Fatty acid synthase inhibitor and application thereof

Abstract

The invention relates to a fatty acid synthase inhibitor and application thereof. Particularly, the invention relates to a compound shown in a general formula (I), a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and application of the compound shown in the general formula (I) or the pharmaceutical composition thereof in preparation of drugs for preventing and / or treating fatty acid synthase (FASN) mediated diseases, and substituents in the general formula (I) are as defined in the specification.

Description

TECHNICAL FIELD

[0001] The present application relates to a fatty acid synthase (FASN) inhibitor, stereoisomers, pharmaceutically acceptable salts, solvates, co-crystals or deuterium derivatives thereof, and uses thereof in the manufacture of a medicament for treating FASN-mediated related diseases. BACKGROUND

[0002] The main sources of liver TG are de novo lipogenesis (DNL) and the 3-phosphate glycerol (glyceraldehyde 3-phosphate, G3P) pathway, the substrate of DNL is acetyl-CoA, and acetyl-CoA can be produced by carbohydrate and fatty acid metabolism, SCD1, fatty acid synthetase (FASN), ACC, DGAT2 are key enzymes in the DNL process, and their expression is regulated by nuclear receptors PPAR, FXR, etc.

[0003] Fatty acid synthase (FASN) is an enzyme in the de novo lipogenesis (DNL) pathway, with a molecular weight of 273.427 kDa, which catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA in the presence of NADPH, forming long-chain saturated fatty acids. This multifunctional protein contains 7 catalytically active (including condensation, transacylation, reduction, and dehydration) and acyl carrier protein ([ACP]) domain 4'-phosphopantetheine prosthetic binding sites.

[0004] Inhibiting FASN has the potential to be a therapeutic approach for a variety of diseases, including cancer, viral diseases, metabolic diseases, NAFLD, NASH, and inflammatory diseases (i.e., rheumatoid arthritis, gout, pulmonary fibrosis, COPD, IBD, and graft rejection). In addition, FASN inhibition can provide therapeutic benefits in cardiovascular disease, type II diabetes, and metabolic syndrome. There is currently no approved fatty acid synthase inhibitor on the market, and there is an urgent need for novel and effective small molecule fatty acid synthase inhibitors to treat these diseases and meet unmet clinical needs. SUMMARY

[0005] The present application provides a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which is a FASN inhibitor, has good physicochemical properties, such as higher solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small side effects, and has the advantages of oral administration, fast absorption, high clearance rate, etc.

[0006] The present application relates to a compound according to Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0007]

[0008] wherein,

[0009] Cy1is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally further substituted by 1-3 R c1 substituents;

[0010] In some embodiments, Cy1is pyrrolidinyl, cyclohexyl, cyclohexenyl, piperidinyl, piperazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinonyl, pyrimidinonyl, pyridazinonyl, benzimidazolyl, indolyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, optionally further substituted by 1-3 R c1 substituents;

[0011] In some embodiments, Cy1is

[0012] optionally further substituted by 1-3 R c1 substituents;

[0013] Cy2is present or absent; when Cy2is present, Cy2is C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, optionally further substituted by 1-3 R c2 substituents;

[0014] In some embodiments, Cy2is C 3-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-12 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl, 6-12 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, optionally further substituted by 1-2 R c2 substituents;

[0015] In some embodiments, Cy2is C 3-6cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-12 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl, optionally further substituted by 1-3 R c2 substituted;

[0016] In some embodiments, Cy2is

[0017] optionally further substituted by 1-3 R c2 substituted;

[0018] Cy3is C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzo C 3-6 cycloalkyl, benzo 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally further substituted by 1-3 R c3 substituted;

[0019] In some embodiments, Cy3is cyclobutyl, cyclohexyl, bicyclo[1.1.1]pentane, phenyl, pyridyl, pyrimidinyl, pyridinonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, benzocyclopentyloxy, benzopyrrolidinyl, optionally further substituted by 1-3 R c3 substituted;

[0020] In some embodiments, Cy3is cyclohexyl, bicyclo[1.1.1]pentane, phenyl, pyridyl, pyrimidinyl, pyridinonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, optionally further substituted by 1-3 R c3 substituted;

[0021] In some embodiments, Cy3is optionally further substituted by 1-2 R c3 substituted;

[0022] each R c1 , R c2 and R c3 is each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkoxyalkyl, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -C(=O)- (3-8 membered heterocycloalkyl), -NHC(=O)- (3-8 membered heterocycloalkyl), -NH- (5-10 membered heteroaryl), C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkylalkyl, 3-8 membered heterocyclic alkylalkyl, C 3-8 Cycloalkyloxy or 3-8-membered heterocyclic alkyloxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkylalkyl, cycloalkyloxy or heterocyclic alkyloxy may optionally be further selected from 1-3 groups selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0023] In some implementations, each R c1 R c2 and R c3 Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Alkoxyalkyl, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-8 Cycloalkylalkyl, 3-8 membered heterocyclic alkylalkyl, C 3-8cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0024] In some embodiments, each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 1-3 alkoxyalkyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkylalkyl, 3-6 membered heterocycloalkylalkyl, C 3-6 cycloalkyloxy, or 3-6 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkyloxy, or heterocycloalkyloxy optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0025] In some embodiments, R c1 is deuterium, halogen, hydroxyl, oxo, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 1-3 alkoxyalkyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy or 4-5 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy being optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0026] In some embodiments, R c1 is oxo, -COOH, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, methoxyethyl,

[0027] R c2 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl;

[0028] In some embodiments, R c2 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, ethenyl, or ethynyl;

[0029] R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy or 4-5 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy being optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0030] In some implementations, R c3 For deuterium, halogen, hydroxyl, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, 4-5 membered heterocyclic alkyl, C 3-4 Cycloalkyloxy, 4-5-membered heterocyclic alkyloxy, 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, cycloalkyloxy, heterocyclic alkyloxy, and heteroaryl groups are optionally further selected by 1-3 groups selected from halogen, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0031] In some implementations, R c3 For deuterium, halogen, hydroxyl, oxo group, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 3-4 Cycloalkyl, 4-5 membered heterocycloalkyl, -C(=O)- (4-6 membered heterocycloalkyl), -NHC(=O)- (4-6 membered heterocycloalkyl), -NH- (5-6 membered heteroaryl), C 3-4 Cycloalkyloxy, 4-5-membered heterocyclic alkyloxy, 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, cycloalkyloxy, heterocyclic alkyloxy, and heteroaryl groups are optionally further selected by 1-3 groups selected from halogen, cyano, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Substitution of cycloalkyl groups;

[0032] In some implementations, R c3haloalkyl, C

[0033]

[0034] In some embodiments, R c3’ haloalkyl, C

[0035]

[0036] In some embodiments, R c3 haloalkyl, C

[0037] In some embodiments, R c3 haloalkyl, C

[0038] In some embodiments, any one of R c2 , L2, and any one of R c3 and the ring atom to which it is attached form a 5-8 membered heterocycloalkyl group, optionally further substituted with 1-3 groups selected from halo, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0039] In some embodiments, any one of R c2 , L2, and any one of R c3 and the ring atom to which it is attached form a 5-6 membered heterocycloalkyl group, optionally further substituted with 1-3 groups selected from halo, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0040] L1and L2are each independently a bond, -(CR y1 R y2 ) m , C 3-6 cycloalkyl, -O-, -CO-, -NR y3 , C 2-4alkenyl or C 2-4 alkynyl;

[0041] R y1 and R y2 are each independently hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

[0042] R y3 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl;

[0043] In some embodiments, L1is a bond, -CR y1 R y2 -, C 3-6 cycloalkyl, -O-, -CO-, -NR y3 -,

[0044] In some embodiments, L1is a bond, -O-, -CO-, -NR y3 -;

[0045] In some embodiments, L1is a bond, -O-, -NH-, -NCH3-, -N(cyclopropyl)-, -CH(cyclopropyl)-, -CH(CF3)-, cyclopropyl;

[0046] In some embodiments, L1is a bond, -O-, -NH-, -NCH3-;

[0047] In some embodiments, L1is a bond;

[0048] In some embodiments, L2is a bond, -CR y1 R y2 -, -CR y1 R y2 CR y1 R y2 -, -O-, -CO-, -NR y3 -, C 2-4 alkynyl, preferably a bond, -O-, -NH-, -NCH3-, methylene, ethylene, ethynylene;

[0049] In some embodiments, L2is a bond, -CR y1 R y2 -, -CR y1 R y2 CR y1 R y2 -, -O-, -CO-, -NR y3 -;

[0050] In some embodiments, L2is a bond, -0-, -CO-, -NR y3 -, C 1-3 alkylene;

[0051] In some embodiments, L2is a bond, -0-, -NH-, -NCH3-, methylene, ethylene;

[0052] In some embodiments, L2is a bond;

[0053] Y is a bond, -(CR y1 R y2 ) m -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y3 -, -S(=0)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -0-CO-, -NR y3 -CO-;

[0054] In some embodiments, Y is a bond, -CR y1 R y2 -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y -, -S(=0)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -0-CO-, -NR y3 -CO-;

[0055] In some embodiments, Y is a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CO-, -CONH-, -CONCH3-, -S(=0)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -0-CO-, -NR y3 -CO-;

[0056] In some embodiments, Y' is selected from -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CONH-, -CONCH3-, -S(=O)2-, -C 2-4 alkenyl-CO-, -C(=N-OR) y3 )-、-C(=CR y1 R y2 -, -O-CO-, -NR y3 -CO-;

[0057] In some implementations, Y represents a bond, -(CR) y1 R y2 ) m -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3 -、-CO-NR y3 -、-S(O)2-;

[0058] R y1 and R y2 Each is independently hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0059] In some implementations, Y is a bond, -CR y1 R y2 -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3 -、-CO-NR y -、-S(=O)2-, preferred bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3-, -CH(CH3-), -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-, -S(=O)2-;

[0060] In some implementations, Y is a bond, -(CR) y1 R y2 ) m -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3-or-CO-NR y3 -;

[0061] In some implementations, Y represents bond, -CO-, or -NR. y3 -or-CO-NR y3 -;

[0062] In some implementations, R y3 It is hydrogen or C 1-3 alkyl;

[0063] In some implementations, Y is a bond, -CR y1 R y2 -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3 -or-CO-NR y ;

[0064] In some embodiments, Y is a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-;

[0065] In some implementations, Y is a bond, -CO-, or -CO-NR. y3 -;

[0066] In some implementations, Y represents a bond, -CO-, -CONH-, or -CONCH3-.

[0067] In some implementations, Y is -CO-;

[0068] R a C 1-6 Alkyl or C 3-6 cycloalkyl;

[0069] In some implementations, R a C 1-3 Alkyl or C 3-6 cycloalkyl;

[0070] In some implementations, R a The compounds are methyl, ethyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0071] R represents hydrogen, deuterium, cyano, amino, hydroxyl, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -S(=O)2-C 1-6 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa , said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino groups are optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0072] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa Rbb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa ,

[0073] In some embodiments, R' is selected from amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa ,

[0074] In some embodiments, R is hydrogen, deuterium, cyano, amino, hydroxyl, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C1-6 alkyl, -C(=O)-NR 1-6 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0075] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb ;

[0076] In some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio or C 1-6alkyl, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0077] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, or C 1-3 alkylamino;

[0078] In some embodiments, R is cyano;

[0079] R aa , R bb each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl;

[0080] In some embodiments, R aa , R bb each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl;

[0081] In some embodiments, R aa , R bb each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 3-6 cycloalkyl;

[0082] In some embodiments, R aa , R bb each independently selected from hydrogen, C1-4 alkyl, C 3-6 cycloalkyl;

[0083] In some embodiments, R aa , R bb each independently is selected from hydrogen, methyl, ethyl, cyclopropyl;

[0084] X1is selected from -N- or -C(R c3 )-;

[0085] In some embodiments, X1is selected from -N-;

[0086] In some embodiments, X1is selected from -C(R c3 )-;

[0087] m is 1, 2, 3; in some embodiments, m is 1, 2; in some embodiments, m is 1;

[0088] with the proviso that is not the following group:

[0089]

[0090] In particular, the first embodiment relates to a compound according to the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0091]

[0092] wherein:

[0093] Cy1is C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally further substituted by 1-3 R c1 ;

[0094] Cy2is present or not; when Cy2is present, Cy2is C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, optionally further substituted by 1-3 R c2 ;

[0095] Cy3is C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzo 3-6 cycloalkyl, benzo 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally further substituted by 1-3 R c3 ;

[0096] each R c1 , R c2 and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkoxyalkyl, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(=0)-(3-8 membered heterocycloalkyl), -NHC(=0)-(3-8 membered heterocycloalkyl), -NH-(5-10 membered heteroaryl), C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, C 3-8 cycloalkyloxy or 3-8 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkyloxy or heterocycloalkyloxy is optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0097] In some embodiments, each R c1 , R c2 , and R c3 are each independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkoxyalkyl, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(=0)-(3-8 membered heterocycloalkyl), -NHC(=0)-(3-8 membered heterocycloalkyl), -NH-(5-10 membered heteroaryl), C 6-10 aryl, 5-10 membered heteroaryl, C 3-8cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkyloxy, or heterocycloalkyloxy groups are optionally further substituted with 1 to 3 groups selected from halo, oxo, C 3-8 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkyloxy, or heterocycloalkyloxy groups are optionally further substituted with 1 to 3 groups selected from halo, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0098] or, any one R c2 , L2, and any one R c3 and the ring atom to which it is attached form a 5-8 membered heterocycloalkyl group, optionally further substituted with 1 to 3 groups selected from halo, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0099] L1and L2are each independently a bond, -(CR y1 R y2 ) m -, C 3-6 cycloalkyl, -O-, -CO-, -NR y3 -, C 2-4 alkenyl, or C 2-4 alkynyl;

[0100] Y is a bond, -(CR y1 R y2 ) m -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y3 -, -S(O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-;

[0101] In some embodiments, Y is a bond, -(CR y1 Ry2 ) m -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3 -、-CO-NR y3 -、-S(O)2-;

[0102] In some implementations, Y is a bond, -(CR) y1 R y2 ) m -、-CR y1 R y2 -CO-, C 3-6 Cycloalkyl, -CS-, -CO-, -NR y3 -or-CO-NR y3 -;

[0103] R y1 and R y2 Each is independently hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0104] In some implementation schemes, R y1 and R y2 Each is independently hydrogen, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0105] R y3 For hydrogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0106] R a C 1-6 Alkyl or C 3-6 cycloalkyl;

[0107] R represents hydrogen, deuterium, cyano, amino, hydroxyl, -COOH, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Alkylamine group, -S(=O)2-C 1-6 Alkyl, -C(=O)-NRaa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa , said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0108] In some embodiments, R is hydrogen, deuterium, cyano, amino, hydroxy, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -S(=O)2-C 1-6 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino groups being optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 haloalkyl.1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0109] In some embodiments, R is cyano, amino, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, or C 1-6 alkylamino, said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or alkylamino optionally further substituted with 1-3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0110] R aa , R bb each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl;

[0111] In some embodiments, R aa , R bb each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl;

[0112] m is 1, 2, 3;

[0113] provided that is not the following group:

[0114]

[0115] In particular, a second embodiment relates to a compound according to Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which satisfies one or more of the following embodiments:

[0116] (1) Cy1is pyrrolidinyl, cyclohexyl, cyclohexenyl, piperidinyl, piperazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinonyl, pyrimidinonyl, pyridazinonyl, benzimidazolyl, indolyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, optionally further substituted with 1-3 R c1 substituted,

[0117] In some embodiments, Cy1is

[0118] optionally further substituted with 1-3 R c1 substituted;

[0119] (2) Cy2is C 3-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-12 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl, 6-12 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, optionally further substituted with 1-2 R c2 substituted;

[0120] In some embodiments, Cy2is C 3-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-12 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl, optionally further substituted with 1-2 R c2 substituted,

[0121] In some embodiments, Cy2is

[0122] optionally further substituted with 1-3 R c2 substituted;

[0123] (3) Cy3is cyclobutyl, cyclohexyl, bicyclo[l. l. l]pentane, phenyl, pyridyl, pyrimidinyl, pyridinonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, benzocyclopentoxy, benzopyrrolodinyl, optionally further substituted with 1-3 R c3 substituents;

[0124] In some embodiments, Cy3is cyclohexyl, bicyclo[l. l. l]pentane, phenyl, pyridyl, pyrimidinyl, pyridinonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, optionally further substituted with 1-3 R c3 substituents,

[0125] In some embodiments, Cy3is or Cy3is optionally further substituted with 1-2 R c3 substituents;

[0126] (4) L1is a bond, -CR y1 R y2 -, C 3-6 cycloalkyl, -O-, -CO-, -NR y3 -,

[0127] In some embodiments, L1is a bond, -O-, -NH-, -NCH3-, -N(cyclopropyl)-, -CH(cyclopropyl)-, -CH(CF3)-, cyclopropyl;

[0128] (5) L2is a bond, -CR y1 R y2 -, -CR y1 R y2 CR y1 R y2 -, -O-, -CO-, -NR y3 -, C 2-4 alkynyl, preferably a bond, -O-, -NH-, -NCH3-, methylene, ethylene, ethynylene;

[0129] In some embodiments, L2is a bond, -CR y1 R y2 -, -CR y1 R y2 CR y1 R y2 -, -O-, -CO-, -NR y3 -,

[0130] In some embodiments, L2is a bond, -O-, -NH-, -NCH3-, methylene, ethylene; In some embodiments, Cy3is cyclohexyl, bicyclo[l. l. l]pentane, phenyl, pyridyl, pyrimidinyl, pyridinonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, optionally further substituted with 1-3 R

[0131] (6) Y is a bond, -CR y1 R y2 -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y -, -S(=O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-;

[0132] In some embodiments, Y is a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CO-, -CONH-, -CONCH3-, -S(=O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-;

[0133] In some embodiments, Y is a bond, -CR y1 R y2 -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y -, -S(=O)2-, preferably a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-, -S(=O)2-;

[0134] In some embodiments, Y is a bond, -CR y1 R y2 -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y -,

[0135] In some embodiments, Y is a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-;

[0136] (7) R a is C 1-3 is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl; 3-6 cycloalkyl,

[0137] In some embodiments, R a is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl;

[0138] (8) R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa ,

[0139] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb ;

[0140] In some embodiments, R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, or C 1-3 alkylamino,

[0141] In some embodiments, R is cyano;

[0142] (9) R c1 is deuterium, halogen, hydroxyl, oxo, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 1-3 alkoxyalkyl, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy, or 4-5 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkyloxy, or heterocycloalkyloxy is optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene,

[0143] In some embodiments, R c1 is oxo, -COOH, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, methoxyethyl,

[0144] (10) R c2 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl,

[0145] In some embodiments, R c2 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, ethenyl, or ethynyl;

[0146] (11) R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, -C(=0)-(4-6 membered heterocycloalkyl), -NHC(=0)-(4-6 membered heterocycloalkyl), -NH-(5-6 membered heteroaryl), C 3-4 cycloalkyloxy, 4-5 membered heterocycloalkyloxy, 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, heteroaryl being optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl;

[0147] In some embodiments, R c3 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methoxy, trifluoromethyl, trifluoromethoxy,

[0148]

[0149] In some embodiments, R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C1-3 deuteroalkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy, 4-5 membered heterocycloalkyloxy, 5-6 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, heteroaryl being optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene, C

[0150] In some embodiments, R c3 is deuterium, halogen, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy or 4-5 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy being optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene, C

[0151] In some embodiments, R c3 is deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, or R c3 is

[0152] A particular third embodiment relates to a compound according to formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to formula (I) further according to formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX):

[0153]

[0154] wherein: Y is a bond, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-, -S(=0)2-;

[0155] In some embodiments, Y is a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-;

[0156] Y' is selected from -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CONH-, -CONCH3-, -S(=0)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-;

[0157] Cy2' is selected from

[0158] optionally further substituted with 1-3 R c2 ;

[0159] Cy3' is selected from optionally further substituted with 1-2 R c3 ;

[0160] R' is selected from amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=0)2-C 1-3 alkyl, -C(=0)-NR aa R bb , -NR aa C(=0)R bb , -NR aa C(=0)OR bb, -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa ,

[0161] R c3’ is selected from deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methoxy, trifluoromethyl, trifluoromethoxy,

[0162] X1is selected from -N- or -C(R c3 )-;

[0163] Cy2, Cy3, R c1 and L2are as described in any of the preceding embodiments.

[0164] In a particular fourth embodiment, the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, is selected from the group consisting of the following Table I:

[0165] Table I:

[0166]

[0167]

[0168]

[0169] In a particular fifth embodiment, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0170] In a particular sixth embodiment, the pharmaceutical composition as described above comprises 1-1500 mg of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, as described in any of the preceding embodiments, and one or more pharmaceutically acceptable carriers or excipients.

[0171] In particular, the seventh embodiment, the present application also provides the use of a compound, stereoisomer thereof or pharmaceutically acceptable salt thereof of any one of the above-mentioned embodiments, or the above-mentioned pharmaceutical composition in the preparation of a medicament, preferably the medicament is for preventing and / or treating FASN-mediated diseases.

[0172] In particular, the eighth embodiment, the FASN-mediated diseases are selected from metabolic-associated steatohepatitis, liver fibrosis, non-alcoholic fatty liver, acne vulgaris, tumor, preferably the tumor is selected from metastatic breast cancer, glioma, metastatic prostate cancer, metastatic non-small cell lung cancer, advanced solid tumor.

[0173] In particular, the ninth embodiment, the present application also provides a method for treating diseases in mammals, the method comprising administering to the subject a therapeutically effective amount of a compound, stereoisomer thereof or pharmaceutically acceptable salt thereof of any one of the above-mentioned embodiments, or the above-mentioned pharmaceutical composition, wherein the therapeutically effective amount is preferably 1-1500 mg, and the diseases are selected from metabolic-associated steatohepatitis, liver fibrosis, non-alcoholic fatty liver, acne vulgaris, tumor, preferably the tumor is selected from metastatic breast cancer, glioma, metastatic prostate cancer, metastatic non-small cell lung cancer, advanced solid tumor.

[0174] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a compound disclosed herein that, when administered, will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of symptoms, signs, or causes of a disease, disorder, or condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound, conjugate, or pharmaceutically acceptable salt thereof disclosed herein that will elicit the biological or medical response (e.g., decrease or alleviation of a disease symptom, signs, or causes) in a tissue system, animal, or human, which is being sought by those skilled in the art. Examples of a therapeutically effective amount include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg;

[0175] In some embodiments, the pharmaceutical composition or formulation of the present application contains a therapeutically effective amount of the compound of any one of the above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0176] The present application further relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the compound of any one of the above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be in the form of a unit formulation (the amount of the active drug in the unit formulation is also referred to as the "formulation strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound of any one of the above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0177] The present application further relates to a method for treating a disease in a mammal, the method comprising administering to the subject a compound of any one of the above described compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients in a daily dose of 1-1500 mg per day, which can be in a single dose or divided doses, in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg per day, 20-1500 mg per day, 25-1500 mg per day, 50-1500 mg per day, 75-1500 mg per day, 100-1500 mg per day, 200-1500 mg per day, 10-1000 mg per day, 20-1000 mg per day, 25-1000 mg per day, 50-1000 mg per day, 75-1000 mg per day, 100-1000 mg per day, 200-1000 mg per day, 25-800 mg per day, 50-800 mg per day, 100-800 mg per day, 200-800 mg per day, 25-400 mg per day, 50-400 mg per day, 100-400 mg per day, 200-400 mg per day, in some embodiments, the daily dose includes, but is not limited to, 1 mg per day, 5 mg per day, 10 mg per day, 20 mg per day, 25 mg per day, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 200 mg per day, 300 mg per day, 400 mg per day, 600 mg per day, 800 mg per day, 1000 mg per day, 1200 mg per day, 1400 mg per day, 1500 mg per day.

[0178] The present application relates to a kit, which can include a single dose or multiple dose forms of the composition, the kit comprising a compound of any one of the above described compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, the amount of the compound of the present application or stereoisomers or pharmaceutically acceptable salts thereof is the same as the amount thereof in the above pharmaceutical composition.

[0179] The amount of the compound of the present application or stereoisomers or pharmaceutically acceptable salts thereof in the present application is converted into the form of free base in each case.

[0180] "Formulation strength" refers to the weight of the main drug contained in each branch, tablet or other unit formulation.

[0181] Synthesis route

[0182] The compounds of the present application can be prepared by those skilled in the art of organic synthesis by adapting known synthetic procedures in conjunction with known starting materials which are either commercially available or described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, including suppliers such as Titan Kogyo, Arjay Chemical, Shanghai Dema, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Drugmaker and Bailingwei Technology, etc.

[0183] Specific and analogous reactants can be identified selectively by the use of the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and on-line. Chemicals that are known but not commercially available can alternatively be prepared by custom chemical synthesis houses, many of which standard chemical supply houses (such as those listed above) offer custom synthesis services.

[0184] Terminology

[0185] Unless otherwise defined, 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. If there is a conflict between the definitions provided in this application and those provided in the art to which this application pertains, the definitions provided in this application control. Where a name, trademark or trade name is used herein, it is intended to represent its corresponding product or active ingredient thereof. All patents, published patent applications, and publications recited herein are incorporated herein by reference.

[0186] The term "alkyl" refers to saturated straight-chain or branched-chain aliphatic hydrocarbon groups having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl group preferably has from 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably from 1 to 8 carbon atoms (i.e., C 1-8 alkyl), further preferably from 1 to 6 carbon atoms (i.e., C 1-6 alkyl), and most preferably from 1 to 3 carbon atoms (i.e., C 1-3Non-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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkyl group is substituted with a substituent, the substituent is not further substituted.

[0187] The term "alkylene" refers to a divalent linear and branched saturated alkyl group. Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0188] The term "alkenyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and still further such as 2 to 4 carbon atoms, examples of which include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; the alkenyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkenyl group is substituted with a substituent, the substituent is not further substituted.

[0189] The term "alkynyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and still further containing 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonylnyl, and 4-decynyl, and the like; the alkynyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkynyl group is substituted with a substituent, the substituent is not further substituted.

[0190] The term "heterocycle" or "heterocyclyl" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, containing, unless otherwise specified, from 1 to 3 heteroatoms selected from N, O, or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spiro heterocycles, and the like, and unless otherwise specified, is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and further preferably a 4- to 7-membered heterocycle. The definition includes heterocycloalkyl and heteroaryl groups. The N, S in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl group can be attached at a heteroatom or carbon atom, non-limiting examples include epoxyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxananyl, azacycloheptanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantanyl, and oxaspiro[3.3]heptanyl, and the like.

[0191] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or a polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl group preferably has from 3 to 12 carbon atoms in the ring (i.e., C 3-12 cycloalkyl), more preferably from 3 to 8 carbon atoms in the ring (i.e., C 3-8 cycloalkyl), further preferably from 3 to 6 carbon atoms in the ring (i.e., C 3-6 cycloalkyl), and most preferably from 3 to 5 carbon atoms in the ring (i.e., C 3-5 cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like. Non-limiting examples of polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0192] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 spirocycloalkyl). The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C 6-14 spirocycloalkyl), more preferably a spirocycloalkyl group having 7 to 10 ring atoms (i.e., C 7-10 spirocycloalkyl). The spirocycloalkyl group is classified as a mono-, bi-, or polycycloalkyl according to the number of spiro atoms shared between the rings, preferably a mono- or bi- spirocycloalkyl, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6- spirocycloalkyl.

[0193] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 fused cycloalkyl). It can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. The fused cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e., C 6-14 fused cycloalkyl), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e., C 7-10 fused cycloalkyl). It is classified as a bi-, tri-, tetra-, or polycyclic fused cycloalkyl according to the number of constituent rings, preferably a bi- or tri- fused cycloalkyl, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6- fused cycloalkyl.

[0194] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20bridged cycloalkyl). It contains one or more double bonds, but no ring has a completely conjugated pi-electron system. The bridged cycloalkyl group preferably has 6 to 14 ring atoms (i.e., C6-14 6-14 bridged cycloalkyl, more preferably a bridged cycloalkyl having 7 to 10 ring atoms (i.e., C7-10 7-10 bridged cycloalkyl). It is classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl depending on the number of rings comprising the ring system, preferably a bicyclic or tricyclic bridged cycloalkyl.

[0195] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring that is attached to the parent structure is a cycloalkyl group, for example, including C 5-6 cycloalkyl and phenyl, C 5-6 cycloalkyl and 5-6 membered heteroaryl, C 5-6 cycloalkyl and 5-6 membered heterocycloalkyl, and the like, preferably cyclopentyl and 5 membered heterocycloalkyl, cyclopentyl and 6 membered heterocycloalkyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, cyclohexyl and 5 membered heterocycloalkyl, cyclohexyl and 6 membered heterocycloalkyl, cyclohexyl and 5 membered heteroaryl, cyclohexyl and 6 membered heteroaryl, and the like. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the cycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0196] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or a polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) nheteroatoms selected from N, O, and S, further preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S, even further preferably 3 to 6 ring atoms (i.e., 3-6 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S, and most preferably 5 to 6 ring atoms (i.e., 5-6 membered heterocycloalkyl) containing 1-4, 1-3, or 1-2 heteroatoms selected from N, O, and S. Non-limiting examples of monocyclic heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanonyl, 2,2-difluorocyclopentanonyl, azepinyl, oxolanyl, or azolidinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0197] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (referred to as the spiro atom) between single rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) na ring member, which is not -0-0-, -0-S-, or -S-S-, the remaining ring members being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The spiroheterocycloalkyl group is preferably a spiroheterocycloalkyl group having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably a spiroheterocycloalkyl group having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is classified as a mono-, bi-, or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monosprioheterocycloalkyl group or a bispiroheterocycloalkyl group, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocycloalkyl group. Non-limiting examples include: etc.

[0198] The term "fused heterocycloalkyl" or "annelated heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n a ring member, which is not -0-0-, -0-S-, or -S-S-, the remaining ring members being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The spiroheterocycloalkyl group is preferably a spiroheterocycloalkyl group having 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably a spiroheterocycloalkyl group having 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is classified as a mono-, bi-, or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monosprioheterocycloalkyl group or a bispiroheterocycloalkyl group, more preferably a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocycloalkyl group. Non-limiting examples include: etc.

[0199] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non-adjacent atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n (herein m, n are integers from 0 to 2) but excluding ring members of -O-O-, -O-S-, or -S-S-, with the remaining ring atoms being carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system. The bridged heterocycloalkyl group preferably has 6 to 14 ring atoms (i.e., 6-14 membered bridged heterocycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7-10 membered bridged heterocycloalkyl). It can be bicyclic, tricyclic, tetracyclic, or polycyclic, depending on the number of rings comprising the ring system, preferably bicyclic or tricyclic. Non-limiting examples include: and the like.

[0200] The heterocycloalkyl group includes polycyclic heterocycloalkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocycloalkyl group, for example, including 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and C 5-6 6 membered heterocycloalkyl, 6 membered heterocycloalkyl and 5 membered heteroaryl, 6 membered heterocycloalkyl and 6 membered heteroaryl, and the like. The heterocycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment). When the heterocycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0201] The term "aryl" refers to an all-carbon monocyclic or fused ring polycyclic ring system (i.e., monocyclic aryl or polycyclic aryl) that contains a conjugated pi-electron system having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms in the ring system (i.e., C 6-14 aryl). The aryl group preferably has 6 to 12 carbon atoms in the ring system (i.e., C 6-12 aryl), more preferably 6 to 10 carbon atoms in the ring system (i.e., C 6-10 aryl), and even more preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group, for example, is phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthryl, phenanthryl, and the like.

[0202] The aryl group includes polycyclic systems that can be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 heterocycloalkyl, benzo5-6 heteroaryl, preferably benzoC 4-6 Cycloalkyl, benzo4-6-membered heterocycloalkyl, benzo5-6-membered heteroaryl, further preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazacyclobutyl, benzooxetyl, benzooxetyl, benzoazapentyl, benzooxetyl, benzooxetyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridinoneyl, benzopyrazinyl, benzopyridazinyl. The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is no longer further substituted.

[0203] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C group. 6-10 Aryl or C 6-10aryl and 5-6 membered heteroaryl, further preferred 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothienyl, pyridopyrrolyl, benzo-γ-pyrone, pyrido-γ-pyrone, etc.

[0204] The heteroaryl groups include polycyclic ring systems fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl and C 3-8 cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, preferably 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl. The heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the heteroaryl groups are substituted with substituents, the substituents are not further substituted. Non-limiting examples include: etc.

[0205] The term "alkoxy" means -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkyl group preferably has 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), most preferably 1 to 3 carbon atoms (i.e., C 1-3 alkoxy). Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like. The alkyl group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkyl group is substituted with substituents, the substituents are not further substituted.

[0206] The term "alkylthio" means -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio group preferably has 1 to 8 carbon atoms (i.e., C1-8 alkylthio), more preferably alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), most preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 alkylthio). Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. The alkylthio group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkylthio group is substituted with a substituent, the substituent is not further substituted.

[0207] The term "halo" or "halogen" or "halogenated" shall be understood to mean a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) atom, preferably a fluorine, chlorine, bromine atom.

[0208] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, and the like, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0209] The term "haloalkoxy" means an alkoxy group as defined above substituted with one or more halogen. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0210] The term "alkylidene" means a divalent free radical alkyl group formed by the loss of two hydrogen atoms, wherein alkyl is as defined above. Non-limiting examples include: methylene ( ), ethylidene ( ), 1-methylethylidene ( ).

[0211] The term "haloalkylidene" means an alkylidene group as defined above substituted with one or more halogen. Non-limiting examples include: fluoromethylene ( ), difluoromethylene ( ).

[0212] The term "alkoxyalkyl" means an alkyl group as defined above substituted with one or more alkoxy groups, wherein alkoxy, alkyl are as defined above. Non-limiting examples include: methoxymethyl ( ), methoxyethyl ( ).

[0213] The term "cycloalkylalkyl" means an alkyl group as defined above substituted with one or more cycloalkyl groups, wherein cycloalkyl, alkyl are as defined above. Non-limiting examples include: cyclopropylmethyl ( ), cyclopropylethyl ( ).

[0214] The term "heteroaralkyl" means an alkyl group, as defined above, having at least one heteroaromatic substituent, wherein heteroaromatic and alkyl are as defined above. Non-limiting examples include:

[0215] The term "cycloalkyloxy" means -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined above, e.g., "C 3-6 Cycloalkyloxy" means cycloalkyloxy groups containing 3-6 carbons, including, but not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0216] The term "heterocycloalkyloxy" means -O-(unsubstituted heterocycloalkyl), wherein heterocycloalkyl is as defined above, including, but not limited to, azetidinyloxy, pyrrolyloxy, and the like.

[0217] The term "mercapto" means -SH.

[0218] The term "hydroxyl" means -OH.

[0219] The term "nitro" means -NO2.

[0220] The term "amino" means -NH2.

[0221] The term "cyano" means -CN.

[0222] The term "carboxyl" means -C(O)OH.

[0223] The term "aldehyde" means -CHO.

[0224] The term "oxo" or "oxo group" means =O.

[0225] The term "carbonyl" means C=O.

[0226] The term "amido" means -C(O)NH2.

[0227] The term "sulfonyl" means -S(O)2.

[0228] The term "deuteroalkyl" means an alkyl group, as defined above, substituted with one or more deuterium, wherein alkyl is as defined above.

[0229] The term "deuteroalkoxy" means an alkoxy group, as defined above, substituted with one or more deuterium, wherein alkoxy is as defined above.

[0230] The term "haloalkoxy" means an alkoxy group, as defined above, substituted with one or more halogen, wherein alkoxy is as defined above.

[0231] The term "hydroxyalkyl" means an alkyl group, as defined above, substituted with one or more hydroxyl, wherein alkyl is as defined above.

[0232] The term "alkylamino" means alkyl-NH-, wherein alkyl is as defined above.

[0233] The term "alkylene" refers to a divalent straight-chain and branched alkyl group.

[0234] The term "alkynylene" refers to a divalent straight-chain and branched alkynyl group.

[0235] The terms "comprise", "comprising", "have", "having", "include", "including", "contain", "containing", or "involve" and other variations thereof, are to be construed as open-ended or inclusive and do not exclude additional, unrecited elements or method steps. It will be understood by those within the art that, as used herein, the term "comprising" encompasses the meanings of "consisting of" and "consisting essentially of".

[0236] The term "one or more" or similar expressions "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0237] When a range of values is disclosed, any value or range of values falling within that range is included. In particular, each numerical range disclosed herein is understood to include each and every value falling within that range and any sub-range encompassed therein.

[0238] In the present text, "Z" and "-Z-" are both meant to represent the same particular group, which can be used interchangeably.

[0239] As used herein, the expression m-n means the range from m to n and subranges and individual points comprised therein. For example, the expression "C2-C8" or "C 2-8 " encompasses the range of 2 to 8 carbon atoms and is understood to also encompass any sub-range and each individual point comprised therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, for example, can encompass any sub-range and point value comprised therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc., and C3, C4, C5, C6, C7, C8, C9, C 10 , etc. For example, the expression "C1-C6" or "C 1-6"comprises a range from 1 to 6 carbon atoms and is to be understood as also encompassing any sub-range of that range, as well as each individual point within the range, e.g., C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. Also, for example, the expression "from three to ten" is to be understood as encompassing any sub-range within that range, as well as each individual point within the range, e.g., from three to five, from three to six, from three to seven, from three to eight, from four to five, from four to six, from four to seven, from four to eight, from five to seven, from five to eight, from six to seven, from six to eight, from nine to ten, etc., as well as three, four, five, six, seven, eight, nine, ten, etc. Other similar expressions are to be understood in a similar manner herein.

[0240] The expressions "X is selected from A, B or C," "X is selected from A, B and C," "X is A, B or C," "X is A, B and C," and the like, are used interchangeably herein and are meant to convey the same meaning, i.e., that X can be any one of A, B, C, or any combination thereof.

[0241] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes instances where the cycloalkyl is substituted with alkyl and instances where the cycloalkyl is not substituted with alkyl.

[0242] The terms "substituted" and "substitution" mean 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 the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. In addition, when a structural unit is substituted, even if the structural unit has been noted as having a hydrogen atom, it does not mean that the hydrogen atom cannot be substituted, e.g., a structural unit The hydrogen atom on the central nitrogen atom can be substituted. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When describing the absence of certain substituents, it is to be understood that the substituent can be one or more hydrogen atoms, provided that the structure results in a stable compound. When describing that each carbon atom in a group can be optionally replaced with a heteroatom, provided that the normal valency of the group is not exceeded, and that a stable compound results. Exemplary substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 aryl, 5-12 membered heteroaryl, -CO-(C 3-8-C(=O)-, -C(=S)-, -S-, -O-, -N(Ra)-, -N(Ra)C(=O)-, -C(=O)N(Ra)-, -N(Ra)S(O)t (t = 1 or 2)-, -S(O)tN(Ra)- (t = 1 or 2), -N(Ra)C(=NRa)-, -C(=NRa)N(Ra)-, -N(Ra)C(=NRa')-, 5-12 aryl), -CO-(5-12 membered heteroaryl), hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, thiol, C 1-6 alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -CH=N(C 1-6 alkyl), -CH=N-O(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 alkyl, and the like.

[0243] If a substituent is described as “optionally substituted,” the substituent can be unsubstituted or can be substituted. If an atom or group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the atom or group are replaced by an independently selected, optional substituent. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is “non-substituted” or “unsubstituted.” Unless indicated, as used herein, the point of attachment for a substituent can be from any suitable position on the substituent.

[0244] When the bond to a substituent group is shown to be attached to a ring at a point where two atoms of the ring are connected, then such substituent group can be bonded to either atom of the ring at which the bond is shown to be attached.

[0245] When any variable (e.g. R) occurs more than one time in a compound or substituent, each occurrence of such variable is independent of the other. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, then the group is optionally substituted with up to four R substituents, and the selection of each R is independent of the others.

[0246] When a linking group is recited without a specified direction of attachment, then the linking group can be attached in either orientation, e.g., A-L-B, where L is selected from -M-W-, includes A-M-W-B and A-W-M-B, with A-M-W-B being preferred.

[0247] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The term stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. All such possible isomers, including enantiomers, rotamers, diastereomers, (D)-isomers, (L)-isomers, racemics, and mixtures thereof, are intended to be within the scope of the present application. In certain embodiments, preferred compounds are those exhibiting greater biological activity. Purified or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the present application are also included within the scope of the present application. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0248] The compounds of the present application also include tautomeric forms. Tautomers refer to a pair of functional groups that can be interconverted by a reversible chemical reaction called tautomerization, usually involving the migration of a hydrogen atom and a pair of electrons. Examples of such pairs are aldehyde / keto-enol, imine-enamine.

[0249] Any hydrogen atom in a compound of the present application can be replaced by its isotope deuterium.

[0250] The compounds of the present application include all suitable isotopic variations of the compounds. The term "isotopic variations" refers to compounds having at least one atom replaced by an atom having the same atomic number but an atomic mass different from the atomic mass of the atom typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I, and 131 I, and the like, preferably deuterium.

[0251] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each of the available hydrogen atoms attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0252] In the compounds of the present application, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% incorporation of deuterium).

[0253] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use.

[0254] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application which is safe and effective for use in mammals, and possesses the desirable biological activity.

[0255] The term "pharmaceutical composition" refers to a composition comprising one or more compounds of the present application or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient to exert a biological activity.

[0256] The term "pharmaceutically acceptable carrier" refers to those agents that do not cause significant irritation to an organism, and do not abrogate the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersing agents, effervescent agents, stabilizers, solvents, or emulsors.

[0257] The terms "administration" or "administering" or the like refer to methods allowing the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0258] As used herein, the term "treatment" includes alleviating, abating or ameliorating a disease or condition, preventing the symptoms of other conditions, improving or preventing the underlying metabolic factors causing the symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, and extending to prophylaxis. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that the patient can experience an improvement in the quality of life without necessarily being cured of the disorder. By prophylactic benefit is meant that the composition is used in a patient prior to the onset of disease to prevent disease, or prior to the onset of symptoms to prevent symptoms.

[0259] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest. The term "neuropsychiatric disorder" refers to the general class of neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0260] The term "effective amount," "therapeutically effective amount," or "prophylactically effective amount" in reference to a drug, drug unit, or active ingredient means an amount of the drug or agent that is acceptable in terms of side effects, but that is sufficient to achieve the intended result. The determination of an effective amount is dependent on the individual, on the age and general condition of the individual, and on the specific active substance, and an appropriate effective amount in an individual case can be determined by the person skilled in the art by routine tests.

[0261] As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) who has a disease, e.g., a disease described herein, or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles), and mammals, e.g., non-human primates, domestic animals, and / or laboratory models, e.g., sheep, dogs, cats, cows, pigs, etc.

[0262] The term "room temperature" refers to a temperature from 10 °C to 40 °C. In some embodiments, "room temperature" refers to a temperature from 15 °C to 30 °C; in other embodiments, "room temperature" refers to a temperature from 18 °C to 25 °C.

[0263] "Equivalent" or its abbreviation "eq" is the equivalent amount of a material needed in a chemical reaction, based on the amount of the primary material used in each step (1 equivalent).

[0264] The following detailed description of the application is intended to illustrate, but not limit, the non-limiting embodiments, to enable those skilled in the art to better understand the technical solutions of the present application, its principles and its practical applications, so that other skilled persons in the art can modify and implement the present application in many forms to best adapt it to the requirements of specific uses. DETAILED DESCRIPTION

[0265] The content of the present application will be described in detail below by way of examples. The specific conditions not mentioned in the examples are carried out according to the conventional experimental methods. The examples are given to better illustrate the content of the present application, but should not be understood as limiting the content of the present application to the examples. The person skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above content of the present application, which still fall within the protection scope of the present application.

[0266] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is expressed in 10 -6NMR measurements were made on (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard;

[0267] MS measurements were made on (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0268] HPLC measurements were made using Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C 18 100 x 4.6 mm, 3.5 μΜ);

[0269] Thin layer chromatography silica gel plates were used from Yantai Huanghai HSG F254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography (TLC) were 0.15 mm - 0.20 mm and the specifications used for thin layer chromatography separation and purification of products were 0.4 mm - 0.5 mm.

[0270] Column chromatography generally used Yantai Huanghai silica gel 200 - 300 mesh silica gel as the carrier.

[0271] Abbreviation explanation:

[0272] NaHMDS: sodium bis(trimethylsilyl)amide;

[0273] NaH: sodium hydride;

[0274] DMSO: dimethyl sulfoxide;

[0275] HC1 / DOX: hydrochloric acid dioxane;

[0276] Pd(dppf)Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride;

[0277] DIPEA: N,N-diisopropylethylamine;

[0278] HOBT: 1-hydroxybenzotriazole;

[0279] EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0280] DMAP: 4-dimethylaminopyridine;

[0281] DMF: N,N-dimethylformamide;

[0282] HATU: 2-(7-Azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0283] Examples

[0284] Embodiments of the present application will be described in detail below with reference to Examples, but those skilled in the art will appreciate that the following Examples are intended to be illustrative only and should not be viewed as limiting the scope of the present application. Where specific conditions are not mentioned in the Examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. Where the manufacturer of the reagent or instrument is not mentioned, it is a conventional product that can be obtained commercially. The proportions or percentages used herein are by weight unless otherwise specified.

[0285] Intermediate 1

[0286]

[0287] First step: Compound 1a (4.5 g, 18.44 mmol), methyl propargyl ether (5.17 g, 73.76 mmol), bis(triphenylphosphine)palladium dichloride (0.65 g, 0.92 mmol), cuprous iodide (0.35 g, 1.84 mmol) and triethylamine (9.33 g, 92.20 mmol) were added into DMF (100 mL) successively, protected by nitrogen, heated to 75 °C and stirred overnight, cooled, quenched with saturated ammonium chloride solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 1b (3 g, 69%).

[0288] LC-MS (ESI): m / z = 233.1 [M+H] + .

[0289] Second step: Compound 1b (2 g, 8.57 mmol), p-toluenesulfonic acid monohydrate (4.43 g, 25.71 mmol), platinum dioxide (0.39 g, 1.71 mmol) were added into methanol (50 mL), protected by nitrogen, heated to 75 °C and stirred overnight, LCMS monitoring showed that the raw material was completely reacted, cooled, filtered, and the filtrate was diluted with water, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound 1c (1.6 g, 74%).

[0290] LC-MS (ESI): m / z = 251.1 [M+H] + .

[0291] Step 3: Compound 1c (3.2 g, 12.79 mmol) was dissolved in dichloromethane (80 mL), then bromine (2.0 g, 12.79 mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, TLC monitored the complete reaction of raw materials, then the reaction solution was slowly dropped into saturated sodium sulfite solution in ice bath, DCM extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target compound 1d (3.2 g, 76%).

[0292] LC-MS (ESI): m / z = 329.0 [M+H] + .

[0293] Step 4: Compound 1d (1.8 g, 5.47 mmol), trifluoroacetamidine (1.23 g, 10.94 mmol), cesium carbonate (3.56 g, 10.94 mmol) were added to a 100 mL sealed tube, then ultra-dry acetonitrile (30 mL) was added, heated to 75°C and stirred for 5 hours, filtered, the filtrate was diluted with water, then extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and then purified by silica gel column chromatography to obtain the target compound 1e (1.0 g, 53%).

[0294] LC-MS (ESI): m / z = 343.1 [M+H] + .

[0295] Step 5: Compound 1e (1.0 g, 2.92 mmol) was added to 10 mL of anhydrous methanol, then 1 mL of 6M aqueous sodium hydroxide solution was added, stirred at room temperature for 10 hours, TLC monitored the complete reaction of raw materials, then concentrated, diluted with water and then adjusted to pH about 7 with 1M aqueous hydrochloric acid solution, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to obtain the intermediate 1 (1.0 g, crude).

[0296] LC-MS (ESI): m / z = 329.1 [M+H] + .

[0297] Example 1

[0298]

[0299] First Step: Compound 1A (2 g, 9.38 mmol), imidazole (1.92 g, 28.14 mmol), triphenylphosphine (4.92 g, 18.76 mmol), iodine (3.57 g, 14.07 mmol) were dissolved in toluene (40 mL) and stirred at 100 °C for 4 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (20 mL). The organic layer was concentrated and the residue was purified by column chromatography to give compound 1B (1.2 g, yield: 39.6 %).

[0300] 1 H NMR (400 MHz, CDCl3-d6) δ 4.33-4.25 (m, 1H), 3.95 (s, 2H), 3.92 (s, 2H), 2.94-2.89 (m, 2H), 2.73-2.68 (m, 2H), 1.42 (s, 9H).

[0301] Second Step: Compound 1B (1.2 g, 3.71 mmol) was dissolved in isopropyl alcohol (30 mL) and (1R,2R)-2-aminocyclohexanol hydrochloride (43 mg, 0.37 mmol), nickel iodide (120 mg, 0.37 mmol), cyanoboronic acid (1.09 g, 7.42 mmol) were added. The reaction mixture was stirred at room temperature for 10 min and NaHMDS (1.36 g, 7.42 mmol) was added. The reaction mixture was stirred at 80 °C for 4 h. The reaction was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to give compound 1C (0.8 g, yield: 72.2 %).

[0302] LC-MS (ESI): m / z = 243.1 [M-56+H] + .

[0303] Third Step: Compound 1C (0.2 g, 0.67 mmol) was dissolved in formic acid (10 mL) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to give compound 1D (150 mg, crude) which was used directly for the next step.

[0304] LC-MS (ESI): m / z = 199.1 [M+H] + .

[0305] Fourth step: Compound intermediate 1 (0.1 g, 0.30 mmol) was dissolved in DMF (10 mL), EDCI (86 mg, 0.45 mmol), HOBT (61 mg, 0.45 mmol), triethylamine (91 mg, 0.90 mmol) were added, after 30 minutes of reaction at room temperature, compound 1D (0.12 g, 0.6 mmol) was added, and stirred at room temperature for 16 hours. TLC detection showed that the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography and HPLC to obtain compound 1 (25 mg, yield: 16%).

[0306] LC-MS (ESI): m / z = 509.2 [M+H] + .

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 13.6 (s, 1H), 7.76-7.73 (m, 2H), 7.42-7.39 (m, 2H), 7.26-7.11 (m, 2H), 4.33-4.13 (m, 3H), 4.07-3.85 (m, 3H), 3.53-3.87 (m, 1H), 3.22-3.19 (m, 3H), 2.63-2.54 (m, 2H), 2.32-2.12 (m, 8H).

[0308] Example 2

[0309]

[0310] First step: Compound 2A (0.8 g, 2.90 mmol), N,N-diisopropyl ethylamine (1.12 g, 8.69 mmol) were dissolved in N,N-dimethylformamide (15 mL), HATU (1.65 g, 4.35 mmol) was added, and stirred at room temperature for half an hour, then 3-(4-pyridyl)-1-azetidine hydrochloride (742 mg, 4.35 mmol) was added, and the reaction was continued at room temperature overnight. After TLC monitoring showed that the raw material disappeared, water (50 mL) was added, and 50 mL of ethyl acetate was extracted twice. The organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 2B (0.72 g, 63.3%).

[0311] LC-MS (ESI): m / z = 393.1 [M+H] + .

[0312] Second Step: Compound 2B (0.72 g, 1.84 mmol), bis(pinacolato)diboron (932 mg, 3.67 mmol), Pd(dppf)Cl2(134 mg, 0.18 mmol) and potassium acetate (0.54 g, 5.51 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 80 °C overnight. After TLC monitoring of the disappearance of the starting material, water (20 mL) was added and extracted with 20 mL of ethyl acetate twice. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated and the residue was purified by column chromatography to obtain compound 2C (0.43 g, yield: 59.7%).

[0313] LC-MS (ESI): m / z = 393.1 [M+H] + .

[0314] Third Step: Compound 2C (0.43 g, 1.10 mmol), intermediate 1 (337 mg, 1.10 mmol), Pd(PPh3)2Cl2(77 mg, 0.11 mmol) and sodium carbonate were dissolved in a mixed solution of tetrahydrofuran and water (10 mL, THF:H2O = 4:1) and stirred at 70 °C for 2 h. After TLC monitoring of the disappearance of the starting material, water (20 mL) was added and extracted with 20 mL of ethyl acetate twice. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by HPLC to obtain compound 2 (6 mg, 1.2%)

[0315] LC-MS (ESI): m / z = 445.4 [M+H] + .

[0316] 1 H NMR (400 MHz, DMSO-d6) d 8.56 - 8.50 (m, 2H), 7.42 - 7.36 (m, 2H), 7.25 (brs, 2H), 4.46 (t, 1H), 4.34 - 4.13 (m, 3H), 4.09 - 3.86 (m, 3H), 3.14 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H).

[0317] Example 3

[0318]

[0319] First step: Compound 3A (500 mg, 2.01 mmol) was dissolved in anhydrous dichloromethane (15 mL), p-nitrophenyl chloroformate (610 mg, 3.03 mmol) and N,N-diisopropyl ethylamine (780 mg, 6.04 mmol) were added under ice bath condition, after the addition was completed, the reaction solution was stirred at room temperature for 16 h. The reaction was quenched by adding water (50 mL) and extracted with dichloromethane (50 mL) twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by normal phase column chromatography to obtain compound 3B (450 mg, yield: 54.06%).

[0320] LC-MS (ESI): m / z = 358.1 [M-56+H] + .

[0321] Second step: Compound 3B (450 mg, 1.09 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), after nitrogen protection, methanol (280 mg, 8.70 mmol) was added, and stirred at 65°C oil bath overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a residue, which was purified by normal phase column chromatography to obtain compound 3C (200 mg, yield: 59.98%).

[0322] LC-MS (ESI): m / z = 251.1 [M-56+H] + .

[0323] Third step: Compound 3C (200 mg, 0.65 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added under ice bath, and stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain compound 3D (crude, 300 mg), which was directly used in the next step reaction.

[0324] LC-MS (ESI): m / z = 207.2 [M+H] + .

[0325] Fourth step: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (5 mL), HATU (120 mg, 0.32 mmol) was added, and stirred at room temperature for 30 min. 3D (300 mg) and N,N-diisopropyl ethylamine (160 mg, 1.23 mmol) were added, after the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (50 mL) was added to dilute the reaction solution, and extracted with ethyl acetate (50 mL) three times, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 3 (23 mg, yield: 14.62%)

[0326] LC-MS (ESI): m / z = 517.1 [M+H]+ .

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.45-7.42 (m, 2H), 7.29-7.27 (m, 2H), 7.24 (s, 2H), 4.45-4.41 (m, 1H), 4.31-4.27 (m, 1H), 4.22 (s, 2H), 4.00-3.96 (m, 1H), 3.93-3.89 (m, 1H), 3.86-3.78 (m, 1H), 3.66 (s, 3H), 3.15 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H).

[0328] Example 4

[0329]

[0330] First Step: Compound 4A (8.00 g, 97.44 mmol) was dissolved in anhydrous dichloromethane (160 mL), N,N-diisopropylethylamine (31.48 g, 243.59 mmol) was added to the reaction solution under ice bath condition, then dimethylamine sulfonyl chloride (16.79 g, 116.92 mmol) was slowly added dropwise, after the addition was completed, the reaction solution was stirred at room temperature for 4 h. The reaction was quenched with water (100 mL) and extracted twice with dichloromethane (50 mL), and the aqueous phase was purified by reverse phase column chromatography to obtain compound 4B (8.00 g, yield: 43.39%).

[0331] LC-MS (ESI): m / z = 190.1 [M+H] + .

[0332] Second Step: Compound 4B (8.00 g, 42.28 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL), after nitrogen protection, n-butyllithium (25.40 mL, 63.41 mmol) was added dropwise at-78 °C, the reaction solution was continued to stir for 1 h, then bromomethyl methyl ether (5.55 g, 44.39 mmol) was added, after the addition was completed, the reaction solution was stirred at room temperature for 2 h. After the reaction was quenched with water (100 mL), the reaction solution was concentrated to a small volume (~ 120 mL) under reduced pressure and extracted twice with ethyl acetate (50 mL), and the aqueous phase was purified by reverse phase column chromatography to obtain compound 4C (6.00 g, yield: 60.84%).

[0333] LC-MS (ESI): m / z = 234.1 [M+H] + .

[0334] 1H NMR (400 MHz, CDCI3) δ 6.88 (s, 1 H), 4.51 (s, 2 H), 3.35 (s, 3 H), 2.95 (s, 6 H), 2.62 (s, 3 H).

[0335] Third step: Compound 4C (3.50 g, 15.00 mmol) was dissolved in 1,4-dioxane (35 mL), 6N hydrochloric acid aqueous solution (15 mL, 90.02 mmol) was added, and after the addition was completed, the reaction liquid was stirred at 50°C oil bath overnight. Slowly add saturated sodium bicarbonate aqueous solution (200 mL) under ice bath to quench the reaction, extract twice with ethyl acetate (50 mL), and purify the obtained aqueous phase by reverse phase column chromatography, then purify by normal phase column chromatography to obtain compound 4D (1.20 g, yield: 63.40%).

[0336] LC-MS (ESI): m / z = 127.2 [M+H] + .

[0337] Fourth step: Compound 4D (1.20 g, 9.51 mmol) was dissolved in acetonitrile (25 mL), NBS (1.73 g, 9.70 mmol) was added, and after the addition was completed, the reaction liquid was stirred at room temperature overnight. The reaction liquid was concentrated to dryness, redissolved in dichloromethane (50 mL), washed with water (10 mL), and the obtained aqueous phase was purified by reverse phase column chromatography to obtain compound 4E (1.30 g, yield: 66.65%).

[0338] 1 H NMR (400 MHz, CDCI3) δ 4.40 (s, 2 H), 3.33 (s, 3 H), 2.38 (s, 3 H).

[0339] Fifth step: Compound 4E (560 mg, 2.73 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL), and after nitrogen protection, 4F (870 mg, 3.00 mmol, refer to patent WO2015095767A1 synthesis) was added, followed by potassium carbonate (945 mg, 6.83 mmol) and Pd(dppf)Cl2(300 mg, 0.41 mmol). After the addition was completed, the reaction liquid was stirred at 80°C oil bath for 16 h. The reaction liquid was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (150 mL) six times, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by normal phase column chromatography and then by reverse phase column to obtain compound 4G (370 mg, yield: 46.99%).

[0340] LC-MS (ESI): m / z = 289.2 [M+H] + .

[0341] 1 H NMR (400 MHz, CDC13) δ 7.82 (s, 2H), 7.13 (s, 1H), 4.26 (s, 2H), 3.85 (s, 3H), 3.31 (s, 3H), 2.59 (s, 3H), 2.41 (s, 3H), 2.28 (s, 3H).

[0342] Step 6: Compound 4G (370 mg, 1.28 mmol) was dissolved in tetrahydrofuran (8 mL), and a solution of lithium hydroxide (220 mg, 5.15 mmol) in water (2 mL) was added. After the addition was completed, the reaction solution was stirred at room temperature overnight. The pH of the reaction solution was adjusted to 3-4 with 6N dilute hydrochloric acid, and the reaction solution was concentrated and purified by reverse phase column chromatography to obtain compound 4H (220 mg, yield: 62.50%).

[0343] LC-MS (ESI): m / z = 275.2 [M+H] + .

[0344] Step 7: Compound 4H (120 mg, 0.44 mmol) was dissolved in N,N-dimethylformamide (6 mL), and after nitrogen protection, HATU (170 mg, 0.45 mmol) was added. After stirring at room temperature for 1 h, 4J (80 mg, 0.46 mmol) and N,N-diisopropylethylamine (170 mg, 0.23 mmol) were added in turn. After the addition was completed, the reaction solution was stirred at room temperature for 16 h. Water (50 mL) was added for dilution, and dichloromethane (100 mL) was extracted three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then HPLC to obtain the target compound 4 (82 mg, yield: 48.00%).

[0345] LC-MS (ESI): m / z = 391.1 [M+H] + .

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.54-8.53 (m, 2H), 7.39-7.38 (m, 2H), 7.19-7.12 (m, 2H), 4.48-4.44 (m, 1H), 4.35-4.31 (m, 1H), 4.18 (s, 1H), 4.06-4.03 (m, 2H), 3.94-3.91 (m, 2H), 3.13 (s, 3H), 2.34 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H).

[0347] Example 5

[0348]

[0349] First Step: Compound 5A (1 g, 3.53 mmol) was dissolved in isopropanol (30 mL), (1R,2R)-2-aminocyclohexanol hydrochloride (41 mg, 0.35 mmol), nickel iodide (110 mg, 0.35 mmol), 4-benzyloxybenzeneboronic acid (1.61 g, 7.06 mmol) were added, the reaction was stirred at room temperature for 10 minutes, then NaHMDS (1.29 g, 7.06 mmol) was added, and the reaction was stirred at 80 °C for 4 hours. TLC detection showed that the reaction was completed, water (100 mL) was added, and ethyl acetate (50 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 5B (0.5 g, yield: 41%).

[0350] LC-MS (ESI): m / z = 284.1 [M-56+H] + .

[0351] Second Step: Compound 5B (0.4 g, 1.18 mmol) was dissolved in methanol (10 mL), wet palladium carbon (10%, 40 mg) was added, and hydrogen was replaced three times. The reaction was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound 5C (250 mg, crude), which was directly used in the next step.

[0352] LC-MS (ESI): m / z = 194.1 [M-56+H] + .

[0353] Third Step: Compound 5C (250 mg, 1.00 mmol) was dissolved in anhydrous dichloromethane (10 mL), p-nitrophenyl chloroformate (300 mg, 1.50 mmol) and N,N-diisopropyl ethylamine (390 mg, 3.00 mmol) were added. After the addition was completed, the reaction was stirred at room temperature for 16 h. Water (20 mL) was added to quench the reaction and extracted with dichloromethane (20 mL) twice. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain compound 5D (250 mg, yield: 60.1%).

[0354] LC-MS (ESI): m / z = 359.0 [M-56+H] + .

[0355] Step 4: Compound 5D (250 mg, 0.60 mmol) was dissolved in dichloromethane (10 mL), and methylamine hydrochloride (56 mg, 1.20 mmol) and N,N-diisopropylethylamine (310 mg, 2.40 mmol) were added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted twice with dichloromethane (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 5E (150 mg, yield: 81.1%).

[0356] LC-MS(ESI):m / z=251.0[M-56+H] + .

[0357] Step 5: Dissolve compound 5E (150 mg, 0.49 mmol) in formic acid (5 mL) and stir at room temperature for 16 h. Concentrate the reaction solution under reduced pressure to obtain compound 5F (crude product, 100 mg), which is used directly in the next step of the reaction.

[0358] LC-MS (ESI): m / z = 207.2 [M+H] + .

[0359] Step 6: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), and HATU (140 mg, 0.36 mmol) was added. The mixture was stirred at room temperature for 30 min, then 5F (74 mg, 0.36 mmol) and N,N-diisopropylethylamine (120 mg, 0.90 mmol) were added. After the addition was complete, the mixture was stirred at room temperature for 16 h. The reaction solution was diluted with water (20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography and then subjected to preparative HPLC to obtain target compound 5 (40 mg, yield: 25.4%).

[0360] LC-MS (ESI): m / z = 517.2 [M+H] + .

[0361] 1 H NMR(400MHz,DMSO-d6)δ7.58-7.55(m,1H),7.36(d,2H),7.30-7.18(m,2H),7.07(d,2H),4.47-4.43 (m,1H),4.35-4.10(m,3H),4.02–3.85(m,3H),3.15(s,3H),2.65(d,3H),2.36(s,3H),2.21(s,3H).

[0362] Example 6

[0363]

[0364] First Step: Compound 6A (0.12 g, 0.43 mmol), N,N-diisopropylethylamine (0.17 g, 1.29 mmol) were dissolved in N,N-dimethylformamide (10 mL), HATU (0.20 g, 0.52 mmol) was added, after stirring at room temperature for half an hour, cyclopropylamine (49 mg, 0.86 mmol) was added, and the reaction was carried out at room temperature for 16 h. After monitoring the disappearance of the raw material by TLC, water (20 mL) was added, and ethyl acetate (20 mL) was extracted twice. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 6B (0.12 g, 87.6%).

[0365] LC-MS (ESI): m / z = 261.1 [M+56+H] + .

[0366] Second Step: Compound 6B (120 mg, 0.38 mmol) was dissolved in formic acid (5 mL), and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound 6C (crude, 100 mg), which was directly used in the next step reaction.

[0367] LC-MS (ESI): m / z = 217.2 [M+H] + .

[0368] Third Step: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), HATU (140 mg, 0.36 mmol) was added, and stirred at room temperature for 30 min. 6C (97 mg, 0.45 mmol) and N,N-diisopropylethylamine (120 mg, 0.90 mmol) were added, and after the addition was completed, the reaction was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction solution to dilute and extracted with ethyl acetate (20 mL) twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 6 (50 mg, yield: 31.1%)

[0369] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0370] 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, 1H), 7.81 (d, 2H), 7.43 (d, 2H), 7.24 (s, 2H), 4.49-4.44 (m, 1H), 4.36-4.30 (m, 1H), 4.22 (s, 2H), 4.05-3.90 (m, 3H), 3.15 (s, 3H), 2.86-2.80 (m, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 0.71-0.66 (m, 2H), 0.58-0.54 (m, 2H).

[0371] Example 7

[0372]

[0373] First Step: Compound 6A (0.1 g, 0.36 mmol), N,N-diisopropyl ethylamine (0.14 g, 1.08 mmol) were dissolved in N,N-dimethylformamide (10 mL), HATU (0.16 g, 0.43 mmol) was added, after stirring at room temperature for half an hour, dimethylamine (43 mg, 0.72 mmol) was added, and the reaction was carried out at room temperature for 16 h. After monitoring the disappearance of the raw material by TLC, water (20 mL) was added, and ethyl acetate (20 mL) was extracted twice. The organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 7A (0.10 g, 87.1%).

[0374] LC-MS (ESI): m / z = 249.1 [M+56+H] + .

[0375] Second Step: Compound 7A (100 mg, 0.31 mmol) was dissolved in formic acid (5 mL), and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound 7B (crude, 100 mg), which was directly used in the next step reaction.

[0376] LC-MS (ESI): m / z = 205.2 [M+H] + .

[0377] Step 3: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N- dimethylformamide (10 mL), HATU (140 mg, 0.36 mmol) was added, and stirred at room temperature for 30 min. 7B (98 mg, 0.45 mmol) and N,N- diisopropylethylamine (120 mg, 0.90 mmol) were added, and stirred at room temperature for 16 h after the addition was completed. Water (20 mL) was added to dilute the reaction solution and extracted with ethyl acetate (20 mL) twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 7 (45 mg, yield: 27.9%)

[0378] LC-MS (ESI): m / z = 515.2 [M+H] + .

[0379] 1 H NMR (400 MHz, DMSO-d6) δ 7.44 - 7.38 (m, 4H), 7.25 (s, 2H), 4.49 - 4.44 (m, 1H), 4.36 - 4.32 (m, 1H), 4.21 (s, 2H), 4.06 - 3.90 (m, 3H), 3.15 (s, 3H), 2.96 - 2.91 (m, 6H), 2.37 (s, 3H), 2.21 (s, 3H).

[0380] Example 8

[0381]

[0382] Step 1: Compound 8A (9 g, 37.33 mmol) was dissolved in DMF (120 mL) under nitrogen protection, and NaH (2.24 g, 55.99 mmol) was added in batches at 0 °C. After the addition was completed, the reaction was stirred at 0 °C for 0.5 h, and iodomethane (6.36 g, 44.8 mmol) was added dropwise. After the addition was completed, the reaction was stirred at room temperature overnight. TLC detection showed that the reaction was completed. The reaction solution was poured into ice water (500 mL), and extracted with ethyl acetate (200 mL). The organic phase was concentrated, and the residue was purified by column chromatography to obtain compound 8B (8 g, yield: 84.0%).

[0383] LC-MS (ESI): m / z = 255.0 [M+H] +

[0384] Second Step: To the reaction flask was added 8B (8 g, 31.36 mmol), bis(pinacolato)diboron (11.95 g, 47.04 mmol), potassium acetate (9.23 g, 94.08 mmol), Pd(dppf)Cl2(2.29 g, 3.14 mmol) and 1,4-dioxane (150 mL), replaced with nitrogen for 3 times, and the reaction was stirred at 90 °C for 3 h. LCMS confirmed the completion of the reaction, and the obtained residue was purified by silica gel column chromatography to obtain compound 8C (8 g, yield: 84.42%).

[0385] LC-MS (ESI): m / z = 303.1 [M+H] + .

[0386] Third Step: Compound 8C (5 g, 16.55 mmol) was dissolved in a mixed solvent of acetone (60 mL) and water (30 mL), and ammonium acetate (10.21 g, 132.4 mmol) and sodium periodate (5.31 g, 24.83 mmol) were added in turn. After the addition was completed, the reaction was stirred at room temperature for 16 h. Water (200 mL) was added for dilution, and the filter cake was washed with water and dried to obtain compound 8D (2.4 g, yield: 65.92%).

[0387] LC-MS (ESI): m / z = 221.1 [M+H] + .

[0388] Fourth Step: Compound 8D (2.4 g, 10.91 mmol), 8E (4.44 g, 13.09 mmol, refer to the synthesis of patent WO2022049134 A1) and potassium carbonate (3.02 g, 21.82 mmol) were dissolved in 1,4-dioxane (200 mL), and heated to 100 °C for 16 h. TLC detection showed that the reaction was completed, the solvent was removed by reduced pressure concentration, water (50 mL) was added for dilution, and ethyl acetate (50 mL) was extracted twice. The organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography to obtain compound 8F (500 mg, yield: 13.83%).

[0389] LC-MS (ESI): m / z = 276.2 [M-55] + .

[0390] Fifth Step: Compound 8F (0.5 g, 1.51 mmol) was dissolved in methanol (5 mL), and HCl / D0X (4 M, 5 mL) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. TLC detection showed that the reaction was completed, and compound 8G (450 mg, crude product) was obtained by reduced pressure concentration.

[0391] LC-MS (ESI): m / z = 232.1 [M+H]+ .

[0392] Sixth Step: To the reaction flask was added 8G (0.12 g, 0.45 mmol), intermediate 1 (0.1 g, 0.30 mmol), HATU (0.14 g, 0.36 mmol), N,N-dimethylformamide (8 mL) and DIPEA (0.19 g, 1.5 mmol) successively. After the addition was completed, the reaction was stirred at room temperature for 1 h. LCMS confirmed the completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL) twice. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC to obtain compound 8 (90 mg, yield: 54.56%).

[0393] LC-MS (ESI): m / z = 542.2 [M+H] + .

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 13.81 - 13.50 (m, 1H), 7.55 - 7.53 (m, 2H), 7.31 - 7.24 (m, 4H), 4.45 - 4.41 (m, 1H), 4.31 - 4.17 (m, 3H), 4.00 - 3.80 (m, 3H), 3.77 - 3.73 (m, 2H), 3.44 - 3.40 (m, 2H), 3.15 (s, 3H), 2.75 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H).

[0395] Example 9

[0396]

[0397] First Step: Compound 9A (0.50 g, 1.60 mmol), pyrazole (0.22 g, 3.20 mmol) were dissolved in DMSO (10 mL), cesium carbonate (1.04 g, 3.20 mmol), cuprous iodide (61 mg, 0.32 mmol) were added, and the mixture was stirred at 100 °C for 16 h. After the disappearance of the starting material was monitored by TLC, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL) twice. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 9B (0.15 g, 31.2%).

[0398] LC-MS (ESI): m / z = 300.1 [M+H] + .

[0399] Second Step: Compound 9B (150 mg, 0.50 mmol) was dissolved in formic acid (5 mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure to give compound 9C (crude, 100 mg), which was used directly in the next step.

[0400] LC-MS (ESI): m / z = 200.1 [M+H] + .

[0401] Third Step: Compound 4H (90 mg, 0.33 mmol) was dissolved in N,N- dimethylformamide (10 mL), and HATU (150 mg, 0.40 mmol) was added and stirred at room temperature for 30 min. 9C (100 mg, 0.49 mmol) and N,N- diisopropylethylamine (130 mg, 0.99 mmol) were added, and after the addition was completed, the reaction was stirred at room temperature for 16 h. Water (20 mL) was added to dilute the reaction, and ethyl acetate (20 mL) was extracted twice, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a residue, which was purified by column chromatography and then by preparative HPLC to give the target compound 9 (15 mg, yield: 10.0%).

[0402] LC-MS (ESI): m / z = 456.1 [M+H] + .

[0403] 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, 1H), 7.82 (d, 2H), 7.73 (d, 1H), 7.50-7.47 (m, 2H), 7.21-7.20 (m, 1H), 7.13 (d, 1H), 6.53 (t, 1H), 4.49-4.45 (m, 1H), 4.36-4.31 (m, 1H), 4.18 (s, 1H), 4.06-3.91 (m, 4H), 3.14-3.12 (m, 3H), 2.35-2.33 (m, 3H), 2.27 (s, 3H), 2.20 (s, 3H).

[0404] Example 10

[0405]

[0406] First Step: Compound 3B (250 mg, 0.60 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), N,N-diisopropyl ethylamine (0.23 g, 1.80 mmol) was added, and after nitrogen protection, 3-methyleneazetidine (83 mg, 1.20 mmol) was added, and the reaction was carried out at room temperature for 4 h. Water (20 mL) was added to dilute the reaction solution, and it was extracted twice with ethyl acetate (20 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, and column chromatography was used for purification to obtain the target compound 10A (200 mg, yield: 96.3%)

[0407] LC-MS (ESI): m / z = 288.1 [M+56+H] + .

[0408] Second Step: Compound 10A (200 mg, 0.58 mmol) was dissolved in formic acid (5 mL), and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound 10B (crude, 150 mg), which was directly used in the next step reaction.

[0409] LC-MS (ESI): m / z = 244.1 [M+H] + .

[0410] Third Step: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), HATU (120 mg, 0.32 mmol) was added, and stirred at room temperature for 30 min. 10B (110 mg, 0.45 mmol) and N,N-diisopropyl ethylamine (120 mg, 0.90 mmol) were added, and after the addition was completed, the reaction was stirred at room temperature for 16 h. Water (20 mL) was added to dilute the reaction solution, and it was extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, and column chromatography was used for purification, and then preparative HPLC was used to obtain the target compound 10 (18 mg, yield: 10.7%)

[0411] LC-MS (ESI): m / z = 554.1 [M+H] + .

[0412] 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.54 (s, 1H), 7.48 (d, 2H), 7.25-7.23 (m, 4H), 5.06-5.04 (m, 2H), 4.51-4.50 (m, 4H), 4.44-4.40 (m, 1H), 4.31-4.18 (m, 3H), 3.99-3.89 (m, 2H), 3.84-3.76 (m, 1H), 3.16 (s, 3H), 2.36 (s, 3H), 2.21 (s, 3H).

[0413] Example 11

[0414]

[0415] First Step: Compound 1B (1.2 g, 3.71 mmol) was dissolved in isopropanol (30 mL), (1R,2R)-2-aminocyclohexanol hydrochloride (43 mg, 0.37 mmol), nickel iodide (120 mg, 0.37 mmol), 4-pyridineboronic acid (1.37 g, 11.14 mmol) were added, the reaction solution was stirred at room temperature for 10 minutes, then NaHMDS (1.36 g, 7.42 mmol) was added, and the reaction solution was stirred at 80 °C for 4 h. TLC detection showed that the reaction was completed, water (100 mL) was added, and ethyl acetate (50 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain compound 11A (900 mg, yield: 88.3%).

[0416] LC-MS (ESI): m / z = 275.1 [M+H] + .

[0417] Second Step: Compound 11A (900 mg, 3.28 mmol) was dissolved in formic acid (10 mL), and the reaction solution was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to obtain compound 11B (700 mg, crude), which was directly used in the next step reaction.

[0418] LC-MS (ESI): m / z = 175.1 [M+H] + .

[0419] Step 3: Intermediate 1 (130 mg, 0.40 mmol) was dissolved in DMF (10 mL), HATU (150 mg, 0.40 mmol) and triethylamine (150 mg, 1.19 mmol) were added, after 30 min of reaction at room temperature, 11B (200 mg, 0.85 mmol) was added, the reaction was stirred at room temperature for 16 h. After the reaction was detected by TLC, water (50 mL) was added, and ethyl acetate (50 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography and then by HPLC to obtain compound 11 (70 mg, yield: 36.5%).

[0420] LC-MS (ESI): m / z = 485.1 [M+H] + .

[0421] 1 H NMR (400 MHz, DMSO-d6) δ 8.66-8.64 (m, 2H), 7.60-7.57 (m, 2H), 7.32-7.31 (m, 1H), 7.22-7.18 (m, 1H), 4.29-4.26 (m, 2H), 4.20 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 3.86 (s, 1H), 3.23-3.21 (m, 3H), 2.61-2.60 (m, 4H), 2.42-2.39 (m, 1H), 2.35-2.34 (m, 3H), 2.23-2.22 (m, 3H).

[0422] Example 12

[0423]

[0424] Step 1: Compound 4H (0.1 g, 0.36 mmol) was dissolved in DMF (10 mL), HATU (160 mg, 0.43 mmol) was added, and stirred at room temperature for 30 min. 1D (110 mg, 0.54 mmol) and N,N-diisopropyl ethylamine (190 mg, 1.44 mmol) were added, and stirred at room temperature for 16 h after the addition was completed. Water (20 mL) was added to dilute the reaction solution and extracted twice with ethyl acetate (20 mL), the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 12 (20 mg, yield: 12.1%)

[0425] LC-MS (ESI): m / z = 455.2 [M+H] + .

[0426] 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.73 (m, 2H), 7.42-7.39 (m, 2H), 7.20-7.00 (m, 2H), 4.16-4.06 (m, 4H), 3.94-3.83 (m, 2H), 3.53 - 3.40 (m, 1H), 3.18 (d, 3H), 2.66 - 2.54 (m, 2H), 2.34-2.18 (m, 11H).

[0427] Example 13

[0428]

[0429] First Step: Compound 3A (200 mg, 0.81 mmol), 3-iodo-l-methylpyrazole (251 mg, 1.22 mmol), BrettPhos Pd G3 (73 mg, 0.08 mmol), potassium tert-butoxide (271 mg, 2.43 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 95 °C for 16 hours. After the reaction was completed by TLC detection, water (20 mL) was added, extracted with ethyl acetate (20 mL), washed twice with saturated brine, and the organic phase was concentrated. The residue was purified by column chromatography to obtain compound 13A (130 mg, yield: 49.2%).

[0430] LC-MS (ESI): m / z = 329.1 [M+H]

[0431] Second Step: Compound 13A (130 mg, 0.40 mmol) was dissolved in formic acid (10 mL) and reacted at room temperature for 16 hours. After the reaction was completed by TLC detection, it was concentrated under reduced pressure to obtain compound 13B (crude, 100 mg), which was directly used in the next step.

[0432] LC-MS (ESI): m / z = 229.2 [M+H] + .

[0433] Third Step: Intermediate 1 (132 mg, 0.40 mmol), N,N-diisopropylethylamine (260 mg, 2.02 mmol) were dissolved in dichloromethane (15 mL), HATU (152 mg, 0.40 mmol) was added, and after stirring at room temperature for 10 minutes, compound 13B (100 mg, crude) was added, and reacted at room temperature for 2 hours. After the raw material disappeared by TLC monitoring, water (20 mL) was added, extracted twice with 50 mL of ethyl acetate, the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography and then by preparative HPLC to obtain the target compound 13 (56 mg, yield: 26%).

[0434] LC-MS (ESI): m / z = 539.1 [M+H] + .

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.48-7.46 (m, 1H), 7.31-7.24 (m, 3H), 7.20 (s, 1H), 7.18-7.13 (m, 2H), 5.75-5.72 (m, 1H), 4.45-4.37 (m 1H), 4.33 - 4.22 (m, 2H), 4.15 (s, 1H), 4.00 - 3.92 (m, 1H), 3.91-3.83 (m, 1H), 3.82 - 3.73 (m, 1H), 3.72 (s, 3H), 3.25-3.10 (m, 3H), 2.36 (s, 3H), 2.28-2.10 (m, 3H).

[0436] Example 14

[0437]

[0438] First step: Compound 4H (140 mg, 0.51 mmol) was dissolved in DMF (10 mL), HATU (195 mg, 0.51 mmol) and triethylamine (200 mg, 1.54 mmol) were added, after 30 min reaction at room temperature, compound 11B (225 mg, 1.02 mmol) was added, the reaction solution was stirred at room temperature for 16 h. After TLC detection, the reaction was completed, water (50 mL) was added, and ethyl acetate (50 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography and then by HPLC to obtain compound 14 (50 mg, yield: 22.8%).

[0439] LC-MS (ESI): m / z = 431.1 [M+H] + .

[0440] 1 H NMR (400 MHz, DMSO-d6) δ 8.68-8.64 (m, 2H), 7.61-7.57 (m, 2H), 7.33-7.31 (m, 1H), 7.23-7.19 (m, 1H), 4.30-4.27 (m, 2H), 4.20 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 3.86 (s, 1H), 3.25-3.22 (m, 3H), 2.61-2.60 (m, 4H), 2.50-2.49 (m, 3H), 2.43-2.37 (m, 1H), 2.35-2.33 (m, 3H), 2.23-2.22 (m, 3H).

[0441] Example 15

[0442]

[0443] First Step: Compound 15A (1.00 g, 6.21 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL), 4F (2.34 g, 8.07 mmol), potassium carbonate (2.58 g, 18.63 mmol) and Pd(dppf)Cl2(800 mg, 0.93 mmol) were added successively, and the reaction was protected by nitrogen after the addition was completed. The reaction was stirred at 80 °C for 16 h. After the reaction was cooled to room temperature, it was concentrated to a small volume (10 mL) under reduced pressure, then diluted with water (100 mL) and extracted with dichloromethane (150 mL) five times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by normal phase column chromatography and then by reverse phase column to obtain compound 15B (90 mg, yield: 5.93%).

[0444] LC-MS (ESI): m / z = 245.3 [M+H] + .

[0445] Second Step: Compound 15B (90 mg, 0.37 mmol) was dissolved in methanol (8 mL), and an aqueous solution of lithium hydroxide (125 mg, 2.96 mmol) (2 mL) was added. After the addition was completed, the reaction was stirred at room temperature overnight. The pH of the reaction was adjusted to 3-4 with 6N dilute hydrochloric acid, and the reaction was concentrated and purified by reverse phase column chromatography to obtain crude compound 15C (100 mg), which was directly used in the next step

[0446] LC-MS (ESI): m / z = 231.1 [M+H] + .

[0447] Third Step: Crude compound 15C (100 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (6 mL), and the reaction was protected by nitrogen after the addition of HATU (175 mg, 0.46 mmol). After stirring at room temperature for 1 h, 4J (110 mg, 0.52 mmol) and N,N-diisopropylethylamine (180 mg, 1.39 mmol) were added successively, and the reaction was stirred at room temperature for 16 h after the addition was completed. The reaction was diluted with water (50 mL) and extracted with dichloromethane (100 mL) three times. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography and then by HPLC to obtain the target compound 15 (23 mg, yield: 15.3%).

[0448] LC-MS (ESI): m / z = 347.2 [M+H] + .

[0449] 1 H NMR (400 MHz, DMSO-d6) δ 8.54-8.53 (m, 2H), 7.39-7.38 (m, 2H), 7.19-7.12 (m, 2H), 6.91 (s, 1H), 4.18 (s, 1H), 4.06-4.03 (m, 2H), 3.94-3.91 (m, 2H), 2.34 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H).

[0450] Example 16

[0451]

[0452] First Step: Compound 3A (0.1 g, 0.40 mmol) and N,N-diisopropylethylamine (0.16 g, 1.20 mmol) were dissolved in dichloromethane (5 mL), then cyclopropyl chloroformate (53 mg, 0.44 mmol) was added slowly under ice-bath, after the addition was completed, the reaction was carried out at room temperature for 2 h. After TLC monitoring, the starting material disappeared, water (20 mL) was added, dichloromethane (20 mL) was extracted twice, the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 16A (0.12 g, 90%).

[0453] LC-MS (ESI): m / z = 333.2 [M+H] + .

[0454] Second Step: Compound 16A (100 mg, 0.32 mmol) was dissolved in ethyl acetate hydrochloride solution (4 M, 3 mL), stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to obtain compound 16B (crude, 84 mg), which was directly used in the next step reaction.

[0455] LC-MS (ESI): m / z = 233.2 [M+H] + .

[0456] Third Step: Intermediate 4H (100 mg, 0.36 mmol) was dissolved in N,N-dimethylformamide (10 mL), HATU (140 mg, 0.36 mmol) was added, and stirred at room temperature for 30 min. 16B (84 mg, 0.36 mmol) and N,N-diisopropylethylamine (120 mg, 0.90 mmol) were added, and after the addition was completed, the reaction was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction solution to dilute and extracted with ethyl acetate (20 mL) twice, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 16 (20 mg, yield: 17%).

[0457] LC-MS (ESI): m / z = 489.2 [M+H] + .

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 11.93 - 11.70 (m, 1H), 9.61 (s, 1H), 7.43 (d, 2H), 7.27 (d, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 4.42 (t, 1H), 4.28 (t, 1H), 4.18 (s, 1H), 4.09 - 4.01 (m, 2H), 4.00 - 3.93 (m, 1H), 3.92 - 3.75 (m, 2H), 3.13 (d, 3H), 3.33 (d, 3H), 2.30 - 2.17 (m, 6H), 0.75 - 0.60 (m, 4H).

[0459] Example 17

[0460]

[0461] Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), HATU (140 mg, 0.36 mmol) was added, stirred at room temperature for 30 min. 16B (84 mg, 0.36 mmol) and N,N-diisopropyl ethylamine (120 mg, 0.90 mmol) were added, after the addition was completed, stirred at room temperature for 16 h. Water (20 mL) was added to dilute the reaction solution and extracted with ethyl acetate (20 mL) twice, the combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a residue, which was purified by column chromatography and then by preparative HPLC to obtain the target compound 17 (20 mg, yield: 17%)

[0462] LC-MS (ESI): m / z = 543.2 [M+H] + .

[0463] 1H NMR (400 MHz, DMSO-d6) δ 13.90 - 13.50 (m, 1H), 9.61 (s, 1H), 7.43 (d, 2H), 7.31 - 7.23 (m, 3H), 7.22 - 7.17 (m, 1H), 4.42 (t, 1H), 4.33 - 4.24 (m, 2H), 4.14 (s, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.86 (m, 2H), 3.86 - 3.76 (m, 1H), 3.18 (s, 1.5H), 3.12 (s, 1.5H), 2.36 (d, 3H), 2.25 (s, 1.5H), 2.16 (s, 1.5H), 0.73 - 0.62 (m, 4H).

[0464] Example 18

[0465]

[0466] First Step: Compound 3A (0.08 g, 0.32 mmol), cyclopropylcarboxylic acid (36 mg, 0.42 mmol), N,N-diisopropylethylamine (0.12 g, 0.96 mmol) were dissolved in N,N-dimethylformamide (5 mL), then HATU (0.18 g, 0.48 mmol) was added, and the reaction was stirred at room temperature for 2 h under nitrogen protection. After the disappearance of the starting material was monitored by TLC, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain compound 18A (0.10 g, 98%).

[0467] LC-MS (ESI): m / z = 317.2 [M+H] + .

[0468] Second Step: Compound 18A (100 mg, 0.32 mmol) was dissolved in ethyl acetate hydrochloric acid solution (4 M, 3 mL) and stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure to obtain compound 18B (crude, 80 mg), which was directly used in the next step.

[0469] LC-MS (ESI): m / z = 217.2 [M+H] + .

[0470] Step 3: Intermediate 1 (100 mg, 0.31 mmol) was dissolved in N,N- dimethylformamide (10 mL), HATU (140 mg, 0.36 mmol) was added and stirred at room temperature for 30 min. 18B (80 mg, 0.32 mmol) and N,N- diisopropylethylamine (120 mg, 0.90 mmol) were added and the reaction was stirred at room temperature for 16 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL) twice. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography and then by preparative HPLC to give the target compound 18 (20 mg, yield: 18%)

[0471] LC-MS (ESI): m / z = 527.2 [M+H] + .

[0472] 1 H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 10.14 (s, 1H), 7.56 (d, 2H), 7.32 - 7.14 (m, 4H), 4.43 (t, 1H), 4.33 - 4.07 (m, 3H), 4.01 - 3.88 (m, 2H), 3.87 - 3.77 (m, 1H), 3.15 (s, 3H), 2.36 (s, 3H), 2.28 - 2.12 (m, 3H), 1.79 - 1.71 (m, 1H), 0.82 - 0.72 (m, 4H).

[0473] Biological test evaluation

[0474] The application is further described and explained in connection with the following test examples, which are not meant to limit the scope of the application.

[0475] I. DNL Assay

[0476] Procedure:

[0477] HepG2 cells are seeded into 96-well cell culture plates at a certain cell density (100 μL / well) and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the 96-well cell culture plates are removed from the incubator and fresh medium is added. Different concentrations of compounds (the compounds are diluted in a certain gradient, and the highest concentration for testing is 10 μM) are added, followed by the addition of a certain concentration of [14C]-acetic acid. The plates are incubated at 37°C in a 5% CO2 incubator for a certain period of time. Then the supernatant is discarded and washed with DPBS. TrypLE™ Express is added and incubated for a certain period of time. Medium is added and mixed, and all the cell solution is transferred to a 2 ml deep 96-well plate and centrifuged. A chloroform and methanol mixture is added, and the plate is spun at 800 rpm for 1.5 minutes every 3 minutes. Methanol and ddH2O are added to each well, and the plate is centrifuged. The chloroform phase is taken and added to Isoplate, and Ultima Gold scintillation liquid is added to each well. Detection is performed using a Microbeta.

[0478] Experimental results: The compounds of the present application can reduce fatty acid synthesis in the in vitro HepG2 cell system, and all show an IC 50 value of less than 1000 nM, some preferred compounds have an IC 50 ≤ 500 nM, some more preferred compounds have an IC 50 ≤ 300 nM, some more preferred compounds have an IC 50 ≤ 100 nM, some more preferred compounds have an IC 50 ≤ 50 nM or even ≤ 10 nM. The IC 50 values of some specific compounds are shown in Table 1, where A represents IC 50 ≤ 100 nM, B represents 100 nM < IC 50 ≤ 500 nM, C represents IC 50 > 500 nM.

[0479] Table 1

[0480] Compound number DNL assay in HepG2(IC 50 : nM) 1 B 2 B 3 A 4 B 5 B 6 B 7 B

[0481] Conclusion: The compounds of the present application, such as the example compounds, can reduce fatty acid synthesis in the in vitro HepG2 cell system.

[0482] II. Mouse Pharmacokinetic Test

[0483] 1. Test animals: male ICR mice, 25-30 g, 6 per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0484] 2. Test design: On the test day, the ICR mice are randomly divided by weight. Fasting for 12-14 h without water restriction 1 day before administration, and feeding 4 h after administration.

[0485] Blood samples were collected from the orbit of the eye before and after administration of isoflurane anesthesia, 0.06 mL was placed in an EDTA K2 centrifuge tube, 5000 rpm, 4℃ centrifugation for 10 min, and the plasma was collected. The blood sampling time points of the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7 and 24 h. Before analysis, all samples were stored at -80℃, and the samples were quantitatively analyzed by LC-MS / MS.

[0486] Conclusion: The compound of the present application, for example, the compound of the examples has good pharmacokinetic characteristics in mice.

[0487] Three, rat pharmacokinetic test

[0488] 1. Test animals: male SD rats, about 220g, 6-8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0489] 2. Test design: On the test day, the SD rats were randomly divided by weight. Fasting for 12-14 h without water 1 day before administration, and feeding 4 h after administration.

[0490] Blood samples were collected from the orbit of the eye before and after administration of isoflurane anesthesia, 0.06 mL was placed in an EDTA K2 centrifuge tube, 5000 rpm, 4℃ centrifugation for 10 min, and the plasma was collected. The blood sampling time points of the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7 and 24 h. Before analysis, all samples were stored at -80℃, and the samples were quantitatively analyzed by LC-MS / MS.

[0491] Conclusion: The compound of the present application, for example, the compound of the examples has good pharmacokinetic characteristics in mice.

[0492] Four, beagle dog pharmacokinetic test

[0493] 1. Test animals: male beagle dogs, about 8-11 kg, 6 dogs per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0494] 2. Test method: On the test day, the beagle dogs were randomly divided by weight. Fasting for 12-14 h without water 1 day before administration, and feeding 4 h after administration.

[0495] Blood samples were collected from the orbit of the eye before and after administration of isoflurane anesthesia, 0.06 mL was placed in an EDTA K2 centrifuge tube, 5000 rpm, 4℃ centrifugation for 10 min, and the plasma was collected. The blood sampling time points of the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7 and 24 h. Before analysis, all samples were stored at -80℃, and the samples were quantitatively analyzed by LC-MS / MS.

[0496] Conclusion: The compound of the present application, for example, the compound of the example has good pharmacokinetic characteristics in beagle dogs.

[0497] V. Monkey pharmacokinetic test

[0498] 1. Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0499] 2. Test method: On the test day, the monkeys were randomly divided into groups according to body weight. Fasting without water for 14-18 h before administration, and feeding 4 h after administration.

[0500] 1.0 mL of blood was taken from the limbs before and after administration, and placed in EDTAK2 centrifuge tubes. 5000 rpm, 4℃ centrifugation for 10 min, collection of plasma. The blood sampling time points of the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis, all samples were stored at -80℃, and the samples were quantitatively analyzed by LC-MS / MS.

[0501] Conclusion: The compound of the present application, for example, the compound of the example has good pharmacokinetic characteristics in monkeys.

[0502] VI. hERG potassium ion channel effect test

[0503] 1. Experimental platform: electrophysiological hand-held patch clamp system

[0504] 2. Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[0505] 3. Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel were used to record hERG potassium current by whole-cell patch clamp technique at room temperature. Glass microelectrode was pulled from glass electrode blank (BF150-86-10, Sutter) by a puller, and the tip resistance was about 2-5 MΩ after filling the electrode with internal solution. The glass microelectrode was inserted into the amplifier probe and then connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the step voltage to induce hERG potassium current (IhERG) was given from -80 mV to +20 mV for 2 s, and then repolarized to -50 mV for 1 s, and then returned to -80 mV. This voltage stimulation was given every 10 s, and after the hERG potassium current was determined to be stable (at least 1 min), the drug administration process was started. Each test concentration of the compound was given for at least 1 min, and at least 2 cells were tested for each concentration (n≥2).

[0506] 4. Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The inhibition degree of different compound concentrations on hERG potassium current (peak value of hERG tail current induced at -50 mV) was calculated by the following formula:

[0507] Inhibition% = [1–(I / Io)]x100%

[0508] wherein Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current after and before drug administration, respectively.

[0509] Compound IC 50 The following equation was used to calculate the IC50 value by GraphPad Prism 5 software:

[0510] Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0511] wherein X is the Log value of the test concentration of the test product, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0512] Table 2

[0513] Compound name IC 50 : (μM) Compound 2 21.1 Compound 4 >40 Compound 5 >40 Compound 6 >40 Compound 7 >40

[0514] Conclusion: The compounds of the present application, such as the example compounds, have no significant inhibitory effect on hERG potassium channel current.

[0515] VII. CYP450 enzyme inhibition test

[0516] The objective of this study is to evaluate the effects of test articles on the activities of five isozymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) using in vitro test systems. Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of test articles, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was completed, the samples were processed and the specific metabolites produced by the specific substrates were quantitatively determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to measure the changes in CYP enzyme activity, and the IC 50 values were calculated to evaluate the inhibitory potential of the test articles on each CYP enzyme subtype.

[0517] Conclusion: The compounds of the present application, such as the example compounds, have no significant inhibitory activity on the five isozymes of human liver microsomal cytochrome P450 (CYP).

Claims

1. A compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: wherein: m is 1, 2, 3; which fulfils one or more of the following conditions: Cy1is C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-10 membered heteroaryl, optionally further substituted by 1-3 R c1 substituents; Cy2is present or absent; when Cy2is present, Cy2is C 3-8 cycloalkyl, 3-12 membered heterocycloalkyl, or 5-10 membered heteroaryl, optionally further substituted by 1-3 R c2 substituents; Cy3 is C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzo 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzo c3 substituted; each R c1 , R c2 , and R c3 is independently deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkoxyalkyl, C 1-6 alkylidene, C 1-6 haloalkylidene, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -C(=0)-(3-8 membered heterocycloalkyl), -NHC(=0)-(3-8 membered heterocycloalkyl), -NH-(5-10 membered heteroaryl), C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkylalkyl, 3-8 membered heterocycloalkylalkyl, C 3-8 cycloalkyloxy, or 3-8 membered heterocycloalkyloxy, said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, cycloalkyloxy, or heterocycloalkyloxy is optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene; or any one of R c2 L2, and any one of R c3 with the ring atom to which it is attached to form a 5-8 membered heterocycloalkyl group, optionally further substituted with 1-3 groups selected from halo, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylalkylene, or C 1-3 haloalkylalkylene; L1and L2are each independently a bond, -(CR y1 R y2 ) m - C 3-6 cycloalkyl, -O-, -CO-, -NR y3 - C 2-4 alkenyl or C 2-4 alkynyl; Y is a bond, -(CR y1 R y2 ) m -, -CR y1 R y2 -CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y3 -, -S(O)2-, -C 2-4 alkylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO- ; R y1 and R y2 each independently is hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl; R y3 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl; R a is C 1-6 alkyl or C 3-6 cycloalkyl; R is hydrogen, deuterium, cyano, amino, hydroxy, -COOH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, C 1-6 halogenated alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -S(=O)2-C 1-6 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa , said amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino groups are optionally further substituted with 1 to 3 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-3 alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylidene, C 1-3 halogenated alkylidene, C 3-6 cycloalkyl; R aa , R bb each independently is selected from the group consisting of hydrogen, deuterium, cyano, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl; General formula (I) is further described by general formula (II), general formula (III), general formula (IV), general formula (V), general formula (VI), general formula (VII), general formula (VIII), general formula (IX): provided that is other than 2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, wherein: Y is a bond, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -CS-, -CO-, -CONH-, -CONCH3-, -S(=0)2-; (1) Cy1is pyrrolidinyl, cyclohexyl, cyclohexenyl, piperidinyl, piperazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridonyl, pyrimidonyl, pyridazinyonyl, benzimidazolyl, indolyl, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridinyl, optionally further substituted with 1-3 R c1 substituents, preferably optionally further substituted with 1-3 R c1 substituents; (2) Cy2is C 3-6 cycloalkyl, 4-6 membered saturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 4-6 membered partially unsaturated monocyclic heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated bridged heterocycloalkyl containing 1-2 nitrogen atoms, 6-8 membered saturated fused heterocycloalkyl containing 1-2 nitrogen atoms, 6-12 membered saturated spiro heterocycloalkyl containing 1-2 nitrogen atoms, 5-6 membered heteroaryl, 6-12 membered partially unsaturated fused heterocycloalkyl containing 1-2 nitrogen atoms, optionally further substituted by 1-2 R c2 substituted, preferably optionally further substituted by 1-3 R c2 substituted; (3) Cy3is cyclobutyl, cyclohexyl, bicyclo[l. l. l]pentane, phenyl, pyridyl, pyrimidinyl, pyridinone, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzopyrrolyl, indolyl, benzocyclopentoxy, benzopyrrolodinyl, optionally further substituted with 1-3 R c3 substituted, preferably optionally further substituted with 1-2 R c3 substituted; (4) L1is a bond, -CR y1 R y2 -, C 3-6 cycloalkyl, -O-, -CO-, -NR y3 -, preferably a bond, -O-, -NH-, -NCH3-, -N(cyclopropyl)-, -CH(cyclopropyl)-, -CH(CF3)-, cyclopropyl; (5) L2is a bond, -CR y1 R y2 -, -CR y1 R y2 CR y1 R y2 -, -O-, -CO-, -NR y3 -, C 2-4 alkynyl, preferably a bond, -O-, -NH-, -NCH3-, methylene, ethylene, ethynylene; (6) Y is a bond, -CR y1 R y2 -, -CR y1 R y2 - CO-, C 3-6 cycloalkyl, -CS-, -CO-, -NR y3 -, -CO-NR y -, -S(=O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-; preferably a bond, -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CO-, -CONH-, -CONCH3-, -S(=O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-; (7) R a is C 1-3 alkyl or C 3-6 cycloalkyl, preferably methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl; (8) R is cyano, amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa , cyano; (9) R c1 is deuterium, halogen, hydroxyl, oxo, -COOH, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 1-3 alkoxyalkyl, C 1-3 alkylidene, C 1-3 halogenated alkylidene, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, C 3-4 cycloalkyloxy or 4-5 membered heterocycloalkyloxy, which alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, cycloalkyloxy or heterocycloalkyloxy is optionally further substituted with 1-3 groups selected from halogen, oxo, C 1-3 alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylidene or C 1-3 halogenated alkylidene, preferably oxo, -COOH, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, methoxyethyl, (10) R c2 halo, hydroxyl, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl, preferably deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, ethenyl, or ethynyl; (11) R c3 deutero, halogen, hydroxy, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 3-4 cycloalkyl, 4-5 membered heterocycloalkyl, -C(=0)-(4-6 membered heterocycloalkyl), -NHC(=0)-(4-6 membered heterocycloalkyl), -NH-(5-6 membered heteroaryl), C 3-4 cycloalkyloxy, 4-5 membered heterocycloalkyloxy, 5-6 membered heteroaryl, which alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, heteroaryl are optionally further substituted with 1-3 groups selected from halogen, cyano, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, C 1-3 haloalkylidene, C 3-6 cycloalkyl, preferably deutero, fluorine, chlorine, hydroxy, oxo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, 3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, is selected from one of the structures in Table I.

5. A pharmaceutical composition comprising a therapeutically effective dose of a compound of any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Y' is selected from -CH2-, -CH2CO-, -CH(F2)-, -CH(CF3)-, -CH(CH3)-, -CH(cyclopropyl)-, cyclopropyl, -C(=S)-, -CONH-, -CONCH3-, -S(=O)2-, -C 2-4 alkenylene-CO-, -C(=N-OR y3 )-, -C(=CR y1 R y2 )-, -O-CO-, -NR y3 -CO-; Cy 2’ selected from optionally further substituted by 1-3 R c2 substituents; Cy 3’ selected from optionally further substituted by 1-2 R c3 substituents; R' is selected from the group consisting of amino, -COOH, C 1-3 alkyl, C 2-3 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, -S(=O)2-C 1-3 alkyl, -C(=O)-NR aa R bb , -NR aa C(=O)R bb , -NR aa C(=O)OR bb , -OC(=O)-NR aa R bb , -NR aa S(=O)2NR aa R bb , -NR aa C(=NH)NR aa R bb , -NR aa C(=NH)NR aa C(=O)R bb , -C(NH2)=N-OR aa , R c3’ selected from deuterium, fluorine, chlorine, hydroxyl, oxo, methyl, methoxy, trifluoromethyl, trifluoromethoxy, X1is selected from -N- or -C(R c3 )-; Cy2, Cy3, R c1 and L2is as described in claim 1 or 2.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein, 6. The pharmaceutical composition of claim 5, comprising 1-1500 mg of a compound of any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of a compound of any one of claims 1-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 5 or 6, for the manufacture of a medicament, preferably a medicament for the prevention and / or treatment of a FASN-mediated disease.

8. The use of claim 7, wherein the FASN-mediated disease is selected from metabolic associated steatohepatitis, liver fibrosis, non-alcoholic fatty liver, acne vulgaris, a tumor, preferably a tumor selected from metastatic breast cancer, glioma, metastatic prostate cancer, metastatic non-small cell lung cancer, advanced solid tumor. ​ ​

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