Fused ring compound, pharmaceutical composition comprising same, use, and method

Abstract

A fused ring compound of formula I, a pharmaceutical composition comprising same, a preparation method, a use for preventing and treating GPR6 receptor-mediated related diseases, such as movement disorders including Parkinson's disease, levodopa-induced dyskinesias, and Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, depression, etc., and a method.

Description

Cyclized compounds, pharmaceutical compositions comprising the same, and uses and methods thereof

[0001] The present disclosure is based on and claims priority to Chinese Patent Application No. 202411360330.1, filed on September 26, 2024, Chinese Patent Application No. 202510638517.1, filed on May 16, 2025, Chinese Patent Application No. 202510688239.0, filed on May 26, 2025, Chinese Patent Application No. 202510817186.8, filed on June 18, 2025, and Chinese Patent Application No. 202511032082.2, filed on July 25, 2025, the disclosures of which are hereby incorporated by reference in their entireties. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to cyclized compounds, pharmaceutical compositions thereof, preparation methods, and uses and methods thereof. BACKGROUND

[0003] GPR6 is a high-activity G-protein coupled receptor that stimulates cellular adenylyl cyclase activity and cyclic adenosine monophosphate (cAMP) accumulation in vitro. GPR6 receptors are highly expressed in the indirect pathway of D2-type MSNs (medium spiny neurons), and less expressed in the direct pathway of D1 dopamine receptor-expressing MSNs, other brain regions, and peripheral tissues. GPR6 knockout mice also show reduced cAMP levels in striatal tissue, which is consistent with GPR6-Gs (stimulatory G protein) protein coupling and cAMP signal transduction in vivo. In vitro studies show that GPR6 and Gs coupling can stimulate adenylyl cyclase activity and cAMP accumulation in cells, thereby activating the indirect pathway. In the indirect pathway of D2-type MSNs, antagonizing or reverse agonizing GRP6 can reduce the excessive activity of the indirect pathway and improve the motor symptoms of Parkinson's disease (PD). Preclinical studies show that PD rodent models lacking GRP6 have increased motor activity and reduced abnormal involuntary movements.

[0004] The existing levodopa compounds are commonly used for treating Parkinson's disease, but such compounds have common serious side effects, including inducing dyskinesia, impulse control disorder, psychotic symptoms and sleep disorders. Patent applications WO2014028479A1, WO2015095728A1 and the like disclose GPR6 modulators for treating Parkinson's disease. Such compounds have obvious inhibitory activity on hERG (voltage-gated potassium ion channel encoded by KCNH2 gene), and hERG inhibition is considered to be a potential factor associated with QT interval prolongation and arrhythmia. Through a large number of studies, the present application develops novel compounds with good effects for treating GPR6 receptor-mediated diseases or disorders. SUMMARY

[0005] The present application aims to provide compounds as G protein-coupled receptor GPR6 modulators, pharmaceutical compositions containing the same, preparation methods, and in the prevention and / or treatment of diseases or disorders mediated by GPR6 receptor, such as dyskinesia, including Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression, etc.

[0006] In one aspect, the present application provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has a structure as shown in Formula I:

[0007] wherein, the A ring is selected from 3-14 membered heterocycle and 3-14 membered carbocycle, the heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ; optionally, the C1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-6 alkyl;

[0008] X, Y are each independently selected from the group consisting of a covalent bond, CR, O, S, NH and N;

[0009] R is each independently selected from the group consisting of H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0010] L is selected from the group consisting of 4-8 membered carbocyclic ring, 3-10 membered heterocyclic ring and 5-10 membered heteroaromatic ring, said carbocyclic ring, heterocyclic ring and heteroaromatic ring are optionally substituted with one or more substituents independently selected from the group consisting of H, deuterium, halogen, hydroxyl, amino, oxo (=0), cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0011] Z is selected from the group consisting of a covalent bond, CR, CR a R b , -0-CR a R b -, C(=NSO2R b ), C(=0)NR b , NR a , O, S, -C(=0)-, -S(=0)-, -S(=0)2-, S(=0)(=NR b ) and S(=NR b )2;

[0012] R 1 is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=0)Rc -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-12 membered heterocyclyl;

[0013] R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)Rd -C(=O)-OR c -OR c -SR c -SOR c -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 lkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0014] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 lkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0015] R c and R d are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 lkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 lkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0016] or, R c , R d and the N atom to which they are attached form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and C

[0017] Ar is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more R 2 substituents;

[0018] R 2 each independently selected from H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1- haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one and more substituents independently selected from H, halogen, hydroxyl, amino, cyano and C 1-6 alkyl;

[0019] each p is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0020] Another aspect of the present application provides a composition or a pharmaceutical combination comprising a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or a prodrug or a pharmaceutically acceptable salt or an ester thereof, optionally further comprising one or more other therapeutic agents.

[0021] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or a prodrug or a pharmaceutically acceptable salt or an ester thereof, and one or more pharmaceutically acceptable carriers.

[0022] Another aspect of the present application provides the use of a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or a prodrug or a pharmaceutically acceptable salt or an ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described in the present application, for the manufacture of a medicament for the prevention and / or treatment of a disease, in particular a GPR6 receptor-mediated related disease.

[0023] Another aspect of the present application provides a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described herein, for use in the prevention and / or treatment of a disease, in particular a GPR6 receptor mediated related disease.

[0024] Another aspect of the present application provides a method of preventing and / or treating a disease, in particular a GPR6 receptor mediated related disease, the method comprising administering to an individual in need thereof an effective amount of a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described herein.

[0025] The GPR6 receptor mediated related disease described herein is selected from the group consisting of movement disorders, including Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression.

[0026] Another aspect of the present application provides a method of preparing a compound of formula I. DETAILED DESCRIPTION

[0027] Definitions

[0028] Unless otherwise defined herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References herein to technical terms used herein are intended to refer to technical terms as commonly understood by those in the art, including variations or replacements of such technical terms that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present application.

[0029] The terms "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", or "provide", "provided", "providing" and other grammatical equivalents thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0030] The term "carbocyclo" refers to a saturated or unsaturated non-aromatic ring, which can be a 3 to 14 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system, which can be fused, bridged or spirocyclic, for example 3-12 membered carbocyclo, 3-10 membered carbocyclo, 3-8 membered carbocyclo, 3-6 membered carbocyclo. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and cyclohexenyl. The carbocyclo group can be optionally further substituted with 1 to multiple (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) substituents selected from F, Cl, Br, I, =0, hydroxyl, thiol, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclo, heterocyclo, carbocycloxy, heterocycloxy, carboxyl or carboxylate.

[0031] The term "heterocyclo" or "heterocyclo group" means a 3- to 14-membered non-aromatic cyclic group consisting of 2 to 13 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, for example 3-14 membered heterocyclo, 3-12 membered heterocyclo, 3-10 membered heterocyclo, 3-8 membered heterocyclo, 3-6 membered heterocyclo, 4-6 membered heterocyclo. The heterocyclo group can be saturated or partially unsaturated. Unless specifically indicated otherwise in the specification, the heterocyclo group can be a monocyclic, bicyclic, tricyclic or more ring ring system, which can include fused ring systems, annulated ring systems, bridged ring systems or spirocyclic ring systems, for example the heterocyclo group can be fused to a C 6-10 aryl, C 3-10 cycloalkyl, 3-12 membered heterocyclo group, 5-10 membered heteroaryl form a fused ring system, annulated ring system or spirocyclic ring system, non-adjacent atoms in the heterocyclo group can also form a bridged ring system, which can also contain 1-5 heteroatoms such as N, O, S.

[0032] Heterocyclyl groups of the present application are preferably 3- to 14-membered non-aromatic monocyclic or bicyclic groups containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, such as 3- to 8-membered non-aromatic monocyclic groups containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, or 3- to 6-membered non-aromatic monocyclic groups containing 1 to 5 heteroatoms selected from nitrogen and oxygen; or 3- to 14-membered non-aromatic polycyclic groups, for example 3- to 14-membered non-aromatic polycyclic groups containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, including fused bicyclic, annulated, bridged, or spirocyclic rings. Nitrogen, carbon, or sulfur atoms in the heterocyclyl group can optionally be oxidized; nitrogen atoms can optionally be quaternized; and the heterocyclyl group can be partially unsaturated or fully saturated. The heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond. Examples of heterocyclyl groups include, but are not limited to: azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, pyrazolyl, dihydropyrazolyl, piperazinyl, piperidinyl, pyrrolyl, pyrrolidinyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrazolidinyl, phthalimidyl, azabicyclo[3.1.0]hexanyl, azaspiro[2.4]heptanyl, and the groups of the formulae: etc. The "heterocycle" or "heterocyclyl" group can optionally be substituted by one or more (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) groups selected from F, Cl, Br, I, =0, hydroxyl, thiol, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate.

[0033] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups, preferably containing from 1 to 20 carbon atoms, more preferably containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched-chain isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available attachment point, preferably with one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, and the like.

[0034] The term "cycloalkyl" refers to saturated cyclic hydrocarbon groups, including but not limited to monocycloalkyl and bicycloalkyl groups (such as spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl groups). The term "C 3-10 Cycloalkyl" refers to cycloalkyl groups having from 3 to 10 (e.g., 3-8, 3-6, 3-4) ring-forming carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Cycloalkyl groups can be substituted or unsubstituted, wherein the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein, for example, F, Cl, Br, I, =0, hydroxyl, thiol, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate.

[0035] The term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0036] The term "haloalkyl" refers to an alkyl group as previously described substituted with a halogen. For example, "C 1-6 Haloalkyl" refers to a C 1-6 alkyl group substituted with 1 or more (e.g., 1, 2, 3, or 4) hydrogen atoms with a halogen (e.g., fluorine, chlorine, bromine, or iodine). 1-6 alkyl group substituted with 1 or more (e.g., 1, 2, 3, or 4) hydrogen atoms with a halogen (e.g., fluorine, chlorine, bromine, or iodine).

[0037] The term "alkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety through an oxygen atom. C 1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, pentyloxy, hexyloxy, and the like.

[0038] The term "haloalkoxy" means an alkoxy group as previously described, for example, C 1-6 An alkoxy group substituted with one or more (e.g., 1, 2, 3, or 4) hydrogen atoms with halogen (e.g., fluorine, chlorine, bromine, or iodine) to yield a group such as C 1-2 haloalkoxy, halo methoxy, haloethoxy, C3haloalkoxy, C4haloalkoxy, C 1-2 fluoroalkoxy, fluoro methoxy, fluoroethoxy, C3fluoroalkoxy, C4fluoroalkoxy, C 1-2 chloroalkoxy, chloro methoxy, chloroethoxy, C3chloroalkoxy, C4chloroalkoxy. Specific examples include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, chloroethoxy, and the like.

[0039] The term "alkenyl" means a straight or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one hydrogen atom replaced by a bond. Alkenyl groups can contain from about 2 to about 15 carbon atoms. In one embodiment, alkenyl groups contain from about 2 to about 12 carbon atoms. In another embodiment, alkenyl groups contain from about 2 to about 6 carbon atoms. The term "C 2-6 The term "alkenyl" means a straight or branched aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one hydrogen atom replaced by a bond. Alkenyl groups can contain from about 2 to about 15 carbon atoms. In one embodiment, alkenyl groups contain from about 2 to about 12 carbon atoms. In another embodiment, alkenyl groups contain from about 2 to about 6 carbon atoms. The term "C

[0040] The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2-6 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2-3 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C 2-6Alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0041] The term "aryl" refers to a C 6-14 A fully carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group, preferably a C 6-10 Aryl, for example, phenyl and naphthyl, more preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0042] The aryl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0043] The term "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" refers to an aromatic monocyclic or polycyclic ring system containing from about 5 to about 10 ring atoms, of which from 1 to 4 ring atoms are independently O, N, or S, and the remainder of the ring atoms are carbon atoms. In another embodiment, the heteroaryl is a monocyclic heteroaryl and has 5 or 6 ring atoms. In another embodiment, the heteroaryl is a bicyclic heteroaryl. The heteroaryl can be optionally substituted with one or more "ring system substituents", which can be the same or different, and are as defined herein below. Any nitrogen atom of the heteroaryl can optionally be oxidized to the corresponding N-oxide. Any C atom of the heteroaryl can optionally be oxo or thioxo. The term "heteroaryl" also includes heteroaryl groups as defined above fused to a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, through a heteroaryl group to the parent structure. Non-limiting examples of heteroaryl groups include: pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[l,2-a]pyridyl, imidazo[2,l- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl, and the like, and all isomeric forms thereof. In one embodiment, the heteroaryl is a 5-membered heteroaryl. In another embodiment, the heteroaryl is a 6-membered heteroaryl, e.g., a 6-membered nitrogen-containing heteroaryl.

[0044] The term "substituted" means that one or more (e.g., one, two, three or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0045] The term "optionally" means that the moiety or substituent described herein can be unsubstituted or substituted with a particular moiety, atom group.

[0046] The term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions.

[0047] When bonds of a substituent are shown to be connected to two atoms of a ring, then such substituent can be bonded to either atom of the substitutable ring.

[0048] If a compound, group or substituent described herein is described as being "optionally" substituted with a specified group or radical, then the compound, group or substituent can be (1) unsubstituted or (2) substituted with the specified group or radical.

[0049] If substituents or values are described as "independently selected from" a group of substituents or values, each substituent or value is selected independently of the other. Thus, each substituent or value can be the same or different from the other substituent or value.

[0050] Bivalent substituents herein, unless specifically limited, are meant to indicate that the group is attached to other groups in either order, e.g., "-C(=O)NH-" can be attached to form a molecule as "group 1-C(=O)NH-group 2" or "group 1-NHC(=O)-group 2".

[0051] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the present application, except that one or more atoms are replaced by an isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as 2 H, 3 H, deuterium, D, tritium, T); isotopes of carbon, such as 11 C, 13 C, and 14 C); isotopes of chlorine, such as 37 Cl); isotopes of fluorine, such as 18 F); isotopes of iodine, such as 123 I, and 125 I); isotopes of nitrogen, such as 13 N, and 15 N); isotopes of oxygen, such as 15 O, 17 O, and 18 O); isotopes of phosphorus, such as 32 P); and isotopes of sulfur, such as 35 S). Certain isotopically-labeled compounds of the present application, for example those into which radioactive isotopes are 3 H), and carbon- 14 (i.e., 14 C), are particularly preferred for their ease of preparation and detectability. Positron emission isotopes such as 11 C, 18 F, 15 O, and 13N) Substitution can be used in positron emission tomography (PET) studies to test substrate receptor occupancy. Isotopically-labeled compounds of the application can be prepared by methods analogous to those described in the accompanying Schemes and / or in the Examples and Preparations, by using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the application include those wherein the solvent can be isotopically substituted, for example, D20, acetone-d6 or DMSO-d6.

[0052] As used herein, the term "suitable substituents" refers to modifications that one of skill in the art can make to a compound according to the needs of the compound's substituents. "Suitable substituents" include oxo (=0), halogen, cyano, NR a R b , carboxyl, thiol, hydroxyl, ester (e.g., -C 1-6 alkyl-C(=0)-OC 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, benzyl, hydroxyl substituted benzyl, indolylmethyl, and C 1-6 haloalkoxy, R a , R b as described herein.

[0053] Whether explicitly stated or not, the numerical values of the present application are modified by the term "about." The term "about" means within ±20% of the stated numerical value, within ±10% of the stated numerical value, within ±5% of the stated numerical value, or within ±2% of the stated numerical value.

[0054] The term "stereoisomers" denotes isomers that have the same molecular formula but different structures, due to the difference in the configuration of the atoms or groups of atoms. In a compound having one or more asymmetric centers, the compound can exist in racemic mixtures, racemic modifications, single enantiomers, non-racemic mixtures of enantiomers, and mixtures of diastereomers. Also, particular individual molecules can exist in geometric isomeric forms (cis / trans). Similarly, the compounds of the present application can exist in mixtures of two or more different structural forms that are in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the application encompasses all such isomers whether in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% of an isomer or mixtures thereof.

[0055] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0056] It is also to be understood that certain compounds of the present application can exist in free form for treatment, or, where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present application, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, metabolite, isotopically-labeled derivative, or prodrug, which upon administration to a patient in need thereof is capable of being converted into the compound of the present application or a metabolite or residue thereof. Accordingly, whenever a compound of the present application is referred to in this text, a derivative thereof is also intended, unless otherwise clear from the context.

[0057] Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of compounds of the present application are known to those skilled in the art.

[0058] The term "ester" means an ester derived from the carboxy group of an ester of the various generic compounds of the present application, including physiologically hydrolysable esters which can be hydrolyzed in vivo to release the free acid or alcohol form of the compound of the present application. The compounds of the present application can also be esters themselves.

[0059] The compounds of the present application can exist in solvate (preferably hydrate) form, wherein the compound of the present application contains a polar solvent as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0060] It will be appreciated by those skilled in the art that not all nitrogen-containing heterocycles are capable of forming N-oxides, since nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides. It will also be recognized by those skilled in the art that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of the heterocycle or tertiary amine with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0061] Also included within the scope of the present application are metabolites of the compounds of the present application, i.e., substances formed in vivo upon administration of a compound of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the present application includes metabolites of compounds of the present application, made by processes which are well known in the art.

[0062] The present application further includes within its scope prodrugs of the compounds of the application, which are certain derivatives of the compounds of the application that have less or no pharmacological activity as such but, when administered into or onto the body, are converted into the compounds of the application having the desired activity, for example, by hydrolytic cleavage. Such prodrugs are typically functionally-derivatized with moieties which are readily cleaved in vivo. For example, see "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (ed. E. B. Roche, American Pharmaceutical Association). Prodrugs of the application can be prepared using methods known to those of ordinary skill in the art (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985) as the replacement of appropriate functionalities in the compounds of the application with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0063] During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic synthesis, John Wiley & Sons, 1991, which are incorporated herein by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0064] Compounds

[0065] The present application provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically-labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I:

[0066] wherein A ring is selected from 3-14 membered heterocycle and 3-14 membered carbocycle, said heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C(=O)-(CH2) 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-6 alkyl;

[0067] X, Y are each independently selected from covalent bond, CR, O, S, NH and N;

[0068] R is each independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0069] L is selected from 4-8 membered carbocycle, 3-10 membered heterocycle and 5-10 membered heteroaromatic ring, said carbocycle, heterocycle and heteroaromatic ring is optionally substituted with one or more substituents independently selected from H, deuterium, halogen, hydroxyl, amino, oxo (=O), cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Substituents of haloalkoxy groups;

[0070] Z is selected from covalent bonds, CR, CR a R b -O-CR a R b -、C(=NSO2R b ), C(=O)NR b NR a ,O,S,-C(=O)-,-S(=O)-,-S(=O)2-,S(=O)(=NR b ) and S(=NR b )2;

[0071] R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1- 6alkyl-C(=O)-NR a R b NR a R b OR a SR a -NR a C(=O)R b -C(=O)-OR a -SOR a -SO2R a C 6-10 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic groups, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally selected from one or more independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group, -C(=O)-(CH2) p -OR a -C(=O)-(CH2) p -NR a R b -C 1-6 Alkylene-NR a R b-C 1-6 alkyl-O-R a substituted by one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0072] R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0073] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0074] R c and R deach independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0075] or, R c , R d and the N atom to which they are attached form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0076] Ar is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said aryl, heteroaryl, and heterocyclyl being optionally substituted with one or more R 2 substituents;

[0077] R 2 each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl being optionally substituted with one and more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, and C 1-6 alkyl;

[0078] each p is independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.

[0079] In some embodiments, the compound of Formula I, A ring is selected from a 3-14 membered heterocycle and a 3-14 membered carbocycle, said heterocycle or carbocycle is optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ;

[0080] X, Y are each independently selected from a covalent bond, CR, O, S, NH, and N;

[0081] R is each independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl;

[0082] L is selected from a 4-8 membered carbocycle, a 3-10 membered heterocyclyl, and a 5-10 membered heteroaryl, said carbocycle, heterocyclyl, and heteroaryl is optionally substituted with one or more substituents selected from H, deuterium, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0083] Z is selected from a covalent bond, CR a R b , -O-CR a Rb -、C(=NSO2R b ), C(=O)NR b NR a ,O,S,-C(=O)-,-S(=O)-,-S(=O)2-,S(=O)(=NR b ) and S(=NR b )2;

[0084] R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1- 6alkyl-C(=O)-NR a R b NR a R b OR a SR a -NR a C(=O)R b -C(=O)-OR a -SOR a -SO2R a C 6-10 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic groups, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally separated by one or more elements selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group, -C(=O)-(CH2) p -OR a -C(=O)-(CH2) p -NR a R b -C 1-6 Alkylene-NR a R b -C 1- 6-alkyl-OR a Substitution with 3-12 membered heterocyclic groups;

[0085] R a and R beach independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0086] or, R a and R b form, together with the atom to which they are attached, a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0087] R c and R d are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1- 6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0088] or, R c , R d and the N atom to which they are attached form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0089] Ar is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R 2 ;

[0090] R 2 each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one and more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano and C 1-6 alkyl;

[0091] each p is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0092] In some embodiments, the compound of Formula I, Ar is selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl, said aryl and heteroaryl are optionally substituted with one or more R 2 .

[0093] In some embodiments, the present application provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I-a:

[0094] wherein A ring is selected from a 3-14 membered heterocycle and a 3-14 membered carbocycle, said heterocycle or carbocycle is optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ; optionally, said C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-6 alkyl;

[0095] X, Y are each independently selected from CR and N;

[0096] R is each independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0097] L is selected from the group consisting of 4-8 membered carbocyclic, 3-10 membered heterocyclic, and 5-10 membered heteroaromatic rings, said carbocyclic, heterocyclic, and heteroaromatic rings being optionally substituted with one or more substituents independently selected from the group consisting of H, deuterium, halogen, hydroxyl, amino, oxo (=0), cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0098] Z is selected from the group consisting of a covalent bond, CR, CR a R b , -0-CR a R b -, C(=NSO2R b ), C(=0)NR b , NR a , O, S, -C(=0)-, -S(=0)-, -S(=0)2-, S(=0)(=NR b ) and S(=NR b )2;

[0099] R 1 is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=0)R c , -C 1- 6alkyl-C(=0)-NR a R b , NR a R b , OR a , SR a , -NR a C(=0)R b , -C(=0)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-12 membered heterocyclyl;

[0100] R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0101] or, R a , R bwith the atom to which it is attached forming a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0102] R c and R d are each independently selected from H, halo, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0103] or, R c , R d and the N atom to which it is attached forming a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0104] Ar is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said aryl, heteroaryl, and 3-12 membered heterocyclyl optionally substituted with one or more R 2 ;

[0105] R 2 are each independently selected from H, halo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C

[0106] each p is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0107] In some embodiments, the compound of Formula I-a, A ring is selected from 3-14 membered heterocycle and 3-14 membered carbocycle, said heterocycle or carbocycle being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b substituted;

[0108] each X, Y is independently selected from CR and N;

[0109] each R is independently selected from H, halo, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0110] L is selected from 4-8 membered carbocycle, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, said carbocycle, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, deuterium, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, substituted by one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C

[0111] Z is selected from the group consisting of a covalent bond, CR a R b , -O-CR a R b -, C(=NSO2R b ), C(=O)NR b , NR a , O, S, -C(=O)-, -S(=O)-, -S(=O)2-, S(=O)(=NR b ) and S(=NR b )2;

[0112] R 1 is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted by one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C1-6 Alkylene-NR a R b -C 1- 6-alkyl-OR a Substitution with 3-12 membered heterocyclic groups;

[0113] R a and R b Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1-6 Alkyl-C(=O)-NR c R d NR c R d -NR c C(=O)R d -C(=O)-OR c -OR c -SR c -SOR c and -SO2R c The alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally separated from one or more groups selected from H, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0114] Or, R a R b The atoms bonded thereto form 3-8 membered carbon rings, 3-12 membered heterocyclic groups, or 5-10 membered heteroaryl groups, wherein the carbon ring, heterocyclic group, or heteroaryl group is optionally bonded by one or more elements selected from H, halogen, hydroxyl, amino, cyano, =O, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0115] R c and Rd each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1- 6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0116] or, R c , R d and the N atom to which they are attached form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0117] Ar is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said aryl, heteroaryl, and 3-12 membered heterocyclyl being optionally substituted with one or more R 2 substituents;

[0118] R 2 each independently selected from H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl being optionally substituted with one and more substituents selected from H, halogen, hydroxyl, amino, cyano, and C 1-6 alkyl;

[0119] each p is independently selected from 0, 1, 2, 3, 4, 5, and 6.

[0120] In some embodiments, the compound of Formula I-a, Ar is selected from C6-10 aryl and 5-10 membered heteroaryl, each optionally substituted with one or more R 2 substituents.

[0121] In one embodiment, the present application provides a compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I-a:

[0122] wherein, A ring is selected from 3-14 membered heterocycle and 3-14 membered carbocycle, said heterocycle or carbocycle optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ; optionally, said C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-6 alkyl;

[0123] X, Y are each independently selected from CR and N;

[0124] R is each independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and C 3-10 cycloalkyl;

[0125] L is selected from the group consisting of 4-8 membered carbocyclic, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl, said carbocyclic, heterocyclic, and heteroaryl rings being optionally substituted with one or more substituents selected from the group consisting of H, deuterium, halogen, hydroxyl, amino, oxo (=0), cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy;

[0126] Z is selected from the group consisting of a covalent bond, CR, C(R a ), CR a R b , -0-CR a R b -, C(=NSO2R b ), C(=0)NR b , NR a , O, S, -C(=0)-, -S(=0)-, -S(=0)2-, S(=0)(=NR b ), and S(=NR b )2;

[0127] R 1 is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=0)R c , -C 1- 6alkyl-C(=0)-NR a R b , NR a R b , OR a , SR a , -NR a C(=0)R b , -C(=0)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b substituted;

[0128] R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0129] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0130] R c and R d Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Haloalkoxy, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally selected from one or more groups independently chosen from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0131] Or, R c R d The N atom attached thereto forms a 3-8 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the heterocyclic group and heteroaryl group are optionally composed of one or more elements independently selected from H, halogen, hydroxyl, amino, cyano, =O, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0132] Ar is selected from C 6-10 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic, wherein the aryl, heteroaryl, and heterocyclic are optionally separated by one or more R 2 replace;

[0133] R 2 Each is independently selected from H, halogen, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10Aryl and 5-10-membered heteroaryl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally separated by one or more groups independently selected from H, halogen, hydroxyl, amino, cyano, and C. 1-6 Alkyl substituents;

[0134] p is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0135] In some embodiments, ring A is selected from 3-14 membered heterocycles and 3-14 membered carbocycles, wherein the heterocycle or carbocycle is optionally surrounded by one or more elements selected from H, halogen, hydroxyl, amino, cyano, nitro, C. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-12 membered heterocyclic, 5-10 membered heteroaryl, C 6- 10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -C 1-6 Alkyl-OR a -C(=O)-(CH2) p -OR a -C(=O)-(CH2) p -NR a R b -C 1-6 Alkylene-NR a R b Substituents of the substituents;

[0136] X and Y are each independently selected from CR and N;

[0137] R is independently selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 Alkyl, 3-12 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl and C 3-10 cycloalkyl;

[0138] L is selected from 4-8 membered carbon rings, 3-10 membered heterocyclic groups, and 5-10 membered heteroaryl groups;

[0139] Z is selected from covalent bonds, C(R) a ), CR a R b -O-CR a R b -、C(=NSO2R b ), C(=O)NRb , NR a , O, S, -C(=O)-, -S(=O)-, -S(=O)2-, S(=O)(=NR b ) and S(=NR b )2;

[0140] R 1 is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ;

[0141] R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0142] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0143] R c and R d are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1- 6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 1-6 haloalkoxy, substituted with substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0144] or, R c , R d and the N atom to which it is attached form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, substituted with substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0145] Ar is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said aryl, heteroaryl and heterocyclyl being optionally substituted with one or more R 2 substituents;

[0146] R 2 each independently selected from the group consisting of H, halo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano and C 1-6 alkyl;

[0147] each p is independently selected from 0, 1, 2, 3, 4, 5 and 6.

[0148] In certain embodiments, the compound of Formula I-a, Ar is selected from the group consisting of C 6-10 aryl and 5-10 membered heteroaryl, said aryl and heteroaryl being optionally substituted with one or more R 2 substituents. In certain embodiments, R 2 each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C 1-4Alkyl substituents.

[0149] In some embodiments, ring A is selected from 3-14 membered heterocycles (e.g., 3-12 membered heterocycles), wherein the heterocycle is optionally composed of one or more elements independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C. 1-4 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl, C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, -C 1-4 Alkyl-OR a -C(=O)-(CH2) p -OR a -C(=O)-(CH2) p -NR a R b -C 1-4 Alkylene-NR a R b Substituents are substituted.

[0150] In some embodiments, ring A is selected from 3- to 10-membered heterocycles, wherein the heterocycle is optionally composed of one or more elements independently selected from H, hydroxyl, C, ... 1-4 Alkyl, 3-8 membered heterocyclic, 5-10 membered heteroaryl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -C 1-4 Substitution of alkyl-OH groups.

[0151] In some embodiments, ring A is selected from 3- to 10-membered heterocycles, wherein the heterocycle is optionally composed of one or more elements independently selected from H, hydroxyl, C, ... 1-4 Alkyl groups, 3-8 membered heterocyclic groups (e.g., 3-8 membered nitrogen- or oxygen-containing heterocyclic groups), 5-10 membered nitrogen-containing heteroaryl groups, C 1-4 Fluoroalkyl, C 1-4 Chloroalkyl, C 1-4 Alkoxy and -C 1-4 Substitution of alkyl-OH groups.

[0152] In some embodiments, ring A is selected from 3- to 10-membered heterocycles, wherein the heterocycle is optionally surrounded by one or more groups independently selected from H, hydroxyl, methyl, ethyl, propyl, isopropyl, 3- to 6-membered heterocyclic groups (e.g., 4-membered oxygen-containing heterocyclic groups), pyrazolyl, -CF3, -CHF2, -CH2CH2F, C 1-4 Substitution with chloroalkyl, methoxy and -CH2CH2OH groups.

[0153] In certain embodiments, the A ring is selected from a 3-10 membered heterocyclic ring; preferably, the heterocyclic ring contains one or several heteroatoms that are N, O, or S atoms.

[0154] In certain embodiments, the A ring is selected from a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, a 7-membered heterocyclic ring, an 8-membered heterocyclic ring, a 9-membered heterocyclic ring, or a 10-membered heterocyclic ring, optionally substituted with one or more substituents independently selected from H, hydroxyl, methyl, ethyl, isopropyl, 4-membered oxygen-containing heterocyclyl, pyrazolyl, -CF3, -CHF2, -CH2CH2F, methoxy, and -CH2CH2OH; preferably, the heterocyclic ring contains one or several heteroatoms that are N, O, or S atoms.

[0155] In certain embodiments, the A ring is selected from a 3-14 membered heterocyclic ring (e.g., a 3-12 membered heterocyclic ring), optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-4 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, -C 1-4 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-4 alkylene-NR a R b .

[0156] In certain embodiments, the A ring is selected from a 3-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from H, hydroxyl, C 1-4 alkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 1-4 haloalkyl, C 1-4 alkoxy, and -C 1-4 alkyl-OH.

[0157] In certain embodiments, the A ring is selected from a 3-10 membered heterocyclic ring, optionally substituted with one or more substituents selected from H, hydroxyl, C 1-4 alkyl, 3-8 membered heterocyclyl (e.g., 3-8 membered nitrogen- or oxygen-containing heterocyclyl), 5-10 membered nitrogen-containing heteroaryl, C 1-4 fluoroalkyl, C1-4 Chloroalkyl, C 1-4 Alkoxy and -C 1-4 Substitution of alkyl-OH groups.

[0158] In some embodiments, ring A is selected from 3-10 membered heterocycles, said heterocycle optionally being surrounded by one or more groups selected from H, hydroxyl, methyl, ethyl, propyl, isopropyl, 3-6 membered heterocyclic groups (e.g., 4 membered oxygen-containing heterocyclic groups), pyrazolyl, -CF3, -CHF2, -CH2CH2F, C 1- Substitution with 4-chloroalkyl, methoxy and -CH2CH2OH substituents.

[0159] In some embodiments, ring A is selected from 3- to 10-membered heterocycles; preferably, the heterocycle contains one or more of N, O, or S atoms.

[0160] In some embodiments, ring A is selected from 4-membered heterocycles, 5-membered heterocycles, 6-membered heterocycles, 7-membered heterocycles, 8-membered heterocycles, 9-membered heterocycles, or 10-membered heterocycles, wherein the heterocycle is optionally substituted by one or more substituents selected from H, hydroxyl, methyl, ethyl, isopropyl, 4-membered oxygen-containing heterocyclic group, pyrazolyl, -CF3, -CHF2, -CH2CH2F, methoxy, and -CH2CH2OH; preferably, the heterocycle contains one or more N, O, or S atoms.

[0161] In some embodiments, the heterocycle is a 4-8 membered lactam or lactone ring. In some embodiments, the lactam or lactone ring optionally further contains another N or O atom.

[0162] In some implementations, ring A is selected from:

[0163] In some implementations, ring A is selected from:

[0164] In some implementations, ring A is selected from...

[0165] In some implementations, ring A is

[0166] In some embodiments, the compound of formula Ia has the structure shown in formula I-1:

[0167] in, Indicates a single or double bond; M, Q, E, and G are each independently selected from covalent bonds. -CRe R f -、-NR j -, -O-, -S-, -C(=O)-, -S(=O)- and -S(=O)2-;

[0168] R e and R f Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1-6 Alkyl-C(=O)-NR c R d NR c R d -NR c C(=O)R d -C(=O)-OR c -OR c -SR c -SOR c and -SO2R c The alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally selected by one or more groups independently chosen from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0169] Or, R e R f The atoms bonded thereto form 3-8 membered carbon rings, 3-12 membered heterocyclic groups, or 5-10 membered heteroaryl groups, wherein the carbon ring, heterocyclic group, or heteroaryl group is optionally composed of one or more elements independently selected from H, halogen, hydroxyl, amino, cyano, =O, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0170] R jeach independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0171] or, R j and R e or R j and R f and the atoms to which they are attached collectively form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0172] each m, n is independently selected from 0, 1, 2, 3, and 4;

[0173] X, Y, L, Z, Ar, R 1 , R c , R d each independently as defined above.

[0174] In certain embodiments, the compound of formula I-1, represents a single or double bond, M, Q, E, G are each independently selected from a covalent bond, CR e , CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-;

[0175] R e and R feach independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0176] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0177] R j each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6haloalkyl and C 1-6 haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0178] or R j and R e or R j and R f and the atoms to which they are attached collectively form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =O, C 1- alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0179] each m, n is independently selected from 0, 1, 2, 3, and 4;

[0180] X, Y, L, Z, Ar, R 1 , R c , R d are each independently as defined above.

[0181] In certain embodiments, the compound of formula I-1 is one wherein R j and R e or R j and R f and the atoms to which they are attached collectively form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl.

[0182] In certain embodiments, the compound of formula I-1 is one wherein R j and R e or R j and R f and the atoms to which they are attached collectively form a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl.

[0183] In certain embodiments, the compound of formula I-1 is one wherein R j and R e or R j and R fand the atoms to which they are attached form a 3-8 membered heterocyclyl or a 5-6 membered heteroaryl.

[0184] In certain embodiments, the compound of formula I-1 is j and R e or R j and R f and the atoms to which they are attached form a 3-8 membered heterocyclyl or a 5-6 membered heteroaryl.

[0185] In certain embodiments, the compound of formula I-1 is j and R e or R j and R f and the atoms to which they are attached form a 3-8 membered heterocyclyl or a 5-6 membered heteroaryl.

[0186] In certain embodiments, the compound of formula I-1 is O, S, -C(=0)-, -S(=0)-, and -S(=0)2-.

[0187] In certain embodiments, the compound of formula I-1 is O, S, -C(=0)-, -S(=0)-, and -S(=0)2-.

[0188] In certain embodiments, the compound of formula I-1 is O, S, -C(=0)-, -S(=0)-, and -S(=0)2-.

[0189] In certain embodiments, the compound of formula I-1 is O, and S.

[0190] In some embodiments, the compound of formula I-1 has the following structure:

[0191] or

[0192] Among them, R 1 m, n, L, Z, Ar and R j As defined above.

[0193] In some embodiments, the compound of formula Ia has the structure shown in formula I-2:

[0194] In this context, Q and E are each independently selected from covalent bonds, CR bonds, and so on. e R f NR j , O, S, -C(=O)-, -S(=O)- and -S(=O)2-;

[0195] M and G are each independently selected from N, O, S, and CR. e ;

[0196] R e and R f Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1-6 Alkyl-C(=O)-NR c R d NR c R d -NR c C(=O)R d -C(=O)-OR c -OR c -SR c -SOR c and -SO2R c The alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally selected by one or more groups independently chosen from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0197] or R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0198] R j each independently selected from the group consisting of H, halo, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0199] or R j and R e or R j and R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0200] m, n are each independently selected from 0, 1, 2, 3, and 4;

[0201] J is selected from -C 1-6alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O-, and -C 1-6 alkyl-S-;

[0202] X, Y, L, Z, Ar, R 1 , R c , R d each independently as defined above.

[0203] In certain embodiments, in the compound of formula I-2, Q and E are each independently selected from a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-;

[0204] M and G are each independently selected from N, O, S, and CR e ;

[0205] R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0206] or R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, which carbocyclic ring, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0207] R j are each independently selected from H, halo, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, which alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl are optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0208] or R j and R e or R j and R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, which carbocyclic ring, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, =0, C 1- 6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0209] m, n are each independently selected from 0, 1, 2, 3, and 4;

[0210] J is selected from -C 1-6 alkyl-, -0-, -S-, -NR j , -C 1-6alkyl-O- and -C 1-6 alkyl-S-;

[0211] X, Y, L, Z, Ar, R 1 , R c , R d each independently as defined above.

[0212] In certain embodiments, in the compound of formula I-2, Q and E are each independently selected from CR e R f .

[0213] In certain embodiments, in the compound of formula I-2, Q and E are each independently selected from CH2.

[0214] In certain embodiments, in the compound of formula I-2, M and G are each independently selected from N, O, S and CH; preferably, M and G are each independently selected from N.

[0215] In certain embodiments, the compound of formula I-a has the structure of formula I-3:

[0216] wherein M and Q are each independently selected from a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)- and -S(=O)2-;

[0217] G and E are each independently selected from N, O, S and CR e ;

[0218] R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -ORc -SR c -SOR c -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0219] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0220] R j each independently is selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 ycloalkyl, C 3-6 ycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 ycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0221] or, R j and R e or R j and R fTogether with the atoms they are connected to form a 3-8 membered carbon ring, a 3-12 membered heterocyclic group, or a 5-10 membered heteroaryl group, wherein the carbon ring, heterocyclic group, and heteroaryl group are optionally composed of one or more elements independently selected from H, halogen, hydroxyl, amino, cyano, =O, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0222] X, Y, L, Z, Ar, R 1 J, m, and n are each defined independently as in Equation I-2 above.

[0223] In some embodiments, in the structure shown in Formula I-3, M and Q are each independently selected from covalent bonds, CR bonds, etc. e R f NR j , O, S, -C(=O)-, -S(=O)- and -S(=O)2-;

[0224] G and E are each independently selected from N, O, S, and CR. e ;

[0225] R e and R f Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1-6 Alkyl-C(=O)-NR c R d NR c R d -NR c C(=O)R d -C(=O)-OR c -OR c -SR c -SOR c and -SO2R c The alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally separated from one or more groups selected from H, halogen, hydroxyl, amino, cyano, C. 1-6 Alkyl, C3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0226] Or, R e R f The atoms bonded thereto form 3-8 membered carbon rings, 3-12 membered heterocyclic groups, or 5-10 membered heteroaryl groups, wherein the carbon ring, heterocyclic group, or heteroaryl group is optionally bonded by one or more elements selected from H, halogen, hydroxyl, amino, cyano, =O, C. 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0227] R j Each is independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclic group, 5-10 membered heteroaryl, C 6-10 Aryl, C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Haloalkoxy, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclic, heteroaryl, and aryl groups are optionally separated from one or more groups selected from H, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0228] Or, R j With R e or R j With R f Together with the atoms they are connected to form a 3-8 membered carbon ring, a 3-12 membered heterocyclic group, or a 5-10 membered heteroaryl group, wherein the carbon ring, heterocyclic group, and heteroaryl group are optionally bonded by one or more elements selected from H, halogen, hydroxyl, amino, cyano, =O, C 1- 6-alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0229] X, Y, L, Z, Ar, R1 each J, m, n is independently as defined above in formula I-2.

[0230] In certain embodiments, in the structure of formula I-3, M and Q are each independently selected from NH and CH2.

[0231] In certain embodiments, in the structure of formula I-3, G and E are each independently selected from CH and N.

[0232] In certain embodiments, the compound of formula I-a has the structure of formula I-4:

[0233] wherein M and G are each independently selected from a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-;

[0234] Q and E are each independently selected from N, O, S, and CR e ;

[0235] R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more groups independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0236] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0237] R j each independently selected from the group consisting of H, halo, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0238] or, R j and R e or R j and R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted by one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 substituted by substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0239] X, Y, L, Z, Ar, R 1 , J, m, n are each independently as defined above in formula I-2.

[0240] In certain embodiments, in the structure of Formula I-4, M and G are each independently selected from a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-;

[0241] Q and E are each independently selected from N, O, S, and CR e ;

[0242] R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0243] Alternatively, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, said substituents of the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0244] R j each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy, said substituents of the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, said substituents of the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0245] or, R j and R e or R j and R f and the atoms to which they are attached together form a 3-8 membered carbocyclic ring, a 3-12 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1- 6alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, said substituents of the alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0246] X, Y, L, Z, Ar, R 1 , J, m, n are each independently as defined above in formula I-2.

[0247] In certain embodiments, in the structure represented by formula I-4, M and G are each independently selected from NH and CH2.

[0248] In certain embodiments, in the structure represented by formula I-4, Q and E are each independently selected from CH and N.

[0249] In certain embodiments, the compound I has a structure as represented by formula I-b or I-c: In certain embodiments, the compound I has a structure as represented by formula I-b or I-c:

[0250] wherein A ring, X, Y, R 1 , L, Z, Ar are each independently as defined in Formula I.

[0251] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are those wherein:

[0252] R j are each independently selected from the group consisting of H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1- alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0253] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are those wherein:

[0254] R j are each independently selected from the group consisting of H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0255] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are those wherein:

[0256] R j are each independently selected from the group consisting of H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CF3, -CH2CH2OH, cyclopropyl, cyclobutyl, and

[0257] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are those wherein:

[0258] R j are each independently selected from the group consisting of H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. -CH2CH2F, -CH2CH2OH, and

[0259] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are:

[0260] R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0261] Alternatively, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.

[0262] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are:

[0263] R e and R f each independently is selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0264] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.

[0265] In certain embodiments, the compounds of Formulae I-1, I-2, I-3, and I-4 are:

[0266] Re and R f each independently is selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; or, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring.

[0267] In certain embodiments, the compounds of Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are:

[0268] R e and R f each independently is selected from H, hydroxyl, methyl, isopropyl, -CF3, and methoxy; or, R e , R f and the atom to which they are attached form a cyclopropyl ring.

[0269] In certain embodiments, the compounds of Formula I-2, Formula I-3, or Formula I-4 are: 1-4 alkyl-, -O-, -S-, -NR j , -C 1-4 alkyl-O-, and -C 1-4 alkyl-S-.

[0270] In certain embodiments, the compounds of Formula I-2, Formula I-3, or Formula I-4 are:

[0271] In certain embodiments, the compounds of Formula I-2, Formula I-3, or Formula I-4 are:

[0272] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are: 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6substituted with a substituent selected from halo, hydroxy, amino, cyano, nitro, C1-C6alkyl,

[0273] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are compounds of Formula I-4: 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 substituted with a substituent selected from halo, hydroxy, amino, cyano, nitro, C1-C6alkyl,

[0274] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are compounds of Formula I-4: 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 substituted with a substituent selected from halo, hydroxy, amino, cyano, nitro, C1-C6alkyl,

[0275] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are compounds of Formula I-4: 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-6 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 substituted by a substituent selected from haloalkoxy.

[0276] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclyl, and a 5-10 membered nitrogen-containing heteroaryl, optionally substituted with one or more substituents independently selected from H, deuterium, and halo.

[0277] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclyl, and a 5-10 membered nitrogen-containing heteroaryl, optionally substituted with one or more substituents independently selected from H, deuterium, and halo.

[0278] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from

[0279] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from

[0280] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from

[0281] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclyl, and a 5-10 membered nitrogen-containing heteroaryl.

[0282] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclyl, and a 5-10 membered nitrogen-containing heteroaryl.

[0283] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring and a 3-10 membered nitrogen-containing heterocyclic ring.

[0284] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from a 4-8 membered carbocyclic ring, a 3-6 membered nitrogen-containing monocyclic ring, a 3-6 membered nitrogen-containing heterocyclic ring, and a 3-6 membered nitrogen-containing heterocyclic ring fused to a 3-6 membered nitrogen-containing heterocyclic ring and a 3-6 membered nitrogen-containing heterocyclic ring fused to a C 3-6 carbocyclic ring.

[0285] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein L is selected from

[0286] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, -S(=O)2-, a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-.

[0287] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, -S(=O)2-,

[0288] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, and -S(=O)2-.

[0289] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, O, -C(=O)-, and -S(=O)2-.

[0290] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein Z is selected from -CF2-, -CH2-, -CHF-, and O.

[0291] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein R a and R b are each independently selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0292] Alternatively, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0293] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein R a and R b are each independently selected from H, halo, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0294] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl, or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0295] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein Ra and R b each independently is selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0296] or, R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-8 membered heterocyclyl or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0297] In certain embodiments, in the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3 and Formula I-4, R a and R b each independently is selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1-4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0298] Alternatively, R a and R b form, with the atom to which they are attached, a 3-8 membered carbocyclic ring, a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-6 alkyl, C 3-6 cycloalkyl, C 1- 6alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0299] In certain embodiments, in the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3 and Formula I-4, R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, C 1-4substituted with substituents of alkyi;

[0300] or R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl) or a 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, =0, C 1-6 substituents of alkyi.

[0301] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R a and R b are each independently selected from H, halo, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , the alkyl, cycloalkyl, and heterocyclyl groups being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, C 1-4 substituents of alkyi.

[0302] or R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl) or a 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, =0, C 1-6 substituents of alkyi.

[0303] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R a and R b are each independently selected from H, halo, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , the alkyl, cycloalkyl, and heterocyclyl groups being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, C

[0304] or R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl) or a 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, =0, C 1-6 substituents of alkyi.

[0305] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-l, formula I-2, formula I-3, and formula I-4 are those wherein R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl;

[0306] Alternatively, R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl), or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, =0, C 1-6 alkyl.

[0307] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-l, formula I-2, formula I-3, and formula I-4 are those wherein R a and R b are each independently selected from the group consisting of H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2,

[0308] Alternatively, R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl), or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, =0, C

[0309] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-l, formula I-2, formula I-3, and formula I-4 are those wherein R a and R b are each independently selected from the group consisting of H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2,

[0310] Alternatively, R a , R bthe atom to which it is attached forms

[0311] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein R a and R b are each independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, and

[0312] or, R a , R b the atom to which it is attached forms

[0313] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 1 is selected from H, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl optionally substituted with one or more H, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2)p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-12 membered heterocyclyl, optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, nitro, C

[0314] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are compounds of Formula I-a, wherein R 1 is selected from H, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl optionally substituted with one or more H, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-10 membered heterocyclyl, optionally substituted with one or more substituents selected from H, halo, hydroxyl, amino, cyano, nitro, C

[0315] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl optionally substituted with one or more H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a , and 3-8 membered heterocyclyl.

[0316] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one or more H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b substituents.

[0317] In certain embodiments, R 1 is selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, -CH2-CH(CH3)2, -NH-CH2-CHF2, -NH-CH2-CF3,

[0318] In certain embodiments, R 1 is selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, -CH2-CH(CH3)2, -NH-CH2-CHF2, -NH-CH2-CF3,

[0319] In certain embodiments, R 1 is selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, and -CH2-CH(CH3)2.

[0320] In certain embodiments, R 1 is selected from -NH-CH(CH3)2,

[0321] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3, and formula I-4 are those wherein R c and R d are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1- 4haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, C 1-4 alkyl;

[0322] Alternatively, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1- 4haloalkyl, C 1-4 haloalkoxy.

[0323] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3, and formula I-4 are those wherein R c and R d are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4haloalkyl and C 1- 4haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C

[0324] or, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.

[0325] In certain embodiments, in the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4, R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1- 4haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano, C 1-4 alkyl, C

[0326] or, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy.

[0327] In certain embodiments, in the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4, R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C1-4 haloalkyl and C 1- haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano, =0, C 1-4 alkyl;

[0328] or, R c , R d and the N atom to which it is attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1- haloalkyl, C 1-4 haloalkoxy.

[0329] In certain embodiments, Ar is selected from C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, said aryl, heteroaryl and heterocyclyl being optionally substituted with one or more R 2 substituents.

[0330] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3 and formula I-4, Ar is selected from C 6-10 aryl and 5-10 membered nitrogen containing heteroaryl, said aryl and heteroaryl being optionally substituted with one or more R 2 substituents.

[0331] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3 and formula I-4, R 2 each independently selected from the group consisting of H, F, Cl, Br, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano and C 1-4 alkyl.

[0332] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 2 each is independently selected from H, F, Cl, Br, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, C 3-8 haloalkyl, C 6-10 cycloalkyl, 3-10 membered heterocyclyl, C 1-4 aryl, and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally substituted with one or more substituents selected from H, F, Cl, Br, hydroxyl, amino, cyano, and C 2 alkyl.

[0333] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Ar is selected from phenyl, said phenyl optionally substituted with one or more (e.g. 2, 3, 4, or 5) substituents selected from F, Cl, methoxy.

[0334] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Ar is selected from phenyl, said phenyl substituted with multiple (e.g. 2, 3, 4, or 5) substituents selected from F, Cl, methoxy.

[0335] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 2 each is independently selected from H, F, Cl, Br, amino, cyano, nitro, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally substituted with one or more substituents selected from H, F, Cl, Br, hydroxyl, amino, cyano, and C 1-4 alkyl.

[0336] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein R 2 each is independently selected from H, F, Cl, Br, amino, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C 1-4 substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C

[0337] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from phenyl, said phenyl being optionally substituted with one or more (e.g. 2, 3, 4 or 5) substituents selected from F, Cl.

[0338] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from phenyl, said phenyl being substituted with a plurality (e.g. 2, 3, 4 or 5) of substituents selected from F, Cl.

[0339] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from

[0340] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from

[0341] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from

[0342] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from 5-10 membered nitrogen-containing heteroaryl, said heteroaryl being optionally substituted with one or more R 2 substituents.

[0343] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3 and Formula I-4 are those wherein Ar is selected from

[0344] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Ar is selected from 3-10 membered heterocyclyl (e.g., 3-10 membered heterocyclyl containing N, O, and / or S), optionally substituted with one or more R 2 substituents.

[0345] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein Ar is selected from

[0346] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein each p is independently selected from 0, 1, 2, and 3.

[0347] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein each X and Y is independently selected from a covalent bond, N, CR, O, S, and NH, R is selected from H, halo, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0348] In certain embodiments, the compounds of Formula I, Formula I-b, Formula I-c are those wherein each X and Y is independently selected from a covalent bond, N, CH, O, S, and NH.

[0349] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein each X and Y is independently selected from N and CR, R is selected from H, halo, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0350] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein each X and Y is independently selected from N and CR, R is selected from H, halo, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0351] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein X and Y are each independently selected from N and CR, R is selected from H, F, Cl, Br, hydroxyl, cyano, nitro, amino, methyl, ethyl, propyl, C 1-3 haloalkyl, and C 3-6 cycloalkyl.

[0352] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein X and Y are each independently selected from N and CR, R is selected from H and F.

[0353] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein X and Y are each independently selected from N and CH.

[0354] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein X and Y are selected from N.

[0355] In certain embodiments, the compounds of Formula I-l, Formula I-2, Formula I-3, and Formula I-4 are those wherein m and n are each independently selected from 0, 1, and 2; preferably, m is selected from 0, 1, and 2, and n is selected from 0 and 1.

[0356] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 have one or more of the following characteristics:

[0357] (1) R j each independently selected from H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0358] (2) R e and R f each independently selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxy, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0359] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, said carbocyclic ring, heterocyclyl ring and heteroaryl ring being optionally substituted with one or more substituents independently selected from H, halogen, hydroxy, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0360] (3) J is selected from -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O- and -C 1-6 alkyl-S-;

[0361] (4) L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen containing heterocyclic ring and a 5-10 membered nitrogen containing heteroaromatic ring, said 4-8 membered carbocyclic ring, 3-10 membered nitrogen containing heterocyclyl ring and 5-10 membered nitrogen containing heteroaryl ring being optionally substituted with one or more substituents independently selected from H, deuterium and halogen;

[0362] (5) Z is selected from a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-;

[0363] (6) R a and R b are each independently selected from H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, C 1-4 alkyl;

[0364] Alternatively, R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl), or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, =O, C 1-6 alkyl;

[0365] (7) R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-10 membered heterocyclyl (e.g., 3-8 membered heterocyclyl, 3-6 membered heterocyclyl) substituted by one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, C

[0366] (8) R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, hydroxy, amino, cyano, C 1-4 alkyl;

[0367] Alternatively, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted by one or more substituents independently selected from the group consisting of H, halogen, hydroxy, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0368] (9) R 2 are each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted by one and more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano and C 1-4 alkyl;

[0369] (10) Ar is selected from phenyl, 5-10 membered nitrogen-containing heteroaryl, and 3-10 membered heterocyclyl, said phenyl, nitrogen-containing heteroaryl, and heterocyclyl optionally substituted with one or more (e.g., 2, 3, 4, or 5) substituents selected from F, CI, methoxy; and / or,

[0370] (11) X and Y are each independently selected from a covalent bond, NH, O, S, N, and CR, R being selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0371] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 have one or more of the following features:

[0372] (1) R j are each independently selected from H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0373] (2) R e and R f are each independently selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -ORc -SR c -SOR c -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 ycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0374] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, said carbocyclic ring, heterocyclyl ring and heteroaryl ring are optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 ycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0375] (3) J is selected from the group consisting of -C 1-6 alkyl-, -0-, -S-, -NR j , -C 1-6 alkyl-0- and -C 1-6 alkyl-S-;

[0376] (4) L is selected from the group consisting of a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring and a 5-10 membered nitrogen-containing heteroaromatic ring, said 4-8 membered carbocyclic ring, 3-10 membered nitrogen-containing heterocyclyl ring and 5-10 membered nitrogen-containing heteroaryl ring are optionally substituted with one or more substituents selected from the group consisting of H, deuterium and halogen;

[0377] (5) Z is selected from the group consisting of a covalent bond, CR a R b , O, S, NR a , -C(=0)-, -S(=0)- and -S(=0)2-;

[0378] (6) R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 ycloalkyl and C 3-6 ycloalkyl-OR c , said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, C 1-4 alkyl;

[0379] or R a , R b and the atom to which it is attached forms a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl group (e.g., a nitrogen-containing heterocyclyl group or an oxygen-containing heterocyclyl group) or a 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups being optionally substituted with one or more substituents selected from H, halo, hydroxyl, =0, C 1-6 alkyl;

[0380] (7) R 1 selected from H, halo, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=0)R c , -C 1-6 alkyl-C(=0)-NR a R b , NR a R b , OR a , SR a , -NR a C(=0)R b , -C(=0)-OR a , -SOR a , -S02R a , C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups being optionally substituted with one or more H, halo, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=0)-(CH2) p -O-R a , -C(=0)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1- 6alkyl-O-R a , and 3-10 membered heterocyclyl (e.g., 3-8 membered heterocyclyl, 3-6 membered heterocyclyl) groups;

[0381] (8) R c and Rd each independently selected from H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C

[0382] or, R c , R d and the N atom to which it is attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, amino, cyano, C

[0383] (9) R 2 each independently selected from H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and more substituents selected from H, F, Cl, Br, hydroxyl, amino, cyano and C 1-4 alkyl, C

[0384] (10) Ar is selected from phenyl, 5-10 membered nitrogen-containing heteroaryl and 3-10 membered heterocyclyl, said phenyl, nitrogen-containing heteroaryl and heterocyclyl being optionally substituted with one or more (e.g. 2, 3, 4 or 5) substituents selected from F, Cl, methoxy; and / or,

[0385] (11) X and Y are each independently selected from a covalent bond, NH, O, S, N, and CR, R being selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0386] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 have one or more of the following features:

[0387] (1) R j each is independently selected from H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CF3, -CH2CH2OH, cyclopropyl, cyclobutyl, and

[0388] (2) R e and R f each is independently selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; or, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring;

[0389] (3) J is selected from -CH2-, -CH2-CH2-, -O-, and -CH2-O-;

[0390] (4) L is selected from

[0391] (5) Z is selected from a covalent bond, -N(CH3)-, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, -S(=O)2-, preferably from a covalent bond, -N(CH3)-, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, and -S(=O)2-;

[0392] (6) R a and R b each is independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2,

[0393] or, R a , R b and the atom to which they are attached form

[0394] (7) R 1-NH-CH(CH3)2, -O-CH(CH3)2, -S-CH(CH3)2, -CH2-CH(CH3)2,

[0395] (8) Ar is selected from and / or,

[0396] (9) X and Y are each independently selected from a covalent bond, N, O, S, CH, and CF.

[0397] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-l, Formula I-2, Formula I-3, and Formula I-4 have one or more of the following features:

[0398] (1) R j is each independently selected from H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CH2OH, and

[0399] (2) R e and R f are each independently selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; or, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring;

[0400] (3) J is selected from -CH2-, -CH2-CH2-, -O-, and -CH2-O-;

[0401] (4) L is selected from

[0402] (5) Z is selected from a covalent bond, -N(CH3)-, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, and -S(=O)2-;

[0403] (6) R a and R beach independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2,

[0404] or, R a , R b and the atom to which they are attached form

[0405] (7) R 1 is selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, -CH2-CH(CH3)2, -NH-CH2-CHF2, -NH-CH2-CF3,

[0406] (8) Ar is selected from and / or,

[0407] (9) X and Y are each independently selected from a covalent bond, N, O, S, and CH.

[0408] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are characterized by one or more of the following:

[0409] (1) R j each independently selected from H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0410] (2) R e and R feach independently selected from H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0411] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0412] (3) J is selected from -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O- and -C 1-6 alkyl-S-;

[0413] (4) L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring, and a 5-10 membered nitrogen-containing heteroaromatic ring, said 4-8 membered carbocyclic ring, 3-10 membered nitrogen-containing heterocyclic ring, and 5-10 membered nitrogen-containing heteroaryl group being optionally substituted with one or more substituents independently selected from H, deuterium, and halogen;

[0414] (5) Z is selected from a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-;

[0415] (6) R a and R b are each independently selected from H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, C 1-4 alkyl;

[0416] alternatively, R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl group (e.g., a nitrogen-containing heterocyclyl group or an oxygen-containing heterocyclyl group), or a 5-10 membered heteroaryl group, said heterocyclyl group and heteroaryl group being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, =O, C 1-6 alkyl;

[0417] (7) R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a , and 3-10 membered heterocyclyl (e.g., 3-8 membered heterocyclyl, 3-6 membered heterocyclyl);

[0418] (8) R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl;

[0419] Alternatively, R c and R d , together with the N atom to which they are attached, form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0420] (9) R 2 are each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-8cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano and C 1-4 substituted with one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano and C

[0421] (10) Ar is selected from phenyl, said phenyl being optionally substituted with one or more (e.g. 2, 3, 4 or 5) substituents selected from the group consisting of F, Cl, methoxy; and / or,

[0422] (11) X and Y are each independently selected from a covalent bond, NH, O, S, N, and CR, R being selected from the group consisting of H, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl and C 3-8 cycloalkyl.

[0423] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3 and formula I-4 are characterized by one or more of the following:

[0424] (1) R j are each independently selected from the group consisting of H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl and C 1-6 haloalkyl, said alkyl, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxy, amino, cyano and C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R

[0425] (2) R e and R f are each independently selected from the group consisting of H, halogen, hydroxy, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4 alkyl-C(=O)-NR c Rd , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 ycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0426] Alternatively, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl ring, or a 5-10 membered heteroaryl ring, said carbocyclic ring, heterocyclyl ring and heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 ycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0427] (3) J is selected from the group consisting of -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O-, and -C 1-6 alkyl-S-;

[0428] (4) L is selected from the group consisting of a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring, and a 5-10 membered nitrogen-containing heteroaromatic ring, said 4-8 membered carbocyclic ring, 3-10 membered nitrogen-containing heterocyclyl ring, and 5-10 membered nitrogen-containing heteroaryl ring being optionally substituted with one or more substituents selected from the group consisting of H, deuterium, and halogen;

[0429] (5) Z is selected from the group consisting of a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-;

[0430] (6) R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C3-6 cycloalkyl and C 3-6 cycloalkyl-OR c The alkyl, cycloalkyl, and heterocyclic groups are optionally replaced by one or more groups selected from H, halogen, hydroxyl, C. 1-4 Alkyl substituents;

[0431] Or, R a R b The atoms bonded thereto form 3-6 membered carbon rings, 3-8 membered heterocyclic groups (e.g., nitrogen-containing heterocyclic groups or oxygen-containing heterocyclic groups), or 5-10 membered heteroaryl groups, wherein the heterocyclic group and heteroaryl group are optionally bonded by one or more elements selected from H, halogen, hydroxyl, =O, C. 1-6 Alkyl substituents;

[0432] (7)R 1 Selected from H, halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -C(=O)R c -C 1-6 Alkyl-C(=O)-NR a R b NR a R b OR a SR a -NR a C(=O)R b -C(=O)-OR a -SOR a -SO2R a C 6-10 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclic groups, wherein the alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally surrounded by one or more H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy group, -C(=O)-(CH2) p -OR a -C(=O)-(CH2) p -NR a R b -C 1-6 Alkylene-NR a R b -C 1-6alkyl-O-R a and substituted by one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, C

[0433] (8)R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted by one or more substituents selected from the group consisting of H, halogen, hydroxy, amino, cyano, C 1-4 alkyl;

[0434] or, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of H, halogen, hydroxy, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0435] (9)R 2 are each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of H, F, Cl, Br, hydroxy, amino, cyano and C 1-4 alkyl;

[0436] (10) Ar is selected from phenyl, said phenyl being optionally substituted by one or more (e.g. 2, 3, 4 or 5) substituents selected from F, Cl, methoxy; and / or,

[0437] (11) X and Y are each independently selected from a covalent bond, NH, O, S, N, and CR, R being selected from the group consisting of H, halogen, hydroxy, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0438] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3, and formula I-4 are characterized by one or more of the following:

[0439] (1) R j each is independently selected from H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CH2OH, and

[0440] (2) R e and R f each is independently selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; or, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring;

[0441] (3) J is selected from -CH2-, -CH2-CH2-, -O-, and -CH2-O-;

[0442] (4) L is selected from

[0443] (5) Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, and -S(=O)2-;

[0444] (6) R a and R b each is independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2,

[0445] or, R a , R b and the atom to which they are attached form a

[0446] (7) R 1 is selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, -CH2-CH(CH3)2,

[0447] (8) Ar is selected from and / or,

[0448] (9) X and Y are each independently selected from a covalent bond, N, O, S, and CH.

[0449] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are characterized by one or more of the following:

[0450] (1) R j is each independently selected from H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0451] (2) R e and R f are each independently selected from H, halo, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SORc and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl are optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0452] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, a 3-10 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, said carbocyclic ring, heterocyclyl ring and heteroaryl ring are optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0453] (3) J is selected from the group consisting of -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O- and -C 1-6 alkyl-S-;

[0454] (4) L is selected from the group consisting of a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring and a 5-10 membered nitrogen-containing heteroaromatic ring;

[0455] (5) Z is selected from the group consisting of a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)- and -S(=O)2-;

[0456] (6) R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl;

[0457] or, R a , R bwith the proviso that when R is -CH2-CH2-CH2- then R is not -CH2-CH2-CH2-CH2-; and wherein the atom to which it is attached forms a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl group (e.g., a nitrogen-containing heterocyclyl group or an oxygen-containing heterocyclyl group) or a 5-10 membered heteroaryl group, said heterocyclyl and heteroaryl groups being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, =0, C 1-6 substituted by one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, =0, C

[0458] (7) R 1 selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=0)R c , -C 1-6 alkyl-C(=0)-NR a R b , NR a R b , OR a , SR a , -NR a C(=0)R b , -C(=0)-OR a , -SOR a , -S02R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=0)-(CH2) p -O-R a , -C(=0)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b substituted by one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, =0, C

[0459] (8) R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4haloalkyl, C 1-4 substituted by one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C

[0460] or, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0461] (9) R 2 each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted by one and more substituents selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C 1-4 alkyl;

[0462] (10) Ar is selected from phenyl, said phenyl being optionally substituted by one or more (e.g. 2, 3, 4 or 5) substituents selected from F, Cl; and / or,

[0463] (11) X and Y are each independently selected from N and CR, R being selected from H, halo, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl and C 3-8 cycloalkyl.

[0464] In certain embodiments, the compounds of formula I, formula I-a, formula I-b, formula I-c, formula I-1, formula I-2, formula I-3 and formula I-4 are characterized by one or more of the following:

[0465] (1) R j each independently selected from the group consisting of H, C 1-6 alkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl and C 1-6 haloalkyl, said alkyl, heterocyclyl and heteroaryl being optionally substituted by one or more substituents selected from the group consisting of H, halo, hydroxyl, amino, cyano, C1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, substituted by one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0466] (2) R e and R f are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=0)R c , -C 1- 4 alkyl-C(=0)-NR c R d , NR c R d , -NR c C(=0)R d , -C(=0)-OR c , -OR c , -SR c , -SOR c and -S02R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, substituted by one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0467] or, R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said carbocyclic ring, heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, substituted by one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =0, C

[0468] (3) J is selected from -C1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O-, and -C 1-6 alkyl-S-;

[0469] (4) L is selected from a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring, and a 5-10 membered nitrogen-containing heteroaromatic ring;

[0470] (5) Z is selected from a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-;

[0471] (6) R a and R b are each independently selected from H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl, and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl, and heterocyclyl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl;

[0472] Alternatively, R a , R b and the atom to which they are attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl), or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from H, halogen, hydroxyl, =O, C 1-6 alkyl;

[0473] (7) R 1 is selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one or more H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b substituted;

[0474] (8) R c and R d are each independently selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl;

[0475] or, R c , R d and the N atom to which they are attached form a 4-8 membered heterocyclyl or a 5-8 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents selected from the group consisting of H, halogen, hydroxyl, amino, cyano, =O, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy;

[0476] (9) R 2 are each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and more substituents selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C1-4 substituted with a substituent selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR, -NR

[0477] (10) Ar is selected from phenyl, which is optionally substituted with one or more (e.g., 2, 3, 4, or 5) substituents selected from F, Cl; and / or,

[0478] (11) X and Y are each independently selected from N and CR, R is selected from H, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, and C 3-8 cycloalkyl.

[0479] In certain embodiments, the compounds of Formula I, Formula I-a, Formula I-b, Formula I-c, Formula I-1, Formula I-2, Formula I-3, and Formula I-4 are characterized by one or more of the following:

[0480] (1) R j are each independently selected from H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CH2OH, and

[0481] (2) R e and R f are each independently selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; or, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring;

[0482] (3) J is selected from -CH2-, -CH2-CH2-, -O-, and -CH2-O-;

[0483] (4) L is selected from

[0484] (5) Z is selected from a covalent bond, -CF2-, -CH2-, -CHF-, O, -C(=O)-, and -S(=O)2-;

[0485] (6) R a and R b are each independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, and

[0486] Or, R a R b The atoms connected to it form

[0487] (7)R 1 Selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH -S-CH(CH3)2、 and -CH2-CH(CH3)2;

[0488] (8) Ar is selected from And / or,

[0489] (9) X and Y are each independently selected from N and CH.

[0490] In some embodiments, in the compounds of formula I-1, formula I-2, formula I-3 and formula I-4, m and n are each independently selected from 0, 1, 2 and 3, for example, m and n are each independently selected from 0, 1 and 2; or m and n are each independently selected from 0 and 1; or m and n are each independently selected from 1 and 2; or m and n are both selected from 1; or m and n are both selected from 2.

[0491] In some embodiments, the compounds of the present invention are selected from:

[0492] In some embodiments, the compounds of the present invention are selected from:

[0493] In some embodiments, the compound of the present invention may optionally be substituted at a suitable position with one or more suitable substituents.

[0494] The groups of all the above embodiments of the present application can be suitably selected in any combination to give different general formula ranges or specific embodiments. These ranges and embodiments all belong to the present application. The present application encompasses compounds obtained by any combination of the individual embodiments.

[0495] Preparation method

[0496] In another aspect, the present application provides a preparation method of the compound of formula I, which is selected from the following methods:

[0497] Route one:

[0498] wherein R 1 , n, R a , L, Z, Ar and R j are as defined above; preferably, n is selected from 0, 1, 2 and 3;

[0499] The preparation method comprises:

[0500] First step: compound I’-1 undergoes a substitution reaction or a coupling reaction to generate compound I’-2;

[0501] Preferably, the substitution reaction is a nucleophilic substitution reaction; preferably, the nucleophilic substitution reaction is usually carried out in the presence of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, etc.) at a temperature ranging from -20°C to 120°C (for example, -20°C to 100°C, -20°C to 80°C, -20°C to 60°C, -20°C to 40°C, -20°C to 20°C, -20°C to 0°C, 0°C to 90°C, 0°C to 70°C, 0°C to 50°C, 0°C to 30°C or 0°C to 10°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C or 110°C);

[0502] The coupling reaction is selected from the Suzuki reaction, the Buchwald cross-coupling reaction and the Ullmann coupling reaction;

[0503] Second step: compound I’-2 undergoes a coupling reaction to generate compound I’-3;

[0504] Preferably, the coupling reaction is selected from the Suzuki reaction, the insertion carbonylation reaction and the Heck reaction;

[0505] Third step: compound I’-3 undergoes a reduction reaction to generate compound I’-4;

[0506] Preferably, the reduction reaction is completed under a hydrogen metal catalysis (such as Pd, Pd(OH)2, Raney nickel, etc.) system;

[0507] Fourth step: compound I’-4 undergoes intramolecular annulation to generate compound I’-5;

[0508] Preferably, said compound I'-4 undergoes intramolecular annulation reaction in the presence of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, and the like) and a solvent; preferably, said solvent is selected from polar solvents; more preferably, said solvent is selected from methanol and ethanol;

[0509] Step 5: Compound I'-5 reacts with halogen or NXS to form compound I'-6;

[0510] Preferably, said reaction is carried out in the presence of halogen (such as bromine, iodine, and the like) or NXS (such as selected from NCS, NBS, and NIS; preferably, NXS is selected from NBS) in a solvent (such as dichloromethane, chloroform, toluene, and the like; preferably, said solvent is selected from chloroform) at a temperature ranging from -20 °C to 80 °C (such as -20 °C to 60 °C, -20 °C to 40 °C, -20 °C to 20 °C, or -20 °C to 0 °C, such as 0 °C to 70 °C, 0 °C to 50 °C, 0 °C to 30 °C, 0 °C to 10 °C, such as 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, or 70 °C);

[0511] Step 6: Compound I'-6 undergoes substitution reaction or undergoes coupling reaction to form compound I'-7;

[0512] Preferably, said substitution reaction is nucleophilic substitution reaction; preferably, said nucleophilic substitution reaction is usually carried out in the presence of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, and the like) at a temperature ranging from -20 °C to 120 °C (such as -20 °C to 100 °C, -20 °C to 80 °C, -20 °C to 60 °C, -20 °C to 40 °C, -20 °C to 20 °C, -20 °C to 0 °C, 0 °C to 90 °C, 0 °C to 70 °C, 0 °C to 50 °C, 0 °C to 30 °C, 0 °C to 10 °C, such as 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, or 110 °C);

[0513] Said coupling reaction is selected from Buchwald cross-coupling reaction and Ullmann coupling reaction;

[0514] Step 7: Compound I'-7 forms compound I-1-1 through alkylation reaction;

[0515] Preferably, said alkylation reaction is carried out in the presence of a basic reagent (preferably, said basic reagent is selected from sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, triethylamine, DIPEA, DBU, and the like) and an alkylating reagent (such as halide, R j -OMs, R j -Ots, and the like) at a temperature ranging from 0 °C to 120 °C.

[0516] Route two:

[0517] wherein R 1 , m, R a , L, Z, Ar and R j are as defined above; preferably, m is selected from 0, 1, 2 and 3;

[0518] The preparation method comprises:

[0519] First step: compound I'-1 undergoes substitution reaction or coupling reaction to generate compound II-1;

[0520] Preferably, the substitution reaction is nucleophilic substitution reaction; preferably, the nucleophilic substitution reaction is usually carried out in the presence of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, etc.) at a temperature ranging from -20°C to 120°C (for example, -20°C to 100°C, -20°C to 80°C, -20°C to 60°C, -20°C to 40°C, -20°C to 20°C, -20°C to 0°C, 0°C to 90°C, 0°C to 70°C, 0°C to 50°C, 0°C to 30°C, 0°C to 10°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C or 110°C);

[0521] The coupling reaction is selected from Buchward cross-coupling reaction and Ullmann coupling reaction;

[0522] Second step: compound II-1 undergoes coupling reaction to generate compound II-2;

[0523] Preferably, the coupling reaction is selected from Suzuki reaction, insertion carbonylation reaction and Heck reaction;

[0524] Third step: compound II-2 undergoes reduction reaction to generate compound II-3;

[0525] Preferably, the reduction reaction is completed under hydrogen metal catalysis (such as Pd, Pd(OH)2, Raney nickel, etc.) system;

[0526] Fourth step: compound II-3 undergoes intramolecular cyclization to generate compound II-4;

[0527] Preferably, compound II-3 undergoes intramolecular cyclization reaction under the condition of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, etc.) and a polar solvent (for example, methanol and ethanol, etc.);

[0528] Fifth step: compound II-4 reacts with halogen or NXS to generate compound II-5;

[0529] Preferably, the reaction is carried out under halogen (such as bromine, iodine, etc.) or NXS (such as NCS, NBS and NIS; preferably NBS) condition, in a solvent (such as solvent is selected from dichloromethane, chloroform, toluene, etc.; preferably the solvent is chloroform), at a temperature of -20 °C to 80 °C (for example -20 °C to 60 °C, -20 °C to 40 °C, -20 °C to 20 °C, or -20 °C to 0 °C, for example 0 °C to 70 °C, 0 °C to 50 °C, 0 °C to 30 °C, 0 °C to 10 °C, for example 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, or 70 °C).

[0530] Step 6: Compound II-5 undergoes a substitution reaction or undergoes a coupling reaction to generate compound II-6;

[0531] Preferably, the substitution reaction is a nucleophilic substitution reaction; preferably, the nucleophilic substitution reaction is usually carried out in the presence of a basic reagent (such as potassium carbonate, cesium carbonate, triethylamine, DBU, etc.) at a temperature in the range of -20 °C to 120 °C (for example -20 °C to 100 °C, -20 °C to 80 °C, -20 °C to 60 °C, -20 °C to 40 °C, -20 °C to 20 °C, -20 °C to 0 °C, 0 °C to 90 °C, 0 °C to 70 °C, 0 °C to 50 °C, 0 °C to 30 °C, 0 °C to 10 °C, for example 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, or 110 °C).

[0532] The coupling reaction is selected from the Suzuki reaction, Buchwald cross-coupling reaction, and Ullmann coupling reaction;

[0533] Step 7: Compound II-6 is converted to compound I-1-2 by an alkylation reaction;

[0534] Preferably, the alkylation reaction is carried out in the presence of a basic reagent (for example sodium hydride, sodium hydroxide, potassium carbonate, cesium carbonate, triethylamine, DIPEA, DBU, etc.) at a temperature in the range of 0 °C to 120 °C (for example -20 °C to 100 °C, -20 °C to 80 °C, -20 °C to 60 °C, -20 °C to 40 °C, -20 °C to 20 °C, -20 °C to 0 °C, 0 °C to 90 °C, 0 °C to 70 °C, 0 °C to 50 °C, 0 °C to 30 °C, 0 °C to 10 °C, for example 20 °C, 30 °C, 40 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, or 110 °C) between compound II-6 and an alkylating agent (such as halide, R j -OMs, R j -Ots, etc.).

[0535] Compositions, pharmaceutical combinations, pharmaceutical compositions, and therapeutic uses and methods

[0536] Another aspect of the present application provides a composition or a pharmaceutical combination comprising a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug thereof, or a pharmaceutically acceptable salt or ester thereof.

[0537] In another embodiment, the composition or the pharmaceutical combination can further comprise one or more other therapeutic agents.

[0538] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable carriers.

[0539] In another embodiment, the pharmaceutical composition can further comprise one or more other therapeutic agents.

[0540] In the present application, "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient or vehicle with which the therapeutic is administered, and which is suitable for use in contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, and other problem or complication commensurate with a reasonable benefit / risk ratio, as defined in the art.

[0541] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this application include, but are not limited to, sterile aqueous, nonaqueous, and mixture of solvents. Among aqueous carriers and formulations include saline, buffered water, buffered saline, and physiologically balanced water and salt solutions. Among nonaqueous carriers and formulations include glycerol, edible oils, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Also among the acceptable vehicles and solvents that can be used are physiologically saline and buffered normal sodium lactate and glycerol. These solutions are sterile and fluid and stable. The pH and the exact buffer composition will be selected to be compatible with the use of the compound described herein and not injurious to the subject. Some stability of the compound described herein can be imparted by adding surfactants and / or preservatives, for example, but not limited to, Tween, sorbic acid, and / or EDTA. Formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes (e.g., millipore or similar filters). Therapeutic compositions can, if necessary, contain minor amounts of wetting or emulsifying agents, or pH adjusting, or isotonic agents, such as sodium acetate, sodium citrate, glucose, sodium chloride, and / or the like. Actual methods of preparation will depend on the particular excipients employed and the particular mode of delivery desired. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Company, 1990, the disclosure of which is hereby incorporated by reference. The pharmaceutical compositions can be formulated to be immediate or modified release. Modified release formulations include delayed-, sustained, pulsatile, or controlled release formulations. Suitable pharmaceutical carriers and their formulation are well known in the art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Company, 1990, the disclosure of which is hereby incorporated by reference.

[0542] The pharmaceutical compositions of the present application can act systemically and / or topically. To this end, they can be administered by suitable routes, for example by injection, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or orally, buccally, nasally, transmucosally, topically, in the form of an ophthalmic preparation or by inhalation.

[0543] For these administration routes, the pharmaceutical compositions of the present application can be administered in a suitable dosage form.

[0544] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

[0545] The content or amount of the compound of the present application in the pharmaceutical composition can be about 0.01 mg to about 1000 mg.

[0546] Another aspect of the present application provides the use of a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described in the present application, for the preparation of a medicament for the prevention and / or treatment of a disease, in particular a GPR6 receptor-mediated related disease.

[0547] Another aspect of the present application provides a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described in the present application, for use in the prevention and / or treatment of a disease, in particular a GPR6 receptor-mediated related disease.

[0548] Another aspect of the present application provides a method for the prevention and / or treatment of a disease, in particular a GPR6 receptor-mediated related disease, comprising administering to an individual in need thereof an effective amount of a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition, a pharmaceutical combination or a pharmaceutical composition described in the present application.

[0549] Another aspect of the present application provides the use of a compound described in the present application, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition described in the present application, for the preparation of a medicament for the prevention and / or treatment of a disease, in particular a GPR6 receptor-mediated related disease.

[0550] Another aspect of the present application provides a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition described herein, for use in the prevention and / or treatment of a disease, in particular a GPR6 receptor mediated related disease.

[0551] Another aspect of the present application provides a method of preventing and / or treating a disease, in particular a GPR6 receptor mediated related disease, comprising administering to an individual in need thereof an effective amount of a compound described herein, or a stereoisomer, a tautomer, a polymorph, a solvate, an N-oxide, an isotopically-labeled compound, or a metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition described herein.

[0552] The GPR6 receptor mediated related disease described herein is selected from the group consisting of movement disorders, including Parkinson, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression.

[0553] The term "effective amount" as used herein refers to the amount of a compound that, when administered, will relieve to some extent one or more of the symptoms of the disorder being treated.

[0554] Dosage regimens can be adjusted to provide the optimum desired response. For example, a single bolus can be administered, several divided doses can be administered over time or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is to be noted that dosage values can vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the

[0555] The amount of a compound of the present application that is administered will depend on the subject to be treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician.

[0556] The term "treating" as used herein, means reversing, alleviating, inhibiting the progress of, or inhibiting one or more symptoms of the disorder or condition to which such term applies, unless otherwise indicated.

[0557] As used herein, the term "prevention" refers to the prior administration of medication to avoid or prevent the onset of one or more symptoms of a disease or condition. Those skilled in the medical field recognize that the term "prevention" is not an absolute term. In the medical field, it should be understood as the preventive administration of medication to substantially reduce the likelihood or severity of a condition or its symptoms, which is the intended meaning of this disclosure. The Physician's Desk Reference, the standard text in the field, uses the term "prevention" hundreds of times. As used therein, the term "prevention" regarding a condition or disease refers to the avoidance of the cause, effect, symptoms, or progression of a disease or condition before it has fully manifested.

[0558] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0559] Example

[0560] To make the objectives and technical solutions of this invention clearer, the embodiments of this invention are described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of this invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0561] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 The determination was made by 1H NMR or mass spectrometry (MS). The NMR spectrometer was a Bruker AVANCEⅢHD 400MHz, and the measuring solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6). The internal standard was tetramethylsilane (TMS). Chemical shifts (δ) were given in parts per million (ppm).

[0562] The instrument used for MS measurements was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 1260 Infinity / Agilent 6120 Quadrupole.

[0563] The rapid column chromatography method uses the Biotage rapid column chromatograph.

[0564] Preparative method of high performance liquid chromatograph:

[0565] Instrument model: Agilent 1260, column: Waters SunFire Prep C18 OBD (19mm x 150mm x 5.0μm); column temperature: 25℃; flow rate: 20.0mL / min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid aqueous solution.

[0566] Thin layer chromatography silica gel plate (TLC) uses pre-made thin layer plate (2x5cm) produced by Leyen, and the specification used for thin layer chromatography separation and purification is GF 254 (1mm) produced by Yantai.

[0567] The monitoring of the reaction uses thin layer chromatography (TLC) or LC-MS; the developing agent system used includes: n-heptane and ethyl acetate system, dichloromethane and methanol system, and petroleum ether and ethyl acetate system, and the volume ratio of the solvents is adjusted according to the polarity of the compound or adjusted by adding triethylamine, etc.

[0568] Unless otherwise specified in the examples, the temperature of the reaction is room temperature (20℃-35℃).

[0569] The reagents used in the present application are purchased from Acros Organics, Aldrich Chemical Company, and Tebo Chemical Co., Ltd.

[0570] The following experimental examples and examples are used to further illustrate but not limit the present application.

[0571] In the conventional synthesis method as well as the examples and intermediate synthesis examples, the meaning of each abbreviation is shown as follows.

[0572] Preparation of control compound CVN424:

[0573] According to the synthesis method of reference literature Changwei Mu et.al., Scalable Synthesis of CVN424, an Inverse Agonist of the GPR6 Receptor, Organic Process Research & Development, 2023, 27, 2, 256-261, control compound CVN424 (671mg) was prepared. MS (ESI): m / z = 474.2 [M+H] + . 1H NMR (400 MHz, DMSO) δ 7.35 - 7.26 (m, 2H), 7.05 - 6.98 (m, 1H), 5.94 (dd, J = 10.6, 6.0 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.43 (d, J = 11.6 Hz, 2H), 4.41 - 4.33 (m, 1H), 3.95 - 3.80 (m, 2H), 3.76 - 3.66 (m, 3H), 3.60 - 3.51 (m, 1H), 3.33 - 3.24 (m, 2H), 2.96 - 2.83 (m, 2H), 2.72 (t, J = 5.6 Hz, 1H), 2.60 (t, J = 5.6 Hz, 1H), 2.23 - 2.13 (m, 1H), 2.09 (d, J = 2.6 Hz, 3H), 2.07 - 2.01 (m, 2H), 2.00 - 1.81 (m, 3H).

[0574] Preparation of Intermediate 1: (R)-3-bromo-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one Synthesis of Intermediate 1

[0575] Step one: Synthesis of compound Int 1-1

[0576] Compound 2-01 (5 g, 28.74 mmol) was dissolved in DMF (7 mL) followed by the addition of (R)-3-aminotetrahydrofuran (3 g, 34.49 mmol) and DIPEA (5.57 g, 43.11 mmol) and the reaction was allowed to warm to room temperature for 12 h. The reaction was monitored to completion by LCMS. The reaction mixture was diluted with saturated brine (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography to yield compound Int 1-1 (5.2 g, 23.15 mmol). MS (ESI): m / z = 225.1 [M+H] +

[0577] Step two: Synthesis of compound Int 1-2

[0578] To a flask was added compound Int 1-1 (5.2 g, 23.15 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-ene acid ethyl ester (7.85 g, 34.72 mmol), DMAC (50 mL), water (5 mL), cesium carbonate (15.08 g, 46.29 mmol), Pd(dppf)Cl2(1.69 g, 2.31 mmol), nitrogen replacement, and then warmed to 120 °C, stirred for 4 h. LCMS detection showed that the reaction was complete, the reaction was restored to room temperature, ethyl acetate (50 mL) and saturated brine (50 mL) were added to dilute the reaction solution, the water layer was extracted with ethyl acetate (50 mL*2), the organic layer was combined, and then washed with brine (30 mL*4), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain compound Int 1-2 (4.2 g, 14.57 mmol), MS [ESI]: m / z = 289.2 [M+H] + .

[0579] Step three: synthesis of compound Int 1-3

[0580] To a flask was added compound Int 1-2 (4.2 g, 14.57 mmol), methanol (50 mL), palladium-carbon (420 mg, 0.1 eq), hydrogen replacement, reaction at room temperature for 12 h, LCMS detection showed that the reaction was complete, the reaction solution was filtered through diatomite, washed with methanol, concentrated under reduced pressure, and then purified by column chromatography to obtain compound Int 1-3 (3.8 g, 13.09 mmol), MS [ESI]: m / z = 291.2 [M+H] + .

[0581] Step four: synthesis of compound Int 1-4

[0582] To a flask was added compound Int 1-3 (3.8 g, 13.09 mmol), methanol (40 mL), Raney nickel (380 mg, 0.1 eq), hydrogen replacement, reaction at 60 °C for 12 h, LCMS detection showed that the reaction was complete, the reaction solution was filtered through diatomite, washed with methanol, concentrated under reduced pressure, and then purified by column chromatography to obtain compound Int 1-4 (2.5 g, 10.07 mmol), MS [ESI]: m / z = 249.2 [M+H] + .

[0583] Step five: synthesis of compound Int 1

[0584] To a flask was added compound Int 1-4 (2.5 g, 10.07 mmol), dichloromethane (25 mL), NBS (2.15 g, 12.08 mmol), and the reaction was stirred at room temperature for 6 hours. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure. Compound Int 1 (2.8 g, 8.56 mmol) was obtained by column chromatography. MS [ESI]: m / z = 327.0 [M+H] + .

[0585] Preparation of Intermediate 2: Synthesis of (R)-3-chloro-2-((tetrahydrofuran-3- yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one .

[0586] To a flask was added compound Int 1-4 (1.0 g, 4.03 mmol), dichloromethane (10 mL), NCS (0.64 g, 4.83 mmol), and the reaction was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure. Int 2 (1.14 g, 3.36 mmol) was obtained by column chromatography. MS [ESI]: m / z = 283.2 [M+H] + .

[0587] Preparation of Intermediate 3: Synthesis of 2-bromo-3-(4-(2,4-difluorophenoxy)piperidin- 1-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one .

[0588] Step one: Synthesis of compound Int 3-2

[0589] To a flask was added compound Int 3-1 (5 g, 9.58 mmol), DMF (50 mL), CsF (6.53 g, 43.0 mmol), DIPEA (6.95 g, 53.57 mmol), 4-(2,4-difluorophenoxy)piperidine (compound 1-02) (9.17 g, 43.0 mmol), and the reaction was stirred at 60 °C for 8 hours. LCMS showed the reaction was complete. The reaction was diluted with ethyl acetate (50 mL) and saturated brine (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined and washed with brine (30 mL*4). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound Int 3-2 (9 g, 28.45 mmol) was obtained by column chromatography. MS [ESI]: m / z = 317.2 [M+H] + .

[0590] Step two: synthesis of compound Int 3-3

[0591] To the flask was added compound Int 3-2 (9 g, 28.45 mmol), dichloroethane (100 mL), NBS (6.08 g, 34.1 mmol), and the reaction was heated to 60 °C for 6 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure. Compound Int 3-3 (10 g, 25.3 mmol) was obtained by column chromatography, MS [ESI]: m / z = 396.2 [M+H] + .

[0592] Step three: synthesis of compound Int 3-4

[0593] To the flask was added compound Int 3-3 (10 g, 25.3 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enoic acid ethyl ester (8.58 g, 37.95 mmol), DMAC (100 mL), water (10 mL), cesium carbonate (16.49 g, 50.61 mmol), Pd(dppf)Cl2(1.85 g, 2.53 mmol), and the reaction was heated to 110 °C for 6 h after replaced with nitrogen. LCMS showed the reaction was completed. The reaction was diluted with ethyl acetate (50 mL) and saturated brine (50 mL). The water layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine (30 mL*4). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound Int 3-4 (6 g, 14.48 mmol) was obtained by column chromatography, MS [ESI]: m / z = 415.2 [M+H] + .

[0594] Step four: synthesis of compound Int 3-5

[0595] To the flask was added compound Int 3-4 (6 g, 14.48 mmol), methanol (50 mL), and palladium on carbon (600 mg, 0.1 eq). The reaction was replaced with hydrogen and stirred at room temperature for 12 h. LCMS showed the reaction was completed. The reaction was filtered through celite, washed with methanol, and concentrated under reduced pressure. Compound Int 3-5 (5.2 g, 12.49 mmol) was obtained by column chromatography, MS [ESI]: m / z = 417.2 [M+H] + .

[0596] Step five: synthesis of compound Int 3-6

[0597] To a flask was added compound Int 3-5 (5.2 g, 12.49 mmol), methanol (50 mL), Raney nickel (500 mg, 0.1 eq), hydrogen gas was replaced, 60 °C for 12 h, LCMS detection reaction was complete, the reaction liquid was filtered through diatomite, washed with methanol, concentrated under reduced pressure, purified by column chromatography to obtain compound Int 3-6 (3.2 g, 8.55 mmol), MS [ESI]: m / z = 375.2 [M+H] + .

[0598] Step six: synthesis of compound Int 3

[0599] To a flask was added compound Int 3-6 (3.2 g, 8.55 mmol), dichloroethane (30 mL), NBS (1.83 g, 10.25 mmol), warmed to 60 °C for 6 h, LCMS detection reaction was complete, the reaction liquid was concentrated under reduced pressure, purified by column chromatography to obtain compound Int 3 (3.5 g, 7.72 mmol), MS [ESI]: m / z = 453.0 [M+H] + .

[0600] Referring to the synthesis method of intermediate 3, the following intermediates can be prepared by replacing compound 1-02 with the following fragments, respectively:

[0601] Preparation of intermediate 4: synthesis of (R)-8-bromo-7-((tetrahydrofuran-3-yl)amino)-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one .

[0602] Step one: synthesis of compound Int 4-2

[0603] Compound Int 4-1 (5 g, 25.00 mmol), (R)-tetrahydrofuran-3-amine (2.40 g, 27.50 mmol) and DIPEA (6.46 g, 50.00 mmol) were dissolved in DMSO (50 mL), warmed to 100 °C for 18 h. LCMS detection reaction was complete, diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound Int 4-2 (6 g, 22.46 mmol). MS [ESI]: m / z = 285.2 [M+NH4] + .

[0604] Step two: synthesis of compound Int 4-3

[0605] Compound Int 4-2 (6 g, 22.46 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (6.09 g, 26.95 mmol) were dissolved in H2O (6 mL) and 1,4-dioxane (60 mL) under nitrogen atmosphere, then Pd(dppf)Cl2(3.29 g, 4.49 mmol) and cesium carbonate (21.96 g, 67.39 mmol) were added, nitrogen was replaced, and the reaction was heated to 95 °C for 12 h. The reaction was checked by LCMS, diluted with H2O (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound Int 4-3 (5.6 g, 19.56 mmol), MS [ESI]: m / z = 304.1 [M+NH4] + .

[0606] Step three: Synthesis of compound Int 4-4

[0607] Compound Int 4-3 (5.6 g, 19.56 mmol) was dissolved in methanol (60 mL), then Pd / C (0.56 g, 0.1 eq) was added, and the reaction was carried out under hydrogen replacement for 12 h at room temperature under 15 Psi. The reaction was checked by LCMS, filtered with celite, washed with MeOH (30 mL x 2), concentrated under reduced pressure, and purified by column chromatography to obtain compound Int 4-4 (5 g, 17.34 mmol), MS [ESI]: m / z = 289.2 [M+H] + .

[0608] Step four: Synthesis of compound Int 4-5

[0609] Compound Int 4-4 (2 g, 6.94 mmol) was dissolved in methanol (40.00 mL), then Raney Ni (200 mg, 0.1 eq) was added, and the reaction was carried out under hydrogen replacement at 60 °C for 4 h under 15 Psi. The reaction was checked by LCMS, washed with MeOH (30 mL x 2) to obtain the crude product, and purified by column chromatography to obtain compound Int 4-5 (800 mg, 3.25 mmol), MS [ESI]: m / z = 247.1 [M+H] + .

[0610] Step five: Synthesis of compound Int 4

[0611] Compound Int 4-5 (360 mg, 1.46 mmol), NBS (234.13 mg, 1.32 mmol) were dissolved in DCM (4 mL) at room temperature, and the reaction was allowed to proceed at room temperature for 1 h. LCMS was used to monitor the reaction. The reaction solution was concentrated under reduced pressure, and compound Int 4 (400 mg, 1.23 mmol) was obtained by column chromatography. MS [ESI]: m / z = 326.0 [M+H] + .

[0612] Preparation of Intermediate 5: Synthesis of 3-bromo-2-(oxetan-3-ylamino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound Int 5) .

[0613] Step one: Synthesis of compound Int 5-1

[0614] Compound 2-01 (20 g, 0.12 mol) and DIPEA (22.3 g, 0.17 mol) were dissolved in super dry DMF (200 mL), and the reaction mixture was cooled to 0 °C in an ice bath. 3-Oxetanamine (9.3 g, 0.13 mol) was slowly added dropwise under a nitrogen atmosphere. After the addition was complete, the reaction mixture was stirred at 0 °C for 2 h. LCMS was used to monitor the reaction. The mixture was slowly introduced into ice water (300 mL), filtered, and dried to obtain compound Int 5-1 (22 g, 0.10 mol).

[0615] Step two: Synthesis of compound Int 5-2

[0616] Compound Int 5-1 (14 g, 66.5 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-ene acid ethyl ester (24.1 g, 106.4 mmol), 1,4-dioxane (200 mL), water (20 mL), potassium carbonate (27.6 g, 199.5 mmol), Pd(dppf)Cl2 (4.9 g, 6.7 mmol), and nitrogen were added to a flask, which was then heated to 90 °C and stirred for 16 h. LCMS was used to monitor the reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and saturated brine, and the water layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound Int 5-2 (14 g, 51.0 mmol) was obtained by column chromatography. MS [ESI]: m / z = 274.1 [M+H] + .

[0617] Step three: Synthesis of compound Int 5-3

[0618] To a flask was added compound Int 5-2 (14 g, 51.0 mmol), methanol (300 mL), palladium on carbon (140 mg, 10% w / w), hydrogen gas replacement, reaction at room temperature for 12 hours, LCMS detection reaction complete, the reaction liquid was filtered through diatomite, washed with methanol, concentrated under reduced pressure, purified by column chromatography to obtain compound Int 5-3 (9 g, 32.57 mmol), MS [ESI]: m / z = 276.7 [M+H] + .

[0619] Step four: synthesis of compound Int 5-4

[0620] To a flask was added compound Int 5-3 (9 g, 32.6 mmol), methanol (100 mL), ammonia water (10 mL), Raney nickel (190 mg, w / w), hydrogen gas replacement, reaction at 70°C for 24 hours, LCMS detection reaction complete, the reaction liquid was filtered through diatomite, washed with methanol, concentrated under reduced pressure, purified by column chromatography to obtain compound Int 5-4 (1.5 g, 6.40 mmol).

[0621] Step five: synthesis of compound Int 5

[0622] To a flask was added compound Int 5-4 (1 g, 4.26 mmol), acetonitrile (20 mL), NBS (760 mg, 4.26 mmol), the mixture was stirred at 0°C for 1 hour under nitrogen atmosphere. After the reaction was completed, filtration to obtain compound Int 5 (700 mg, 2.24 mmol).

[0623] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (t, J = 5.6 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 4.90-4.79 (m, 1H), 4.72 (t, J = 6.4 Hz, 2H), 4.58 (t, J = 6.0 Hz, 2H), 4.23 (d, J = 5.6 Hz, 2H), 2.93-2.86 (m, 2H), 2.72-2.65 (m, 2H).

[0624] Preparation of intermediate 6: synthesis of 8-bromo-7-(oxetan-3-ylamino)-1,2,4,5- tetrahydro-3H-benzo[c]azepin-3-one (compound Int 6)

[0625] Step one: synthesis of compound Int 6-1

[0626] ​Compound Int 4-1 (20 g, 100 mmol), 3-oxetanamine (8.8 g, 120 mmol) and DIPEA (41.46 g, 300 mmol) were dissolved in DMSO (200 mL) and warmed to 100 °C for 4 h. After the reaction was completed, the reaction was allowed to cool to room temperature and was poured into 500 mL of ice water. Compound Int 6-1 (24 g, 94.82 mmol) was obtained by filtration.

[0627] Step two: synthesis of compound Int 6-2

[0628] Compound Int 6-1 (24 g, 94.82 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)acrylate (25.7 g, 113.7 mmol) were dissolved in H2O (20 mL) and 1,4-dioxane (200 mL) under nitrogen atmosphere. Pd(dppf)Cl2CH2Cl2(7.7 g, 9.48 mmol) and potassium carbonate (39.31 g, 284.4 mmol) were added and the reaction was purged with nitrogen. The reaction was warmed to 100 °C for 4 h. The reaction was complete by LCMS. The reaction was diluted with H2O (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Compound Int 6-2 (18 g, 66.1 mmol) was obtained by purification by column chromatography, MS [ESI]: m / z = 290.05 [M+NH4] + .

[0629] Step three: synthesis of compound Int 6-3

[0630] Compound Int 6-2 (18 g, 66.1 mmol) was dissolved in methanol (200 mL) and Pd / C (1.8 g, 10% w / w) was added. The reaction was purged with hydrogen three times and stirred at room temperature for 12 h at 15 Psi. The reaction was complete by LCMS. After filtration over celite, the reaction was washed with MeOH (30 mL x 2) and concentrated under reduced pressure. Compound Int 6-3 (16 g, 58.33 mmol) was obtained by purification by column chromatography, MS [ESI]: m / z = 292.05 [M+NH4] + .

[0631] Step four: synthesis of compound Int 6-4

[0632] Compound Int 6-3 (16 g, 58.33 mmol) was dissolved in a mixture of ethanol (200 mL) and NH3.H2O (20 mL). The reaction mixture was stirred at 80 °C under hydrogen atmosphere for 72 h. After the reaction was completed, the reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The obtained crude was purified by flash silica gel column chromatography to give compound Int 6-4 (10 g, 42.69 mmol), MS [ESI]: m / z = 233.05 [M+H] + .

[0633] Step five: synthesis of compound Int 6

[0634] Compound Int 6-4 (3.5 g, 15.1 mmol) was dissolved in dichloromethane (35 mL) at room temperature, and NBS (2.7 g, 15.1 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. After the reaction was completed, the temperature was allowed to rise to room temperature. The reaction was diluted with water and extracted with dichloromethane. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude, which was purified by column chromatography to give compound Int 6 (3 g, 9.64 mmol), MS [ESI]: m / z = 310.95 [M+H] + .

[0635] Preparation of intermediate 7: synthesis of 7-bromo-8-(4-(2,4-difluorophenoxy)piperidin-1-yl)-1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (compound Int-7)

[0636] Step one: synthesis of compound Int 7-2

[0637] Compound Int 7-1 (6 g, 19.49 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1- ene acetate (4.19 g, 18.51 mmol), potassium carbonate (5.39 g, 38.97 mmol, 2.35 mL), and Pd(dppf)Cl2 (1.43 g, 1.95 mmol) were dissolved in 1,4-dioxane (60 mL) and H2O (6 mL) under nitrogen atmosphere, and the reaction mixture was replaced with nitrogen and heated to 90 °C for 12 h. The reaction was monitored by LCMS, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a residue, which was purified by column chromatography to give compound Int 7-2 (4.2 g, 14.99 mmol). MS (ESI): m / z = 297.0 [M+NH4] + .​

[0638] Step two: synthesis of compound Int 7-3

[0639] Compound Int 7-2 (4.2 g, 14.99 mmol), 4-(2,4-difluorophenoxy)piperidine (3.84 g, 17.99 mmol), cesium carbonate (14.66 g, 44.98 mmol), RuPhos Pd G3 (1.25 g, 1.50 mmol) and RuPhos (1.40 g, 3.00 mmol) were dissolved in toluene (50 mL) under nitrogen atmosphere, replaced by nitrogen, and heated to 120 °C for 12 hours. The reaction was monitored by LCMS to be completed, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a residue, which was purified by column chromatography to obtain compound Int 7-3 (4.13 g, 10.37 mmol), MS (ESI): m / z = 413.2 [M+H] + .

[0640] Step three: synthesis of compound Int 7-4

[0641] Compound Int 7-3 (4.28 g, 10.37 mmol) was dissolved in methanol (100 mL) under nitrogen atmosphere, and then Pd / C (500 mg, 4.70 mmol) was added, replaced by hydrogen, and reacted at room temperature for 8 hours. After the reaction was completed as monitored by LCMS, methanol was added for dilution, filtered on diatomite, and the filtrate was concentrated to obtain the product Int 7-4 (3.6 g, 8.69 mmol) in crude form. MS (ESI): m / z = 415.2 [M+H] + .

[0642] Step four: synthesis of compound Int 7-5

[0643] Compound Int 7-4 (2.6 g, 6.49 mmol) was dissolved in methanol (50 mL) under nitrogen atmosphere, and then Raney nickel (260.00 mg, 4.43 mmol) was added, replaced by hydrogen, and then heated to 60 °C for 4 hours. After the reaction was completed as monitored by LCMS, methanol was added for dilution, filtered, and the filtrate was concentrated under reduced pressure to obtain Int 7-5 (2.8 g) in crude form, MS (ESI): m / z = 419.2 [M+H] + .

[0644] Step five: synthesis of compound Int 7-6

[0645] Compound Int 7-5 (2.8 g, 6.69 mmol) was dissolved in methanol (50 mL) at room temperature, potassium carbonate (2.77 g, 20.07 mmol) was added, stirred at room temperature for 2 hours, the reaction was monitored to be completed by LCMS, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated to give a residue, the residue was purified by reverse phase to give compound Int 7-6 (2.46 g, 6.61 mmol). MS (ESI): m / z = 373.2 [M+H] + .

[0646] Step six: synthesis of compound Int 7

[0647] Int 7-6 (500 mg, 1.34 mmol) was dissolved in DCM (5 mL) at room temperature, then NBS (227.02 mg, 1.28 mmol) was added, and the reaction was carried out for 2 h, the product was monitored by LCMS, the reaction mixture was diluted with H2O and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The product Int 7 (350 mg, 775.53 μmol) was obtained by reverse phase preparation purification. MS (ESI): m / z = 451.1 [M+H] + .

[0648] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (t, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.35-7.26 (m, 2H), 7.05-7.01 (m, 1H), 7.00 (s, 1H), 4.55-4.45 (m, 1H), 4.23 (d, J = 5.4 Hz, 2H), 3.17-3.08 (m, 2H), 2.97-2.89 (m, 2H), 2.85 (t, J = 8.4 Hz, 2H), 2.63-2.56 (m, 2H), 2.09-1.99 (m, 2H), 1.87-1.76 (m, 2H).

[0649] Preparation of intermediate 8: synthesis of 8-bromo-2-methyl-7-(oxetan-3-ylamino)- 1,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (compound Int 8)

[0650] ​Compound Int 6 (1.5 g, 4.8 mmol) and sodium hydride (60% wt, 0.43 g, 11.0 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 0 °C for 1 h, then iodomethane (0.75 g, 5.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. When the reaction was completed, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The obtained crude was purified by flash column chromatography on silica gel to give Int 8 (0.5 g). MS (ESI): m / z = 325.0 [M+H] + .

[0651] 1 H NMR (400 MHz, DMSO-d6) δ 7.34 (s, 1H), 6.17 (s, 1H), 5.63 (s, 1H), 4.86-4.74 (m, 2H), 4.55-4.45 (m, 3H), 4.40 (s, 2H), 2.93-2.86 (m, 2H), 2.86-2.80 (m, 3H), 2.77-2.71 (m, 2H).

[0652] Example 1: Synthesis of 3-[4-(2,4-difluorophenoxy)-1-piperidinyl]-2-(isopropylamino)- 6,7-dihydropyrrolo[3,4-b]pyrazin-5-one (Compound 1)

[0653] Step one: Synthesis of Compound 1-03

[0654] To a solution of 3,5-dichloropyrazine-2-carbonitrile (3 g, 17.24 mmol) in DMF (30 mL) was added DIPEA (3.57 g, 27.59 mmol, 4.81 mL) and 4-(2,4-difluorophenoxy)piperidine (4.41 g, 20.69 mmol) at 0 °C and stirred for 2 h. The reaction was monitored by TLC (n-Heptane: ethyl acetate = 3:1) which showed the starting material was consumed. The crude was purified by flash column chromatography (eluent: n-Heptane / ethyl acetate gradient elution) to give Compound 1-03 (6 g), MS (ESI): m / z = 351.1 [M+H] + .

[0655] Step two: Synthesis of Compound 1-04

[0656] Compound 1-03 (1.7 g, 4.85 mmol) was added into methanol (30 mL), Pd(dppf)Cl2(709.28 mg, 969.35 μmol) and triethylamine (1.47 g, 14.54 mmol, 2.02 mL) were added, carbon monoxide was replaced for 3 times and then pressurized to 1 MPa, the temperature was increased to 90 °C, and the reaction was carried out for 12 hours. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely reacted. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), and compound 1-04 (830 mg) was obtained when the methanol volume fraction was from 0 to 4%, MS (ESI): m / z = 375.1 [M+H] + .

[0657] Step three: synthesis of compound 1-05

[0658] Compound 1-04 (830 mg, 2.22 mmol) was added into methanol (20 mL), and Raney Ni (390.41 mg) was added, hydrogen gas was replaced, and the reaction was carried out for 12 hours under the condition of 0.1 MPa. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely reacted. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), and the target compound 1-05 (40 mg) was obtained when the methanol volume fraction was from 0 to 8%, MS (ESI): m / z = 347.1 [M+H] + .

[0659] Step four: synthesis of compound 1-06

[0660] Compound 1-05 (40 mg, 115.50 μmol) was added into CHCl3(1.5 mL), and NBS (30.83 mg, 173.24 μmol) was added, and the reaction was carried out for 3 hours at room temperature. LCMS showed that the starting material was completely converted to the product. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely reacted. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), and compound 1-06 (40 mg) was obtained when the methanol volume fraction was from 0 to 10%, MS (ESI): m / z = 425.0 / 427.0 [M+H] + .

[0661] Step five: synthesis of compound 1

[0662] In a microwave tube, compound 1-06 (30 mg, 70.55 pmol) was added into DMSO (1.5 mL), isopropylamine (12.51 mg, 211.65 pmol), DIPEA (27.35 mg, 211.65 pmol), 130 °C for 1 h. LCMS showed the starting material was completely converted to product. The crude product was prepared by Pre-HPLC to get compound 1 (4.5 mg, 11.15 pmol). MS (ESI): m / z = 404.2 [M+H] + .

[0663] 1 H NMR (400 MHz, DMSO) d 8.18 (s, 1H), 7.37 - 7.26 (m, 2H), 7.07 - 6.98 (m, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.60 - 4.52 (m, 1H), 4.31 - 4.22 (m, 1H), 4.14 (s, 2H), 3.31 - 3.24 (m, 2H), 2.97 - 2.88 (m, 2H), 2.15 - 2.08 (m, 2H), 1.98 - 1.87 (m, 2H), 1.23 (d, J = 6.5 Hz, 6H).

[0664] Example 2: Synthesis of 3-[4-(2,4-difluorophenoxy)-1-piperidinyl]-2-(isopropylamino)- 5,6-dihydropyrrolo[3,4-b]pyrazin-7-one (Compound 2)

[0665] Step one: Synthesis of compound 2-02

[0666] To a solution of compound 2-01 (1.0 g, 5.48 mmol) in DMF (10 mL) was added DIPEA (1.91 g, 14.7 mmol, 2.68 mL) and isopropylamine (0.48 g, 7.74 mmol, 0.68 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was monitored by TLC (n-Heptane / Ethyl acetate = 3:1) and LCMS. The crude product was purified by flash column chromatography (eluent: n-Heptane / Ethyl acetate gradient elution) to give compound 2-02 (1.0 g).

[0667] Step two: Synthesis of compound 2-03

[0668] Compound 2-02 (2 g, 10.17 mmol) was added into methanol (20 mL), then Pd(dppf)Cl2(372 mg, 508.55 μmol) and triethylamine (3.09 g, 30.51 mmol) were added, CO was replaced, and the pressure was increased to 1 MPa, and the reaction was carried out at 90 °C for 12 hours. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely reacted, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), to obtain compound 2-03 (930 mg, 4.22 mmol) at a methanol volume ratio of 0 to 4%, MS (ESI): m / z = 221.1 [M+H] + .

[0669] Step three: synthesis of compound 2-04

[0670] Compound 2-03 (930 mg, 4.22 mmol) was dissolved in methanol (20 mL), and then Raney nickel (701.4 mg) was added, hydrogen was replaced, and the reaction was carried out at 0.1 MPa overnight. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to obtain compound 2-04 (290 mg) at a methanol volume ratio of 0 to 8%, MS (ESI): m / z = 193.1 [M+H] + .

[0671] Step four: synthesis of compound 2-05

[0672] Compound 2-04 (50 mg, 260.12 μmol) was dissolved in CHCl3(1 mL) under ice bath, and then NBS (55.56 mg, 312.15 μmol) was added, and the reaction was carried out at room temperature for 2 h. TLC (DCM:MeOH = 10:1) showed that the starting material was completely converted, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to obtain compound 2-05 (27 mg) at a methanol volume ratio of 0 to 8%, MS (ESI): m / z = 271.1 [M+H] + .

[0673] Step five: synthesis of compound 2

[0674] Compound 2-05 (27 mg, 99.59 μmol) was dissolved in DMF (1 mL), and then cesium carbonate (58.41 mg, 179.26 μmol) and 4-(2,4-difluorophenoxy)piperidine (25.48 mg, 119.51 μmol) were added, and the temperature was increased to 95 °C, and the reaction was carried out for 12 hours. LCMS showed that the starting material was completely converted, and the product was generated. The crude product was purified by Pre-HPLC to obtain compound 2 (1 mg). MS (ESI): m / z = 404.2 [M+H] + .

[0675] 1 H NMR (400 MHz, CDC13) δ 6.99 - 6.91 (m, 1H), 6.85 - 6.77 (m, 1H), 6.76 - 6.70 (m, 1H), 6.28 (s, 1H), 4.77 (d, J = 7.6 Hz, 1H), 4.41 - 4.29 (m, 2H), 4.23 (s, 2H), 3.48 - 3.40 (m, 2H), 3.05 - 2.95 (m, 2H), 2.11 - 2.03 (m, 2H), 1.99 - 1.87 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H).

[0676] Example 3: Synthesis of 3-[4-(2,4-difluorophenoxy)-1-piperidinyl]-2-(isopropylamino)- 6,8-dihydro-5H-pyrido[3,4-b]pyrazin-7-one (Compound 4)

[0677] Step one: Synthesis of compound 3-01

[0678] Compound 3-01 (3.2 g, 10.95 mmol) was added into methanol (9.94 mL) at room temperature, then Raney nickel (642.58 mg) was added, hydrogen was replaced for 3 times, and the reaction was carried out under 0.1 MPa for 12 hours. TLC (DCM:MeOH = 10:1) showed that the starting material was completely reacted, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), to obtain compound 3-02 (1.9 g) at methanol volume ratio from 0 to 7%, MS (ESI): m / z = 265.1 [M+H] + .

[0679] Step two: Synthesis of compound 3-02

[0680] Compound 3-01 (3.2 g, 10.95 mmol) was added into methanol (9.94 mL) at room temperature, then Raney nickel (642.58 mg) was added, hydrogen was replaced for 3 times, and the reaction was carried out under 0.1 MPa for 12 hours. TLC (DCM:MeOH = 10:1) showed that the starting material was completely reacted, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), to obtain compound 3-02 (1.9 g) at methanol volume ratio from 0 to 7%, MS (ESI): m / z = 265.1 [M+H] + .

[0681] Step three: Synthesis of compound 3-03

[0682] To a solution of compound 3-02 (500 mg, 1.89 mmol) in methanol (5 mL) was added lithium hydroxide monohydrate (476.35 mg, 11.35 mmol). The reaction was heated to reflux for 4 hours, then cooled to room temperature. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely consumed, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 3-03 (36 mg) at methanol volume ratio from 0 to 10%, MS (ESI): m / z = 207.1 [M+H] + .

[0683] Step four: synthesis of compound 3-04

[0684] Compound 3-03 (36 mg, 174.55 μmol) was added to CHCl3(1 mL), then NBS (46.60 mg, 261.83 μmol) was added, and the reaction was allowed to proceed for 3 hours. TLC (DCM:MeOH = 10:1) monitoring showed that the starting material was completely consumed, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 3-04 (50 mg) at methanol volume ratio from 0 to 10%.

[0685] Step five: synthesis of compound 4

[0686] Compound 3-04 (10 mg, 35.07 μmol) was added to DMSO (1 mL) at room temperature, then 4-(2,4-difluorophenoxy)piperidine (1-02) (11.22 mg, 52.61 μmol) was added, and the reaction was allowed to proceed for 3 hours under microwave. LCMS showed that the starting material was completely converted to the product. The crude product was prepared by Pre-HPLC to give trifluoroacetate salt of compound 4 (1.5 mg). MS (ESI): m / z = 418.1 [M+H] + .

[0687] 1 H NMR (400 MHz, DMSO) δ 7.94 (s, 1H), 7.35-7.23 (m, 2H), 7.05-6.98 (m, 1H), 5.63 (d, J = 8.0 Hz, 1H), 4.57-4.47 (m, 1H), 4.21-4.18 (m, 2H), 4.18-4.08 (m, 1H), 3.37-3.33 (m, 2H), 3.29 -3.23 (m, 2H), 2.92-2.83 (m, 2H), 2.13-2.01 (m, 2H), 1.94-1.81 (m, 2H), 1.19 (d, J = 6.6 Hz, 6H). 19F NMR (376 MHz, DMSO) d -73.42, -119.42, -128.82.

[0688] Example 4: Synthesis of 3-[4-(2,4-difluorophenoxy)-1-piperidinyl]-2-(isopropylamino)- 5,6,8,9-tetrahydropyrazino[2,3-c]azepine-7-one (Compound 5)

[0689] Step one: Synthesis of compound 4-02

[0690] Compound 2-02 (2 g, 10.07 mmol) and (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)prop-2-enoic acid ethyl ester (2.73 g, 12.08 mmol) were dissolved in 1,4-dioxane (20 mL) and H2O (2 mL), after nitrogen replacement, tetra-triphenylphosphine palladium (2.33 g, 2.01 mmol) and K2CO3 (2.78 g, 20.14 mmol) were added, after nitrogen replacement, the reaction was heated to 80 °C for 12 hours. TLC (n-heptane: ethyl acetate = 1:1) monitoring showed that the starting material was completely consumed, the crude product was purified by flash column chromatography (eluent: n-heptane / ethyl acetate gradient elution), when the volume ratio of ethyl acetate was from 0 to 55%, compound 4-02 (1 g) was obtained. MS (ESI): m / z = 278.1 [M+NH4] + .

[0691] Step two: Synthesis of compound 4-03

[0692] Compound 4-02 (1 g, 3.84 mmol) was dissolved in ethanol (30 mL), palladium on carbon (761.04 mg) was added, after hydrogen replacement, the reaction was carried out for 24 hours. TLC (DCM: MeOH = 10:1) monitoring showed that the starting material was completely consumed, the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), when the volume ratio of methanol was from 0 to 5%, compound 4-03 (220 mg) was obtained. MS (ESI): m / z = 263.1 [M+H] + .

[0693] Step three: Synthesis of compound 4-04

[0694] ​Compound 4-03 (220 mg, 838.71 μmol) was dissolved in methanol (2 mL) and then added Raney nickel (96.00 mg, 1.64 mmol) and tert-butyloxycarbonyl tert-butyl carbonate (399.37 mg, 1.83 mmol, 419.95 μL). After hydrogen replacement, the reaction was carried out at 0.4 MPa for 12 hours. LCMS showed that the starting material was completely converted to the product. Filtration and concentration of the filtrate gave the crude compound 4-04 (320 mg). MS (ESI): m / z = 367.2 [M+H] + .

[0695] Step four: synthesis of compound 4-05

[0696] Compound 4-04 (320 mg, 873.23 μmol) was added to DCM (3 mL) and then 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added. The reaction was carried out for 1 hour. TLC (DCM:MeOH = 10:1) showed that the starting material was completely converted to the product. After water washing with saturated sodium bicarbonate solution, extraction with DCM:MeOH = 10:1 and concentration of the organic phase, the crude compound 4-05 (300 mg) was obtained. MS (ESI): m / z = 267.2 [M+H] + .

[0697] Step six: synthesis of compound 4-06

[0698] Compound 4-05 (300 mg, 1.13 mmol) was dissolved in methanol (2 mL) and then potassium carbonate (467.02 mg, 3.38 mmol) was added. The reaction was carried out at room temperature for 3 hours. LCMS showed that the starting material was completely converted to the product. TLC (DCM:MeOH = 10:1) showed that the starting material was completely converted to the product. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 4-06 (150 mg) at a methanol volume ratio of 0 to 10%. MS (ESI): m / z = 253.2 [M+MeOH+H] + .

[0699] Step seven: synthesis of compound 4-07

[0700] Compound 4-06 (40 mg, 181.60 μmol) was dissolved in CHCl3(1 mL) under ice-bath, then NBS (48.48 mg, 272.39 μmol) was added, the reaction was carried out for 1.5 h. TLC (DCM:MeOH=10:1) showed the starting material was consumed completely, the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), when the volume ratio of methanol was from 0 to 10%, compound 4-07 (50 mg) was obtained, MS (ESI): m / z = 299.0 / 301.1 [M+H] + .

[0701] Step eight: synthesis of compound 5

[0702] Compound 4-07 (20 mg, 66.85 μmol) was dissolved in DMF (1 mL), 4-(2,4- difluorophenoxy)piperidine (17.11 mg, 80.22 μmol) and cesium carbonate (39.21 mg, 120.33 μmol) were added, the reaction was carried out at 130 °C for 12 h. LCMS showed the starting material was consumed completely, the product was generated. The crude product was prepared by Pre-HPLC to obtain compound 5 (5.3 mg). MS (ESI): m / z = 432.2 [M+H] + .

[0703] 1 H NMR (400 MHz, DMSO) δ 7.91 (t, J = 5.6 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.05 - 6.97 (m, 1H), 5.52 (d, J = 8.0 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.18 (d, J = 5.6 Hz, 2H), 4.15 - 4.05 (m, 1H), 3.29 - 3.20 (m, 2H), 2.92 - 2.80 (m, 4H), 2.70 - 2.63 (m, 2H), 2.10 - 2.00 (m, 2H), 1.93 - 1.81 (m, 2H), 1.17 (d, J = 6.6 Hz, 6H).

[0704] Example 5: Synthesis of 2-[4-(2,4-difluorophenoxy)-1-piperidinyl]-3-(isopropylamino)- 5,6,8,9-tetrahydropyrazino[2,3-c]azepin-7-one (compound 6)

[0705] Step one: synthesis of compound 5-01

[0706] ​Compound 1-03 (3 g, 8.50 mmol), compound 4-01 (2.31 g, 10.21 mmol), potassium carbonate (2.35 g, 17.01 mmol) and Pd(dppf)Cl2(1.24 g, 1.70 mmol) were added to a three-necked flask, which was replaced with nitrogen three times, and then 1,4-dioxane (30 mL) and H2O (3 mL) were added and heated to 80 °C, and the reaction was carried out for 12 h. TLC (n-heptane: ethyl acetate = 1:1) showed that the starting material was completely consumed. The crude product was purified by flash column chromatography (eluent: n-heptane / ethyl acetate gradient elution), and compound 5-01 (3.1 g) was obtained when the volume ratio of ethyl acetate was from 0 to 50%.

[0707] Step two: synthesis of compound 5-02

[0708] Compound 5-01 (3.1 g, 4.80 mmol) was added to ethanol (50 mL) at room temperature, and then 10% palladium-carbon (1.00 g) was added, and the reaction was carried out under hydrogen replacement at 0.1 MPa for 12 h. TLC (DCM:MeOH = 10:1) showed that the starting material was completely consumed. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), and compound 5-02 (1.86 g) was obtained when the volume ratio of methanol was from 0 to 10%, MS (ESI): m / z = 417.1 [M+H] + .

[0709] Step three: synthesis of compound 5-03

[0710] Compound 5-02 (1.86 g, 4.45 mmol) was added to methanol (90 mL) at room temperature, and then Raney nickel (260.90 mg) and tert-butyloxycarbonyl tert-butyl carbonate (970.13 mg, 4.45 mmol) were added, and the reaction was carried out under hydrogen replacement at a pressure of 0.4 MPa for 16 h. TLC (DCM:MeOH = 10:1) showed that the starting material was completely consumed, and the crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution), and compound 5-03 (3 g) was obtained when the volume ratio of methanol was from 0 to 10%, MS (ESI): m / z = 521.2 [M+H] + .

[0711] Step four: synthesis of compound 5-04

[0712] Compound 5-03 (2 g, 3.84 mmol) was added into DCM (14.00 mL) under ice bath, then 2,2,2-trifluoroacetic acid (20.72 g, 181.72 mmol, 14.00 mL) was added. The reaction was stirred for 2 hours. TLC (DCM:MeOH = 10:1) showed the starting material was consumed completely. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 5-04 (712 mg) at methanol volume ratio from 0 to 10%, MS (ESI): m / z = 421.2 [M+H] + .

[0713] Step five: synthesis of compound 5-05

[0714] Compound 5-04 (712 mg, 1.69 mmol) was added into methanol (9.80 mL) at room temperature, then potassium carbonate (1.17 g, 8.47 mmol) was added. The reaction was stirred for 8 hours. TLC (DCM:MeOH = 10:1) showed the starting material was consumed completely. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give product compound 5-05 (250 mg) at methanol volume ratio from 0 to 10%, MS (ESI): m / z = 375.2 [M+H] + .

[0715] Step six: synthesis of compound 5-06

[0716] Compound 5-05 (150 mg, 400.66 μmol) was added into CHCl3(1 mL) at room temperature, then NBS (106.97 mg, 600.99 μmol) was added. The reaction was stirred for 3 hours. TLC (DCM:MeOH = 10:1) showed the starting material was consumed completely. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 5-06 (100 mg) at methanol volume ratio from 0 to 10%, MS (ESI): m / z = 453.0 / 455.0 [M+H] + .

[0717] Step seven: synthesis of compound 6

[0718] Compound 5-06 (100 mg, 220.61 μmol) was added into DMSO (1 mL) at room temperature, then DIPEA (85.54 mg, 661.84 μmol) and isopropylamine (26.08 mg, 441.23 μmol) were added. The reaction was stirred for 3 hours under microwave. LCMS showed the starting material was consumed completely and the product was generated. The crude product was purified by Pre-HPLC to give compound 6 (1.5 mg). MS (ESI): m / z = 431.49 [M+H]+ .

[0719] 1 H NMR (400 MHz, DMSO) δ 7.87 (t, J = 5.6 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.06 - 6.97 (m, 1H), 5.45 (d, J = 8.0 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.20 (d, J = 5.6 Hz, 2H), 4.15 - 4.06 (m, 1H), 3.32 - 3.23 (m, 4H), 2.90 - 2.81 (m, 2H), 2.70 - 2.63 (m, 2H), 2.11 - 2.00 (m, 2H), 1.90 - 1.78 (m, 2H), 1.18 (d, J = 6.6 Hz, 6H).

[0720] Example 6: Synthesis of 3-[4-(2,4-difluorophenoxy)-1-piperidinyl]-6- isopropyl-2-(isopropylamino)-8,9-dihydro-5H-pyrazino[2,3-c]azepin-7-one (Compound 8)

[0721] Step one: Synthesis of compound 6-01

[0722] Sodium hydride (14.5 mg, 363.19 μmol) was added to DMF (1 mL) under nitrogen atmosphere at 0 °C, compound 4-06 (40 mg, 181.60 μmol) was added and reacted for 0.5 h, then 2-iodopropane (34 mg, 199.75 μmol) was added and the temperature was raised to 60 °C for 2 h. TLC (DCM:MeOH = 10:1) showed the reaction was complete. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 6-01 (20 mg) at methanol volume ratio from 0 to 7%, MS (ESI): m / z = 263.2 [M+H] + .

[0723] Step two: Synthesis of compound 6-02

[0724] Compound 6-01 (20 mg, 76.23 μmol) was added to CHCI3(1 mL) at room temperature, NBS (20.4 mg, 114.35 μmol) was added and reacted for 4 h. TLC (DCM:MeOH = 10:1) showed the reaction was complete. The crude product was purified by flash column chromatography (eluent: DCM / MeOH) to give product compound 6-02 (20 mg) at methanol volume ratio from 0 to 6%, MS (ESI): m / z = 341.0 / 343.0 [M+H]​+ .

[0725] Step three: synthesis of compound 8

[0726] Compound 6-02 (20 mg, 58.61 μmol) was added into DMF (1 mL), then 4-(2,4-difluorophenoxy)piperidine (1-02) (18.8 mg, 87.91 μmol) and cesium carbonate (57.3 mg, 175.83 μmol) were added, and the mixture was warmed to 130 °C by microwave for 1 h. LCMS showed the starting material was completely converted to the product. The crude product was purified by Pre-HPLC to give compound 8 (4.7 mg).

[0727] MS (ESI): m / z = 474.2 [M+H] + , 1 H NMR (400 MHz, DMSO) δ 7.36 - 7.23 (m, 2H), 7.06 - 6.95 (m, 1H),

[0728] 5.54 (d, J = 8.0 Hz, 1H), 4.72 - 4.61 (m, 1H), 4.58 - 4.47 (m, 1H), 4.34 (s, 2H), 4.14 - 4.02 (m, 1H), 3.31 - 3.20 (m, 2H), 2.93 - 2.82 (m, 4H), 2.83 - 2.74 (m, 2H), 2.11 - 2.00 (m, 2H), 1.92 - 1.79 (m, 2H), 1.16 (d, J = 6.5 Hz, 6H), 0.95 (d, J = 6.8 Hz, 6H).

[0729] Example 7: Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-2-(isopropylamino)-6-methyl-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 7)

[0730] Step one: synthesis of compound 7-01

[0731] ​Sodium hydride (14.53 mg, 19 μmol) was added to DMF (2 mL) at 0 °C under nitrogen atmosphere, compound 4-06 (40 mg, 181.60 μmol) was added and the reaction was stirred for 0.5 h, then iodomethane (51.6 mg, 363.19 μmol) was added and the reaction was stirred at 60 °C for 2 h. TLC (DCM:MeOH = 10:1) monitoring showed the reaction was complete. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 7-01 (20 mg) at methanol volume ratio from 0 to 7%, MS (ESI): m / z = 235.2 [M+H] + .

[0732] Step two: synthesis of compound 7-02

[0733] Compound 7-01 (20 mg, 85.36 μmol) was added to CHCl3(1 mL) at room temperature, then NBS (22.79 mg, 128.04 μmol, 10.86 μL) was added and the reaction was stirred for 4 h. TLC (DCM:MeOH = 10:1) monitoring showed the reaction was complete. The crude product was purified by flash column chromatography (eluent: DCM / MeOH gradient elution) to give compound 7-02 (10 mg) at methanol volume ratio from 0 to 7%, MS (ESI): m / z = 313.1 [M+H] + .

[0734] Step three: synthesis of compound 7

[0735] Compound 7-02 (10 mg, 31.93 μmol) was added to DMF (1 mL), then 4-(2,4- difluorophenoxy)piperidine (10.2 mg, 47.89 μmol) and cesium carbonate (31.2 mg, 95.79 μmol) were added and the reaction was heated to 130 °C in microwave for 1 h. LCMS monitoring showed the reaction was complete. The crude product was purified by Prep-HPLC to give product compound 7 (1 mg). MS (ESI): m / z = 446.2 [M+H] + .

[0736] 1H NMR (400 MHz, DMSO) δ 7.34 - 7.22 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.54 (t, J = 7.0 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.46 (s, 2H), 4.12 - 4.04 (m, 1H), 3.30 - 3.23 (m, 2H), 2.91 (s, 3H), 2.89 - 2.85 (m, 2H), 2.84 - 2.78 (m, 2H), 2.61 - 2.56 (m, 2H), 2.13 - 2.03 (m, 2H), 1.92 - 1.81 (m, 2H), 1.17 (d, J = 6.6 Hz, 6H).

[0737] Example 8: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 9-A)

[0738] Intermediate Int 1 (35 mg, 106.98 μmol) and compound 1-02 (34.2 mg, 160.46 μmol) were dissolved in DMF (1 mL), then cesium carbonate (104.6 mg, 320.93 μmol) was added, and the mixture was subjected to microwave reaction at 130 °C for 1 h. LC-MS detection showed that the reaction was complete. After dilution with water, the ethyl acetate extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a residue. The residue was purified by Prep-HPLC to obtain the target product 9-A (14 mg, 30.47 μmol). MS (ESI): m / z = 460.2 [M+H] + .

[0739] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (t, J = 5.6 Hz, 1H), 7.36 - 7.22 (m, 2H), 7.06 - 6.96 (m, 1H), 5.89 (d, J = 6.2 Hz, 1H), 4.55 - 4.46 (m, 1H), 4.43 - 4.35 (m, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.93 - 3.79 (m, 2H), 3.70 (td, J = 8.0, 6.2 Hz, 1H), 3.53 (dd, J = 8.8, 4.8 Hz, 1H), 3.28 - 3.24 (m, 2H), 2.95 - 2.83 (m, 4H), 2.72 - 2.63 (m, 2H), 2.22 - 2.12 (m, 1H), 2.09 - 2.01 (m, 2H), 1.99 - 1.82 (m, 3H).​

[0740] Example 9: Synthesis of (R)-3-(4-(2,4-difluorobenzyl)piperazin-l-yl)-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7- one (Compound 46-R)

[0741] Step one: Synthesis of compound 9-02

[0742] 9-01 (500 mg, 3.52 mmol) was added into DCM (5 mL) at room temperature, then triethylamine (1.07 g, 10.56 mmol) was added, and the reaction was continued for 30 minutes before sodium triacetoxyborohydride (2.24 g, 10.56 mmol) was added, and the reaction was continued for 12 hours. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The crude product was purified by flash column chromatography (eluent: n-heptane / ethyl acetate system gradient elution) to give compound 9-02 (1 g, 3.20 mmol) at ethyl acetate volume ratio from 0% to 30%, MS (ESI): m / z = 313.2 [M+H] + .

[0743] Step two: Synthesis of compound 9-03.

[0744] 9-02 (200 mg, 640.3 μmol) was added into DCM (3 mL) at ice bath, then 2,2,2-trifluoroacetic acid (1.48 g, 12.98 mmol, 1 mL) was added, and the reaction was continued for 2 hours. LCMS showed that the starting material was completely consumed. The crude product was concentrated and purified by flash column chromatography (eluent: DCM / MeOH system gradient elution) to give target compound 9-03 (300 mg) at methanol volume ratio from 0% to 7%, MS (ESI): m / z = 213.1 [M+H] + .

[0745] Step three: Synthesis of compound 46-R.

[0746] ​(R)-3-bromo-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H- pyrazino[2,3-c]azepin-7-one (25 mg, 76.41 μmol) and compound 9-03 (81.09 mg, 382.06 μmol) were added into DMF (1 mL), then cesium carbonate (248.96 mg, 764.11 μmol) was added, and the mixture was heated to 130 °C for 1 h. LCMS showed the starting material was completely converted to the product. Prep-HPLC purification gave compound 46-R (1.2 mg). MS (ESI): m / z = 459.2 [M+H] + .

[0747] 1 H NMR (400 MHz, DMSO) δ 7.92 (t, J = 5.6 Hz, 1H), 7.47 (dd, J = 15.6, 8.6 Hz, 1H), 7.28 - 7.15 (m, 1H), 7.08 (td, J = 8.6, 2.4 Hz, 1H), 5.76 (d, J = 6.2 Hz, 1H), 4.37 (td, J = 11.3, 6.0 Hz, 1H), 4.19 (d, J = 5.8 Hz, 2H), 3.91 - 3.79 (m, 2H), 3.74 - 3.64 (m, 1H), 3.59 (s, 2H), 3.53 (dd, J = 8.8, 4.6 Hz, 1H), 3.07 - 2.95 (m, 4H), 2.93 - 2.95 (m, 2H), 2.70 - 2.63 (m, 2H), 2.61 - 2.54 (m, 4H), 2.21 - 2.09 (m, 1H), 1.96 - 1.84 (m, 1H).

[0748] Referring to the synthetic method of Example 7, the following compound can be prepared by replacing the starting material compound 4-06 used in Example 7 with the following fragment:

[0749] Example 11: Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(2- hydroxyethyl)-2-(isopropylamino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (compound 12)

[0750] Step one: Synthesis of compound 11-1

[0751] ​Sodium hydride (21.79 mg, 907.98 umol) was dissolved in DMF (2 mL) solution, replaced by N2 for 3 times, compound 4-06 (100 mg, 453.99 umol) was added, stirred at 60 °C for 12 hr. LCMS detected that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The mixture was purified by column chromatography to give compound 11-1 (25 mg, 94.58 umol). MS (ESI): m / z = 265.1 [M+H] + .

[0752] Step two: synthesis of compound 11-2

[0753] Compound 11-1 (25 mg, 94.58 umol) was dissolved in CHCl3(1 mL) under ice bath and N2 protection, then NBS (25.25 mg, 141.87 umol) was added, reacted at room temperature for 3 hr. LCMS detected that the reaction was complete. The mixture was purified by column chromatography to give 11-2 (22 mg, 64.10 umol). MS (ESI): m / z = 343.1 [M+H] + .

[0754] Step three: synthesis of compound 12

[0755] Compound 11-2 (12 mg, 34.96 umol) was dissolved in DMF (1 mL) under nitrogen protection, then cesium carbonate (34.17 mg, 104.89 umol), 4-(2,4-difluorophenoxy)piperidine (8.95 mg, 41.95 umol) were added, and the mixture was heated to 130 °C in a microwave reactor for 1 hr. LCMS detected that the reaction was complete. The reaction mixture was purified by reverse phase preparation to give compound 12 (0.6 mg, 1.26 umol). MS (ESI): m / z = 476.1 [M+H] + .

[0756] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.35-7.25 (m, 2H), 7.06-6.98 (m, 1H), 5.54 (d, J = 8.0 Hz, 1H), 4.64 (s, 1H), 4.56-4.45 (m, 3H), 4.14-4.02 (m, 1H), 3.25-3.24 (m, 3H), 2.93-2.83 (m, 4H), 2.83-2.73 (m, 2H), 2.13-1.99 (m, 3H), 1.94-1.79 (m, 3H), 1.17 (d, J = 6.4 Hz, 6H).

[0757] Example 12: Synthesis of (R)-2-(4-(2,4-difluorophenoxy)piperidin-l-yl)-3-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-c]azepin-7-one (Compound 60-R)

[0758] Step one: Synthesis of compound 12-2

[0759] Compound 12-1 (3 g, 14.93 mmol), (R)-3-aminotetrahydrofuran (2.21 g, 17.91 mmol) and DIPEA (3.86 g, 29.85 mmol) were dissolved in DMF (7 mL) and warmed to 90 °C for 12 hr. LCMS was used to detect the completion of the reaction. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified using normal phase (PE / ethyl acetate system) and purified by column chromatography to get compound 12-2 (3.89 g, 14.5 mmol). MS [ESI]: m / z = 269.1 [M+H] + .

[0760] Step two: Synthesis of compound 12-3

[0761] Compound 12-2 (3.89 g, 14.5 mmol), Pd(dppf)Cl2(1.09 g, 1.49 mmol) and K2C03(3.09 g, 22.38 mmol) were taken in a 100 mL reaction flask under nitrogen protection, dissolved in 1,4-dioxane (40 mL) and stirred, 2-(ethoxycarbonyl)vinyl acetate (2.02 g, 8.95 mmol) and H20 (4 mL) were added, after nitrogen replacement, warmed to 95 °C for 20 hr. LC-MS was used to detect the completion of the reaction, and the heating was stopped. The reaction mixture was diluted with H20 (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the product compound 12-3 (2.03 g, 7.1 mmol) was obtained by column chromatography. MS [ESI]: m / z = 288.1 [M+H] + .

[0762] Step three: Synthesis of compound 12-4

[0763] ​Compound 12-3 (1.3 g, 4.52 mmol) was dissolved in EtOH (30 mL) and DCM (10 mL), after stirring to dissolve, Pd / C (130 mg, 0.1 eq) was added, after H2 replacement, the reaction was carried out at room temperature for 12 h. LCMS detection showed that the raw material was completely reacted, the reaction solution was filtered through diatomite, washed with methanol, concentrated under reduced pressure, and the product compound 12-4 (760 mg, 2.6 mmol) was obtained by column chromatography. MS [ESI]: m / z = 290.1 [M+H] + .

[0764] Step four: synthesis of compound 12-5

[0765] Compound 12-4 (600 mg, 2.07 mmol) was dissolved in methanol (20 mL) under a nitrogen atmosphere, and then Raney Ni (60 mg, 0.1 eq) was added, and hydrogen replacement was carried out at 60°C for 8 h. LCMS detection showed that the reaction was complete, the reaction solution was filtered through diatomite, washed with methanol, concentrated under reduced pressure, and compound 12-5 (350 mg, 1.42 mmol) was obtained by column chromatography. MS [ESI]: m / z = 248.1 [M+H] + .

[0766] Step five: synthesis of compound 12-6

[0767] Compound 12-5 (350 mg, 1.42 mmol) was dissolved in DCM, and then NBS (71.97 mg, 404.38 μmol,) was added, and the reaction was carried out at room temperature for 3 h. LCMS detection showed that the raw material was completely reacted. The reaction solution was concentrated under reduced pressure, and the product compound 12-6 (50 mg, 153.29 μmol) was obtained by column chromatography. MS [ESI]: m / z = 327.1 [M+H] + .

[0768] Step six: synthesis of compound 60-R

[0769] Compound 12-6 (50 mg, 153.29 μmol) was dissolved in DMSO (1 mL), and then 4-(2,4-difluorophenoxy)piperidine (52.29 mg, 245.26 μmol) and DIPEA (47.55 mg, 367.89 μmol) were added, and the reaction was carried out by microwave heating to 150°C for 1 h. LCMS detection showed that the reaction was complete. The reaction mixture was prepared and purified by Prep-HPLC to obtain compound 60-R (12.8 mg, 27.92 μmol), MS [ESI]: m / z = 459.1 [M+H] + .

[0770] 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 5.4 Hz, 1H), 7.36 - 7.24 (m, 2H), 7.06 - 6.97 (m, 1H), 6.71 (s, 1H), 4.66 (d, J = 6.8 Hz, 1H), 4.52 - 4.44 (m, 1H), 4.21 (d, J = 5.6 Hz, 2H), 4.04 - 3.95 (m, 1H), 3.91 - 3.80 (m, 2H), 3.76 - 3.69 (m, 1H), 3.56 (dd, J = 8.8, 3.6 Hz, 1H), 3.19 (d, J = 6.0 Hz, 2H), 2.95 - 2.88 (m, 2H), 2.88 - 2.76 (m, 2H), 2.66 - 2.60 (m, 2H), 2.25 - 2.15 (m, 1H), 2.10 - 2.00 (m, 2H), 1.88 - 1.76 (m, 3H).

[0771] Example 13: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-2-((tetrahydrofuran-3-yl)amino)-5,6-dihydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 137-R)

[0772] Step one: Synthesis of compound 13-1

[0773] To a flask was added compound Int 1-4 (0.2 g, 0.80 mmol), DMF (2 mL), N- chlorosuccinimide (0.23 g, 1.77 mmol). The temperature was raised to 110 °C and stirred for 4 hr. TLC indicated the reaction was complete, the mixture was allowed to cool to room temperature, ethyl acetate (30 mL*2) and saturated brine (30 mL) were added to extract the mixture. The organic layers were combined, washed with brine (20 mL*1), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 13-1 (0.15 g, 0.53 mmol), MS [ESI]: m / z = 281.2 [M+H] + .

[0774] Step two: Synthesis of compound 137-R

[0775] ​To a microwave tube was added compound 13-1 (0.1 g, 0.35 mmol), DMF (1 mL), cesium carbonate (0.17 g, 0.53 mmol), 4-(2,4-difluorophenoxy)piperidine (91.15 mg, 0.42 mmol). The microwave reactor was then placed under the following microwave conditions: 130 °C, 100 W, for 1 hr. The reaction was checked by LCMS and was complete. Upon cooling to room temperature, ethyl acetate (20 mL*2) and saturated brine (20 mL) were added to the mixture. The organic layers were combined, washed with brine (20 mL*1), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Prep-HPLC purification gave compound 137-R (52 mg, 113.6 μmol). MS [ESI]: m / z = 458.2 [M+H] + .

[0776] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (dt, J = 5.6, 4.0 Hz, 1H), 7.37 - 7.26 (m, 2H), 7.05 - 6.97 (m, 1H), 6.95 (d, J = 12.4 Hz, 1H), 6.19 (dd, J = 12.4, 2.0 Hz, 1H), 6.12 (d, J = 6.0 Hz, 1H), 4.63 - 4.49 (m, 1H), 4.46 - 4.37 (m, 1H), 4.01 - 3.89 (m, 3H), 3.85 (dd, J = 14.8, 8.0 Hz, 1H), 3.76 - 3.67 (m, 1H), 3.57 (dd, J = 8.8, 4.8 Hz, 1H), 3.45 (d, J = 7.2 Hz, 2H), 3.09 - 2.97 (m, 2H), 2.25 - 2.14 (m, 1H), 2.07 (d, J = 6.4 Hz, 2H), 2.01 - 1.82 (m, 3H).

[0777] Example 14: Synthesis of 3-((3S,4S)-4-(2,4-difluorophenoxy)-3-fluoropiperidin-l- yl)-2-(((R)-tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin- 7-one (Compound 138-R)

[0778] Step one: Synthesis of compound 14-2

[0779] ​Compound 14-1 (200 mg, 912.19 pmol), 2,4-difluorophenol (142.40 mg, 1.09 mmol) and triphenylphosphine (717.76 mg, 2.74 mmol) were dissolved in THF (4 mL) under nitrogen atmosphere, sparged with N2for 5 min, then DIAD (553.36 mg, 2.74 mmol) was added to the mixture, stirred at 25 °C for 12 hr, TLC detection showed the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Compound 14-2 (100 mg, 301.81 pmol) was obtained by column chromatography.

[0780] Step two: synthesis of compound 14-3

[0781] Compound 14-2 (100 mg, 301.81 pmol) was dissolved in DCM (1 ml) under ice-bath, then HCl / D0 (0.5 mL, 4 M) was added. It was removed from ice-bath and stirred for 1 h. LC-MS detection showed the reaction was complete. The reaction mixture was adjusted to basic with NaHCO3, diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and Compound 14-3 (67 mg, 289.78 pmol) was obtained by column chromatography. MS [ESI]: m / z = 232.2 [M+H] + .

[0782] Step three: synthesis of compound 138-R

[0783] Compound 14-3 (50.88 mg, 220.06 pmol), compound Int 1 (60 mg, 183.39 pmol), cesium carbonate (119.50 mg, 366.77 pmol), RuPhos PdG3 (15.34 mg, 18.34 pmol) and RuPhos (8.56 mg, 18.34 pmol) were dissolved in DMSO (1 mL) under nitrogen protection, sparged with N2, warmed to 95 °C for 12 hr. LCMS detection showed the reaction was complete. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and Compound 138-R (13.5 mg, 28.27 pmol) was obtained by prep-HPLC. MS [ESI]: m / z = 478.2 [M+H] + .

[0784] 1H NMR (400 MHz, CD3OD) δ 7.30-7.20 (m, 1H), 7.02-6.96 (m, 1H), 6.91-6.84 (m, 1H), 5.04-4.94 (m, 1H), 4.53-4.39 (m, 2H), 4.37 (d, J = 4.8 Hz, 2H), 4.02-3.92 (m, 2H), 3.88-3.79 (m, 1H), 3.68 (dd, J = 9.2, 3.6 Hz, 1H), 3.61-3.50 (m, 1H), 3.49-3.36 (m, 1H), 3.20-3.09 (m, 1H), 3.06-2.99 (m, 2H), 2.96-2.79 (m, 3H), 2.37-2.25 (m, 1H), 2.23-2.13 (m, 1H), 1.99-1.86 (m, 2H).

[0785] Referring to the synthetic method of Example 14, the following compound can be synthesized:

[0786] Example 15: Synthesis of 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-l-yl)-2-(((R)- tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 139-R)

[0787] Step one: Synthesis of compound 15-2

[0788] Compound 15-1 (1 g, 3.07 mmol) was dissolved in MeOH (10 mL) at room temperature, then NaBH4 (255.82 mg, 6.7 mmol) was added, and the reaction was allowed to react at room temperature for 1 hr. The reaction was detected to be complete by LCMS. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15-2 (0.9 g, 2.75 mmol), MS [ESI]: m / z = 328.2 [M+H] + .

[0789] Step two: Synthesis of compound 15-3

[0790] ​Compound 15-2 (0.9 g, 2.75 mmol) was dissolved in DCM (10 mL) under ice bath, then DAST (1.22 g, 5.50 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hr under nitrogen protection. LCMS showed the reaction was completed. The reaction mixture was adjusted to neutral with NaHC03, diluted with H20 (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15-3 (850 mg, 2.58 mmol). MS [ESI]: m / z = 330.2 [M+H] + .

[0791] Step three: synthesis of compound 15-4

[0792] Compound 15-3 (850 mg, 2.58 mmol) was dissolved in DCM (9 mL) under ice bath, then TFA (3 mL) was added, and the reaction mixture was stirred at room temperature for 1 hr. LCMS showed the reaction was completed. The reaction mixture was adjusted to basic with NaHC03, diluted with H20 (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 15-4 (67 mg, 289.78 μmol). MS (ESI): m / z = 230.2 [M+H] + .

[0793] Step four: synthesis of compound 139-R

[0794] Compound Int 2 (50 mg, 176.85 μmol), compound 15-4 (48.65 mg, 212.22 μmol), and Cs2C03(69.15 mg, 212.22 μmol) were dissolved in DMF (1 mL), and the reaction mixture was heated to 130 °C for 3 hrs under microwave. LCMS showed the reaction was completed. The reaction mixture was purified by Prep-HPLC to obtain compound 139-R (1.8 mg, 3.79 μmol). MS [ESI]: m / z = 476.2 [M+H] + .

[0795] 1H NMR (400 MHz, CD3OD) δ 7.54 - 7.45 (m, 1H), 7.08 - 6.97 (m, 2H), 5.57 (d, J = 7.5 Hz, 0.5H), 5.45 (d, J = 7.4 Hz, 0.5H), 4.61 (s, 1H), 4.54 - 4.46 (m, 1H), 4.36 - 4.31 (m, 2H), 4.01 - 3.91 (m, 2H), 3.87 - 3.78 (m, 1H), 3.69 - 3.62 (m, 1H), 3.54 - 3.34 (m, 2H), 3.06 - 2.98 (m, 2H), 2.86 - 2.77 (m, 2H), 2.74 - 2.54 (m, 2H), 2.35 - 2.22 (m, 1H), 2.03 - 1.97 (m, 1H), 1.95 - 1.87 (m, 1H), 1.72 - 1.49 (m, 2H), 1.45 - 1.38 (m, 1H).

[0796] Example 17: (R)-3-(4-(2,5-dichlorobenzyl)piperazin-l-yl)-2-((tetrahydrofuran-3- yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 141-R) synthesis

[0797] Step one: synthesis of compound 17-2

[0798] Compound 17-1 (1 g, 5.37 mmol) was dissolved in DCM (10 mL) at 0 °C, TEA (814.95 mg, 8.05 mmol) was added, stirred for 5 min, then 1,4-dichloro-2- (chloromethyl)benzene (1.05 g, 5.37 mmol) was added, and the reaction was allowed to proceed at room temperature for 4 hr. TLC detected that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 17-2 (1.4 g, 4.05 mmol).

[0799] Step two: synthesis of compound 17-3

[0800] ​Compound 17-2 (1.4 g, 4.05 mmol) was dissolved in DCM (9 mL) under ice bath conditions, followed by the addition of TFA (4 mL). The reaction mixture was reacted at room temperature for 1 h. The reaction was confirmed to be complete by LC-MS. The reaction mixture was adjusted to alkaline pH with NaHCO3, diluted with H2O (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 17-3 (900 mg, 3.67 mmol). MS [ESI]: m / z = 246.2 [M+H] + .

[0801] Step 3: Synthesis of compound 141-R

[0802] Compounds Int 2 (50 mg, 176.85 μmol), 17-3 (52.03 mg, 212.22 μmol), and Cs₂CO₃ (69.15 mg, 212.22 μmol) were dissolved in DMF (1 mL), and the mixture was microwaved to 130 °C for 3 hours. The reaction was confirmed to be complete by LC-MS. The reaction mixture was purified by Prep-HPLC to give compound 141-R (2.1 mg, 4.27 μmol), MS [ESI]: m / z = 491.2 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ7.94(t,J=5.6Hz,1H),7.56(d,J=2.4Hz,1H),7.49(d,J=8.4Hz,1H) ,7.38(dd,J=8.4,2.4Hz,1H),5.79(d,J=6.4Hz,1H),4.43-4.34(m,1H),4.20(d,J=5.6Hz,2 H),3.91-3.80(m,2H),3.71(dd,J=8.0,6.4Hz,1H),3.64(s,2H),3.52(dd,J=8.8,4.4Hz,1H ),3.02(s,4H),2.94-2.86(m,2H),2.71-2.59(m,6H),2.22-2.12(m,1H),1.96-1.87(m,1H).

[0803] Referring to the synthesis method of Example 17, the following compounds can be synthesized:

[0804] Example 19: (R)-3-(4-(2,5-dichlorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]aza Synthesis of 7-one (compound 50-R)

[0805] Step one: Synthesis of compound 19-2

[0806] Compound 19-1 (1 g, 4.97 mmol), 2,5-dichlorophenol (728.91 mg, 4.47 mmol) and triphenylphosphine (3.91 g, 14.91 mmol) were dissolved in THF (10 mL) under nitrogen protection, stirred for 5 min at 0 °C, then DIAD (3.01 g, 14.91 mmol) was added to the mixture, stirred for 12 hr at 25 °C. TLC detection showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 19-2 (1.3 g, 3.75 mmol).

[0807] Step two: Synthesis of compound 19-3

[0808] Compound 19-2 (1.4 g, 4.04 mmol) was dissolved in DCM (10 mL) under ice bath, then TFA (5 mL) was added, and the reaction was carried out at room temperature for 1 hr. LCMS detection showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 19-3 (900 mg, 3.66 mmol). MS [ESI]: m / z = 246.2 [M+H] + .

[0809] Step three: Synthesis of compound 50-R

[0810] Compound 19-3 (52.23 mg, 212.22 umol), compound Int 1 (50 mg, 176.85 umol) and cesium carbonate (69.15 mg, 212.22 umol) were dissolved in DMF (1 mL), and the reaction was carried out in a microwave reaction device at 130 °C for 3 hr. LCMS detection showed that the reaction was complete. The reaction mixture was purified by Preparative-HPLC to obtain compound 50-R (1.7 mg, 3.45 umol). MS [ESI]: m / z = 492.2

[0811] [M+H] + .

[0812] 1H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J = 5.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.4, 2.4 Hz, 1H), 5.95 (d, J = 6.4 Hz, 1H), 4.78 (d, J = 4.0 Hz, 1H), 4.44 - 4.33 (m, 1H), 4.20 (d, J = 5.2 Hz, 2H), 3.93 - 3.80 (m, 2H), 3.76 - 3.65 (m, 1H), 3.53 (dd, J = 8.8, 4.8 Hz, 1H), 3.29 - 3.24 (m, 2H), 2.98 (d, J = 4.0 Hz, 2H), 2.91 - 2.87 (m, 2H), 2.73 - 2.64 (m, 2H), 2.22 - 2.12 (m, 1H), 2.12 - 2.05 (m, 2H), 1.97 - 1.83 (m, 3H).

[0813] Referring to the synthetic method of Example 19, the following compound can be synthesized

[0814] Example 20: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl-4-d)-2-((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 143-R)

[0815] Step one: Synthesis of compound 20-2

[0816] Compound 20-1 (500 mg, 2.51 mmol) was dissolved in MeOH (5 mL) under ice bath, replaced by nitrogen, then sodium borodeuteride (231.09 mg, 5.52 mmol) was added slowly, and the reaction was allowed to warm to room temperature for 4 hr. LCMS showed that the starting material was completely converted. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 20-2 (500 mg, 2.47 mmol). MS [ESI]: m / z = 203.2 [M+H] + .

[0817] Step two: Synthesis of compound 20-3

[0818] ​Compound 20-2 (500 mg, 2.47 mmol), 2,4-difluorophenol (321.58 mg, 2.47 mmol) and triphenylphosphine (972.54 mg, 3.71 mmol) were dissolved in THF (10 mL) under nitrogen protection, stirred at 0 °C for 5 min, DIAD (749.78 mg, 3.71 mmol, 730.06 μL) was added, stirred at 25 °C for 12 hr. TLC detection showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 20-3 (560 mg, 1.78 mmol). MS [ESI]: m / z = 315.2 [M+H] + .

[0819] Step three: synthesis of compound 20-4

[0820] Compound 20-3 (560 mg, 1.78 mmol) was dissolved in DCM (9 mL) under ice bath, then TFA (4 mL) was added, and the reaction was allowed to proceed at room temperature for 1 hr. LCMS detection showed that the reaction was complete, the reaction mixture was adjusted to basic with NaHCO3, diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 20-4 (200 mg, 3.66 mmol). MS [ESI]: m / z = 215.2 [M+H] + .

[0821] Step four: synthesis of compound 143-R

[0822] Compound Int 2 (43.21 mg, 152.82 μmol), 20-4 (39.29 mg, 183.39 μmol) and cesium carbonate (59.75 mg, 183.39 μmol) were dissolved in DMF (1 mL), and the reaction was allowed to proceed at 130 °C for 3 hr in a microwave reaction device. LCMS detection showed that the reaction was complete. The reaction mixture was purified by Prep-HPLC to give compound 143-R (7.6 mg, 16.50 μmol), MS [ESI]: m / z = 461.2 [M+H] + .

[0823] 1H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J = 5.6 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.06 - 6.97 (m, 1H), 5.92 (d, J = 6.4 Hz, 1H), 4.46 - 4.33 (m, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.94 - 3.79 (m, 2H), 3.75 - 3.65 (m, 1H), 3.53 (dd, J = 8.8, 4.8 Hz, 1H), 3.29 - 3.24 (m, 2H), 2.96 - 2.81 (m, 4H), 2.72 - 2.62 (m, 2H), 2.22 - 2.12 (m, 1H), 2.09 - 2.00 (m, 2H), 2.00 - 1.81 (m, 3H).

[0824] Example 21: Synthesis of (R)-3-(4-((2,4-difluorophenyl)difluoromethyl)piperidin-l-yl)-2- ((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 144-R)

[0825] Step one: Synthesis of compound 21-1

[0826] Compound 15-1 (1 g, 3.07 mmol) was dissolved in CHCl3(10 mL) under nitrogen saturation, then BAST (3.40 g, 15.37 mmol) was added, and the temperature was raised to 60 °C for 24 hr. LCMS showed that the starting material was completely converted. The reaction mixture was diluted with H2O (50 mL), the pH was adjusted to 7 with aqueous sodium bicarbonate solution, and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 21-1 (600 mg, 1.73 mmol), MS [ESI]: m / z = 348.2 [M+H] + .

[0827] Step two: Synthesis of compound 21-2

[0828] ​Compound 21-1 (600 mg, 1.73 mmol) was dissolved in DCM (6 mL), and then HCl (1 mL, 4 M) was added, and the reaction was allowed to proceed for 2 hr. LCMS detection showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL), the pH was adjusted to 7 with an aqueous NaHC03 solution, and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude compound 21-2 (300 mg, 1.2 mmol), MS [ESI]: m / z = 248.2 [M+H] + .

[0829] Step three: synthesis of compound 144-R

[0830] Compound Int 2 (50 mg, 176.85 pmol), compound 21-2 (52.47 mg, 212.22 pmol), cesium carbonate (115.24 mg, 353.70 pmol), RuPhos Pd G3 (14.79 mg, 17.68 pmol), RuPhos (8.25 mg, 17.88 pmol) were added into dioxane (2 mL) under nitrogen protection, and the reaction was allowed to proceed at 110 °C for 12 hr. LCMS detection showed that the reaction was complete. The mixture was filtered through celite, and concentrated under reduced pressure to obtain the crude product. Purification by reverse phase preparative purification to obtain the product 144-R (15.2 mg, 30.80 pmol). MS [ESI]: m / z = 494.2 [M+H] + ,

[0831] 1 H NMR (400 MHz, DMSO-d6) d 7.92 (t, J = 5.6 Hz, 1H), 7.62 - 7.54 (m, 1H), 7.51 - 7.43 (m, 1H), 7.28 - 7.20 (m, 1H), 5.92 (d, J = 6.4 Hz, 1H), 4.42 - 4.33 (m, 1H), 4.17 (d, J = 5.6 Hz, 2H), 3.91 - 3.79 (m, 2H), 3.73 - 3.65 (m, 1H), 3.51 (dd, J = 8.8, 4.8 Hz, 1H), 3.46 - 3.39 (m, 2H), 2.91 - 2.83 (m, 2H), 2.70 - 2.62 (m, 2H), 2.63 - 2.52 (m, 2H), 2.38 - 2.26 (m, 1H), 2.21 - 2.08 (m, 1H), 1.98 - 1.87 (m, 1H), 1.80 - 1.60 (m, 4H).

[0832] Example 26: (R)-3-(4-(2,4-difluorophenoxy)piperidin-1-yl)-2-((tetrahydrofuran-3- yl)amino)-5,7,8,9-tetrahydro-6H-pyrazino[2,3-d]azepine Synthesis of 6-ketone (Compound 189-A)

[0833] Step one: Synthesis of compound 26-2

[0834] To the flask was added compound 26-1 (5 g, 21.94 mmol), THF (50 mL), sodium hydride (1.05 g, 43.88 mmol) was added slowly under ice-bath, the reaction was half an hour, then tert-butyl methyl malonate (4.59 g, 26.33 mmol) was added. The temperature was raised to 80 °C, and stirred for 12 hrs. TLC detection reaction was complete, the temperature was recovered to room temperature, ethyl acetate (100 mL*2) and saturated brine (100 mL) were added to extract the mixture. The organic layers were combined, washed with brine (100 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 26-2 (5.2 g, 14.22 mmol), MS [ESI]: m / z = 366.2 [M+H] + .

[0835] Step two: Synthesis of compound 26-3

[0836] To the flask was added compound 26-2 (5.2 g, 14.2 mmol), DCM (50 mL), TFA (5 mL) was added slowly under ice-bath. Then the reaction was carried out at room temperature for 12 hrs. LCMS detection reaction was complete, the reaction liquid was added saturated NaHCO3 to adjust pH to 7-8, then DCM (50 mL*2) and saturated brine (50 mL) were added to extract the mixture. The organic layers were combined, washed with brine (50 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 26-3 (3.3 g, 11.81 mmol), MS [ESI]: m / z = 266.2 [M+H] + .

[0837] Step three: Synthesis of compound 26-4

[0838] To a Schlenk flask was added compound 26-3 (3.3 g, 11.81 mmol), 1,4-dioxane (30 mL), water (3 mL), followed by tert-butyl N-(2-(trifluoroborane)ethyl)carbamate potassium salt (3.75 g, 14.92 mmol), Pd(dppf)2Cl2(909.5 mg, 1.24 mmol), cesium carbonate (8.10 g, 24.86 mmol). After nitrogen replacement, the temperature was raised to 95 °C and stirred for 12 hr. LCMS detection showed the reaction was complete, the reaction was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by column chromatography to give compound 26-4 (2.5 g, 7.58 mmol), MS [ESI]: m / z = 330.2 [M+H] + .

[0839] Step four: synthesis of compound 26-5

[0840] To a flask was added compound 26-4 (2.5 g, 7.58 mmol), DCM (20 mL), HCl / D0 solution (4 mL, 6N) was added slowly under ice bath. Then the reaction was stirred at room temperature for 4 hr. LCMS detection showed the reaction was complete, the reaction was concentrated and dried to give crude compound 26-5 (1.3 g, 5.66 mmol), MS [ESI]: m / z = 230.2 [M+H] + .

[0841] Step five: synthesis of compound 26-6

[0842] To a flask was added compound 26-5 (1.3 g, 5.66 mmol), methanol (10 mL), cesium carbonate (4.06 g, 12.45 mmol). Then the reaction was stirred at 60 °C for 6 hr. LCMS detection showed the reaction was complete, the reaction was concentrated and dried, purified by column chromatography to give compound 26-6 (0.8 g, 4.05 mmol), MS [ESI]: m / z = 198.2 [M+H] + .

[0843] Step six: synthesis of compound 26-7

[0844] To a microwave tube was added compound 26-6 (0.8 g, 4.05 mmol), DMF (10 mL), DIPEA (0.78 g, 6.07 mmol), 4-(2,4-difluorophenoxy)piperidine (1.04 g, 4.86 mmol). The microwave reactor was then placed in the microwave and the conditions were 130 °C, 100 W, for 1 hr. LCMS indicated the reaction was complete, the reaction was allowed to cool to room temperature, ethyl acetate (20 mL*2) and saturated brine (20 mL) were added to the mixture. The organic layers were combined, washed with brine (20 mL*1), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Prep-HPLC purification gave compound 26-7 (1.0 g, 2.67 mmol). MS [ESI]: m / z = 375.2 [M+H] + .

[0845] NMR: 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H). 7.85 (t, J = 6.0 Hz, 1H), 7.37-7.27 (m, 2H), 7.06-6.98 (m, 1H), 4.62-4.52 (m, 1H), 4.02-3.91 (m, 2H), 3.82 (s, 2H), 3.51 (dd, J = 12.0, 6.0 Hz, 2H), 3.40-3.34 (m, 2H), 2.96-2.89 (m, 2H), 2.04-1.91 (m, 2H), 1.69-1.56 (m, 2H).

[0846] Step Seven: Synthesis of compound 26-8

[0847] To a flask was added compound 26-7 (300 mg, 2.67 mmol), chloroform (3 mL), N-bromosuccinimide (0.17 g, 0.96 mmol). The temperature was raised to 60 °C and stirred for 4 hr. TLC indicated the reaction was complete, the reaction was concentrated and dried in vacuo. Prep- column chromatography purification gave compound 26-8 (0.26 g, 0.57 mmol), MS [ESI]: m / z = 454.2 [M+H] + .

[0848] Step Eight: Synthesis of compound 189-A

[0849] To a Schlenk flask was added compound 26-8 (0.1 g, 11.81 mmol), 1,4-dioxane (30 mL), cesium carbonate (0.14 g, 0.44 mmol), Pd-PEPPSI-IPent Cl (21.46 mg, 0.02 mmol). After nitrogen purging, it was warmed to 95 °C with stirring for 12 hr. LCMS showed the reaction was complete, it was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, prep-purified by Prep-HPLC to give compound 189-A (35 mg, 0.07 mmol). MS [ESI]: m / z = 460.2 [M+H] + .

[0850] NMR: 1 H NMR (400 MHz, DMSO-d6) d 7.75 (t, J = 6.0 Hz, 1H), 7.36 - 7.25 (m, 2H), 7.05 - 6.96 (m, 1H), 5.88 (d, J = 6.0 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.37 (dd, J = 13.2, 5.6 Hz, 1H), 3.91 - 3.81 (m, 2H), 3.73 - 3.64 (m, 3H), 3.53 (dd, J = 8.8, 4.8 Hz, 1H), 3.49 - 3.41 (m, 2H), 3.31 - 3.25 (m, 2H), 2.95 - 2.76 (m, 4H), 2.23 - 2.12 (m, 1H), 2.10 - 1.99 (m, 2H), 1.98 - 1.81 (m, 3H).

[0851] Example 27: Synthesis of 3-((3S,4R)-4-(2,4-difluorophenoxy)-3-fluoropiperidin-l-yl)-2-(((R)- tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 138-E)

[0852] Step one: Synthesis of compound 27-2

[0853] ​Compound 27-1 (1.00 g, 4.56 mmol) was dissolved in dichloromethane (2 mL), triethylamine (692.28 mg, 6.84 mmol) was added, and the reaction was stirred at 0 °C for 15 min. Methylsulfonic anhydride (953.40 mg, 5.47 mmol) was added, and the reaction was stirred at room temperature for 4 hr. TLC indicated the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded compound 27-2 (1.1 g, 3.70 mmol).

[0854] Step two: synthesis of compound 27-3

[0855] Compound 27-2 (1 g, 3.36 mmol), 2,4-difluorophenol (525.02 mg, 4.04 mmol), and cesium carbonate (1.64 g, 5.04 mmol) were dissolved in DMF (1 mL) and the reaction was stirred at 95 °C for 12 hr. TLC indicated the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded compound 27-3 (300 mg, 905.44 µmol).

[0856] Step three: synthesis of compound 27-4

[0857] Compound 27-3 (300 mg, 905.44 µmol) was dissolved in dichloromethane (3 mL), hydrochloric acid dioxane (5 mL, 2M) was added, and the reaction was stirred at room temperature for 4 hr. LCMS indicated the reaction was complete. The reaction mixture was adjusted to neutral pH with NaHCO3 solution, and the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded compound 27-4 (200 mg). MS [ESI]: m / z = 232.2 [M+H] + .

[0858] Step four: synthesis of compound 138-E

[0859] Compound Int 1 (100 mg, 305.65 μmol), compound 27-4 (106.00 mg, 458.47 μmol) and cesium carbonate (298.76 mg, 916.94 μmol), Ruphos Pd G3 (25.56 mg, 30.56 μmol), Ruphos (14.26 mg, 30.56 μmol) were dissolved in DMSO (2 mL) under nitrogen atmosphere, the reaction was heated to 95 °C in a reaction device for 18 hr. LCMS detection reaction was complete, the reaction mixture was purified by Pre-HPLC to obtain the target compound (1.4 mg, 2.93 μmol). MS [ESI]: m / z = 478.2 [M+H] + .

[0860] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (t, J = 5.6 Hz, 1H), 7.43 - 7.26 (m, 2H), 7.08 - 6.99 (m, 1H), 5.82 (d, J = 6.2 Hz, 1H), 5.06 (d, J = 54.4 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.42 - 4.35 (m, 1H), 4.20 (d, J = 5.6 Hz, 2H), 3.90 - 3.82 (m, 2H), 3.73 - 3.67 (m, 1H), 3.54 - 3.51 (m, 2H), 3.46 - 3.42 (m, 2H), 3.00 - 2.86 (m, 3H), 2.70 - 2.68 (m, 1H), 2.26 - 2.11 (m, 2H), 2.02 - 1.84 (m, 3H).

[0861] Referring to the synthetic method of Example 27, the following compound can be synthesized

[0862] Example 29: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-6-(oxetan-3-yl)-2- ((tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 14-R)

[0863] Step one: Synthesis of compound 29-1

[0864] ​Compound Int 1-3 (150 mg, 604.16 μmol) was dissolved in DMSO (1 mL) under ice-bath, replaced by nitrogen, then sodium hydride (46.30 mg, 1.16 mmol) was added, the reaction was carried out for 30 min, then aziridine iodide (122.26 mg, 664.57 μmol) was added, the temperature was raised to 80 °C, and the reaction was carried out for 2 h. LCMS detection showed that the reaction was complete. The reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 29-1 (120 mg, 394.29 μmol). MS [ESI]: m / z = 305.2 [M+H] + .

[0865] Step two: synthesis of compound 29-2

[0866] Compound 29-1 (120 mg, 394.29 μmol) was dissolved in DCM (2 mL) at room temperature, and NBS (70.18 mg, 394.29 μmol) was added, and the reaction was carried out for 1 h. LCMS detection showed that the reaction was complete. Concentration under reduced pressure, and purification by column chromatography to obtain compound 29-2 (50 mg, 130.47 μmol), MS [ESI]: m / z = 384.2 [M+H] + .

[0867] Step three: synthesis of compound 14-R

[0868] Compound 29-2 (50 mg, 130.47 μmol), compound 1-02 (41.73 mg, 195.70 μmol) and cesium carbonate (127.53 mg, 391.40 μmol) were dissolved in DMF (1 mL), and the temperature was raised to 130 °C in a microwave reaction device for 1 h. LCMS detection showed that the reaction was complete. The reaction mixture was purified by Prep-HPLC to obtain compound 14-R (6.7 mg, 13.00 μmol). MS [ESI]: m / z = 516.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.36 - 7.26 (m, 2H), 7.05 - 6.98 (m, 1H), 6.02 (d, J = 6.0 Hz, 1H), 5.51 - 5.43 (m, 1H), 4.70 (dd, J = 16.0, 8.4 Hz, 4H), 4.58 - 4.45 (m, 3H), 4.38 (d, J = 7.2 Hz, 1H), 3.92 - 3.80 (m, 2H), 3.70 (dd, J = 14.4, 8.0 Hz, 1H), 3.54 (dd, J = 8.8, 4.8 Hz, 1H), 3.47 - 3.40 (m, 1H), 2.96 - 2.81 (m, 5H), 2.22 - 2.11 (m, 2H), 2.11 - 2.02 (m, 2H), 2.01 - 1.82 (m, 4H).

[0869] Example 30: Synthesis of (R)-3-(6-(2,4-difluorophenoxy)pyridin-3-yl)-2-((tetrahydrofuran-3- yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 151-R)

[0870] Step one: Synthesis of compound 30-2

[0871] To a flask was added compound 2,4-difluorophenol (1 g, 7.69 mmol), THF (50 mL), ice bath, sodium hydride (0.27 g, 11.53 mmol) was added slowly, the reaction was half an hour, then compound 30-1 (1.35 g, 7.69 mmol) was added. The temperature was raised to 60 °C, and stirred for 12 hr. TLC detection reaction was complete, restore to room temperature, ethyl acetate (100 mL*2) and saturated brine (100 mL) was added to extract the mixture. The organic layer was combined, washed with brine (100 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. Purified by column chromatography to obtain compound 30-2 (1.2 g, 4.19 mmol), MS [ESI]: m / z = 287.2 [M+H] + .

[0872] Step two: Synthesis of compound 30-3

[0873] ​To a flask was added compound 30-2 (1.2 g, 4.19 mmol), 1,4-dioxane (10 mL), potassium acetate (0.8 g, 8.39 mmol), Pd(dppf)2Cl2(0.3 g, 0.41 mmol), bis(pinacolato)diboron (1.28 g, 5.03 mmol). After nitrogen purging, it was warmed to 95 °C and stirred for 12 hr. LCMS showed the reaction was complete, it was allowed to cool to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by column chromatography to afford compound 30-3 (1.1 g, 3.3 mmol), MS [ESI]: m / z = 334.2 [M+H] + .

[0874] Step three: synthesis of compound 151-R

[0875] To a flask was added compound 30-3 (0.12 g, 0.36 mmol), compound Int 1 (0.1 g, 0.3 mmol), 1,4-dioxane (1 mL), water (0.1 mL), cesium carbonate (0.19 g, 0.61 mmol), Pd(dppf)Cl2(0.02 g, 0.03 mmol), it was warmed to 95 °C after nitrogen purging, stirred for 12 hr. LCMS showed the reaction was complete, it was allowed to cool to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by Prep-HPLC to afford compound 151-R (70 mg, 0.15 mmol). MS [ESI]: m / z = 454.1 [M+H] + .

[0876] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 2.0 Hz, 1H), 8.10 (dd, J = 8.4, 2.4 Hz, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.52 - 7.37 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.56 (d, J = 6.0 Hz, 1H), 4.44 - 4.35 (m, 1H), 4.30 (d, J = 6.0 Hz, 2H), 3.90 (dd, J = 8.4, 6.4 Hz, 1H), 3.78 (dd, J = 14.4, 8.0 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.48 (dd, J = 8.8, 5.2 Hz, 1H), 3.05 - 2.90 (m, 2H), 2.79 - 2.68 (m, 2H), 2.19 - 2.05 (m, 1H), 1.93 - 1.75 (m, 1H).

[0877] Example 31: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-2- ((tetrahydrofuran-3-yl)amino)-8,9-dihydrooxo pyrazino[3,4-b]pyrazin-7(5H)-one (Compound 152-R)

[0878] Step one: Synthesis of compound 31-2

[0879] To the flask was added compound (R)-tetrahydrofuran-3-amine (2.53 g, 28.98 mmol), compound 31-1 (5 g, 24.15 mmol), DMF (50 mL), triethylamine (3.67 g, 36.23 mmol), and the reaction was stirred for 12 hr. TLC indicated the reaction was complete, the mixture was extracted with ethyl acetate (100 mL*2) and saturated brine (100 mL). The organic layers were combined, washed with brine (100 mL*3), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 31-2 (4 g, 15.52 mmol), MS [ESI]: m / z = 258.2 [M+H] + .

[0880] Step two: Synthesis of compound 31-3

[0881] To the flask was added compound 31-2 (4 g, 4.19 mmol), anhydrous tetrahydrofuran (40 mL). After nitrogen substitution, LAH was slowly added at -78 °C, and the reaction was stirred for 4 hr, then slowly warmed to room temperature for 2 hr. LCMS indicated the reaction was complete, 1 mL water, 3 mL sodium hydroxide solution (15%), 1 mL water, anhydrous magnesium sulfate were added to the reaction under ice bath for 15 min, filtered, concentrated under reduced pressure, and purification by column chromatography gave compound 31-3 (2.2 g, 9.58 mmol), MS [ESI]: m / z = 330.2 [M+H] + .

[0882] Step three: Synthesis of compound 31-4

[0883] To the flask was added compound 31-3 (2.2 g, 9.58 mmol), dichloromethane (20 mL), imidazole (0.97 g, 14.37 mmol), DMAP (0.23 g, 1.92 mmol), and the reaction was stirred for 15 min at room temperature, then TBDMSCl (1.73 g, 11.5 mmol) was added, and the reaction was stirred for another 4 hr. LCMS indicated the reaction was complete, the reaction was restored to room temperature, concentrated under reduced pressure, and purification by column chromatography gave 31-4 (2.58 g, 7.50 mmol), MS [ESI]: m / z = 345.2 [M+H] + .

[0884] Step four: synthesis of compound 31-5

[0885] To the flask was added compound 31-4 (2.58 g, 7.50 mmol), (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-enoic acid ethyl ester (2.54 g, 11.25 mmol), DMAC (20 mL), water (2 mL), cesium carbonate (4.89 g, 15 mmol), Pd(dppf)Cl2(0.54 g, 0.75 mmol), nitrogen replacement, and then warmed to 120 °C, stirred for 6 hr. LCMS detected that the reaction was complete, cooled to room temperature, diluted with ethyl acetate (50 mL) and saturated brine (50 mL), the water layer was extracted with ethyl acetate (50 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 31-5 (2.5 g, 6.13 mmol), MS [ESI]: m / z = 408.2 [M+H] + .

[0886] Step five: synthesis of compound 31-6

[0887] To the flask was added compound 31-5 (2.5 g, 6.13 mmol), methanol (20 mL), palladium on carbon (250 mg, 0.1 eq), hydrogen replacement, room temperature reaction for 12 hr, LCMS detected that the reaction was complete, the reaction liquid was filtered through diatomite, washed with methanol, concentrated under reduced pressure, and purified by column chromatography to give compound 31-6 (2.2 g, 5.37 mmol), MS [ESI]: m / z = 410.2 [M+H] + .

[0888] Step six: synthesis of compound 31-7

[0889] To the flask was added compound 31-6 (2.2 g, 5.37 mmol), dichloromethane (20 mL), NBS (1.3 g, 7.32 mmol), room temperature reaction for 4 hr, LCMS detected that the reaction was complete, the reaction liquid was concentrated under reduced pressure, and purified by column chromatography to give compound 31-7 (2.3 g, 4.71 mmol), MS [ESI]: m / z = 489.2 [M+H] + .

[0890] Step seven: synthesis of compound 31-8

[0891] To a Schlenk flask was added compound 31-7 (1 g, 2.05 mmol), 1,4-dioxane (10 mL), followed by compound 1-02 (0.52 g, 2.46 mmol), Ruphos Pd G3 (0.17 g, 0.20 mmol), cesium carbonate (1.33 g, 4.09 mmol). After nitrogen substitution, the temperature was raised to 90 °C and stirred for 12 hr. LCMS detection showed the reaction was complete, the reaction was cooled to room temperature, filtered through celite, washed with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to give compound 31-8 (0.82 g, 1.32 mmol), MS [ESI]: m / z = 621.2 [M+H] + .

[0892] Step Eight: Synthesis of compound 31-9

[0893] To a flask was added compound 31-8 (0.82 g, 1.32 mmol), tetrahydrofuran (10 mL), TBAF tetrahydrofuran solution (13.21 mmol), and the reaction was stirred at room temperature for 4 hr. LCMS detection showed the reaction was complete, the reaction was quenched with saturated NaHCO3, and the reaction was extracted with ethyl acetate (50 mL). The organic layer was concentrated under reduced pressure, and purified by column chromatography to give compound 31-9 (0.5 g, 0.98 mmol), MS [ESI]: m / z = 507.2 [M+H] + .

[0894] Step Nine: Synthesis of compound 31-10

[0895] To a flask was added compound 31-9 (0.5 g, 0.98 mmol), tetrahydrofuran (5 mL), water (5 mL), sodium hydroxide (78.9 mg, 1.97 mmol), and the reaction was stirred at 60 °C for 4 hr. LCMS detection showed the reaction was complete, the pH was adjusted to 5-6 by adding 2N hydrochloric acid, and the reaction was concentrated under reduced pressure. Compound 31-10 (0.4 g, 0.83 mmol) was obtained by purification by C18 reverse phase, MS [ESI]: m / z = 479.2 [M+H] + .

[0896] Step Ten: Synthesis of compound 152-R

[0897] To a dry round bottom flask, was added compound 31-10 (0.1 g, 0.21 mmol), DMF (2 mL), N-methylimidazole (51.48 mg, 0.62 mmol), TCFH (87.9 mg, 0.31 mmol) under ice bath, then moved to room temperature for 2 hr. LCMS showed the reaction was complete. Purified by Prep-HPLC to get compound 152-R (60 mg, 0.13 mmol). MS [ESI]: m / z = 461.1 [M+H] + .

[0898] 1 H NMR (400 MHz, CDCl3) δ 6.97-6.88 (m, 1H), 6.84-6.76 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 6.4 Hz, 1H), 4.48 (s, 1H), 4.28 (s, 1H), 3.97-3.88 (m, 2H), 3.84-3.74 (m, 1H), 3.63 (dd, J = 9.2, 3.2 Hz, 1H), 3.44-3.17 (m, 2H), 3.11-3.06 (m, 1H), 3.03-2.98 (m, 1H), 2.92-2.84 (m, 1H), 2.35-2.22 (m, 1H), 2.13-2.04 (m, 2H), 1.94-1.73 (m, 3H), 1.61-1.42 (m, 2H), 0.85-0.70 (m, 3H).

[0899] Example 32: Synthesis of (R)-8-(4-(2,4-difluorophenoxy)piperidin-l-yl)-7-((tetrahydrofuran-3-yl)amino)-l,2,4,5-tetrahydro-3H-benzo[c]azepin-3-one (Compound 153-R) .

[0900] To a dry round bottom flask, was added compound Int 4 (200 mg, 615.01 umol), compound 1-02 (157.36 mg, 738.01 umol), cesium carbonate (601.14 mg, 1.85 mmol), Pd-PEPPSI-IPentCl (299.13 mg, 307.50 umol) in toluene (2 mL), replaced by nitrogen, warmed to 120 °C for 12 hr. LCMS showed the reaction was complete. The reaction mixture was purified by Prep-HPLC to get compound 153-R (38.8 mg, 84.81 umol), MS [ESI]: m / z = 458.1 [M+H] + .

[0901] 1H NMR (400 MHz, DMSO-d6) δ 7.83 (t, J = 5.2 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.06 - 6.98 (m, 1H), 6.76 (s, 1H), 6.42 (s, 1H), 4.76 (d, J = 7.2 Hz, 1H), 4.46 (s, 1H), 4.11 (d, J = 5.2 Hz, 2H), 4.08 - 3.97 (m, 1H), 3.92 - 3.85 (m, 1H), 3.85 - 3.78 (m, 1H), 3.78 - 3.68 (m, 1H), 3.55 (dd, J = 8.8, 3.6 Hz, 1H), 3.01 - 2.92 (m, 2H), 2.92 - 2.84 (m, 2H), 2.75 - 2.61 (m, 2H), 2.61 - 2.53 (m, 2H), 2.29 - 2.14 (m, 1H), 2.10 - 1.99 (m, 2H), 1.90 - 1.72 (m, 3H).

[0902] Referring to the synthetic method of Example 32, the following compound can be synthesized

[0903] Example 33: Synthesis of 3-(4-(2,4-difluorophenoxy)piperidin-l-yl)-2-(l-ethyl-lH- pyrazol-4-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 43)

[0904] Compound Int 3 (100 mg, 220.61 μmol), l-ethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboro-2- yl)pyrazole (58.80 mg, 264.74 μmol), cesium carbonate (215.64 mg, 661.84 μmol), Pd(dppf)Cl2(16.14 mg, 22.06 μmol) were dissolved in H2O (0.2 mL) and 1,4-dioxane (2 mL), replaced by nitrogen, and warmed to 95 °C for 12 hr. LCMS detected that the reaction was complete. The reaction mixture was prepared and purified by Prep-HPLC to obtain Compound 43 (52.1 mg, 111.21 μmol), MS [ESI]: m / z = 469.1 [M+H] + .

[0905] 1 ​H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.99 (t, J = 5.2 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 4.51 (s, 1H), 4.35 (d, J = 5.2 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.33 - 3.24 (m, 2H), 3.12 - 3.02 (m, 2H), 2.95 (t, J = 9.6 Hz, 2H), 2.82 - 2.71 (m, 2H), 2.05 (s, 2H), 1.92 - 1.76 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).

[0906] Referring to the synthesis of Example 33, the following compound can be synthesized

[0907] Example 34: Synthesis of 2-((2,2-difluoroethyl)amino)-3-(4-(2,4- difluorophenoxy)piperidin-l-yl)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 154)

[0908] To a Schlenk flask was added compound Int 3 (0.1 g, 0.22 mmol), 1,4-dioxane (1 mL), cesium carbonate (0.14 g, 0.44 mmol), Pd-PEPPSI-IPent CI (21.46 mg, 0.02 mmol), 2,2-difluoroethan-l-amine (26.83 mg, 0.33 mmol). After nitrogen purging, the temperature was raised to 90 °C and stirred for 12 hr. LCMS showed the reaction was complete, cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by Prep-HPLC to give compound 154 (35 mg, 0.07 mmol), MS [ESI]: m / z = 454.0 [M+H] + .

[0909] 1 ​H NMR (400 MHz, DMSO-d6) δ 7.93 (t, J = 5.6 Hz, 1H), 7.35 - 7.25 (m, 2H), 7.06 - 6.97 (m, 1H), 6.46 (t, J = 6.0 Hz, 1H), 6.33 - 5.99 (m, 1H), 4.52 (d, J = 4.0 Hz, 1H), 4.21 (d, J = 5.6 Hz, 2H), 3.76 - 3.63 (m, 2H), 3.30 - 3.18 (m, 2H), 2.96 - 2.83 (m, 4H), 2.68 (t, J = 6.4 Hz, 2H), 2.13 - 2.03 (m, 2H), 1.92 - 1.81 (m, 2H).

[0910] Referring to the synthesis method of Example 34, the following compound can be synthesized

[0911] Example 35: Synthesis of 3-(4-(2,4-difluorophenoxy)cyclohex-1-en-1-yl)-2-(((R)- tetrahydrofuran-3-yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (Compound 155-R)

[0912] Step one: Synthesis of compound 35-2

[0913] To a flask was added compound 35-1 (0.2 g, 2.06 mmol), 2,4-difluorophenol (0.32 g, 2.47 mmol), toluene (5 mL), CMBP (0.99 g, 4.12 mmol), and the reaction was stirred for 12 hr. TLC indicated the reaction was complete, the mixture was extracted with ethyl acetate (100 mL*2) and saturated brine (100 mL). The organic layers were combined, washed with brine (100 mL*3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 35-2 (70 mg, 0.33 mmol).

[0914] Step two: Synthesis of compound 155-R

[0915] ​To a flask was added Int 1 (50 mg, 0.15 mmol), compound 35-2 (61.6 mg, 0.18 mmol), DO (2 mL), water (0.2 mL), cesium carbonate (0.1 g, 0.3 mmol), Pd(dppf)Cl2(11.1 mg, 0.01 mmol), nitrogen was replaced, and then the temperature was raised to 90 °C, and stirred for 6 hr. LCMS detected that the reaction was complete, the reaction was restored to room temperature, the reaction was diluted with ethyl acetate (50 mL) and saturated brine (50 mL), the water layer was extracted with ethyl acetate (50 mL), the organic layer was combined, and then washed with brine, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by Prep-HPLC to obtain compound 155-R (60 mg, 0.13 mmol). MS [ESI]: m / z = 457.1 [M+H] + .

[0916] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (t, J = 5.6 Hz, 1H), 7.34-7.27 (m, 2H), 7.08-6.99 (m, 1H), 6.02-5.93 (m, 2H), 4.67 (d, J = 5.6 Hz, 1H), 4.45-4.33 (m, 1H), 4.24 (d, J = 5.6 Hz, 2H), 3.93-3.77 (m, 2H), 3.69 (dd, J = 14.4, 8.0 Hz, 1H), 3.55-3.42 (m, 1H), 2.98-2.90 (m, 2H), 2.74-2.58 (m, 3H), 2.50-2.30 (m, 3H), 2.20-2.03 (m, 2H), 1.93-1.81 (m, 2H).

[0917] Example 36: Synthesis of (R)-3-(4-(2,4-difluorophenoxy)cyclohexyl)-2-((tetrahydrofuran-3- yl)amino)-5,6,8,9-tetrahydro-7H-pyrazino[2,3-c]azepin-7-one (compound 58-R) .

[0918] To a flask was added compound 155-R (60 mg, 0.13 mmol), methanol (5 mL), palladium on carbon (6 mg, 0.1 eq), hydrogen was replaced, and then the reaction was carried out at room temperature for 4 hr. LCMS detected that the reaction was complete, the reaction was filtered through diatomite, washed with methanol, and concentrated under reduced pressure. Purification by Prep-HPLC gave compound 58-R (50 mg, 0.11 mmol). MS [ESI]: m / z =...

Claims

1. A compound, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I: ###0001### Formula I wherein, A ring is selected from a 3-14 membered heterocyclic ring and a 3-14 membered carbocyclic ring, said heterocyclic or carbocyclic ring being optionally substituted with one or more substituents independently selected from H, halo, hydroxy, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C 1-6 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b ; optionally, said C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-6 alkyl; X, Y are each independently selected from the group consisting of a covalent bond, CR, O, S, NH, and N; R is each independently selected from the group consisting of H, halogen, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 3-10 cycloalkyl; L is selected from the group consisting of 4-8 membered carbocyclic, 3-10 membered heterocyclic, and 5-10 membered heteroaromatic rings, said carbocyclic, heterocyclic, and heteroaromatic rings being optionally substituted with one or more substituents independently selected from the group consisting of H, deuterium, halogen, hydroxyl, amino, oxo (=0), cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; Z is selected from a covalent bond, CR a R b , -O-CR a R b , -C(=NSO2R b ), C(=O)NR b , NR a , O, S, -C(=O)-, -S(=O)-, -S(=O)2-, S(=O)(=NR b ) and S(=NR b )2; R 1 selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1- 6alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-12 membered heterocyclyl; R a and R b are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; or R a , R b and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; R c and R d are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; or R c , R d and the N atom to which it is attached form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; Ar is selected from C 6-10 aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl, said aryl, heteroaryl, and heterocyclyl optionally substituted with one or more R 2 substituents; R 2 each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl being optionally substituted with one and multiple substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano and C 1-6 alkyl; p is each independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6.

2. The compound of claim 1, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein, A ring is selected from a 3-14 membered heterocyclic ring, said heterocyclic ring is optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, nitro, C 1-4 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, -C 1-4 alkyl-O-R a , -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-4 alkylene-NR a R b ; optionally, said C 1-4 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 2-6 alkenyl and C 2-6 alkynyl are each independently substituted with one or more C 1-4 alkyl.

3. The compound of any one of claims 1-2, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein, The compounds have a structure according to Formula I-a, I-b or I-c: wherein A ring, X, Y, R 1 , L, Z, Ar are each independently as defined in claims 1-2.

4. The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein, The compounds have a structure according to Formula I-1 : wherein represents a single or double bond, M, Q, E, G are each independently selected from a covalent bond, -CR e R f - and -NR j -, -O-, -S-, -C(=O)-, -S(=O)- and -S(=O)2-; R e and R f are each independently selected from the group consisting of H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; or R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, which carbocyclic ring, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; R j each independently selected from H, halogen, hydroxyl, cyano, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl, and aryl optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; or R j with R e or R j with R f and the atom to which they are attached together form a 3-8 membered carbocyclic ring, 3-12 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; m, n are each independently selected from the group consisting of 0, 1, 2, 3, and 4; X, Y, L, Z, Ar, R 1 , R c , R d each independently as defined in any one of claims 1-2.

5. The compound of claim 4, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, R j with R e or R j with R f and the atom to which they are attached together form a 3-8 membered carbocyclic ring, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl.

6. The compound of claim 5, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, R j with R e or R j with R f and the atom to which they are attached collectively form 7. The compound of any one of claims 4-6, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein: M, Q, E, G are each independently selected from the group consisting of a covalent bond, CH, CH2, -CH(CH(CH3)2)-, -CH(CH3)-, -C(CH3)2-, -CH(CF3)-, -CH(OH)-, -CH(-OCH3)-, NH, O, S, -C(=O)-, -S(=O)-, and -S(=O)2-.

8. The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I-2: ###00010### I-2. ​ wherein, Q and E are each independently selected from the group consisting of a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-; M and G are each independently selected from the group consisting of N, O, S and CR e ; J is selected from the group consisting of -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O-, and -C 1- 6alkyl-S-; X, Y, L, Z, Ar, R 1 each independently as defined in any one of claims 1-7, R e , R f , R j , m and n are each independently as defined in any one of claims 4-7.

9. The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or a metabolite, prodrug, or pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure shown in formulas I-3: wherein M and Q are each independently selected from the group consisting of a covalent bond, CR e R f , NR j , O, S, -C(=O)-, -S(=O)-, and -S(=O)2-; G and E are each independently selected from the group consisting of N, O, S, and CR e ; X, Y, L, Z, Ar, R 1 each independently as defined in any one of claims 1 to 7, R e , R f , R j , m and n are each independently as defined in any one of claims 4 to 8, J is as defined in claim 8.

10. The compound of any one of claims 1-3, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug thereof, or a pharmaceutically acceptable salt or ester thereof, wherein the compound has the structure of Formula I-4: ###00010### I-4. ​ wherein, M and G are each independently selected from the group consisting of a covalent bond, CR e R f , NR j , O, S, -C(=0)-, -S(=0)-, and -S(=0)2-; Q and E are each independently selected from N, O, S and CR e ; X, Y, L, Z, Ar, R 1 each independently as defined in any one of claims 1 to 7, R e , R f , R j , m and n are each independently as defined in any one of claims 4 to 9, J is as defined in claim 8.

11. The compound of any one of claims 1-10, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, having one or more of the following features: (1) R j each independently selected from H, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 1-6 haloalkyl, said alkyl, heterocyclyl, and heteroaryl groups being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; (2)R e and R f each independently is selected from the group consisting of H, halogen, hydroxyl, cyano, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-OR c , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, -C(=O)R c , -C 1- 4 alkyl-C(=O)-NR c R d , NR c R d , -NR c C(=O)R d , -C(=O)-OR c , -OR c , -SR c , -SOR c , and -SO2R c , said alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, heterocyclyl, heteroaryl and aryl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; or R e , R f and the atom to which they are attached form a 3-8 membered carbocyclic ring, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; (3) J is selected from -C 1-6 alkyl-, -O-, -S-, -NR j , -C 1-6 alkyl-O-, and -C 1-6 alkyl-S-; (4) L is selected from the group consisting of a 4-8 membered carbocyclic ring, a 3-10 membered nitrogen-containing heterocyclic ring, and a 5-10 membered nitrogen-containing heteroaromatic ring, said 4-8 membered carbocyclic ring, 3-10 membered nitrogen-containing heterocyclic ring, and 5-10 membered nitrogen-containing heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of H, deuterium, and halogen; (5) Z is selected from a covalent bond, CR a R b , O, S, NR a , -C(=O)-, -S(=O)-, and -S(=O)2-; (6) R a and R b are each independently selected from the group consisting of H, halogen, 3-6 membered heterocyclyl, C 1-4 alkyl, C 3-6 cycloalkyl and C 3-6 cycloalkyl-OR c , said alkyl, cycloalkyl and heterocyclyl being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxy, C 1-4 alkyl; or R a , R b and the atom to which it is attached form a 3-6 membered carbocyclic ring, a 3-8 membered heterocyclyl (e.g., a nitrogen-containing heterocyclyl or an oxygen-containing heterocyclyl) or a 5-10 membered heteroaryl, said heterocyclyl and heteroaryl being optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, =0, C 1-6 alkyl; (7) R 1 selected from H, halogen, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, -C(=O)R c , -C 1-6 alkyl-C(=O)-NR a R b , NR a R b , OR a , SR a , -NR a C(=O)R b , -C(=O)-OR a , -SOR a , -SO2R a , C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl groups being optionally substituted with one or more substituents independently selected from H, halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -C(=O)-(CH2) p -O-R a , -C(=O)-(CH2) p -NR a R b , -C 1-6 alkylene-NR a R b , -C 1-6 alkyl-O-R a and 3-8 membered heterocyclyl; (8) R c and R d each independently is selected from the group consisting of H, F, Cl, Br, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, said alkyl, alkoxy, haloalkyl, haloalkoxy being optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, hydroxyl, amino, cyano, C 1-4 alkyl; or R c , R d and the N atom to which it is attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, which is optionally substituted with one or more substituents independently selected from H, halo, hydroxyl, amino, cyano, =0, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy; (9) R 2 each independently selected from the group consisting of H, F, Cl, amino, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of H, F, Cl, Br, hydroxyl, amino, cyano and C 1-4 alkyl; (10) Ar is selected from the group consisting of phenyl, 5-10 membered nitrogen-containing heteroaryl, and 3-10 membered heterocyclyl, said phenyl, nitrogen-containing heteroaryl, and heterocyclyl are optionally substituted with one or more (e.g., 2, 3, 4, or 5) substituents independently selected from the group consisting of F, Cl, methoxy; and / or, (11) X and Y are each independently selected from the group consisting of a covalent bond, NH, O, S, N and CR, R being selected from the group consisting of H, halogen, hydroxyl, cyano, nitro, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl and C 3-8 cycloalkyl.

12. The compound of claim 11, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein, said compound has one or more of the following features: (1) R j each independently selected from H, methyl, ethyl, isopropyl, 3-6 membered heterocyclyl (e.g. ), -CHF2, -CH2CH2F, -CH2CF3, -CH2CH2OH, cyclopropyl, cyclobutyl and (2) R e and R f each independently is selected from H, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, and -OR c ; alternatively, R e , R f and the atom to which they are attached form a 3-6 membered carbocyclic ring; (3) J is selected from the group consisting of -CH2-, -CH2-CH2-, -O-, and -CH2-O-; (4) L is selected from (5) Z is selected from the group consisting of a covalent bond, -N(CH3)-, -CF2-, -CH2-, -CHF-, -CH(CH3), O, -C(=O)-, -S(=O)2-, (6) R a and R b are each independently selected from H, F, methyl, isopropyl, cyclopropyl, -CH(CH3)-CH2-OH, -cyclopropyl-OH, -CH2-CHF2, or R a or R b with the atom to which it is attached forms (7) R 1 selected from -NH-CH(CH3)2, -O-CH(CH3)2, -NH-cyclopropyl, -NH-CH(CH3)-CH2-OH, -NH-cyclopropyl-OH, -S-CH(CH3)2, -CH2-CH(CH3)2, -NH-CH2-CHF2, -NH-CH2-CF3, (8) Ar is selected from and / or, (9) X and Y are each independently selected from the group consisting of a covalent bond, N, O, S, CH, and CF.

13. The compound of any one of claims 1-12, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is selected from:

14. The compound of any one of claims 1-13, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, wherein the compound is selected from:

15. A composition or pharmaceutical combination comprising a compound of any one of claims 1-14, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, optionally further comprising one or more other therapeutic agents.

16. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of a compound of any one of claims 1-14, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients.

17. Use of a compound of any one of claims 1-14, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition or pharmaceutical combination of claim 15, or a pharmaceutical composition of claim 16, for the manufacture of a medicament for the prevention and / or treatment of a disease, in particular a GPR6 receptor mediated related disease; preferably, the GPR6 receptor mediated related disease is selected from the group consisting of movement disorders, including Parkinson, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression.

18. A compound of any one of claims 1-14, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition or pharmaceutical combination of claim 15, or a pharmaceutical composition of claim 16, for use in the prevention and / or treatment of a disease, in particular a GPR6 receptor mediated related disease; preferably, the GPR6 receptor mediated related disease is selected from the group consisting of movement disorders, including Parkinson, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression.

19. A method of preventing and / or treating a disease, in particular a GPR6 receptor mediated related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-14, or a stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, or metabolite or prodrug or pharmaceutically acceptable salt or ester thereof, or a composition or pharmaceutical combination of claim 15, or a pharmaceutical composition of claim 16; preferably, the GPR6 receptor mediated related disease is selected from the group consisting of movement disorders, including Parkinson, levodopa-induced dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder and depression.

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