For halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl or -OR 11 wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl or aryl is optionally substituted by one to five Z 1 replace.

[0272] In certain embodiments, R 1 For halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl or -OR 11 wherein said C 1-6 Alkyl or C 3-10 The cycloalkyl group is optionally substituted with one to five Z 1 replace.

[0273] In certain embodiments, R 1 Fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CN, -OCF3 , cyclopropyl optionally substituted with methyl, or phenyl.

[0274] In certain embodiments, R 1 Fluorine, chlorine, cyano, methyl, ethyl, -CF 3 、-CH 2 CN, -OCF 3 Or cyclopropyl.

[0275] In certain embodiments, R 1 Fluorine, chlorine, cyano, methyl, ethyl, isopropyl, -CHF 2 , -CF 3 、-CH 2 CN, -OCF 3 , cyclopropyl optionally substituted with methyl, or phenyl.

[0276] In certain embodiments, R is replaced by one to five R 8 Substituted C 1-6 In certain embodiments, R is substituted by one to five R 8 Substituted C 1-2 alkyl.

[0277] In certain embodiments, each R 8 are independently halogen, C 3-10 Cycloalkyl, heterocyclyl or -OR 11 In certain embodiments, each R 8 are independently halogen, C 3-10 Cycloalkyl, heterocyclyl or -OH.

[0278] In certain embodiments, R is:

[0279]

[0280] In certain embodiments, R is optionally substituted with one to five Z 1 Substituted C 3-10 In certain embodiments, R is optionally substituted with one to five Z 1 Substituted C 3-7 Cycloalkyl.

[0281] In certain embodiments, R is:

[0282] Each of which is independently optionally replaced by one to five Z 1 replace.

[0283] In certain embodiments, R is:

[0284] Each of which is independently optionally replaced by one to five Z 1 replace.

[0285] In certain embodiments, each Z 1 are independently halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 A haloalkoxy group or a hydroxy group.

[0286] In certain embodiments, R is:

[0287]

[0288] In certain embodiments, R is:

[0289]

[0290] In certain embodiments, R is:

[0291]

[0292] In certain embodiments, R is optionally substituted with one to five Z 1 Substituted heterocyclyl. In certain embodiments, the heterocyclyl is bonded to the carbonyl portion of the amide via a carbon atom.

[0293] In certain embodiments, R is optionally substituted with one to five Z 1 Substituted 4- to 7-membered heterocyclyl.

[0294] In certain embodiments, R is:

[0295] Each of which is independently optionally replaced by one to five Z 1 replace.

[0296] In certain embodiments, R is:

[0297] Each of which is independently optionally replaced by one to five Z 1 replace.

[0298] In certain embodiments, each Z 1 Independently for C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 11 、-C(O)R 11 , C 3-10 Cycloalkyl, aryl or heteroaryl.

[0299] In certain embodiments, each Z1 Independently for C 1-6 Haloalkyl.

[0300] In certain embodiments, R is:

[0301]

[0302]

[0303] In certain embodiments, R is:

[0304]

[0305] In certain embodiments, R is -OR 7 , where R 7 is optionally replaced by one to five Z 1 Substituted C 1-6 alkyl.

[0306] In certain embodiments, Z1 is independently C 3-10 Cycloalkyl or aryl.

[0307] In certain embodiments, R or a portion for:

[0308]

[0309] In certain embodiments, R or a moiety of a formula described herein for: Each of which is independently optionally replaced by one to five Z 1 replace.

[0310] In certain embodiments, R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace.

[0311] In certain embodiments, R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by halo, -OH, -C(O)OC 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, aryl or heteroaryl; wherein the C 1-6 The alkyl or heteroaryl group is optionally substituted by one to five Z 1a replace.

[0312] In certain embodiments, R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -OH, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, aryl or -C(O)OC 1-6 Alkyl substitution.

[0313] In certain embodiments, the compound is represented by Formula IIF:

[0314]

[0315] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0316] In certain embodiments, the compound is represented by Formula IIG:

[0317]

[0318] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0319] In certain embodiments, the compound is represented by Formula IIG-1:

[0320]

[0321] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0322] In certain embodiments, the compound is represented by Formula IIG-2:

[0323]

[0324] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R1 and R 6 Independently as defined herein.

[0325] In certain embodiments, the compound is represented by Formula IIH:

[0326]

[0327] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0328] In certain embodiments, the compound is represented by Formula IIJ:

[0329]

[0330] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0331] In certain embodiments, the compound is represented by Formula IIK:

[0332]

[0333] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0334] In certain embodiments, the compound is represented by Formula IIK:

[0335]

[0336] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z 1 Replace, and each R 1 and R 6 Independently as defined herein.

[0337] In certain embodiments, the compound is represented by Formula IIK:

[0338]

[0339] Wherein ring A is a 4-15 membered heterocyclic group, which may be further independently optionally substituted by one to five Z1 Replace, and each R 1 and R 6 Independently as defined herein.

[0340] In certain embodiments, R, a portion of the formula described herein Or ring A is:

[0341] Each of which is independently optionally replaced by one to five Z 1 replace.

[0342] In certain embodiments, R, a portion of the formula described herein Or ring A is: Each of which is independently optionally replaced by one to five Z 1 replace.

[0343] In certain embodiments, each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, heteroaryl, -OR 12 or-C(O)OR 12 ; Each C 1-6 Alkyl, C 1-6 The haloalkyl and heteroaryl groups are independently optionally substituted with one to five hydroxyl groups, methoxy groups or methyl groups.

[0344] In certain embodiments, each Z 1 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, heteroaryl, C 1-6 Alkoxy or -C(O)OC 1-6 Alkyl; each C 1-6 Alkyl, C 1-6 The haloalkyl and heteroaryl groups are independently optionally substituted with one to five hydroxyl groups, methoxy groups or methyl groups.

[0345] In certain embodiments, R, a portion of the formula described herein Or ring A is:

[0346]

[0347]

[0348] In certain embodiments, R, a portion of the formula described herein Or ring A is:

[0349]

[0350]

[0351] In certain embodiments, R, a portion of the formula described herein Or ring A is:

[0352]

[0353]

[0354] In certain embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, prodrug, stereoisomer or stereoisomer mixture thereof is provided:

[0355] Table 1

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] In certain embodiments, a compound selected from Table 2 or a pharmaceutically acceptable salt thereof is provided.

[0396] Table 2

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] 3. Methods

[0441] "Treatment" or "treating" is an approach for obtaining a beneficial or desired result, including a clinical result. A beneficial or desired clinical result may include one or more of the following: a) inhibiting a 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 stabilizing 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 deterioration 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., regression of 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 the quality of life and / or prolonging survival).

[0442] "Prevention" or "preventing" means the treatment of any disease or disorder that causes clinical symptoms of the disease or disorder not to develop. In certain embodiments, the compound may be administered to a subject (including a human) who is at risk for the disease or disorder or has a family history of the disease or disorder.

[0443] "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 applicable to human therapy and / or veterinary applications. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0444] 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 achieve treatment to provide a therapeutic benefit (e.g., improving symptoms or slowing disease progression) when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to alleviate the symptoms of a disease or disorder as described herein. The therapeutically effective amount may vary depending on the subject and disease or disorder to be treated, the subject's weight and age, the severity of the disease or disorder, and the mode of administration, which can be readily determined by one of ordinary skill in the art.

[0445] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as within an animal or human. In this case, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained using methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this case, 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 for the compounds disclosed herein 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 regimen. 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 check safety or tolerable doses in human or non-human subjects. Such properties can be checked using methods generally known to those skilled in the art.

[0446] In certain embodiments, provided are compounds that inhibit the activity of a protein containing sterile alpha and a TIR motif 1 (SARM1), or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof. In certain embodiments, provided herein are compounds, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers, or a prodrug thereof, that inhibit SARM1.

[0447] In certain methods, uses and compositions provided herein, the compound is a compound of Formula I:

[0448]

[0449] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0450] X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0451] R is C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0452] R 1 Hydrogen, halogen, cyano, -NO 2 , 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) 2 R 11、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0453] R 2 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 is independently optionally substituted by one to five Z 1 replace;

[0454] R 3 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, C3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0455] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0456] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 3-10Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0457] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0458] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , C1-6 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0459] R 7 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 2-6Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0460] Each R 8 are independently halo, cyano, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(R 11 ) 2 、-OC(O)N(R 11 ) 2 or -NR 11 C(O)OR 11 wherein said C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0461] 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 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0462] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z1a replace;

[0463] 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 is independently optionally substituted by one to five Z 1b replace;

[0464] Each Z 1a are independently halo, cyano, -NO 2 , 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13 C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0465] 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 is independently optionally substituted by one to five Z 1b replace;

[0466] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0467] 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 2-6alkenyl)-, -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) 2 NH-;

[0468] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

[0469] In certain methods, uses and compositions provided herein, the compound is a compound of formula II, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0470]

[0471] or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein:

[0472] X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N;

[0473] R 1 Halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0474] R 2 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 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0475] R 3 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 is independently optionally substituted by one to five Z 1 replace;

[0476] or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace;

[0477] R 4 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0478] R 5 is hydrogen, halogen, 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 is independently optionally substituted by one to five Z 1 replace;

[0479] Each R 6 are independently hydrogen, halide, cyano, -NO 2 , 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) 2 R 11 、-C(O)N(R 11 ) 2 、-NR 11 C(O)R 11 、-NR 11 S(O)R 11 、-NR 11 S(O) 2 R 11 、-S(O)N(R 11 ) 2 、-S(O) 2 N(R 11 ) 2 、-NR 11 C(O)N(R 11 ) 2 、-NR 11 S(O)N(R 11 ) 2 、-NR 11 S(O) 2 N(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 2-6Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace;

[0480] 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 is independently optionally substituted by one to five Z 1a replace;

[0481] Each Z 1 are independently halo, cyano, -NO 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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) 2 R 12 、-C(O)N(R 12 ) 2 、-NR 12 C(O)R 12 、-NR 12 S(O)R 12 、-NR 12 S(O) 2 R 12 、-S(O)N(R 12 ) 2 、-S(O) 2 N(R 12 ) 2 、-NR 12 C(O)N(R 12 ) 2 、-NR 12 S(O)N(R 12 ) 2 、-NR 12 S(O) 2 N(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 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1a replace;

[0482] 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 is independently optionally substituted by one to five Z 1b replace;

[0483] Each Z 1a are independently halo, cyano, -NO 2 , 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) 2 R 13 、-C(O)N(R 13 ) 2 、-NR 13 C(O)R 13 、-NR 13 S(O)R 13 、-NR 13 S(O) 2 R 13 、-S(O)N(R 13 ) 2 、-S(O) 2 N(R 13 ) 2 、-NR 13C(O)N(R 13 ) 2 、-NR 13 S(O)N(R 13 ) 2 、-NR 13 S(O) 2 N(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 is independently optionally substituted by one to five Z 1b replace;

[0484] 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 is independently optionally substituted by one to five Z 1b replace;

[0485] Each Z 1b are independently halo, cyano, -OH, -SH, -NH 2 、-NO 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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

[0486] Each L is independently -O-, -NH-, -S-, -S(O)-, -S(O)- 2 -、-N(C 1-6 Alkyl)-, -N(C 2-6alkenyl)-, -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) 2 NH-;

[0487] Where Z 1b and each C of L 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl and heteroaryl are further independently optionally substituted by one to five halo, cyano, -OH, -SH, -NH 2 、-NO 2 、-SF 5 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution;

[0488] In certain embodiments, the compound is not N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide.

[0489] In certain embodiments, the compound is not N-[3-(3-amino-1,2,4-triazin-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide.

[0490] In certain embodiments, the compound is not 2-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-[(4-morpholinylcarbonyl)amino]benzenesulfonic acid.

[0491] In certain embodiments, the compound is not N-[4-fluoro-3-[2-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-4-pyrimidinyl]phenyl]-1-piperazinecarboxamide.

[0492] In certain embodiments, the compound is not or 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridinyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide.

[0493] In certain embodiments, when X 2 N, R 1 is methyl, R 4 is hydrogen, and R 5 When X is hydrogen, 1 and X 3 None of them is C-morpholinyl.

[0494] In certain embodiments, a method of inhibiting SARM1 activity is provided, the method 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 may be in vitro or in vivo.

[0495] In certain embodiments, provided is a compound as 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).

[0496] In certain embodiments, the present disclosure provides use of a compound as 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).

[0497] In certain embodiments, a compound as disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof is provided for inhibiting the NADase activity of SARM1. In certain embodiments, a method of inhibiting SARM1 NADase activity and / or treating neurodegeneration or a nervous system disease or disorder 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 a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof.

[0498] In certain embodiments, a method for treating a disease or condition mediated at least in part by SARM1 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.

[0499] In certain embodiments, a method for treating axonal degeneration 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 a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof. In certain embodiments, the compound or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug inhibits axonal degeneration, including axonal degeneration caused by reduction or depletion of NAD+. In certain embodiments, the compound or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug prevents axonal degeneration distal to axonal injury.

[0500] In certain embodiments, a method for treating degeneration of peripheral nervous system neurons or a portion thereof 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.

[0501] In certain embodiments, a method for treating degeneration of central nervous system neurons or a portion thereof 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.

[0502] In certain embodiments, the treating comprises reducing one or more symptoms or characteristics of neurodegeneration.

[0503] In certain embodiments, a method for inhibiting axonal degeneration 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.

[0504] In certain embodiments, a method for treating a neurodegenerative or nervous system disease or disorder 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.

[0505] In certain embodiments, a method for treating axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, neurological injury disease or condition, 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, stereoisomer mixture or prodrug thereof.

[0506] In certain embodiments, provided is a compound as 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.

[0507] In certain embodiments, provided is a compound as 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.

[0508] In certain embodiments, the present disclosure provides use of a compound as 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.

[0509] In certain embodiments, the present disclosure provides the use of a compound as 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 nervous system 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, mitochondrial disease, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

[0510] In certain embodiments, the disease or disorder is an acute disorder. In certain embodiments, the disease or disorder is a chronic disorder.

[0511] In certain embodiments, the disease or disorder is characterized by axonal degeneration in the central nervous system, the peripheral nervous system, the optic nerves, the cranial nerves, or a combination thereof.

[0512] In certain embodiments, the disease or illness 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 illness 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 illness is or comprises chronic traumatic encephalopathy (CTE).

[0513] 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 disease, or Alzheimer's disease.

[0514] 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 a variety of 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).

[0515] In certain embodiments, the disease or disorder 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.

[0516] In certain embodiments, the disease or condition is glaucoma (see, e.g., Ko, KW et al., J. Cell Bio. 2020, 219(8), e201912047).

[0517] 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.

[0518] 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 congenital amaurosis, Leber hereditary optic neuropathy (LHON), primary open-angle glaucoma, or autosomal dominant optic atrophy.

[0519] 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).

[0520] In certain embodiments, one or more compounds and / or compositions as described herein can be used, for example, to treat one or more neurodegenerative diseases, disorders or illnesses selected from the group consisting of neuropathy or axonopathy. In certain embodiments, one or more compounds and / or compositions as 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.

[0521] In certain embodiments, one or more compounds or compositions as described herein are characterized by, when applied to a subject population, reducing one or more symptoms or features of neurodegeneration. For example, in certain embodiments, the relevant symptoms or features 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, synaptic loss, dendrite loss, synaptic density loss, dendrite arborization loss, axonal branch loss, neuronal density loss, myelination loss, neuronal cell body loss, synaptic enhancement loss, action potential enhancement loss, cytoskeleton stability loss, axonal transport loss, ion channel synthesis and conversion loss, neurotransmitter synthesis loss, neurotransmitter release and reuptake ability 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 occurrence of inclusion bodies, plaques and / or neurofibrillary tangles. In certain embodiments, neuronal destruction is characterized by the occurrence of stress granules. In certain embodiments, neuron destruction is characterized by one or more members of the cysteine-aspartic acid protease (Caspase) family being activated in the cell. In certain embodiments, neuron destruction is characterized by neuron undergoing programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis and / or necrosis) and / or inflammation.

[0522] In certain embodiments, the neurodegeneration or neurological disease or disorder is associated with axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, a neurological injury disease or disorder, a metabolic disease, mitochondrial disease, metabolic axonal degeneration, axonal damage caused by 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), Waller's 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, 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, tropical spastic paresis, human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy, west Nile virus encephalopathy, La Crosse virus encephalitis, Bunyavirus encephalitis encephalitis, viral encephalitis in children, 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), Friedrich's 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-Barre 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 disease, Strumpell-Lorrain disease, or nonalcoholic steatohepatitis (NASH).

[0523] In certain embodiments, the disclosure provides a SARM1 activity inhibitor for treating neurodegeneration or neurological diseases or conditions involving axonal degeneration or axonopathy. The disclosure also provides methods of using SARM1 activity inhibitors to treat, prevent or improve axonal degeneration, axonopathy and neurodegeneration or neurological diseases or conditions involving axonal degeneration. In certain embodiments, the disclosure provides a method for inhibiting axonal degeneration, the method comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof to a subject in need thereof.

[0524] In certain embodiments, the present disclosure provides methods of treating axonal degeneration, axonal damage, axonopathy, demyelinating disease, central pontine myelinolysis, neurological damage diseases or disorders, metabolic diseases, mitochondrial diseases, metabolic axonal degeneration, axonal damage caused by white matter disease, or leukodystrophy.

[0525] In certain embodiments, neuropathy and axonopathy include any disease or illness involving neurons and / or supporting cells, such as glial cells, muscle cells or fibroblasts, and particularly those diseases or illnesses involving axonal damage. Axonal damage can be caused by traumatic injury or by non-mechanical damage caused by disease, illness or exposure to toxic molecules or drugs. The result of such damage can be degeneration or dysfunction of axons and loss of functional neuronal activity. Diseases and illnesses that produce or are relevant to such axonal damage are one of a large number of neurological diseases and illnesses. Such neuropathy can include peripheral neuropathy, central neuropathy or a combination thereof. 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 substantially peripheral or systemic diseases.

[0526] In certain embodiments, peripheral neuropathy may involve damage to peripheral nerves and / or may be caused by a neurological disease or as a result of a systemic disease. Some such diseases include diabetes, uremia, infectious diseases such as 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 injuries, contusions, fractures, or dislocations; pressure involving 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.

[0527] In certain embodiments, peripheral neuropathy is a metabolic and endocrine neuropathy, which includes a wide spectrum of peripheral neuropathy associated with metabolic systemic diseases. These diseases include, for example, diabetes, hypoglycemia, uremia, hypothyroidism, liver failure, polycythemia, amyloidosis, acromegaly, porphyria, lipid / glycolipid metabolism disorders, nutrition / vitamin deficiency or mitochondrial disorders. The common hallmark of these diseases is that the structure or function of myelin and axons is changed due to metabolic pathway disorders, thereby involving peripheral nerves.

[0528] 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 neuropathy 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.

[0529] In certain embodiments, neurodegenerative diseases associated with neuropathy or axonopathy in the central nervous system include a variety of diseases. Such diseases include those involving the following: progressive dementia, such as Alzheimer's disease, senile dementia, Pick's disease and Huntington's disease; central nervous system diseases affecting 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 agents) can lead to central nervous system neuropathy.

[0530] In certain embodiments, the 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 may 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, the above-mentioned neurodegenerative diseases and subsets of the above-mentioned diseases can also be treated with the methods of the present disclosure. Such disease subsets may include Parkinson's disease or Alzheimer's disease.

[0531] 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 developing 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 developing a disease characterized by axonal degeneration. In certain embodiments, 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, the subject is identified as having a risk of axonal degeneration.

[0532] In certain embodiments, the subject is at risk of developing 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 neurodegenerative diseases. 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.

[0533] In certain embodiments, neurodegenerative diseases, disorders or conditions may 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).

[0534] In certain embodiments, the subject has been 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 high chance of developing traumatic neuronal injury or TBI.

[0535] In certain embodiments, a method for treating a neurodegenerative disease, disorder or illness is provided, the method comprising administering one or more of a compound as described herein and a DLK inhibitor or a NAMPT inhibitor to a patient in need. 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. 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.

[0536] 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 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 a 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.

[0537] Exemplary DLK inhibitors are provided in WO2013174780, WO2014111496, WO2014177524, WO2014177060, WO2015091889, WO2016142310, US20180057507, WO2018107072, WO2019241244, WO2020168111, and CN104387391A, which are hereby incorporated by reference in their entireties.

[0538] 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.

[0539] In certain embodiments, NAMPT inhibitors prevent the formation of nicotinamide mononucleotide (NMN). In certain embodiments, inhibition of NAMPT inhibits the mammalian NAD+ salvage pathway.

[0540] In certain embodiments, provided compositions include a compound as described herein, formulated for administration to a subject in combination with a DLK inhibitor and / or a NAMPT inhibitor.

[0541] In certain embodiments, provided compositions include compounds as described herein for use in combination with a DLK inhibitor and / or a NAMPT inhibitor. In certain embodiments, such compositions are pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0542] 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).

[0543] In certain embodiments, SARM1 inhibition as described herein can be used in combination with one or more other therapies to treat related diseases, disorders or illnesses. In certain embodiments, the administration of the SARM1 inhibitor is changed when used in the combination therapy compared to when it is administered as a monotherapy; alternatively or in addition, the therapy administered in combination with SARM1 inhibition as described herein is administered according to a different scheme or protocol when it is administered alone or in combination with one or more therapies other than SARM1 inhibition. In certain embodiments, a composition comprising an additional therapeutic agent, the additional therapeutic agent and the provided compound can act synergistically. In certain embodiments, one or two therapies used in the combination regimen are administered at a lower level or less frequency than when they are used as a monotherapy.

[0544] In certain embodiments, a compound provided herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, or a composition thereof and 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 B 3 ) are used in combination.

[0545] In certain embodiments, a compound as disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof is provided for use in inhibiting the activity of sterile alpha and TIR motif-containing protein 1 (SARM1) (e.g., in vitro or in vivo).

[0546] In certain embodiments, the present disclosure provides a compound as disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug thereof in the manufacture of a method for inhibiting the activity of sterile alpha and TIR motif-containing protein 1 (SARM1) (e.g., in vitro or in vivo) and supplementing axonal NAD + Use in pharmaceutical preparations of the level.

[0547] 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.

[0548] In certain embodiments, a method for treating a disease or condition mediated at least in part by SARM1 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, stereoisomer mixture, or prodrug thereof and NAD + or NAD + Precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3 ) combination.

[0549] In certain embodiments, the present disclosure provides a compound as disclosed herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof and NAD + or NAD + Precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3 ) in the manufacture of a medicament for treating or preventing a neurodegenerative disease in a subject in need thereof.

[0550] In certain embodiments, a method for treating any disease caused by SARM1 activity 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, stereoisomer mixture or prodrug thereof and NAD + or NAD + Precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3 ) combination.

[0551] In certain embodiments, the disease or disorder may be a disease or disorder of the central nervous system and / or may 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.

[0552] In certain embodiments, a method for treating a neurodegenerative disease 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, stereoisomer mixture, or prodrug thereof and NAD + or NAD + Precursors (e.g., NR, NA, NaR, NAM, NMN, NaMN, TRP, NAAD, or vitamin B 3 ) combination.

[0553] Other embodiments include the use of the compounds disclosed herein in therapy.

[0554] 4. Medicine Box

[0555] Also provided herein is a medicine kit, which includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug, and suitable packaging. In certain embodiments, the medicine kit also includes instructions for use. In one aspect, the medicine kit includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, a mixture of stereoisomers or a prodrug and a label and / or instructions for the compound in a therapeutic indication (including a disease or disorder described herein).

[0556] Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture, or prodrug thereof in a suitable container. The container may be a vial, a jar, an ampoule, a preloaded syringe, or an intravenous bag.

[0557] 5. Pharmaceutical composition and mode of administration

[0558] 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, stereoisomer mixtures 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 (GS Banker and CT Rhodes).

[0559] 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 intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant.

[0560] One mode of administration is parenteral administration, such as by injection. The pharmaceutical compositions described herein may be combined with forms for administration by injection including, for example, aqueous or oil suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose or sterile aqueous solutions and similar pharmaceutical vehicles.

[0561] Oral administration can be another route of administration for the compounds described herein. Administration can be via, for example, 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 may be in the form of a capsule, a sachet, paper, or other container. When an excipient is used as a diluent, it may 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 may be in the form of tablets, pills, powders, lozenges, sachets, pouches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), ointments containing, for example, up to 10% by weight of active compounds, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0562] Some examples of suitable excipients include, for example, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0563] Compositions including at least one compound described herein or its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, stereoisomer mixture or prodrug can be formulated by using procedures known in the art so as 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 polymer coating reservoirs or drug-polymer matrix formulations. Another preparation used in the methods disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide compounds described herein with continuous or discontinuous infusions of controlled amounts. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches can be configured for continuous, pulsating or on-demand delivery of pharmaceutical agents.

[0564] To prepare solid compositions such as tablets, the principal active ingredient may 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.

[0565] The tablet or pill of compound as herein described can be coated or otherwise compounded, to provide the dosage form that can provide the advantage of prolonged action, or to protect it from the influence of the acidic conditions of the stomach.For example, tablet or pill can include inner dosage and outer dosage component, the latter is the shell form on the former.These two components can be separated by enteric layer, and the enteric layer is used to resist the disintegration in the stomach, and allows the inner component to enter the duodenum intact or delay release.Various materials can be used for such enteric layer or coating, and such materials include a mixture of various polymeric acids and polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0566] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the composition is administered via the oral or nasal respiratory route for local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent 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 mask inhaler or an 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.

[0567] The amount of the compound in the pharmaceutical composition or formulation can vary within the full range used by those skilled in the art. Typically, the formulation will contain about 0.01-99.99wt% 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 1-80wt%. Representative pharmaceutical formulations are described below.

[0568] Formulation Example 1 - Tablet Formulation

[0569] The following ingredients are mixed thoroughly and compressed into single scored tablets.

[0570]

[0571] Formulation Example 2 - Capsule Formulation

[0572] Mix the following ingredients thoroughly and pack into hard shell gelatin capsules

[0573]

[0574] Formulation Example 3 - Suspension Formulation The following ingredients are mixed to form a suspension for oral administration.

[0575] Element quantity Compounds of the Disclosure 1.0g Fumaric acid 0.5g Sodium chloride 2.0g Methylparaben 0.15g Propylparaben 0.05g granulated sugar 25.0g Sorbitol (70% solution) 13.00g Veegum K (Vanderbilt Co.) 1.0g Flavoring 0.035mL Colorants 0.5mg Distilled water Make up to 100mL

[0576] Formulation Example 4 - Injectable Formulation The following ingredients are mixed to form an injectable formulation.

[0577] Element quantity Compounds of the Disclosure 0.2mg-20mg Sodium acetate buffer solution, 0.4 M 2.0mL HCl (1N) or NaOH (1N) Make up to the appropriate pH Water (distilled, sterile) Make up to 20mL

[0578] Formulation Example 5 - Suppository Formulation

[0579] By combining the compounds of the present disclosure with H-15 (triglycerides of saturated vegetable fatty acids; Riches-Nelson, Inc., New York) was mixed to prepare a suppository with a total weight of 2.5 g and having the following composition:

[0580]

[0581] 6. Administration

[0582] 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 (mg / kg) of the compound described herein per kilogram of subject body weight. 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 / kg body weight, about 0.001 to about 50 mg compound / kg body weight or about 0.01 to about 10 mg compound / kg body weight per day may be appropriate. Normalization to the subject's body weight is particularly useful when adjusting a dose between subjects of widely varying sizes, such as when using the drug in children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose suitable for a human subject.

[0583] 7. Synthesis of compounds

[0584] Compounds can be prepared using methods disclosed herein and conventional modifications thereof (which will be apparent in view of the disclosure herein and methods well known in the art). In addition to the teachings herein, conventional and well-known synthetic methods can also be used. The synthesis of typical compounds described herein can be achieved as described in the following examples. If available, reagents and starting materials can be commercially available from, for example, Sigma Aldrich or other chemical suppliers.

[0585] It should be understood that, unless otherwise stated, where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, other process conditions may also be used. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions can be determined by one skilled in the art through routine optimization procedures.

[0586] In addition, conventional protecting groups ("PG") may be necessary to prevent certain functional groups from undergoing undesired reactions. Protecting groups suitable for various functional groups and conditions suitable for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in Wuts, PGM, Greene, TW and Greene, TW (2006). Greene's protective groups in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references cited therein. For example, the protecting group of an alcohol, such as a hydroxyl group, includes silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), triisopropylsiloxymethyl (TOM) and triisopropylsilyl (TIPS) ether), which can be removed by acid or fluoride ions such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py or HF-NEt 3 Other protecting groups for alcohols include acetyl, which is removed by acid or base, benzoyl, which is removed by acid or base, benzyl, which is removed by hydrogenation, methoxyethoxymethyl ether, which is removed by acid, dimethoxytrityl, which is removed by acid, methoxymethyl ether, tetrahydropyranyl or tetrahydrofuranyl, which are removed by acid, and trityl, which is removed by acid. Examples of protecting groups for amines include carbonylbenzyloxy, which is removed by hydrogenolysis, p-methoxybenzylcarbonyl, which is removed by hydrogenolysis, and p-methoxybenzylcarbonyl, which is removed by strong concentrated acids such as HCl or CF 3COOH) or by heating to greater than about 80° C., 9-fluorenylmethoxycarbonyl by a base such as piperidine, acetyl by treatment with a base, benzoyl by treatment with a base, benzyl by hydrogenolysis, carbamate groups by acid and mild heating, p-methoxybenzyl by hydrogenolysis, 3,4-dimethoxybenzyl by hydrogenolysis, p-methoxyphenyl by cerium(IV) ammonium nitrate, thiazolyl by concentrated acid such as HBr or H 2 SO 4 ) 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.

[0587] 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 as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as mixtures enriched in stereoisomers. Unless otherwise indicated, all such 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, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0588] 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).

[0589] General Synthesis

[0590] Scheme 1 shows a general method that can be used to synthesize compounds described herein (eg, Formula I), wherein each X 1 , X 2 , X 3 , X 4 , R, R 1 , R 4 and R 5 Each independently as defined herein, LG is a leaving group (e.g., halo, alkoxy, -OCCl 3 , imidazolyl, 4-nitrobenzyloxy-O-, -SC 1-6 Alkyl, -Sn(C 1-6 alkyl) 3 etc.), and each R 50 They are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic borate ester.

[0591] Scheme I

[0592]

[0593] In Scheme I, the compound of Formula I can be prepared by contacting Compound I-1 with Compound I-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection if desired. Alternatively, the compound of Formula I can be prepared by contacting Compound I-3 with Compound I-4 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl 2 ) and the presence of a base, followed by optional functionalization or deprotection when necessary to prepare. 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, etc.

[0594] 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 with respect to Formula I.

[0595] Scheme II shows a general method that can be used to synthesize compounds described herein (eg, Formula II), wherein each X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 and R 5 Each independently as defined herein, LG is a leaving group (e.g., halo, alkoxy, -OCCl 3 , imidazolyl, 4-nitrobenzyloxy-O-, -SC 1-6 Alkyl, -Sn(C 1-6 alkyl) 3 etc.), and each R 50 They are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic borate ester.

[0596] Solution II

[0597]

[0598] In Scheme II, the compound of formula II can be prepared by contacting compound I-1 with compound II-2 under suitable coupling reaction conditions, followed by optional functionalization or deprotection when necessary. Alternatively, the compound of formula II can be prepared by contacting compound II-3 with compound II-4 or a salt thereof under suitable coupling reaction conditions, followed by optional functionalization or deprotection when necessary. Alternatively, the compound of formula II can be prepared by contacting compound II-5 with compound I-4 under suitable coupling reaction conditions, such as in the presence of a palladium catalyst (e.g., Pd(dppf)Cl 2 ) and the presence of a base, followed by optional functionalization or deprotection when necessary to prepare. 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, etc.

[0599] Further derivatization of the compounds or any intermediates provided by the steps outlined in Scheme II provides additional compounds of Formula II. 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 II can be derived at any step to provide various compounds of Formula II. In certain embodiments, various substituents of the compounds or intermediates used in Scheme I are as defined for Formula II.

[0600] For example, compounds I-1 and II-5 can be prepared according to a similar procedure as described in Scheme II according to the following Scheme III, wherein each X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 and R 5 Each independently as defined herein, X is a leaving group (e.g., a halide, Sn(C 1-6 alkyl) 3 etc.), and each R 50 They are independently -OH, -O-alkyl, or together with the boron atom to which they are attached form a cyclic borate ester.

[0601] Scheme III

[0602]

[0603] Scheme IV shows a general method that can be used to synthesize compounds described herein (e.g., Formula II and Formula III), wherein each X 1 , X 2 , X 3 , X 4, R 1 , R 2 , R 3 , R 4 , R 5 and R 7 Each LG is independently a leaving group (e.g., a halide, an alkoxyl group, -OCCl 3 , imidazolyl, 4-nitrobenzyloxy-O-, -SC 1-6 Alkyl, -Sn(C 1-6 alkyl) 3 wait).

[0604] Scheme IV

[0605]

[0606] In Scheme IV, the compound of formula II can be prepared by contacting compound I-1 with compound IV-2 under suitable coupling reaction conditions to provide an acylated intermediate, followed by contacting the acylated intermediate with compound II-4 or a salt thereof. The compound of formula III can be prepared by contacting compound I-1 with compound IV-2 under suitable coupling reaction conditions to provide an acylated intermediate, followed by contacting the acylated intermediate with compound IV-3.

[0607] In certain embodiments, the acylated intermediate is a compound of formula IV-1:

[0608]

[0609] Where X 1 , X 2 , X 3 , X 4 , R 1 , R 4 , R 5 and LG are each independently as defined herein.

[0610] 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.

[0611] It should be understood that any of the compounds or intermediates shown in Schemes II, III or IV can be prepared using conventional methods or purchased from commercial sources. In addition, any intermediate or any product obtained by the methods outlined in Schemes II or III can be derived at any step to provide various compounds of Formula I. In certain embodiments, various substituents of the compounds or intermediates used in Schemes II, III or IV are as defined for Formula I.

[0612] In certain embodiments, a method for providing a compound of Formula I is provided, the method comprising:

[0613] 1) making the compound of formula I-1:

[0614]

[0615] With the compound of formula IV-2:

[0616]

[0617] contacting under conditions sufficient to provide an acylated intermediate; and

[0618] 2) contacting the acylated intermediate with a compound of formula HR under conditions sufficient to provide a compound of formula I; wherein X 1 , X 2 , X 3 , X 4 , R, R 1 , R 4 and R 5 Each is independently as defined herein, and each LG is independently a leaving group. In certain embodiments, each LG is independently selected from halo, alkoxy, -OCCl 3 , imidazolyl, 4-nitrobenzyloxy-O- and -SC 1-6 alkyl.

[0619] In certain embodiments, the compound of formula HR is -OR 7 , where R 7 As defined herein.

[0620] In certain embodiments, the compound of formula HR is -NR 2 R 3 , where R 2 and R 3 Each is independently as defined herein.

[0621] In certain embodiments, the acylated intermediate is a compound of formula IV-1.

[0622] In certain embodiments, a method for providing a compound of formula I is provided, the method comprising making a compound of formula I-1:

[0623]

[0624] With the compound of formula I-2:

[0625]

[0626] contacting under conditions sufficient to provide a compound of formula I; wherein X 1 , X2 , X 3 , X 4 , R, R 1 , R 4 and R 5 Each is independently as defined herein, and LG is a leaving group. In certain embodiments, LG is halo, alkoxy, -OCCl 3 , imidazolyl, 4-nitrobenzyloxy-O- and -SC 1-6 alkyl.

[0627] In certain embodiments, a method for providing a compound of formula I is provided, the method comprising making a compound of formula I-3:

[0628]

[0629] With the compound of formula I-4:

[0630]

[0631] contacting under conditions sufficient to provide a compound of formula I; wherein X 1 , X 2 , X 3 , X 4 , R, R 1 , 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. In certain embodiments, LG is a halide, -SC 1-6 Alkyl or -Sn(C 1-6 alkyl) 3 . Example

[0632] 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 techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure, and therefore can be considered to constitute a specific mode of its practice. However, it will be appreciated by those skilled in the art that, in accordance with the present disclosure, many changes may be made in the disclosed specific embodiments without departing from the spirit and scope of the present disclosure, and still similar or similar results may be obtained.

[0633] General experimental methods

[0634] All solvents used were commercially available and were used without further purification. Reactions were generally carried out using anhydrous solvents under an inert atmosphere of nitrogen.

[0635] 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 probe DUAL 400 MHzS1, a Bruker Avance 600 instrument equipped with a probe 6S1 400 MHz 5 mm 1 H- 13 Bruker Avance 400 instrument for C ID, Bruker Avance III 400 instrument with nanobay equipped with direct probe Broadband BBFO 5 mm, Bruker Mercury Plus 400 NMR spectrometer equipped with Bruker 400BBO 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 δ0.00). 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 stated solvents, unless otherwise stated. In all cases, the NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are in parts per million, and conventional abbreviations are used to designate major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplet; br, broad.

[0636] Thin layer chromatography: In the case of thin layer chromatography (TLC), it refers to silica gel TLC using silica gel F254 (Merck) plates, and Rf is 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 Mancherey-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 plate was treated with iodine (by adding about 1 g of iodine to 10 g of silica gel). 2 and mixed thoroughly), ninhydrin (commercially available from Aldrich), or Magic Stain (produced by mixing 450 mL of water and 50 mL of concentrated H 2 SO 4 Mix thoroughly with 25g (NH4 ) 6 Mo 7 O 24 .4H 2 O, 5g(NH 4 ) 2 Ce(IV)(NO 3 ) 6 To produce) imaging, so that the compound is developed.

[0637] 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, H 2 O + 0.037% (v / v) TFA): Mobile phase B (MPB, ACN + 0.018% (v / v) TFA) (0.01min, 10% MPB; 4min, 80% MPB; 4,9min, 80% MPB; 4.92min, 10% MPB; 5.5min, 10% MPB). LCMS is detected at 220 and 254nm or using evaporative light scattering (ELSD) detection and positive electrospray ionization (MS). Semi-preparative HPLC is carried out under acidic or neutral conditions. Acidic: Luna C18 100×30mm, 5μm; MPA: HCl / H 2 O = 0.04%, or formic acid / H 2 O=0.2% (v / v); MPB: ACN. Neutral: Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH 4 HCO 3 H 2 O solution; MPB: ACN. Gradient under two conditions: 10% MPB to 80% MPB over 12 min, flow rate of 20 mL / min, then 100% MPB over 2 min, 10% MPB over 2 min, UV detector. SFC analysis was performed on a Thar 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, flow rate of 4 mL / min, with gradient solvent mobile phase A (MPA, CO 2): 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, wherein the gradient solvent mobile phase A (MPA, CO 2 ): Mobile phase B (MPB, MeOH + 0.1% (v / v) NH 3 H 2 O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min, 10% MPB). LC-MS data were also obtained using a UPLC-MS Acquity TM The system collected, and the mass spectrometer was operated in alternating positive and negative electrospray ionization modes. The column used was Cortecs UPLC C18, 1.6 μm, 2.1×50 mm. A linear gradient was applied, starting at 95% A (A: 0.1% formic acid in water) over 2.0 min, and ending at 95% B (B: MeCN containing 0.1% formic acid), with a total run time of 2.5 min. The column temperature was 40° C., and the flow rate was 0.8 mL / min.

[0638] Intermediate 1

[0639] Methyl-6-azabicyclo[3.1.1]heptane

[0640]

[0641] Methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 25°C, in N 2 To a mixture of N-(3-methylcyclohexyl)picolinamide (20 g, 91.62 mmol) in 1,1,2,2-tetrachloroethane (300 mL) were added AgOAc (45.88 g, 274.86 mmol), benzoquinone (4.95 g, 45.81 mmol), Na 3 PO 4 (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 h. 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 1: 1) to give the title compound. LCMS: m / z = 217.10 [M+H] + .

[0642] 3-Methyl-6-azabicyclo[3.1.1]heptane: at 25 °C, in N 2 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 h. 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 obtain the title compound as a mixture of about 10: 1 of cis and trans isomers. LCMS: m / z=112.2[M+H] + .

[0643] Intermediate 2

[0644] trans-3-methyl-6-azabicyclo[3.1.1]heptane

[0645]

[0646] 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 obtain separated cis and trans isomers. The first eluting peak was concentrated under reduced pressure and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH = 7-8 and extracted with DCM (3 x 500 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a colorless oil. LCMS: m / z = 219.2 [M+H] + .

[0647] (trans-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone was heated at 25°C in N 2 To a mixture of N-(cis-3-methylcyclohexyl)picolinamide (10 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (300 mL) were added AgOAc (22.94 g, 137.43 mmol), benzoquinone (2.48 g, 22.90 mmol), Na 3 PO 4 (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 h. 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 1: 1) to give the title compound as a brown oil. LCMS: m / z = 217.0 [M + H] + .

[0648] trans-3-methyl-6-azabicyclo[3.1.1]heptane: at 25 °C, in N 2 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 h. 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 obtain the title compound as a brown slurry as a free base. TFA was added and the mixture was stirred at 20 ° C for 0.5 h, then concentrated under reduced pressure to obtain the TFA salt. LCMS: m / z=112.2[M+H] + .

[0649] Intermediate 3

[0650] cis-3-methyl-6-azabicyclo[3.1.1]heptane

[0651]

[0652] 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 obtain separated cis and trans isomers. The second eluting peak was concentrated under reduced pressure and purified by saturated NaHCO 3 The aqueous solution was adjusted to pH = 7-8 and extracted with DCM (3 x 300 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a colorless oil. LCMS: m / z = 219.2 [M+H] + .

[0653] (cis-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone was heated at 25°C in N 2 To a mixture of N-(trans-3-methylcyclohexyl)picolinamide (6 g, 27.49 mmol) in 1,1,2,2-tetrachloroethane (200 mL) was added AgOAc (13.76 g, 82.46 mmol), benzoquinone (1.49 g, 13.74 mmol), Na 3 PO 4 (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 h. 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 1: 1) to give the title compound as a brown oil. LCMS: m / z = 217.0 [M + H] + .

[0654] cis-3-methyl-6-azabicyclo[3.1.1]heptane: at 25 °C, in N 2Under 30 ℃, to the mixture of (cis-3-methyl-6-azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone (2.4g, 11.1mmol) in EtOH (30mL) was added NaOH (4.44g, 111mmol). The mixture was stirred at 90 ° C for 4h. The reaction mixture was concentrated under reduced pressure (water pump, less than 35 ° C) to obtain a mixture containing the product, NaOH and the sodium salt of the acid. The mixture was stirred in DCM (20mL) and filtered through a celite pad. The filtrate was concentrated under reduced pressure (water pump, less than 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 as a free base. TFA was added and the mixture was stirred at 20 ° C for 0.5h, then concentrated under reduced pressure to obtain the TFA salt. LCMS: m / z=112.2[M+H] + .

[0655] Intermediate 4

[0656] 2-Methyl-6-azabicyclo[3.1.1]heptane

[0657]

[0658] (2-Methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 25°C, in N 2 To a mixture of N-(4-methylcyclohexyl)picolinamide (5 g, 22.90 mmol) in 1,2-dichloroethane (50 mL) was added AgOAc (11.47 g, 68.71 mmol), benzoquinone (1.24 g, 11.45 mmol), Na 3 PO 4 (11.27 g, 68.71 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (67.33 g, 229.05 mmol) and Pd(OAc) 2 (514 mg, 2.29 mmol). The mixture was stirred at 140°C for 12 h. The mixture was filtered and the filtrate was 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=217.2 [M+H] + .

[0659] 2-Methyl-6-azabicyclo[3.1.1]heptane: at 25 °C, in N 2To a mixture of (2-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (1 g, 4.62 mmol) in EtOH (15 mL) was added NaOH (1.85 g, 46.24 mmol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was slurried in DCM (10 mL), filtered, and the filtrate was concentrated under reduced pressure. The post-treatment procedure was repeated 2-3 times to give the title compound. LCMS: m / z=112.2[M+H] + .

[0660] Intermediate 5

[0661] trans-3-methoxy-6-azabicyclo[3.1.1]heptane

[0662]

[0663] N-(cis-3-methoxycyclohexyl)picolinamide: at 0°C, in N 2 To a solution of 3-methoxycyclohexylamine (7.9 g, 47.69 mmol) in DCM (150 mL) was added pyridine-2-carboxylic acid (7.04 g, 57.23 mmol), TEA (14.48 g, 143.06 mmol), DMAP (583 mg, 4.77 mmol) and EDCI (13.71 g, 71.53 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was filtered through a celite pad. The filtrate was washed with H 2 O (100 mL), the organic layer was separated, washed with brine (50 mL), and 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 1: 1 to 0: 1) to give the title compound. LCMS: m / z = 235.2 [M+H] + .

[0664] (trans-3-methoxy-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 25°C, in N 2 To a solution of N-(3-methoxycyclohexyl)pyridine-2-carboxamide (5.1 g, 21.77 mmol) in 1,1,2,2-tetrachloroethane (150 mL) was added Na 3 PO 4(10.71 g, 65.30 mmol), BQ (1.18 g, 10.88 mmol), AgOAc (10.90 g, 65.30 mmol), 1,2,3,4,5-pentafluoro-6-iodo-benzene (63.99 g, 217.68 mmol) and Pd(OAc) 2 (489 mg, 2.18 mmol). The mixture was stirred at 140 °C for 12 h. The 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 = 233.1 [M+H] + .

[0665] trans-3-methoxy-6-azabicyclo[3.1.1]heptane: at 25 °C, in N 2 To a solution of (trans-3-methoxy-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (100 mg, 0.43 mmol) in EtOH (2 mL) was added NaOH (172 mg, 4.31 mmol). The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture was slurried with DCM (10 mL) and then filtered through a celite pad, and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z=128.2[M+H] + .

[0666] Intermediate 6

[0667] 3-Methyl-3,6-diazabicyclo[3.1.1]heptan-2-one

[0668]

[0669] 3,6-Diazabicyclo[3.1.1]heptane-3,6-dicarboxylic acid 6-benzyl 3-tert-butyl ester: at 0 °C, in N 2 To a solution of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (500 mg, 2.52 mmol) in DCM (5 mL) was added TEA (510 mg, 5.04 mmol) followed by dropwise addition of CbzCl (559 mg, 3.28 mmol). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=1:0 to 1:1) to give the title compound. LCMS: m / z=233.1 [M-Boc+H] + .

[0670] 2-Oxo-3,6-diazabicyclo[3.1.1]heptane-3,6-dicarboxylic acid 6-benzyl 3-tert-butyl ester: at 0 °C, in N 2 3,6-diazabicyclo[3.1.1]heptane-3,6-dicarboxylic acid 6-benzyl 3-tert-butyl ester (2.1 g, 6.32 mmol) was dissolved in EtOAc (12 mL) and H 2 O (4 mL) was added with RuCl 3 (655 mg, 3.16 mmol) and NaIO 4 (4.05 g, 18.95 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with H 2 O (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 247.0 [M-Boc + H] + .

[0671] Benzyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: To a solution of 6-benzyl 3-tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-3,6-dicarboxylate (1.4 g, 4.04 mmol) in EtOAc (5 mL) was added HCl / EtOAc (12 mL, 4 M) at 20°C. The mixture was stirred at 20°C for 1 h and then concentrated under reduced pressure to give the title compound. LCMS: m / z=247.0 [M+H] + .

[0672] 3-Methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester: at 0°C, in N 2 To a solution of 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid benzyl ester (700 mg, 2.84 mmol) in THF (8 mL) was added NaH (159 mg, 3.98 mmol, 60% purity) and MeI (605 mg, 4.26 mmol, 0.26 mL) under 4% CO. The mixture was stirred at 20 °C for 2 h. The reaction mixture was heated to 40 °C by adding H2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=1:0 to 0:1) to give the title compound. LCMS: m / z=261.0 [M+H] + .

[0673] 3-Methyl-3,6-diazabicyclo[3.1.1]heptan-2-one: 2 To a solution of benzyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (450 mg, 1.73 mmol) in MeOH (8 mL) was added Pd / C (450 mg, 10% on carbon) under vacuum. The suspension was degassed under H 2 The mixture was stirred at 20 °C under H 2 Stir at 400 psi for 2 h. Filter the reaction mixture through a pad of celite and concentrate the filtrate under reduced pressure to give the title compound. LCMS: m / z = 127.0 [M+H] + .

[0674] Intermediate 7

[0675] 2,3,4,5-Tetrahydro-2,5-methoxybenzo[f][1,4]oxazepine

[0676]

[0677] 4,5-Dihydro-2,5-methoxybenzo[f][1,4]oxazepin-3(2H)-one: at 20°C, in N 2 To a mixture of ethyl 4-aminochroman-2-carboxylate hydrochloride (900 mg, 3.49 mmol) in toluene (30 mL) was added TEA (1.06 g, 10.48 mmol). The reaction mixture was stirred at 110 °C for 16 h. The mixture was concentrated under reduced pressure, and the resulting residue was purified by HPLC. 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The resulting residue is triturated with MTBE, collected by filtration, and the solid is dried under reduced pressure to give the title compound. LCMS: m / z=176.1 [M+H] + .

[0678] 2,3,4,5-Tetrahydro-2,5-methoxybenzo[f][1,4]oxazepine: at 0°C, in N 2 To a mixture of 4,5-dihydro-2,5-methanobenzo[f][1,4]oxazepin-3(2H)-one (395 mg, 2.25 mmol) in THF (15 mL) was added LiAlH 4 (428 mg, 11.27 mmol). The mixture was stirred at 70°C for 16 h. 2 SO 4 10H 2 O quenched until bubbling stopped, and stirred for 30 min. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z=162.2 [M+H] + .

[0679] Intermediate 8

[0680] cis-3-Fluoro-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0681]

[0682] 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 Boc 2 O (12.45 g, 57.06 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was washed with H 2 O (50 mL) and extracted with MTBE (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is 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] + .

[0683] tert-Butyl trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate: To a solution of tert-butyl trans-3-(benzyloxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate (3.55 g, 11.70 mmol) in MeOH (50 mL) was added Pd / C (2 g, 10% on carbon) at 25 °C under Ar. The suspension was degassed and heated with H 2The mixture was purged three times at 30 °C under H 2 Stir at 50 psi for 12 h. Filter the reaction mixture through a pad of celite and concentrate the filtrate under reduced pressure to give the title compound. LCMS: m / z = 158.2 [M-tBu+H] + .

[0684] tert-Butyl cis-3-fluoro-6-azabicyclo[3.1.1]heptane-6-carboxylate: at 0 °C, in N 2 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) was added DAST (166 mg, 0.19 mmol). The mixture was stirred at 0°C for 2 h. The reaction mixture was washed with saturated NaHCO 3 The aqueous solution was adjusted to pH = 7-8 and extracted with DCM (3 x 5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. LCMS: m / z = 160.2 [M-tBu+H] + .

[0685] Cis-3-fluoro-6-azabicyclo[3.1.1]heptane trifluoroacetate: TFA (1.54 g, 14 mmol, 1 mL) was added 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) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. The material was used directly in the next step.

[0686] Intermediate 9

[0687] trans-3-(Difluoromethoxy)-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0688]

[0689] trans-tert-butyl 3-(difluoromethoxy)-6-azabicyclo[3.1.1]heptane-6-carboxylate: tert-butyl trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylate (100 mg, 0.47 mmol) in DCM (1.5 mL) and H 2 Add KHF to the solution in O (1.5 mL) 2 (220 mg, 2.81 mmol) and (bromodifluoromethyl)trimethylsilane (286 mg, 1.41 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was washed with H2 O (3 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. LCMS: m / z = 208.1 [M-tBu] + .

[0690] Trans-3-(difluoromethoxy)-6-azabicyclo[3.1.1]heptane trifluoroacetate: To a solution of trans-3-(difluoromethoxy)-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (75 mg, 0.28 mmol) in DCM (1.5 mL) was added TFA (2.3 g, 20.26 mmol, 1.50 mL) at 20°C. The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=164.2 [M+H] + .

[0691] Intermediate 10

[0692] cis-3-methoxy-6-azabicyclo[3.1.1]heptane

[0693]

[0694] N-(trans-3-methoxycyclohexyl)picolinamide: at 0°C, in N 2 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). The mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with H 2 O (20 mL), the organic layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL), 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is 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] + .

[0695] (cis-3-methoxy-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 25°C, in N 2To a mixture of N-((1S,3S)-3-methoxycyclohexyl)picolinamide (1.6 g, 6.83 mmol) in 1,1,2,2-tetrachloroethane (50 mL) were 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). The mixture was stirred at 140 °C for 12 h. 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 1: 1) to give the title compound. LCMS: m / z = 232.9 [M+H] + .

[0696] Cis-3-methoxy-6-azabicyclo[3.1.1]heptane: To a mixture of (cis-3-methoxy-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (270 mg, 1.16 mmol) in EtOH (5 mL) was added NaOH (465 mg, 11.62 mmol) at 25 °C. The mixture was stirred at 90 °C for 4 h and then concentrated under reduced pressure. The resulting residue was slurried in DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure. The post-treatment was repeated three times to give the title compound. The material was used directly in the next step.

[0697] Intermediate 11

[0698] trans-1,6,7-trimethyl-3-azabicyclo[4.1.0]heptane hydrochloride

[0699]

[0700] 3-tert-Butyl 7-ethyl trans-3-azabicyclo[4.1.0]heptane-3,7-dicarboxylate: at 80 °C, in N 2 5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10 g, 54.57 mmol) and Rh(OAc) were added. 2To a mixture of (603 mg, 2.73 mmol) in DCE (300 mL) was added ethyl 2-diazoacetate (18.68 g, 163.71 mmol) in DCE (200 mL) dropwise and stirred at 80 ° C for 16 h. The 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 = 10: 1 to 8: 1) to give the title compound.

[0701] tert-Butyl 7-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate: at 0°C, in N 2 To a mixture of 3-tert-butyl 7-ethyl trans-3-azabicyclo[4.1.0]heptane-3,7-dicarboxylate (3 g, 11.14 mmol) in DCM (60 mL) was added DIBAL-H (22.28 mmol, 1 M in toluene, 22.28 mL) and stirred at 25 °C for 16 h. The mixture was washed with H 2 O (20 mL), potassium sodium tartrate (10 g) was added and the mixture was stirred for 30 min. The mixture was filtered through a pad of celite and the filtrate was extracted with DCM (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate 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.

[0702] tert-Butyl 7-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate: at 0°C, in N 2 To a mixture of trans-7-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (562 mg, 2.47 mmol) and TEA (500 mg, 4.95 mmol, 0.69 mL) in DCM (10 mL) was added MsCl (312 mg, 2.72 mmol, 0.21 mL) and stirred at 25 °C for 30 min. The mixture was poured into water (15 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with saturated NaHCO 3 (5 mL) aqueous solution, washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound.

[0703] tert-Butyl 7-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate: at 0 °C, in N 2To a mixture of trans-7-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (559 mg, 1.83 mmol) in THF (15 mL) was added LiBHEt 3 (3.66 mmol, 1 M in THF, 3.66 mL) and stirred at 25 °C for 16 h. The mixture was poured into saturated NH 4 The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The resulting residue was purified by silica gel column chromatography (PE:EtOAc=7:1 to 5:1) to give the title compound.

[0704] trans-7-methyl-3-azabicyclo[4.1.0]heptane hydrochloride: A solution of tert-butyl trans-7-methyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (60 mg, 0.28 mmol) in HCl / EtOAc (20 mmol, 4 M, 5 mL) was stirred for 2 h at 25° C. The mixture was concentrated under reduced pressure to give the title compound.

[0705] Intermediate 12

[0706] trans-6-azabicyclo[3.1.1]heptan-3-ol

[0707]

[0708] N-(cis-3-(benzyloxy)cyclohexyl)picolinamide: at 0°C, in N 2 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) followed by T3P (242.82 g, 381.58 mmol, 50% solution in EtOAc). The mixture was stirred at 25 °C for 12 h. The reaction mixture was washed with H 2 O (1 L) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is 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] + .

[0709] (trans-3-(benzyloxy)-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 20°C, in N 2 To a solution of N-(cis-3-(benzyloxy)cyclohexyl)picolinamide (39 g, 125.58 mmol) in 1,1,2,2-tetrachloroethane (500 mL) were 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-iodo-benzene (369.33 g, 1.26 mol) and Pd(OAc) 2 (2.81 g, 12.48 mmol). The mixture was stirred at 140 °C for 12 h. 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 (EtOAc) to give the title compound. The material was used directly in the next step.

[0710] trans-3-(Benzyloxy)-6-azabicyclo[3.1.1]heptane: at 20°C, in N 2 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). The mixture was stirred at 90 °C for 12 h. 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] + .

[0711] trans-6-azabicyclo[3.1.1]heptan-3-ol: at 25°C, in N 2 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). The suspension was degassed and heated with H 2 The mixture was purged 3 times at 30 °C under H 2 Stir at 400 psi for 12 h. Filter the mixture through a pad of celite and concentrate the filtrate under reduced pressure to give the title compound. LCMS: m / z = 114.2 [M+H] + .

[0712] Intermediate 13

[0713] 4-Fluoro-5,6,7,8-tetrahydro-5,8-cycloiminoisoquinoline hydrochloride

[0714]

[0715] 5-Fluoropyridin-3-yl diethylcarbamate: To a mixture of 5-fluoropyridin-3-ol (40 g, 353.70 mmol) in toluene (400 mL) was added TEA (42.95 g, 424.44 mmol) at 0°C and stirred for 0.5 h, then heated at 0°C under N 2 To the mixture was added diethylcarbamoyl chloride (57.55 g, 424.44 mmol) in toluene (120 mL). The mixture was stirred at 120 ° C for 2 h. The reaction mixture was filtered 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 = 213.0 [M + H] + .

[0716] 5-Fluoro-4-(triethylsilyl)pyridin-3-yl diethylcarbamate: at -78 °C in N 2 To a mixture of 5-fluoropyridin-3-yl diethylcarbamate (10 g, 47.12 mmol) in THF (100 mL) was added LDA (25.92 mL, 2 M in THF) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min, and then chloro(triethyl)silane (7.81 g, 51.83 mmol, 8.82 mL) was added to the mixture at -78 °C. The reaction mixture was stirred at 25 °C for another 2 h. The reaction mixture was poured into saturated NH 4 The solution was added into aqueous Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:MTBE=10:1 to 3:1) to give the title compound. LCMS: m / z=327.1 [M+H] + .

[0717] 5-Fluoro-4-(triethylsilyl)pyridin-3-ol: at 0°C, in N 2 To a mixture of 5-fluoro-4-(triethylsilyl)pyridin-3-yl diethylcarbamate (2 g, 6.13 mmol) in THF (40 mL) was added LiAlH 4(581 mg, 15.31 mmol). The mixture was stirred at 25 °C for 2 h. Na was added to the reaction mixture at 0 °C. 2 SO 4 .10H 2 The mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 2: 1 to 1: 1) to give the title compound. LCMS: m / z = 228.0 [M+H] + .

[0718] Trifluoromethanesulfonic acid 5-fluoro-4-(triethylsilyl)pyridin-3-yl ester: at 0°C, in N 2 To a mixture of 5-fluoro-4-(triethylsilyl)pyridin-3-ol (1.4 g, 6.16 mmol) in pyridine (20 mL) was added Tf 2 O (3.82 g, 13.54 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was washed with H 2 O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give the title compound. LCMS: m / z = 360.0 [M+H] + .

[0719] Tert-butyl 4-fluoro-5,8-dihydro-5,8-cycloiminoisoquinoline-9-carboxylate: at 25 °C, in N 2 To a mixture of 5-fluoro-4-(triethylsilyl)pyridin-3-yl trifluoromethanesulfonate (1.15 g, 3.20 mmol) in MeCN (25 mL) was added CsF (972 mg, 6.40 mmol) and tert-butyl 1H-pyrrole-1-carboxylate (2.67 g, 16.00 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give the title compound. LCMS: m / z = 263.0 [M+H] + .

[0720] 4-Fluoro-5,6,7,8-tetrahydro-5,8-cycloiminoisoquinoline-9-carboxylic acid tert-butyl ester:2 To a solution of tert-butyl 4-fluoro-5,8-dihydro-5,8-cycloiminoisoquinoline-9-carboxylate (750 mg, 2.86 mmol) in EtOAc (10 mL) was added Pd / C (300 mg, 10% purity). The suspension was degassed under vacuum and heated with H 2 The mixture was stirred at 25 °C under H 2 The reaction mixture was stirred at 30 psi for 12 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 265.1 [M+H] + .

[0721] 4-Fluoro-5,6,7,8-tetrahydro-5,8-cycloiminoisoquinoline hydrochloride: at 25 °C, in N 2 To a mixture of tert-butyl 4-fluoro-5,6,7,8-tetrahydro-5,8-cycloiminoisoquinoline-9-carboxylate (700 mg, 2.65 mmol) in EtOAc (2 mL) was added HCl / EtOAc (10 mL, 4 M). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. The material was used directly in the next step.

[0722] Intermediate 14

[0723] 4-Methyl-3-(pyridin-2-yl)aniline

[0724]

[0725] 4-Methyl-3-(pyridin-2-yl)aniline: at 25°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20 g, 85.80 mmol) was dissolved in DMF (200 mL) and H 2 O (20 mL) were added with 2-bromopyridine (20.34 g, 128.70 mmol), K 2 CO 3 (35.58 g, 257.38 mmol) and Pd(PPh 3 ) 4 (9.92 g, 8.58 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered through a celite pad and the filtrate was washed with H 2 O (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na 2 SO 4The resulting residue was adjusted to pH = 3 by 1 M HCl and extracted with EtOAc (3 x 50 mL). The organic layer was discarded and the aqueous phase was washed with saturated NaHCO 3 The aqueous solution was adjusted to pH = 7-8 and then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 4: 1 to 1: 1) to give the title compound. LCMS: m / z = 185.0 [M+H] + .

[0726] Intermediate 15

[0727] 3-(5-Fluoropyridin-2-yl)-4-methylaniline

[0728]

[0729] 3-(5-Fluoropyridin-2-yl)-4-methylaniline: at 25°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5 g, 21.45 mmol) and 2-bromo-5-fluoro-pyridine (5.66 g, 32.17 mmol) were dissolved in DMF (50 mL) and H 2 O (5 mL) was added to the mixture 2 CO 3 (8.89 g, 64.35 mmol) and Pd(PPh 3 ) 4 (2.48 g, 2.14 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:MTBE=10:1 to 1:1) to give the title compound. LCMS: m / z=203.0 [M+H] + .

[0730] Intermediate 16

[0731] 3-(Pyridin-2-yl)-4-(trifluoromethyl)aniline

[0732]

[0733] 3-(Pyridin-2-yl)-4-(trifluoromethyl)aniline: at 20°C, in N 2 To a solution of 3-bromo-4-(trifluoromethyl)aniline (400 mg, 1.67 mmol) in DMF (5 mL) was added 2-(tributylstannyl)pyridine (736 mg, 2.00 mmol) and Pd(PPh 3 ) 4 (192 mg, 0.16 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 239.1 [M+H] + .

[0734] Intermediate 17

[0735] 2-(4-amino-2-(pyridin-2-yl)phenyl)acetonitrile

[0736]

[0737] 2-(4-amino-2-(pyridin-2-yl)phenyl)acetonitrile: at 20°C, in N 2 To a mixture of 2-(4-amino-2-bromophenyl)acetonitrile (210 mg, 0.99 mmol) and 2-(tributylstannyl)pyridine (440 mg, 1.19 mmol) in DMF (8 mL) was added Pd(PPh 3 ) 4 (115 mg, 0.10 mmol). The mixture was stirred at 130 °C for 12 h. 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give the title compound. LCMS: m / z = 210.1 [M+H] + .

[0738] Intermediate 18

[0739] N-(4-ethyl-3-(5-fluoropyridin-2-yl)phenyl)-1H-imidazole-1-carboxamide

[0740]

[0741] N-(4-ethyl-3-(5-fluoropyridin-2-yl)phenyl)-1H-imidazole-1-carboxamide: at 25°C, in N 2 To a mixture of 3-bromo-4-ethyl-aniline (200 mg, 1.00 mmol) and tributyl-(5-fluoro-2-pyridyl)stannane (463 mg, 1.20 mmol) in DMF (4 mL) was added Pd(t-Bu 3 P) 2 (51 mg, 0.10 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 3: 1) to give the title compound. LCMS: m / z = 217.1 [M+H] + .

[0742] Intermediate 19

[0743] 3-(3-Methoxypyridin-2-yl)-4-methylaniline

[0744]

[0745] 3-(3-methoxypyridin-2-yl)-4-methylaniline: at 25°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) and 2-chloro-3-methoxypyridine (924 mg, 6.43 mmol) were dissolved in 1,4-dioxane (10 mL) and H 2 O (1 mL) was added to the mixture 2 CO 3 (1.78 g, 12.87 mmol) and Pd(dppf)Cl 2 (314 mg, 0.43 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 215.1 [M+H] + .

[0746] Intermediate 20

[0747] 4-Ethyl-3-(pyridin-2-yl)aniline

[0748]

[0749] 4-Ethyl-3-(pyridin-2-yl)aniline: at 20°C, in N 2 To a mixture of 3-bromo-4-ethylaniline (200 mg, 1 mmol) and 2-(tributylstannyl)pyridine (441.61 mg, 1.20 mmol) in DMF (4 mL) was added Pd(t-Bu 3 P) 2 (51.09 mg, 0.1 mmol). The mixture was stirred at 110 °C for 16 h. The reaction mixture was washed with H 2 O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 199.0 [M+H] + .

[0750] Intermediate 21

[0751] 4-Amino-2-(pyridin-2-yl)benzonitrile

[0752]

[0753] 4-amino-2-(pyridin-2-yl)benzonitrile: at 25°C, in N 2 To a solution of 4-amino-2-bromo-benzonitrile (1 g, 5.08 mmol) and tributyl(2-pyridyl)stannane (2.24 g, 6.09 mmol) in DMF (20 mL) was added Pd(t-Bu 3 P) 2 (259 mg, 0.51 mmol). The mixture was stirred at 100 °C for 12 h and then heated with H 2 O (30 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 196.2 [M+H] + .

[0754] Intermediate 22

[0755] 3-(3-Cyclopropylpyridin-2-yl)-4-methylaniline

[0756]

[0757] 3-(3-cyclopropylpyridin-2-yl)-4-methylaniline: 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 2-chloro-3-cyclopropyl-pyridine were dissolved in 1,4-dioxane (10 mL) and H 2 O (1 mL) was added with K 2 CO 3 (1.35 g, 9.77 mmol) and Pd(dppf)Cl 2 (238 mg, 3.20 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 The product was diluted with 1% HCl (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined, washed with brine (10 mL), 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 = 225.2 [M+H] + .

[0758] Intermediate 23

[0759] 2-(5-Amino-2-methylphenyl)nicotinonitrile

[0760]

[0761] 2-(5-amino-2-methylphenyl)nicotinamide carbonitrile: at 25°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) and 2-chloronicotinonitrile (892 mg, 6.43 mmol) were dissolved in 1,4-dioxane (10 mL) and H 2 O (1 mL) was added to the mixture 2 CO 3(1.78 g, 12.87 mmol) and Pd(dppf)Cl 2 (314 mg, 0.43 mmol). The mixture was stirred at 100 °C for 12 h. 2 O (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give the title compound. LCMS: m / z = 210.1 [M+H] + .

[0762] Intermediate 24

[0763] 4-Cyclopropyl-3-(pyridin-2-yl)aniline

[0764]

[0765] 4-Cyclopropyl-3-(pyridin-2-yl)aniline: at 25°C, in N 2 To a solution of 3-bromo-4-cyclopropyl-aniline (440 mg, 2.07 mmol) in DMF (5 mL) was added tributyl(2-pyridyl)stannane (914 mg, 2.48 mmol) and Pd(t-Bu 3 P) 2 (106 mg, 0.21 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was washed with H 2 O (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (15 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 2) to give the title compound. LCMS: m / z = 211.1 [M+H] + .

[0766] Intermediate 25

[0767] 4-Chloro-3-(5-fluoropyridin-2-yl)aniline

[0768]

[0769] 2-(2-Chloro-5-nitrophenyl)-5-fluoropyridine: at 20°C, in N 2 To (2-chloro-5-nitrophenyl)boronic acid (1 g, 4.97 mmol) in DMF (15 mL) and H 2O (1.5 mL) were added with 2-bromo-5-fluoropyridine (1.31 g, 7.45 mmol), K 2 CO 3 (1.37 g, 9.93 mmol) and Pd(PPh 3 ) 4 (574 mg, 0.45 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=1:1 to 0:1) to give the title compound. LCMS: m / z=253.0, 255.1 [M+H] + .

[0770] 4-Chloro-3-(5-fluoropyridin-2-yl)aniline: 2-(2-chloro-5-nitrophenyl)-5-fluoropyridine (1 g, 3.95 mmol) in EtOH (5 mL) and H 2 NH 4 Cl (423 mg, 7.92 mmol) and Fe powder (1.10 g, 19.79 mmol). The mixture was stirred at 70 °C for 1 h. The reaction was filtered through a celite pad. The filtrate was washed with H 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 3: 1) to give the title compound. LCMS: m / z = 223.1, 225.1 [M+H] + .

[0771] Intermediate 26

[0772] 4-Cyclopropyl-3-(5-fluoropyridin-2-yl)aniline

[0773]

[0774] 4-Cyclopropyl-3-(5-fluoropyridin-2-yl)aniline: at 20°C, in N 2To a solution of 5-fluoro-2-(tributylstannyl)pyridine (3.06 g, 7.92 mmol) in DMF (8 mL) was added 3-bromo-4-cyclopropylaniline (1.3 g, 6.60 mmol) and Pd(t-Bu 3 P) 2 (337 mg, 0.66 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was washed with H 2 O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 7: 3 to 1: 1) to give the title compound. LCMS: m / z = 229.0 [M+H] + .

[0775] Intermediate 27

[0776] N-(3-(5-Fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0777]

[0778] N-(3-(5-fluoropyridin-2-yl)-4-(trifluoromethyl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide: at 25°C, in N 2 To a solution of 3-bromo-4-(trifluoromethyl)aniline (3.00 g, 12.50 mmol) in DMF (50 mL) was added tributyl-(5-fluoro-2-pyridyl)stannane (5.79 g, 15.00 mmol), Pd(t-Bu 3 P) 2 (639 mg, 1.25 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was washed with H 2 O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 257.0 [M+H] + .

[0779] Intermediate 28

[0780] 6-(5-Amino-2-methylphenyl)pyridinecarbonitrile

[0781]

[0782] 6-(5-amino-2-methylphenyl)pyridinecarbonitrile: at 25°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) was dissolved in 1,4-dioxane (25 mL) and H 2 O (2.5 mL) were added with 6-bromopyridine-2-carbonitrile (0.94 g, 5.15 mmol), K 2 CO 3 (1.19 g, 8.58 mmol) and Pd(dppf)Cl 2 (314 mg, 0.43 mmol). The mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 0: 1) to give the title compound. LCMS: m / z = 210 [M+H] + .

[0783] Intermediate 29

[0784] (1S,4S)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl

[0785] Formamide hydrochloride

[0786]

[0787] Tert-butyl (1S,4S)-5-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate: at -20 °C, in N 2 Under 40 ℃, to the solution of CDI (370mg, 2.28mmol) in DCM (10mL), a solution of 4-methyl-3-pyrimidin-2-yl-phenylamine (350mg, 0.27mmol) in DCM (10mL) was added dropwise over 10min. The mixture was stirred at 20°C for 2h. Then a mixture of (1S, 4S)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (250mg, 1.26mmol) and TEA (383mg, 3.78mmol) in DCM (2mL) was added to the reaction solution. The mixture was stirred at 50°C for another 0.5h. The reaction mixture was washed with H 2O (10 mL) and extracted with DCM (3×5 mL), the organic layers were combined, washed with brine (5 mL), and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=1:2 to 0:1) to give the title compound. LCMS: m / z=409.3 [M+H] + .

[0788] (1S,4S)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide hydrochloride: To a solution of tert-butyl (1S,4S)-5-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500.00 mg, 1.22 mmol) in EtOAc (5 mL) was added HCl / EtOAc (10 mL, 4 M in EtOAc) and the solution was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=309.1 [M+H] + .

[0789] Intermediate 30

[0790] (1R,4R)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide hydrochloride

[0791]

[0792] Tert-butyl (1R,4R)-5-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate: at -20 °C, in N 2 To a solution of CDI (370 mg, 2.28 mmol) in DCM (10 mL) was added a solution of 4-methyl-3-(pyridin-2-yl)aniline (350 mg, 1.9 mmol) in DCM (10 mL) over 10 min. The mixture was stirred at 20 ° C for 2 h. A mixture of (1R, 4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (214 mg, 1.08 mmol) and TEA (383 mg, 3.78 mmol) in DCM (2 mL) was then added to the reaction solution. The mixture was stirred at 50 ° C for another 2 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with DCM (3×5 mL). The organic layers were combined and washed with anhydrous Na 2 SO4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=1:2 to 0:1) to give the title compound. LCMS: m / z=409.3 [M+H] + .

[0793] (1R,4R)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide hydrochloride: To a solution of tert-butyl (1R,4R)-5-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (500 mg, 1.22 mmol) in EtOAc (5 mL) was added HCl / EtOAc (10 mL, 4 M in EtOAc), and the mixture was stirred at 25°C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=309.1 [M+H] + .

[0794] Intermediate 31

[0795] N-[4-Methyl-3-(2-pyridyl)phenyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate

[0796]

[0797] tert-Butyl 6-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate: at -20 °C, in N 2 To a solution of CDI (2 g, 1.31 mmol) in DCM (100 mL) was added a solution of 4-methyl-3-(pyridin-2-yl)aniline (2 g, 10.86 mmol) in DCM (100 mL) over 30 min. The mixture was stirred at 20 ° C for 2 h. A mixture of tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (1.57 g, 7.90 mmol) and TEA (2.18 g, 21.56 mmol) in DCM (10 mL) was then added to the reaction solution. The mixture was stirred at 50 ° C for 2 h. The reaction mixture was washed with H 2 O (20 mL) and extracted with DCM (3×10 mL). The organic layers were combined, washed with brine (20 mL), and purified by anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 0: 1) to give the title compound. LCMS: m / z = 409.2 [M+H] + .

[0798] N-[4-methyl-3-(2-pyridinyl)phenyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate: To a mixture of tert-butyl 6-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (300 mg, 0.73 mmol) in DCM (3 mL) at 25°C was added TFA (1 mL). The mixture was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=309.2 [M+H] + .

[0799] Intermediate 32

[0800] N-[4-methyl-3-(2-pyridyl)phenyl]imidazole-1-carboxamide

[0801]

[0802] N-[4-methyl-3-(2-pyridyl)phenyl]imidazole-1-carboxamide To a solution of 4-methyl-3-(2-pyridyl)aniline (125.0 mg, 0.68 mmol) in DCM (6.8 mL) was added CDI (132.02 mg, 0.81 mmol). This was stirred at room temperature for 12 hours. The reaction mixture was concentrated and then ether was added to the resulting residue followed by concentration to give the title compound. The material was used directly in the following step.

[0803] Intermediate 33

[0804] N-(2-Fluoro-4-methyl-5-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate

[0805]

[0806] 2-Fluoro-4-methyl-5-(pyridin-2-yl)aniline: at 20°C, in N 2 To a solution of 5-bromo-2-fluoro-4-methylaniline (3 g, 14.70 mmol) in DMF (100 mL) was added 2-(tributylstannyl)pyridine (6.50 g, 17.64 mmol), Pd(PPh 3 ) 4(1.70 g, 1.47 mmol). The mixture was stirred at 110 °C for 12 h. The reaction was filtered through a celite pad. The filtrate was washed with H 2 O (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×60 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 20: 1 to 3: 1) to give the title compound. LCMS: m / z = 203.2 [M+H] + .

[0807] tert-Butyl 6-((2-fluoro-4-methyl-5-(pyridin-2-yl)phenyl)carbamoyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate: at -20°C, in N 2 Under 4% 4-nitropropene, a solution of 2-fluoro-4-methyl-5-(pyridin-2-yl)aniline (300mg, 1.48mmol) in DCM (5mL) was added dropwise to a solution of CDI (289mg, 1.78mmol) in DCM (10mL) over 10min. The mixture was stirred at 20°C for 2h. Then a mixture of tert-butyl 3,6-diazabicyclo [3.1.1] heptane-3-carboxylate (535mg, 2.70mmol) and TEA (190mg, 1.89mmol) in DCM (10mL) was added to the reaction solution. The mixture was stirred at 50°C for 2h and then 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 = 427.2 [M + H] + .

[0808] N-(2-Fluoro-4-methyl-5-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate: To a solution of tert-butyl 6-((2-fluoro-4-methyl-5-(pyridin-2-yl)phenyl)carbamoyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (200 mg, 0.47 mmol) in DCM (4 mL) at 25°C was added TFA (2.31 g, 20.26 mmol, 1.5 mL). The mixture was stirred at 25°C for 2 h. The reaction was concentrated under reduced pressure to give the title compound. LCMS: m / z=327.2 [M+H] + .

[0809] Intermediate 34

[0810] trans-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

[0811]

[0812] At 0°C, in N 2 To a mixture of triphosgene (127 mg, 0.43 mmol) in THF (20 mL) was added TEA (260 mg, 2.57 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg, 0.86 mmol). The mixture was stirred at 20 ° C for 1 h. Then trans-3-methyl-6-azabicyclo[3.1.1]heptane (129 mg, 1.16 mmol) and TEA (260 mg, 2.57 mmol) were added to the reaction solution. The reaction solution was stirred at 20 ° C for 1 h. The reaction solution was heated with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give the title compound. LCMS: m / z = 371.2 [M+H] + .

[0813] Intermediate 35

[0814] 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

[0815]

[0816] At 0°C, in N 2 To a mixture of triphosgene (32 mg, 0.10 mmol) in THF (1.5 mL) was added 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). The mixture was stirred at 20 ° C for 1 h. 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 h. The reaction solution was heated with H 2O (2 mL) and extracted with EtOAc (3×2 mL). The organic layers were combined and washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. 2 , PE:EtOAc=1:1) to obtain the title compound. LCMS: m / z=371.2[M+H] + .

[0817] Intermediate 36

[0818] 4-Methyl-3-(pyrimidin-2-yl)aniline

[0819]

[0820] At 25°C, N 2 2-Bromopyrimidine (2 g, 12.58 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.52 g, 15.10 mmol) in 1,4-dioxane (40 mL) and H 2 O (4 mL) was added with K 2 CO 3 (5.22g, 37.74mmol) and Pd(dppf)Cl 2 (920 mg, 1.26 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (60 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) to give the title compound. LCMS=186.1[M+H] + .

[0821] Intermediate 37

[0822] 4-Methyl-3-(pyrazin-2-yl)aniline

[0823]

[0824] At 25°C, N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) and 2-chloropyrazine (409 mg, 3.57 mmol) were dissolved in 1,4-dioxane (20 mL) and H2 O (2 mL) was added to the solution 2 CO 3 (1.48 g, 10.72 mmol) and Pd(dppf)Cl 2 (261 mg, 0.35 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE:EtOAc=10:1 to 1:1) to give the title compound. LCMS=186.1[M+H] + .

[0825] Intermediate 38

[0826] 4-Methyl-3-(pyridazin-3-yl)aniline

[0827]

[0828] At 25°C, N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (800 mg, 3.43 mmol) was dissolved in 1,4-dioxane (30 mL) and H 2 O (6 mL) were added with 3-bromopyridazine (818 mg, 5.15 mmol), Pd(dppf)Cl 2 (251 mg, 0.34 mmol) and K 2 CO 3 (949 mg, 6.86 mmol). The mixture was stirred at 105 °C for 12 h. 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 = 10: 1 to 0: 1) to give the title compound. LCMS: m / z = 186.0 [M+H] + .

[0829] Intermediate 39

[0830] 3-(5-Fluoropyrimidin-2-yl)-4-methylaniline

[0831]

[0832] At 25°C, N 24-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1 g, 4.29 mmol) and 2-bromo-5-fluoropyrimidine (1.14 g, 6.43 mmol) were dissolved in DMF (20 mL) and H 2 O (2 mL) was added to the mixture 2 CO 3 (1.78 g, 12.87 mmol) and Pd(PPh 3 ) 4 (496 mg, 0.43 mmol). The mixture was stirred at 100 °C for 12 h. The reaction mixture was washed with H 2 O (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 2: 1) to give the title compound. LCMS: m / z = 204.1 [M+H] + .

[0833] Intermediate 40

[0834] 3-Fluoro-4-methyl-5-(pyridin-2-yl)aniline

[0835]

[0836] 3-Chloro-5-fluoro-4-methylaniline: at 25°C, in N 2 4-Bromo-3-chloro-5-fluoroaniline (1 g, 4.46 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborin (503 mg, 4.01 mmol) were dissolved in 1,4-dioxane (20 mL) and H 2 O (2 mL) was added to the mixture 2 CO 3 (1.54 g, 11.14 mmol) and Pd(dppf)Cl 2 (326 mg, 0.45 mmol). The mixture was stirred at 100 °C for 16 h. 2 O (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 160.1 [M+H] + .

[0837] 3-Fluoro-4-methyl-5-(pyridin-2-yl)aniline: at 25°C, in N 2 To a mixture of 3-chloro-5-fluoro-4-methylaniline (300 mg, 1.88 mmol) and tributyl(2-pyridyl)stannane (1.04 g, 2.82 mmol) in DMF (5 mL) was added Pd(t-Bu 3 P) 2 (96 mg, 0.19 mmol). The mixture was stirred at 110 °C for 16 h. The resulting residue was washed with H 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 203.3 [M+H] + .

[0838] Intermediate 41

[0839] cis-6-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-2-carboxylic acid

[0840]

[0841] Methyl trans-4-(picolinamido)cyclohexanecarboxylate: To a solution of methyl trans-4-aminocyclohexanecarboxylate hydrochloride (10 g, 51.63 mmol) in DCM (200 mL) was added pyridine-2-carboxylic acid (7.63 g, 61.96 mmol), EDCI (14.85 g, 77.44 mmol) and DMAP (631 mg, 5.16 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 12 h and heated with H 2 O (100 mL) and extracted with DCM (3×80 mL). The combined organic layers were washed with anhydrous Na 2 SO4 was dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 0: 1) to give the title compound. LCMS: m / z = 263.1 [M+H] + .

[0842] Cis-6-pyridinyl-6-azabicyclo[3.1.1]heptane-2-carboxylic acid methyl ester: at 25 °C, in N 2 To a solution of trans-4-(picolinamido)cyclohexanecarboxylic acid methyl ester (3 g, 11.44 mmol) in 1,1,2,2-tetrachloroethane (90 mL) was added 1,2,3,4,5-pentafluoro-6-iodo-benzene (33.62 g, 114.37 mmol), Na 3 PO4 (5.63 g, 34.31 mmol), benzoquinone (618 mg, 5.72 mmol), AgOAc (5.73 g, 34.31 mmol) and Pd(OAc) 2 (514 mg, 2.29 mmol). The mixture was stirred at 140 °C for 12 h. 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 0: 1) to give the title compound. LCMS: m / z = 261.1 [M + H] + .

[0843] Cis-6-azabicyclo[3.1.1]heptane-2-carboxylic acid: To a solution of cis-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-2-carboxylic acid methyl ester (1.6 g, 6.15 mmol) in EtOH (20 mL) was added NaOH (2.46 g, 61.47 mmol) at 25 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was adjusted to pH = 7 with 2M HCl, and the mixture was lyophilized to give the title compound. LCMS: m / z = 142.1 [M+H] + .

[0844] cis-6-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-6-azabicyclo[3.1.1]heptane-2-carboxylic acid: at -20°C, in N 24-methyl-3-(pyridin-2-yl)aniline (200 mg, 1.09 mmol) in DCM (5 mL) was added dropwise to a solution of CDI (211 mg, 1.30 mmol) in DCM (5 mL). The mixture was stirred at -20 ° C for 1 h. Then cis-6-azabicyclo [3.1.1] heptane-2-carboxylic acid (152 mg, 1.08 mmol) and TEA (218 mg, 2.16 mmol) in THF (2 mL) were added. The mixture was stirred at 30 ° C for 12 h and then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; B% in A: 1%-30%, 8 min) was purified to give the title compound. LCMS: m / z=352.2 [M+H] + .

[0845] Intermediate 42

[0846] 2,4-Dimethyl-5-(pyridin-2-yl)aniline

[0847]

[0848] At 20°C, N 2 To a mixture of 5-bromo-2,4-dimethyl-aniline (300 mg, 1.50 mmol) and tributyl(2-pyridyl)stannane (717 mg, 1.95 mmol) in DMF (2 mL) was added Pd(t-Bu 3 P) 2 (77 mg, 149.94 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give the title compound. LCMS: m / z = 199.2 [M+H] + .

[0849] Intermediate 43

[0850] 3-Chloro-4-methyl-5-(pyridin-2-yl)aniline

[0851]

[0852] 3,5-Dichloro-4-methylaniline: At 20°C, in N 2 1,3-Dichloro-2-methyl-5-nitrobenzene (1 g, 4.85 mmol) was dissolved in EtOH (10 mL) and H 2 NH 4 Cl (519 mg, 9.71 mmol) and Fe (1.36 g, 24.27 mmol). The mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 9: 1) to give the title compound. LCMS: m / z = 176.2 [M+H] + .

[0853] 3-Chloro-4-methyl-5-(pyridin-2-yl)aniline: at 20°C, in N 2 To a solution of 2-(tributylstannyl)pyridine (669 mg, 1.82 mmol) in DMF (5 mL) was added 3,5-dichloro-4-methylaniline (400 mg, 2.27 mmol) and Pd(t-Bu 3 P) 2 (116 mg, 0.23 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a celite pad. The filtrate was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 1: 1 to 2: 3) to give the title compound. LCMS: m / z = 219.1 [M+H] + .

[0854] Intermediate 44

[0855] 4-Chloro-3-(pyridazin-3-yl)aniline

[0856]

[0857] At 25°C, N 2To a solution of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg, 0.78 mmol) and 3-bromopyridazine (150 mg, 0.94 mmol) in 1,4-dioxane (3 mL) was added K 3 PO 4 (418 mg, 1.97 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)palladium(II) (62 mg, 0.07 mmol). The mixture was stirred at 80°C for 12 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. 2 , DCM:MeOH=10:1) to obtain the title compound. LCMS=206.2[M+H] + .

[0858] Intermediate 45

[0859] 3-Bromo-4-methyl-5-(pyridin-2-yl)aniline

[0860]

[0861] At 20°C, N 2 To a solution of 2-(tributylstannyl)pyridine (3.78 g, 10.27 mmol) in DMF (20 mL) was added 3,5-dibromo-4-methylaniline (3.40 g, 12.83 mmol) and Pd(PPh 3 ) 4 (1.48 g, 1.28 mmol). The mixture was stirred at 110 °C for 12 h. The reaction mixture was filtered through a celite pad. The filtrate was washed with H 2 O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 1: 1 to 1: 2) to give the title compound. LCMS: m / z = 263.1, 265.0 [M+H] + .

[0862] Intermediate 46

[0863] trans-3-ethoxy-6-azabicyclo[3.1.1]heptane trifluoroacetate

[0864]

[0865] tert-Butyl 3-ethoxy-6-azabicyclo[3.1.1]heptane-6-carboxylate: at 20 °C, in N 2 To a solution of trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (50 mg, 0.23 mmol) in MeCN (2 mL) was added iodoethane (0.59 mg, 3.75 mmol) and Ag. 2 O (136 mg, 0.59 mmol). The mixture was stirred at 80°C for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude title compound. LCMS: m / z = 186.2 [Mt-Bu+H] + .

[0866] trans-3-ethoxy-6-azabicyclo[3.1.1]heptane trifluoroacetate: at 20 °C, in N 2 To a solution of trans-3-hydroxy-6-azabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (50 mg, 0.21 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=142.2 [M+H] + .

[0867] Intermediate 47

[0868] N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[0869]

[0870] DCM (5mL) was added to a dry round-bottom flask containing triphosgene (636mg, 2.1mmol) and the resulting solution was cooled to 0°C. A solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500mg, 2.1mmol) and triethylamine (0.9mL, 6.4mmol) in DCM (5mL) was added dropwise. The reaction mixture was warmed to room temperature from 0°C over 2h, and then the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in DCM (10.8mL), and 6-azabicyclo [3.1.1] heptane hydrochloride (315mg, 2.4mmol) was added to the mixture, followed by triethylamine (0.9mL, 6.4mmol). The reaction mixture was stirred at room temperature for 4h. The reaction was cooled to 0°C and saturated NaHCO was added dropwise. 3 The reaction was extracted with DCM (3 x 20 mL) and washed with Na 2 SO 4 Dry, filter and concentrate 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] + .

[0871] Intermediate 48

[0872] 3-(1-Methyl-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane trifluoroacetate

[0873]

[0874] tert-Butyl 3-(1-methyl-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate: at 20°C, in N 2 To a solution of 3-iodo-1-methyl-1H-pyrazole (2.31 g, 11.10 mmol) in toluene (15 mL) was added tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (2.00 g, 10.09 mmol), t-BuONa (1.94 g, 20.18 mmol), Xphos (962 mg, 2.02 mmol) and Pd 2 (dba) 3 (924 mg, 1.01 mmol). The mixture was stirred at 110°C for 12 h, 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=1:2 to 1:4) to give the title compound. LCMS: m / z=279.2 [M+H] + .

[0875] 3-(1-Methyl-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane trifluoroacetate: at 20 °C, in N 2 To a solution of tert-butyl 3-(1-methyl-1H-pyrazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (300 mg, 1.08 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=179.2[M+H] + .

[0876] Intermediate 49

[0877] 2-(5-Amino-2-methyl-phenyl)-5-fluoro-pyrimidine-4-carbonitrile

[0878]

[0879] 2-Chloro-5-fluoropyrimidine-4-carbonitrile: 2,4-dichloro-5-fluoro-pyrimidine (5 g, 29.95 mmol) and DABCO (336 mg, 2.99 mmol) were dissolved in DMF (50 mL) and H 2 To the solution in 2% O (10 mL), NaCN (1.61 g, 32.94 mmol) was added. The mixture was stirred at 0 °C for 1 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure.The residue is purified by silica gel chromatography (PE:EtOAc=1:0 to 0:1) to give the title compound.

[0880] 2-(5-amino-2-methylphenyl)-5-fluoropyrimidine-4-carbonitrile: at 20°C, in N 2 4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.14 mmol) was dissolved in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) were added with 2-chloro-5-fluoro-pyrimidine-4-carbonitrile (675 mg, 4.29 mmol), Pd(dppf)Cl 2 (156 mg, 0.22 mmol) and K 2 CO 3(889 mg, 6.43 mmol). The reaction was heated to 100 °C and stirred for 2 h. 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (PE: EtOAc = 3: 1 to 0: 1) and by preparative TLC (SiO 2 , PE:EtOAc=1:1) to obtain the title compound. LCMS: m / z=229.2[M+H] + .

[0881] Intermediate 50

[0882] 2,3-Difluoro-5-(5-fluoropyrimidin-2-yl)-4-methylaniline

[0883]

[0884] 2,3-Difluoro-5-(5-fluoropyrimidin-2-yl)aniline: at 20°C, in N 2 2,3-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 1.96 mmol) was dissolved in 1,4-dioxane (10 mL) and H 2 O (1 mL) was added with 2-bromo-5-fluoro-pyrimidine (416 mg, 2.35 mmol), K 2 CO 3 (541 mg, 3.92 mmol) and Pd(dppf)Cl 2 (143 mg, 0.20 mmol). The mixture was stirred at 100 °C for 5 h. 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 = 226.1 [M+H] + .

[0885] 2,3-Difluoro-5-(5-fluoropyrimidin-2-yl)-4-iodoaniline: at 0°C, in N 2 To a solution of 2,3-difluoro-5-(5-fluoropyrimidin-2-yl)aniline (270 mg, 1.20 mmol) in MeCN (10 mL) was added NIS (270 mg, 1.2 mmol). The mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was washed with H 2O (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 352.0 [M+H] + .

[0886] 2,3-Difluoro-5-(5-fluoropyrimidin-2-yl)-4-methylaniline: at 20°C, in N 2 2,3-difluoro-5-(5-fluoropyrimidin-2-yl)-4-iodo-aniline (120 mg, 0.34 mmol) was dissolved in 1,4-dioxane (2 mL) and H 2 O (0.2 mL) was added with 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborin (172 mg, 0.68 mmol, 50% purity), K 2 CO 3 (142 mg, 1.03 mmol) and Pd(dppf)Cl 2 (251 mg, 0.34 mmol). The mixture was heated at 100° C. and stirred for 3 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was analyzed by preparative TLC (SiO 2 , PE:EtOAc=5:1) to obtain the title compound. LCMS: m / z=240.2[M+H] + .

[0887] Intermediate 51

[0888] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(5-fluoropyrimidin-2-yl)aniline

[0889]

[0890] Tert-butyl((2-iodo-4-nitrobenzyl)oxy)dimethylsilane: To a solution of (2-iodo-4-nitro-phenyl)methanol (1 g, 3.58 mmol) and TBSCl (648 mg, 4.30 mmol) in DCM (10 mL) was added imidazole (293 mg, 4.30 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate 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.

[0891] Tert-butyldimethyl((4-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane: at 20°C, in N 2 To a solution of tert-butyl((2-iodo-4-nitrobenzyl)oxy)dimethylsilane (1 g, 2.54 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.29 g, 5.09 mmol) in 1,4-dioxane (10 mL) was added KOAc (749 mg, 7.63 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (208 mg, 0.25 mmol). The mixture was heated to 100°C and stirred for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE:EtOAc=100:1 to 10:1) to give the title compound. LCMS: m / z=394.2 [M+H] + .

[0892] 2-(2-(((tert-butyldimethylsilyl)oxy)methyl)-5-nitrophenyl)-5-fluoropyrimidine: at 20°C, in N 2 To a solution of tert-butyldimethyl((4-nitro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)silane (400 mg, 1.02 mmol) and 2-bromo-5-fluoro-pyrimidine (216 mg, 1.22 mmol) in 1,4-dioxane (5 mL) and H 2 O (0.5 mL) was added to the mixture with Pd(dppf)Cl 2 (74 mg, 0.10 mmol) and K 2 CO 3 (281 mg, 2.03 mmol). The mixture was heated to 100 °C and stirred for 3 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 5: 1) to give the title compound. LCMS: m / z = 364.1 [M+H] + .

[0893] 4-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(5-fluoropyrimidin-2-yl)aniline: 2-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-nitrophenyl)-5-fluoropyrimidine (1.5 g, 4.13 mmol) in EtOH (15 mL) and H 2 NH 4 Cl (1.10 g, 20.64 mmol) and Fe (1.15 g, 20.64 mmol). The mixture was then heated at 90 °C and stirred for 1 h. The reaction mixture was treated with H 2 O (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 334.1 [M+H] + .

[0894] Intermediate 53

[0895] 2-Fluoro-4-methyl-5-(1,3,5-triazin-2-yl)aniline

[0896]

[0897] 4-Fluoro-2-methyl-5-nitrobenzimidate methyl ester hydrochloride: A solution of 4-fluoro-2-methyl-5-nitro-benzonitrile (1 g, 5.55 mmol) in HCl / MeOH (15 mL) was stirred at 20 °C for 16 h. The mixture was concentrated under reduced pressure. The residue was slurried with MTBE (10 mL), filtered and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z=213.1 [M+H] + .

[0898] 2-(4-Fluoro-2-methyl-5-nitrophenyl)-1,3,5-triazine: At 20°C, in N 21,3,5-triazine (210 mg, 2.59 mmol) and AcOH (283 mg, 4.71 mmol) were added to a solution of 4-fluoro-2-methyl-5-nitrobenzenecarboximidate hydrochloride (500 mg, 2.36 mmol) in EtOH (10 mL) under 4% argon. The mixture was heated to 80 ° C and stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (PE: EtOAc = 5: 1) to give the title compound. LCMS: m / z = 235.1 [M + H] + .

[0899] 2-Fluoro-4-methyl-5-(1,3,5-triazin-2-yl)aniline: 2-(4-Fluoro-2-methyl-5-nitrophenyl)-1,3,5-triazine (100 mg, 0.43 mmol) was dissolved in EtOH (4 mL) and H 2 To the solution in O (1 mL) were added Fe (119 mg, 2.14 mmol) and NH 4 Cl (114 mg, 2.14 mmol). The mixture was heated to 80° C. and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the crude product was washed with DCM:MeOH (V 1 :V 2 =10:1) into a slurry. The filtrate was then concentrated under reduced pressure to obtain the title compound. LCMS: m / z=205.2[M+H] + .

[0900] Intermediate 54

[0901] 1-(3-(2-aminoethoxy)pyridin-2-yl)ethanone

[0902]

[0903] Tert-butyl (2-((2-acetylpyridin-3-yl)oxy)ethyl)carbamate: at 25°C, in N 2 To a solution of 1-(3-hydroxypyridin-2-yl)ethanone (2 g, 14.58 mmol) in DMF (25 mL) was added K 2 CO 3 (4.03 g, 29.17 mmol). The mixture was stirred at 25°C for 0.5 h, and then tert-butyl (2-bromoethyl)carbamate (3.6 g, 16.04 mmol) was added to the solution at 25°C. The mixture was heated to 70°C and stirred for 12.5 h. The reaction mixture was then washed with H 2 O (75 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (75 mL) and dried over anhydrous Na 2 SO4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 2) to give the title compound. LCMS: m / z = 281.2 [M+H] + .

[0904] 1-(3-(2-Aminoethoxy)pyridin-2-yl)ethanone hydrochloride: A solution of tert-butyl (2-((2-acetylpyridin-3-yl)oxy)ethyl)carbamate (3.2 g, 11.42 mmol) in HCl / EtOAc (4M, 90 mL) was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z=181.1 [M+H] + .

[0905] 5-Methyl-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine: at 25°C, in N 2 To a solution of 1-(3-(2-aminoethoxy)-2-pyridinyl)ethanone hydrochloride (1 g, 4.62 mmol) in MeOH (15 mL) was added TEA (934 mg, 9.23 mmol) and AcOH (554 mg, 9.23 mmol) and stirred for 2 h. The reaction was then cooled to 0 °C and stirred under N 2 Add NaBH 3 CN (580 mg, 9.23 mmol). The mixture was warmed to 25 °C and stirred for 1 h. The reaction mixture was washed with saturated Na 2 CO 3 The aqueous solution was adjusted to pH = 7 and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. The crude material was used directly in the next step. LCMS: m / z = 165.2 [M+H] + .

[0906] Intermediate 55

[0907] (2S,4S)-1-(tert-Butoxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid

[0908]

[0909] (2S,4S)-1-(tert-Butyloxycarbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid: at 25 °C, in N 2To a solution of 1-(tert-butyl)-2-methyl (2S,4S)-4-(trifluoromethyl)pyrrolidine-1,2-dicarboxylate (410 mg, 1.38 mmol) in THF (4 mL) and H 2 To a solution of 1% 4-nitropropene in 4% pyruvate (1 mL) was added LiOH (132 mg, 5.52 mmol) and the mixture was stirred for 6 h. The reaction mixture was washed with H 2 O (3 mL), adjusted to pH about 5-6 with 2N HCl and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate 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.

[0910] Intermediate 56

[0911] trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]heptane

[0912]

[0913] (trans-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 0°C, in N 2 Under the condition of 1% paraformyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester (1 g, 3.65 mmol) and CaCl 2 (1.62 g, 14.58 mmol) in MeOH (30 mL) was added with NaBH 4 (828 mg, 21.87 mmol). The reaction was then warmed to 20 °C and stirred for 1 h. The reaction was washed with saturated NH 4 The mixture was quenched with aqueous Cl (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (3×5 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is 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] + .

[0914] (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 (600 mg, 2.44 mmol) in DMF (12 mL) was added NaH (146 mg, 3.65 mmol, 60% in mineral oil) at 0°C. The reaction mixture was warmed to 20°C and stirred for 0.5 h. The reaction was then cooled to 0°C and MeI (692 mg, 4.87 mmol) was added. The mixture was warmed to 20°C and stirred for 2 h. The reaction was washed with saturated NH 4 The solution was quenched with aqueous Cl (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (3×2 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give the title compound. LCMS: m / z = 261.2 [M+H] + .

[0915] trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]heptane: at 25°C, in N 2 To a solution of (trans-1-(methoxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (450 mg, 1.73 mmol) in EtOH (10 mL) was added NaOH (692 mg, 17.29 mmol). The mixture was heated to 90 ° C and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure (water pump, below 35 ° C) to give the crude product. The crude material was stirred in DCM (20 mL), filtered through a celite pad, and concentrated under reduced pressure (water pump, below 35 ° C). If the residue still contains solids, the above procedure is repeated until no solids remain (2-3 times) to give the title compound. LCMS: m / z=156.2[M+H] + .

[0916] Intermediates 57 and 58

[0917] (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone

[0918]

[0919] cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid: To a solution of cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester (2 g, 7.29 mmol) in MeOH (20 mL) was added NaOH (437 mg, 10.94 mmol) in H2O at 20 °C. 2 O (4 mL) and the reaction mixture was stirred for 3 h. The reaction mixture was adjusted to pH = 3 by adding 2M HCl. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound. LCMS: m / z=261.2 [M+H] + .

[0920] cis-N-methoxy-N,3-dimethyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxamide: at 20°C, in N 2 To a solution of cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]heptane-1-carboxylic acid (1.7 g, 6.53 mmol) in DMF (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (701 mg, 7.18 mmol), HATU (2.73 g, 7.18 mmol) and DIEA (2.53 g, 19.59 mmol) and the mixture was stirred for 3 h. The mixture was washed with H 2 O (50 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine (3×10 mL), and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 304.2 [M+H] + .

[0921] 1-(cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)ethan-1-one: at –78°C, in N 2 To a solution of cis-N-methoxy-N,3-dimethyl-6-(pyridine-2-carbonyl)-6-azabicyclo[3.1.1]heptane-1-carboxamide (1.7 g, 5.60 mmol) in THF (20 mL) was added MeLi (2.7 M in THF, 2.70 mL). The reaction mixture was stirred at -78 °C for 2 h. The mixture was heated to 40 °C by adding saturated NH 4The solution was quenched with aqueous Cl (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 1: 1) to give the title compound. LCMS: m / z = 259.2 [M+H] + .

[0922] (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: To a solution of 1-(cis-3-methyl-6-pyridinecarbonyl-6-azabicyclo[3.1.1]hept-1-yl)ethan-1-one (750 mg, 2.90 mmol) in MeOH (10 mL) was added NaBH at 0 °C. 4 (220 mg, 5.81 mmol) and the mixture was stirred for 2 h. At 0 °C, the mixture was heated by adding saturated NH 4 The reaction mixture was concentrated under reduced pressure to remove organic matter and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a mixture of 4 diastereomers. LCMS: m / z=261.2 [M+H] + .

[0923] (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 0°C, in N 2 To a solution of (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (700 mg, 2.69 mmol) in DMF (8 mL) was added NaH (161 mg, 4.03 mmol, 60% in mineral oil). The mixture was stirred at 0° C. for 0.5 h, then MeI (763 mg, 5.38 mmol) was added and stirred for another 2 h. The mixture was heated to 40° C. by adding saturated NH 4The solution was quenched with aqueous Cl (30 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give (cis-1- (1-methoxyethyl) -3-methyl-6-azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone, intermediate 57 as the first eluting mixture of enantiomers and intermediate 58, which was in the form of (cis-1- (1-methoxyethyl) -3-methyl-6-azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone and unreacted (cis-1- (1-hydroxyethyl) -3-methyl-6-azabicyclo [3.1.1] hept-6-yl) (pyridin-2-yl) ketone LCMS: m / z = 275.1 [M + H] + mixture.

[0924] Intermediate 59

[0925] cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane and 1-(cis-3-methyl-6-azabicyclo[3.1.1]hept-1-yl)ethan-1-ol

[0926]

[0927] cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane and 1-(cis-3-methyl-6-azabicyclo[3.1.1]hept-1-yl)ethan-1-ol: at 0°C, in N 2 To a mixture of intermediate 58, (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (400 mg, 1.46 mmol) in THF (10 mL) was added MeMgBr (3 M in Et 2 O, 2.43 mL). The mixture was warmed to 20 °C and stirred for 7 h. The reaction was stirred by adding saturated NH 4 The resulting residue was slurried with DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure to give the title compound LCMS: m / z = 170.3 [M+H] + and LCMS: m / z=156.2[M+H] + mixture.

[0928] Intermediate 60

[0929] cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane

[0930]

[0931] cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]heptane: at 0°C, in N 2 To a mixture of (cis-1-(1-methoxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone, intermediate 57 (250 mg, 0.91 mmol) in THF (10 mL) was added MeMgBr (3 M in Et 2 O, 1.52 mL). The mixture was warmed to 20 °C and stirred for 7 h. The reaction was stirred by adding saturated NH 4 The product was quenched with aqueous Cl (1 mL) and concentrated under reduced pressure. The residue was slurried with DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 170.3 [M+H] + .

[0932] Intermediates 61 and 62

[0933] (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone

[0934]

[0935] To a solution of 1-(cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)ethan-1-one (5.5 g, 21.29 mmol) in MeOH (100 mL) was added NaBH in portions at -30 °C. 4 (1.61 g, 42.58 mmol). The mixture was stirred at 0 °C for 2 h, then heated to 40 °C by adding saturated NH 4 Cl (100 mL) was quenched. The mixture was concentrated under reduced pressure to remove MeOH and the remaining aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4The resulting residue was purified by silica gel column chromatography (PE: EtOAc = 3: 1 to 1: 1) to give (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone intermediate 61 as the first eluting isomer. LCMS: m / z = 261.3 [M+H] + and (cis-1-(1-hydroxyethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone intermediate 62 as the second eluting isomer. LCMS: m / z=261.3 [M+H] + .

[0936] Intermediate 64

[0937] 2-(cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)-2-oxoacetate

[0938]

[0939] (5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione and (5S,7S)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione: at 20 °C in N 2 (R)-3-methylcyclohexan-1-one and (S)-3-methylcyclohexan-1-one (50 g, 445.76 mmol, 54.59 mL) were dissolved in EtOH (250 mL) and H 2 O (250 mL) was added to the mixture 4 ) 2 CO 3 (128.49 g, 1.34 mol) and KCN (43.54 g, 669 mmol). The mixture was heated to 65 °C and stirred for 3 h. The reaction mixture was filtered and the filter cake was washed with H 2 O and dried under reduced pressure. The crude product was triturated with EtOH at 20°C for 30 min, filtered, and the solid was dried under reduced pressure to give the title compound. LCMS: m / z=183.2 [M+H] + .

[0940] (1R,3R)-1-amino-3-methylcyclohexane-1-carboxylic acid and (1S,3S)-1-amino-3-methylcyclohexane-1-carboxylic acid: (5R,7R)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione and (5S,7S)-7-methyl-1,3-diazaspiro[4.5]decane-2,4-dione (78.5 g, 430.80 mmol) were added to H at 25 °C.2 O (1000 mL) was added to the solution 2 (738 g, 4.31 mol). The mixture was heated in a 5 L autoclave at 140 °C for 12 h. The reaction was cooled to 0 °C and washed with 3 M H 2 SO 4 The pH was adjusted to pH = 3. 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 = 158.2 [M+H] + .

[0941] (1R,3R)-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride and (1S,3S)-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride: at 0°C, in N 2 To a mixture of (1R,3R)-1-amino-3-methylcyclohexane-1-carboxylic acid and (1S,3S)-1-amino-3-methylcyclohexane-1-carboxylic acid (60 g, 382 mmol) in MeOH (600 mL) was added SOCl 2 (227 g, 1.91 mol, 138.43 mL). The mixture was heated at 75°C for 12 h. The reaction mixture was concentrated under reduced pressure to give the title compound. LCMS: m / z = 172.2 [M+H] + .

[0942] (1R,3R)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylic acid methyl ester (1S,3S)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylic acid methyl ester: at 0 °C, in N 2 To a solution of (1R, 3R)-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride and (1S, 3S)-1-amino-3-methylcyclohexane-1-carboxylic acid methyl ester hydrochloride (24 g, 140 mmol) and picolinic acid (25.88 g, 210 mmol) in DCM (300 mL) was added DIEA (54.34 g, 420 mmol, 73.24 mL), DMAP (1.71 g, 14 mmol) and EDCI (40.30 g, 210 mmol). The mixture was warmed to 25 ° C and stirred for 16 h. The reaction mixture was washed with H 2 O (200 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 3: 1) to give the title compound. LCMS: m / z = 277.2 [M+H]+ .

[0943] 2-(cis-3-methyl-6-pyridinyl-6-azabicyclo[3.1.1]hept-1-yl)-2-oxoacetic acid methyl ester: at 25°C, in N 2 To a solution of methyl (1R,3R)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate and methyl (1S,3S)-3-methyl-1-(picolinamido)cyclohexane-1-carboxylate (19 g, 68.76 mmol) in 1,1,2,2-tetrachloroethane (900 mL) was added Na 3 PO 4 (33.82 g, 206 mmol, 33.82 mL), 1,2,3,4,5-pentafluoro-6-iodo-benzene (202.12 g, 688 mmol), AgOAc (34.43 g, 206 mmol, 10.56 mL), BQ (3.72 g, 34 mmol, 7.74 mL) and Pd(OAc) 2 (3.09 g, 13.75 mmol). The mixture was heated to 145 ° C and stirred for 16 h, and then the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and 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 = 275.2 [M + H] + .

[0944] Intermediate 67

[0945] 3-Chloro-5-(difluoromethoxy)pyridazine

[0946]

[0947] 6-Chloropyridazin-4-ol: 3,5-dichloropyridazine (5 g, 33.56 mmol) was dissolved in 1,4-dioxane (20 mL) and H 2 O (20mL) was added with NaOH (2g, 50mmol). The mixture was heated to 100°C and stirred for 12h. The reaction mixture was adjusted to pH = 4 by adding dilute HCl at 0°C. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The crude product was slurried with DCM:MeOH = 10: 1 (20mL). The mixture was filtered and the filter cake was dried under reduced pressure to give the title compound. LCMS: m / z = 131.3, 133.3 [M + H] + .

[0948] 3-Chloro-5-(difluoromethoxy)pyridazine: 6-chloropyridazin-4-ol (500 mg, 3.83 mmol) in DMF (12 mL) and H2 To the solution in O (4 mL) were added sodium 2-chloro-2,2-difluoro-acetate (1.34 g, 8.81 mmol) and K 2 CO 3 (1.32 g, 9.58 mmol). The mixture was heated to 110° C. and stirred for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was washed with H 2 O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 181.1, 183.2 [M+H] + .

[0949] Intermediate 68

[0950] 3-Methylsulfanyl-6-(trifluoromethyl)-1,2,4-triazine and 3-methylsulfanyl-5-(trifluoromethyl)-1,2,4-triazine

[0951]

[0952] To a stirred solution of NaOAc (5.75 g, 70.12 mmol) in H 2 3,3-dibromo-1,1,1-trifluoro-propan-2-one (20.43 g, 75.73 mmol) was added to a solution in 4% 4-nitropropane (50 mL). The solution was heated to 80 °C and stirred for 30 min, then allowed to cool to 20 °C before adding solid (Z)-[amino(hydrazine)methylene]-methyl-sulfonium hydrochloride (5 g, 35.06 mmol). The mixture was stirred at 20 °C for 12 h. The reaction solution was then extracted with EtOAc (3×40 ml) and the combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EtOAc = 100: 1 to 10: 1) to give the title compound. LCMS: m / z = 196.1 [M+H] + .

[0953] Intermediate 69

[0954] 4-Methyl-3-(5-(trifluoromethyl)-1,2,4-triazin-3-yl)aniline and 4-methyl-3-[6-(trifluoromethyl)-1,2,4-triazin-3-yl]aniline

[0955]

[0956] At 25°C, N 2 To a mixture of 3-methylsulfanyl-5-(trifluoromethyl)-1,2,4-triazine and 3-methylsulfanyl-6-(trifluoromethyl)-1,2,4-triazine (2 g, 10.25 mmol) and (5-amino-2-methyl-phenyl)boronic acid (1.86 g, 12.30 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh 3 ) 4 (378 mg, 1.02 mmol) and thiophene-2-carbonyl copper oxide; hydrate (4.71 g, 22.54 mmol). The mixture was heated to 100 ° C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the crude product was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; B% in A: 25%-55%, 8 min) was purified to give the title compound. LCMS: m / z = 255.1 [M+H] + .

[0957] Intermediate 70

[0958] 3-Chloro-5-(fluoromethoxy)pyridazine

[0959]

[0960] At 25°C, N 2 To a solution of 6-chloropyridazin-4-ol (500 mg, 3.83 mmol) in DMF (6 mL) was added fluoro(iodo)methane (1.41 g, 8.81 mmol) and K 2 CO 3 (1.32 g, 9.58 mmol). The mixture was heated to 110°C and stirred for 2 h. The reaction mixture was then filtered through a celite pad and the filtrate was washed with H 2 O (20 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine (2×10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 10: 1 to 1: 1) to give the title compound. LCMS: m / z = 163.1 [M+H] + .

[0961] Intermediate 72

[0962] cis-1-((difluoromethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane

[0963]

[0964] (cis-1-((difluoromethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone: at 25°C, in N 2 To (cis-1-(hydroxymethyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (450 mg, 1.83 mmol) was dissolved in DCM (7.5 mL) and H 2 Add KHF to the mixture in O (7.5 mL) 2 (1.14 g, 14.62 mmol) and the reaction was stirred for 10 min. (Bromodifluoromethyl)trimethylsilane (1.11 g, 5.48 mmol) was then added to the reaction mixture and stirred for 12 h. The reaction mixture was washed with H 2 O (10 mL) and extracted with DCM (3×5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE: EtOAc = 5: 1 to 3: 1) to give the title compound. LCMS: m / z = 297.1 [M+H] + .

[0965] cis-1-((difluoromethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]heptane: at 0°C, in N 2 To a mixture of (cis-1-((difluoromethoxy)methyl)-3-methyl-6-azabicyclo[3.1.1]hept-6-yl)(pyridin-2-yl)methanone (130 mg, 0.44 mol) in THF (5 mL) was added MeMgBr (3 M in THF, 0.73 mL). The mixture was warmed to 25 °C and stirred for 1 h. The reaction was concentrated by adding saturated NH 4 The reaction mixture was quenched with aqueous Cl (1 mL) and concentrated under reduced pressure. The reaction mixture was then diluted with DCM (10 mL), filtered and the filtrate was concentrated under reduced pressure to give the title compound. LCMS: m / z = 192.2 [M+H] + .

[0966] Example 1

[0967] (1S,4S)-5-((4-methyl-3-(pyridin-2-yl)phenyl)carbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

[0968]

[0969] At 0°C, in N 2 To a mixture of (1S,4S)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide hydrochloride (100 mg, 0.26 mmol) in DCM (2 mL) was added TEA (80 mg, 0.79 mmol) and methyl chloroformate (27 mg, 0.29 mmol). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with DCM (3×3 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. 2 , PE:EtOAc=0:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ8.67-8.61(m,1H),7.72(td,J=2.0,7.6Hz,1H),7.42-7.33(m,3H),7.25-7.21(m,1H),7.17(d,J=8 .8Hz,1H),6.51(s,1H),4.75-4.50(m,2H),3.73-3.64(m,3H),3.56-3.33(m,4H),2.29(s,3H),1.82(br s,2H). LCMS:m / z=367.2[M+H] + .

[0970] Example 2

[0971] N-(4-methyl-3-(pyridin-2-yl)phenyl)-3-(1,1,1-trifluoropropan-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0972]

[0973] At 0°C, in N 2To a mixture of N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate (300 mg, 0.56 mmol) and DIEA (361 mg, 2.80 mmol) in THF (5 mL) was added crude 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid trifluoropropan-2-yl ester (328 mg, 0.67 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: A: 10 mM NH 4 HCO 3 Purification by HPLC-MS / MS (5% HPLC-MS / ... 1 H NMR (400 MHz, CDCl 3 ): δ8.68(d,J=4.8Hz,1H),7.74(td,J=1.6,7.6Hz,1H),7.47(dd,J=2.4,8.4Hz,1H),7.42(d,J=7 .6Hz,1H),7.33(d,J=2.0Hz,1H),7.27-7.23(m,1H),7.21(d,J=8.4Hz,1H),6.20(s,1H),4.21-4. 14(m,2H),3.68-3.57(m,1H),3.55-3.45(m,1H),3.28-3.16(m,1H),3.10(d,J=10.0Hz,1H),2.86 (d,J=10.4Hz,1H),2.61-2.51(m,1H),2.32(s,3H),1.57(d,J=8.0Hz,1H),1.22(d,J=6.8Hz,3H). LCMS: m / z=405.2[M+H] + .

[0974] Example 3

[0975] N-(2-Fluoro-4-methyl-5-(pyridin-2-yl)phenyl)-3-(2,2,2-trifluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0976]

[0977] To a solution of N-(2-fluoro-4-methyl-5-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate (100 mg, 0.23 mmol) and DIEA (147 mg, 1.14 mmol) in THF (2 mL) at 0°C was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (63 mg, 0.30 mmol). The mixture was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution; B: MeCN; % of B in A: 25%-60%, 8 min) was purified to give the title compound. 1 H NMR (400 MHz, CDCl 3 ):δ8.66(br d,J=4.8Hz,1H),8.13(d,J=8.4Hz,1H),7.73(td,J=1.6,7.6Hz,1H),7.42(d,J=8.0Hz,1H),7.25-7.22(m,1H),7.00(d,J=12.0Hz,1H),6.20(br s,1H),4.24(d,J=6.0Hz,2H),3.45(d,J=10.4Hz,2H),3.23-3.14(m,4H),2.62-2.56(m,1H),2.32(s,3H),1.78(d,J=8.0Hz,1H). LCMS: m / z=409.1[M+H] + .

[0978] Example 4

[0979] N-(4-methyl-3-(pyridin-2-yl)phenyl)-3-(2,2,2-trifluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0980]

[0981] At 0°C, in N 2 To a mixture of N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate (300 mg, 0.56 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (156 mg, 0.67 mmol) in THF (5 mL) was added DIEA (217 mg, 1.68 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with H 2O (10 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; % of B in A: 25%-45%, 8 min) was purified to give the title compound. 1 H NMR (400 MHz, CDCl 3 ):δ8.69(br d,J=4.8Hz,1H),7.75(t,J=7.2Hz,1H),7.49-7.40(m,2H),7.35(d,J=2.0Hz,1H),7.27-7.19(m,2H),6.14(s,1H),4. 18(d,J=6.0Hz,2H),3.45-3.42(m,2H),3.25-3.09(m,4H),2.55(q,J=6.4Hz,1H),2.32(s,3H),1.76(d,J=8.4Hz,1H). LCMS:m / z=391.2[M+H] + .

[0982] Example 5

[0983] 3-(2,2-Difluoroethyl)-N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0984]

[0985] At 0°C, in N 2 To a mixture of N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate (200 mg, 0.37 mmol) and DIEA (144.56 mg, 1.12 mmol) in THF (5 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (95.80 mg, 0.45 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4Dry, filter and concentrate under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex LunaC18 75×30 mm×3 μm; mobile phase: A: 10 mM FA aqueous solution, B: MeCN; B in A: 5%-25%, 8 min) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ):δ8.68(br d,J=4.8Hz,1H),7.75(td,J=1.6,7.6Hz,1H),7.49-7.41(m,2H),7.36(d,J=2.4Hz,1H),7.26-7.20(m,2H),6.16(s,1H),5.82(tt,J=4.4, 56.0Hz, 1H), 4.18 (d, J = 6Hz, 2H), 3.78-3.01 (m, 4H), 2.94 (td, J = 3.6, 14.8Hz, 2H), 2.57-2.47 (m, 1H), 2.32 (s, 3H), 1.81 (d, J = 8.4Hz, 1H). LCMS:m / z=373.2[M+H] + .

[0986] Example 6

[0987] 3-Cyclobutyl-N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0988]

[0989] At 25°C, N 2 To a mixture of cyclobutanone (57 mg, 0.81 mmol) and N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide (100 mg, 0.32 mmol) in MeOH (2 mL) was added AcOH (58 mg, 0.97 mmol). The mixture was stirred at 25 °C for 30 min, and then NaBH 3 CN (41 mg, 0.65 mmol) was added to the mixture and stirred at 25 °C for 12 h. The mixture was washed with saturated Na 2 CO 3 The aqueous solution was adjusted to pH = 7-8 and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The residue was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; % of B in A: 25%-55%, 8 min) was purified to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ8.68(d,J=4.8Hz,1H),7.74(td,J=1.6,7.6Hz,1H),7.47(dd,J=2.4,8.4Hz,1H),7.43( d,J=7.6Hz,1H),7.35(d,J=2.4Hz,1H),7.26-7.23(m,1H),7.21(d,J=8.0Hz,1H),6.18(br s,1H),4.19(d,J=5.6Hz,2H),3.15-3.03(m,3H),2.82(d,J=11.2Hz,2H),2.49-2. 42(m,1H),2.32(s,3H),2.00-1.92(m,2H),1.92-1.84(m,3H),1.69-1.60(m,2H). LCMS:m / z=363.3[M+H] + .

[0990] Example 7

[0991] 3-Ethyl-N-(4-methyl-3-(pyridin-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide

[0992]

[0993] At 0°C, in N 2 To a mixture of N-[4-methyl-3-(2-pyridyl)phenyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxamide trifluoroacetate (300 mg, 0.97 mmol) and DIEA (377 mg, 2.92 mmol) in THF (5 mL) was added iodoethane (182 mg, 1.17 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with anhydrous Na 2 SO 4The residue was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; % of B in A: 30%-50%, over 8 min) was purified to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ8.68(d,J=4.8Hz,1H),7.73(td,J=1.6,7.6Hz,1H),7.51-7.39(m,2H),7.36( d,J=2.0Hz,1H),7.26-7.22(m,1H),7.20(d,J=8.4Hz,1H),6.18(s,1H),4.19(br d,J=5.6Hz,2H),3.11-2.88(m,4H),2.56(q,J=7.2Hz,2H),2.44(q,J=6.4Hz,1H),2.31(s,3H),1.89(d,J=7.6Hz,1H),1.04(t,J=7.2Hz,3H). LCMS: m / z = 337.2 [M+H] + .

[0994] Example 8

[0995] N-[4-methyl-3-(2-pyridyl)phenyl]-11-azatricyclo[6.2.1.02,7]undec-2,4,6-triene-11-carboxamide

[0996]

[0997] [4-Methyl-3-(2-pyridyl)phenyl]imidazole-1-carboxamide (40.0 mg, 0.14 mmol) was suspended in THF (1.4 mL) and treated with 11-azatricyclo[6.2.1.0,2,7]undec-2,4,6-triene hydrochloride (78.33 mg, 0.43 mmol). The reaction mixture was stirred at 65 °C for 0.5 h and then concentrated to dryness. The crude reaction mixture was purified by column chromatography 20-70% EtOAc / hexanes to give the title compound. LCMS: m / z=356.2 [M+H] + . 1 H-NMR (400MHz, CDCl 3): δ8.66(d,J=4.3Hz,1H),7.72(td,J=7.7,1.7Hz,1H),7.43–7.40(m,3H),7.28–7.24(m,3H),7.17(dt,J =5.8,3.1Hz,3H),6.76(s,1H),5.21(t,J=2.0Hz,2H),2.31(s,3H),2.24–2.21(m,2H),1.39–1.35(m,2H).

[0998] Example 9

[0999] 6-[[4-methyl-3-(2-pyridyl)phenyl]carbamoyl]-6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl ester

[1000]

[1001] To a solution of 4-methyl-3-(2-pyridyl)aniline (50.0 mg, 0.3 mmol) in THF (2.7 mL) was added CDI (52.8 mg, 0.3 mmol) at -20 °C. It was allowed to warm to room temperature over 0.5 h. A solution of 6-azabicyclo[3.1.1]heptane-1-carboxylic acid methyl trifluoroacetate (73.0 mg, 0.3 mmol) and TEA (0.08 mL, 0.5 mmol) in 0.5 mL DCM was then added and the reaction mixture was heated at 50 °C for 0.5 h. The reaction mixture was concentrated and purified by reverse phase HPLC to give the title compound as a mixture of enantiomers. LCMS: m / z=366.2. 1 H-NMR (400MHz, CDCl3): δ8.95 (s, 1H), 8.75 (dd, J = 5.1, 0.9Hz, 1H), 7.89 (t, J = 7 .3Hz,1H),7.57–7.50(m,3H),7.38(t,J=6.4Hz,1H),7.23(d,J=8.2Hz,1H),4.18 –4.15(m,1H),3.85(s,3H),2.65–2.61(m,2H),2.43–2.37(m,1H),2.34(s,3H), 1.99–1.96(m,2H),1.85–1.80(m,1H),1.75(d,J=8.7Hz,1H),1.67–1.61(m,1H).

[1002] Example 10

[1003] trans-3-methyl-N-(4-methyl-3-(pyridin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[1004]

[1005] At -20 °C, in N 2 To a solution of CDI (53 mg, 0.325 mmol) in DCM (2 mL) was added a solution of 4-methyl-3-(2-pyridyl)aniline (50 mg, 0.27 mmol) in DCM (2 mL) over 10 min. The mixture was stirred at 20 ° C for 1 h. Then, at 25 ° C, a mixture of trans-3-methyl-6-azabicyclo[3.1.1]heptane (59 mg, 0.53 mmol) and TEA (65 mg, 0.65 mmol) in DCM (2 mL) was added to the above solution. The mixture was stirred at 25 ° C for 12 h. The reaction mixture was washed with H 2 O (2 mL) and extracted with DCM (3×3 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 Purification by HPLC (water solution, B: MeCN; B in A: 25%-55%, 8 min) gave the title product. 1 H NMR (400 MHz, CDCl 3 ): δ8.68(d,J=4.4Hz,1H),7.73(td,J=1.6,7.6Hz,1H),7.50(dd,J=2.4,8.4Hz,1H),7.43(d,J=7.8Hz,1H),7.37(d,J=2.4Hz,1H ),7.26-7.22(m,1H),7.21(d,J=8.4Hz,1H),6.05(s,1H),4.20(d,J=6.0Hz,2H),2.39-2.35(m,1H),2.32-2.26(m,4H),1.93(br d, J=8.6Hz, 4H), 1.67 (d, J=8.6Hz, 1H), 0.98 (d, J=6.8Hz, 3H). LCMS: m / z = 322.2 [M+H] + .

[1006] Embodiment 11

[1007] cis-3-methyl-N-(4-methyl-3-(pyridin-2-yl)phenyl)-6-azabicyclo[3.1.1]heptane-6-carboxamide

[1008]

[1009] At -20 °C, in N 2 To a mixture of CDI (211 mg, 1.30 mmol) in DCM (6 mL) was added a solution of 4-methyl-3-(2-pyridyl)aniline (200 mg, 1.09 mmol) in DCM (6 mL) at 4 ° C. The mixture was stirred at -20 ° C for 1 h. Then, at 25 ° C, a mixture of cis-3-methyl-6-azabicyclo[3.1.1]heptane (80 mg, 0.72 mmol) and TEA (218 mg, 2.16 mmol) in DCM (3 mL) was added to the above mixture. The mixture was stirred at 50 ° C for 0.5 h. The reaction mixture was washed with H 2 O (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 80×40 mm×3 μm; mobile phase: A: 10 mM NH 4 HCO 3 Aqueous solution, B: MeCN; % of B in A: 25%-55%, 8 min) was purified to give the title compound. 1 H NMR (400 MHz, CDCl 3 ): δ8.69(d,J=4.4Hz,1H),7.74(td,J=1.6,7.6Hz,1H),7.48(dd,J=2.4,8 .0Hz,1H),7.44(d,J=8.0Hz,1H),7.39-7.37(m,1H),7.26-7.19(m,2H),6 .09(s,1H),4.24-4.15(m,2H),2.67-2.53(m,3H),2.32(s,3H),2.14-2.0 0(m,1H),1.39-1.29(m,2H),1.07(d,J=8.4Hz,1H),1.03(d,J=6.8Hz,3H). LCMS:m / z=322.2[M+H] + .

[1010] The following compounds as shown in Table 1 were or can be prepared via procedures similar to those described above. Example 12 was prepared from a commercially available amine with unknown stereochemistry. Only one racemate was obtained, but it is not known whether the final compound is a cis or trans isomer.

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019] ...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N; R is tert-butyl, substituted by one to five R 8 Substituted C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C 3-10 Cycloalkyl or heterocyclic group; and said C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace; R 1 Halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 2 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 is independently optionally substituted by one to five Z 1 replace; R 3 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 is independently optionally substituted by one to five Z 1 replace; or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; Each R 6 are independently hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 7 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 is independently optionally substituted by one to five Z 1 replace; Each R 8 are independently halo, cyano, 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 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is 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 is independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is 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 is independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halogen, 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 is 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 is 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 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Haloalkyl, 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 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution; The conditions are: i) the compound is not N-[3-[6-ethoxy-5-(tetrahydro-2H-pyran-4-yl)-3-pyridazinyl]-4-methylphenyl]-2,3-dihydro-1H-isoindole-5-carboxamide, (3R)-1-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethyl]-N-[4-hydroxy-3-(2-pyridyl)phenyl]-3-pyrrolidinecarboxamide, 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridyl)phenyl]-6-(trifluoromethyl)-1H-indole-1-carboxamide, N-[3-[3-chloro-5-(trifluoromethyl)-2-pyridyl]-4-methoxyphenyl]hexahydro-1,3-dimethyl -4,6-dioxo-2-thioxo-5-pyrimidinecarboxamide, (3R,5aS,6R,8aS,9S,11R,11aR)-N-[4-chloro-3-(2-pyridyl)phenyl]octahydro-3,6,9-trimethyl-3,11-epoxy-3H,11H-furo[3,4-j]-1,2-benzodioxepane-9-carboxamide, 1-(1,3-benzodioxol-5-yl)-N-[4-methyl-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, N-[4-[(4-propyl-1-piperazinyl)carbonyl]-3-(2-pyridyl)phenyl]-cyclopropanecarboxamide, 4,4'-(((2-(pyridin-2-yl)-1,4 -phenylene)bis(azanediyl))bis(carbonyl))bis(cyclohexane-1-carboxylic acid) dibutyl ester, N-[3-(2-amino-4-pyrimidinyl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, N-[3-(3-amino-1,2,4-triazin-5-yl)-4-fluorophenyl]-1-pyrrolidinecarboxamide, 2-[4-methyl-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-[(4-morpholinylcarbonyl)amino]benzenesulfonic acid, N-[4-fluoro-3-[2-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-4-pyrimidinyl]phenyl]-1-piperazinecarboxamide, 2,3-dihydro-5-methoxy-N-[4-methyl-3-(2-pyridinyl)- 1H-indole-1-carboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-hydroxycyclobutanecarboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-3,3-difluorocyclobutanecarboxamide, rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-fluorocyclopropanecarboxamide or rel-N-[3,4-difluoro-5-[6-[[(3aR,6aS)-octahydro-2-[(tetrahydro-2H-pyran-4-yl)methyl]cyclopenta[c]pyrrol-5-yl]amino]-3-pyridazinyl]phenyl]-1-(trifluoromethyl)cyclopropanecarboxamide; ii) When X 2 N, R 1 is methyl, R 4 is hydrogen or fluorine, and R 5 When X is hydrogen, 1 and X 3 None of them are C-morpholinyl; iii) When R is -OR 7 When R 1 is methyl; iv) When R is substituted C 1-6 When it is an alkyl group, R 1 is substituted or unsubstituted C 1-6 Alkyl; and v) When R is a substituted or unsubstituted heterocyclic group, the substituted or unsubstituted heterocyclic group is not a substituted or unsubstituted pyridin-2(1H)-onyl group.

2. The compound as claimed in claim 1, wherein R is tert-butyl, C 1-6 Alkyl, C 3-10 Cycloalkyl or heterocyclic group; wherein the C 1-6 The alkyl group is replaced by one to five R 8 Replaced, and the C 3-10 Cycloalkyl or heterocyclyl is optionally substituted by one to five Z 1 replace.

3. The compound according to claim 1, which is represented by Formula II:

4. The compound according to claim 1, which is represented by formula III:

5. A compound as claimed in any one of the preceding claims, wherein X 1 is N.

6. A compound as claimed in any one of the preceding claims, wherein X 2 , X 3 and X 4 CR 6 .

7. A compound as described in any one of claims 1 to 4, wherein X 2 is N.

8. The compound of claim 7, wherein X 1 , X 3 and X 4 CR 6 .

9. The compound of any one of claims 1 to 4, wherein X 3 is N.

10. The compound of claim 9, wherein X 1 , X 2 and X 4 CR 6 .

11. The compound of claim 9, wherein X 1 is N and X 2 and X 4 CR 6 .

12. The compound of any one of claims 1 to 4, wherein X 4 is N.

13. The compound of claim 11, wherein X 1 , X 2 and X 3 CR 6 .

14. The compound of claim 12, wherein X 1 is N and X 2 and X 3 CR 6 .

15. The compound of claim 12, wherein X 2 is N and X 1 and X 3 CR 6 .

16. The compound of claim 12, wherein X 3 is N and X 1 and X2 CR 6 .

17. A compound of formula IV: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: R 1 For hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 2 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 is independently optionally substituted by one to five Z 1 replace; R 3 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 is independently optionally substituted by one to five Z 1 replace; or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; Each R 6 are independently hydrogen, halogen, 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 is 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 is independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is 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 is independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halogen, 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 is 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 is 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 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Haloalkyl, 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 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 cycloalkyl, heterocyclyl, aryl or heteroaryl substitution; The conditions are: Part a) Not for and b) the compound is not N-[3-[4-[3-(hydroxymethyl)phenyl]-6-(4-morpholinyl)-2-pyrimidinyl]phenyl]-1-piperazinecarboxamide, N-[3-[4-(1H-indazol-5-ylamino)-2-pyrimidinyl]phenyl]-4-morpholinecarboxamide, N-[3-ethyl-5-(2-pyrimidinyl)phenyl]-7,8-dihydro-4-(2-methylphenyl)-2-(3-pyridinyl)pyrido[4,3-d]pyrimidine-6(5H)-carboxamide or 5-[[(1,1-dimethylethoxy)carbonyl][2-[3-[(4-morpholinylcarbonyl)amino]phenyl]-4-pyrimidinyl]amino]-1H-indazole-1-carboxylic acid 1,1-dimethylethyl ester.

18. A compound as claimed in any one of the preceding claims, wherein R 4 It is hydrogen, fluorine, chlorine, bromine, cyano or methyl.

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

20. A compound as claimed in any one of the preceding claims, wherein R 4 and R 5 For hydrogen.

21. The compound of claim 1, which is represented by Formula IA:

22. The compound of claim 1, which is represented by Formula IIA:

23. The compound of claim 1, which is represented by Formula IIIA:

24. A compound as claimed in any one of the preceding claims, wherein each R 6 are independently hydrogen, halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, -OC 1-6 Alkyl or -OC 1-6 Haloalkyl.

25. A compound as described in any one of claims 1-23, wherein each R 6 and 1,2-difluoromethoxy and 1,2-difluoromethoxy.

26. A compound as claimed in any one of the preceding claims, wherein R 1 For halogen, cyano, C 1-6 Alkyl, C 3-10 Cycloalkyl, aryl or -OR 11 wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl or aryl is optionally substituted by one to five Z 1 replace.

27. A compound as claimed in any one of the preceding claims, wherein R 1 is fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, -CH2F, -CHF2, -CF3, -CH2CN, -OCF3, cyclopropyl optionally substituted by methyl, or phenyl.

28. A compound as described in any one of claims 1, 3, 17 or 22, wherein R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace.

29. The compound of claim 28, wherein R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by halo, -OH, -C(O)OC 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, aryl or heteroaryl; wherein the C 1-6 The alkyl or heteroaryl group is optionally substituted by one to five Z 1a replace.

30. A compound as described in any one of claims 1, 3, 22 or 28-29, wherein R or part for:

31. A compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

32. A compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, and a pharmaceutically acceptable carrier.

34. A method for inhibiting SARM1 activity, the method comprising contacting a cell with an effective amount of: a compound of any one of claims 1-32 or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, a pharmaceutical composition of claim 33; or a compound of formula I: or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, tautomer, or mixture of stereoisomers thereof, wherein: X 1 , X 2 , X 3 and X 4 Each of which is independently N or CR 6 ; The condition is X 1 , X 2 , X 3 and X 4 No more than two of them are N; R is C 1-6 Alkyl, -NR 2 R 3 、-OR 7 , C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted by one to five Z 1 replace; R 1 For hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 2 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 is independently optionally substituted by one to five Z 1 replace; R 3 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 is independently optionally substituted by one to five Z 1 replace; or R 2 and R 3 together to form a heterocyclic group, which may be further independently optionally substituted by one to five Z 1 replace; R 4 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 5 is hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; Each R 6 are independently hydrogen, halogen, 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 is independently optionally substituted by one to five Z 1 replace; R 7 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 is independently optionally substituted by one to five Z 1 replace; Each R 8 are independently halo, cyano, 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 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is 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 is independently optionally substituted by one to five Z 1a replace; Each Z 1 are independently halogen, cyano, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, 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 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, aryl or heteroaryl is 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 is independently optionally substituted by one to five Z 1b replace; Each Z 1a are independently halogen, 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 is 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 is 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 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Haloalkyl, 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 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-10 The cycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted.

35. The method of claim 34, wherein the contacting is in vivo.

36. A method for treating a disease or condition mediated at least in part by SARM1, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition of claim 33.

37. A method for inhibiting axonal degeneration, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-32 or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition of claim 33.

38. A method for treating neurodegeneration or a nervous system disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer, or mixture of enantiomers thereof, or a pharmaceutical composition of claim 33.

39. The method of claim 38, 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, mitochondrial disease, metabolic axonal degeneration, axonal damage caused by traumatic axonal injury (TAI), leukoencephalopathy, or leukodystrophy.

40. The method of claim 36, 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, Lou Gehrig'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 12deficiency, 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, viral encephalitis in children, essential tremor, Charcot-Marie-Tooth disease, motor neurone 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).

41. Use of a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition according to claim 33, for treating a disease or condition mediated at least in part by SARM1.

42. The use of claim 41, 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, Lou Gehrig'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 12deficiency, 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 neurone 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 compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition as described in claim 33, for use in therapy.

44. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition as described in claim 33, 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, Lou Gehrig'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 12deficiency, 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 neurone 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).

45. Use of a compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt, isotopically enriched analog, enantiomer, tautomer or mixture of enantiomers thereof, or a pharmaceutical composition as described in claim 33, for the manufacture of a medicament for 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, Lou Gehrig'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 12deficiency, 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 neurone 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).

Images