FTO inhibitors

Abstract

There is provided a compound of formula (I) as an FTO inhibitor having improved and selective FTO inhibition; a pharmaceutical composition comprising the compound; and a method for inhibiting weight gain, promoting weight loss, reducing serum LDL, cholesterol, LDL-c, or triglyceride by inhibiting FTO using the compounds disclosed herein. Or methods of treating obesity or obesity-related diseases (in particular obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases) or Alzheimer's disease.

Description

Technical Field

[0001] Disclosed herein is a compound of formula (I) as an FTO inhibitor having improved and selective FTO inhibition. Also disclosed herein is a pharmaceutical composition comprising the same and a method for inhibiting weight gain, promoting weight loss, lowering serum LDL, cholesterol, LDL-c or triglycerides, or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease) or Alzheimer's disease by inhibiting FTO using the compounds disclosed herein. Background Art

[0002] Obesity is a serious health problem worldwide, and many factors contribute to this chronic disease, including environmental and genetic factors. A genome-wide association study investigating obese patients revealed that the FTO (fat mass and obesity) gene is closely related to obesity. The function of FTO in obesity has been confirmed in transgenic animal models such as FTO knockout mice, FTO overexpression mice, and FTO-I367F mutant mice. The FTO protein is an α-ketoglutarate and iron (II) dependent nucleic acid demethylase. Its preferred substrate is N6-meA in messenger RNA, which is located near the stop codon and affects gene translation.

[0003] US2014 / 0148383 A1 first identified the known FDA-approved drug entacapone as a FTO inhibitor using a structure-based virtual screening approach combined with bioactivity measurements, including enzyme activity, cell activity, and a high-fat diet-induced obesity (DIO) animal model. Entacapone is a COMT (catechol-O-methyltransferase) inhibitor used to treat Parkinson's disease.

[0004] WO 2016206573 A1 discloses entacapone analogs showing FTO inhibition.

[0005] However, it is undesirable that FTO inhibitors inhibit COMT because inhibiting COMT may affect the metabolism of important neurotransmitters (including dopamine, epinephrine and norepinephrine) in the body, which further leads to effects unrelated to FTO inhibition and causes potential side effects. In addition, inhibiting COMT may also affect the metabolism of drugs or small molecules containing catechol groups, leading to adverse drug interactions.

[0006] Therefore, there is a need for new FTO inhibitors having comparable or improved FTO inhibition as well as improved selectivity of FTO inhibition relative to COMT inhibition. Summary of the invention

[0007] Disclosed herein are compounds useful as FTO inhibitors, pharmaceutical compositions comprising the same, and methods of using the same. In particular, the compounds disclosed herein show comparable or improved FTO inhibition and improved FTO inhibition selectivity relative to COMT inhibition or even no COMT inhibition through structural modification.

[0008] In one aspect, there is provided a compound of formula (I)

[0009]

[0010] or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof,

[0011] L1 is -NR a - or a single bond, where R a It is C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Each of the alkoxy groups is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted;

[0012] L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne or a single bond, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy;

[0013] L3 is a single bond, -O-, -S-, -SO-, -SO2-, -NR c -, -C(O)-, -C(O)O-, -C(O)NR c -、-OC(O)NR c -、-C(O)ONR c -、-C(O)N(R c )O-、-OC(O)NR c -or-NR c C(O)-; where R c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 alkyl, phenyl, phenylalkyl-, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

[0014] R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with R b Replaced, and the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace;

[0015] in

[0016] R b It is halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 3-6 Each of the cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to three substituents selected from the group consisting of cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclyl;

[0017] R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0018] in

[0019] R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0020] R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0021] R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0022] R2 is hydrogen, halogen, cyano, C 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy;

[0023] R3 is hydrogen, halogen, cyano, C 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy;

[0024] R4 is cyano; hydrogen; halogen; hydroxyl; C 1-6 Alkoxy; C 1-6 Alkyl-S-; nitro (-NO2); or -SF5, the C 1-6 Alkoxy or C 1-6 Each of the alkyl-S- is unsubstituted or substituted with halogen, hydroxyl or C 1-6 Alkoxy substituted; or C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted;

[0025] R5 is hydrogen, nitro (-NO2), cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)OR 5a 、-SO2-R 5a or -SF5; where R 5a It is hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0026] Provided that if L1, L2 and L3 are each a single bond, then R1 is not hydrogen;

[0027] There is a further proviso that the compound is not (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide.

[0028] R2

[0029] In some embodiments, R2 is hydrogen, fluorine, chlorine or bromine. In some embodiments, R2 is hydrogen. In some embodiments, R2 is -CN, -CH3, -OH or -OCH3.

[0030] R3

[0031] In some embodiments, R3 is hydrogen, fluorine, chlorine or bromine. In some embodiments, R3 is hydrogen. In some embodiments, R3 is -CN, -CH3, -OH or -OCH3.

[0032] R4

[0033] In some embodiments, R4 is hydrogen; halogen; hydroxyl; nitro; cyano; -SF5; unsubstituted or substituted with halogen, hydroxyl or C 1-6 Alkoxy substituted C 1-6 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substituted C 1-6 Alkyl-S-; unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted C 1-6 Alkyl; C 2-6 Alkenyl; or C 2-6 Alkynyl.

[0034] In some embodiments, R4 is unsubstituted or substituted with halogen, hydroxyl or C 1-4 Alkoxy substituted C 1-4 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-4 Alkoxy substituted C 1-4Alkyl-S-; unsubstituted or substituted by halogen, hydroxyl, C 1-4 Alkoxy or C 1-4 Alkyl-S-substituted C 1-4 Alkyl; C 2-4 Alkenyl; or C 2-4 Alkynyl.

[0035] In some embodiments, R4 is unsubstituted or substituted with halogen, hydroxyl or C 1-2 Alkoxy substituted C 1-2 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-2 Alkoxy substituted C 1-2 Alkyl-S-; or unsubstituted or substituted with halogen, hydroxyl, C 1-2 Alkoxy or C 1-2 Alkyl-S-substituted C 1-2 alkyl.

[0036] In some embodiments, R4 is hydrogen, nitro, cyano, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, trifluoromethylthio, vinyl, ethynyl, fluorine, chlorine, bromine or iodine. In some embodiments, R4 is hydrogen, hydroxyl, methoxy, fluorine, chlorine, methyl, nitro, cyano, difluoromethoxy or trifluoromethoxy.

[0037] R5

[0038] In some embodiments, R5 is nitro, cyano, halogen, C 1-4 Alkyl, halogenated C 1-6 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, -SF5, -C(O)OR 5a and -SO2-R 5a , where R 5a It is hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0039] In some embodiments, R5 is nitro, cyano, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, ethynyl, vinyl, methoxycarbonyl, carboxyl or methylsulfonyl. In some embodiments, R5 is nitro, fluorine, chlorine or cyano.

[0040] R4 and R5

[0041] In some embodiments, R4 is nitro; cyano; hydrogen; halogen; hydroxyl; unsubstituted or substituted with halogen, hydroxyl or C1-6 Alkoxy substituted C 1-6 Alkoxy; unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted C 1-6 Alkyl, the C 1-6 Alkoxy or C 1-6 Alkyl-S- is unsubstituted or substituted with halogen; and R5 is nitro, halogen, cyano or haloC 1-6 alkyl.

[0042] In some embodiments, R4 is nitro; cyano; hydrogen; halogen; hydroxyl; unsubstituted or halogen-substituted C 1-6 Alkoxy; or unsubstituted or halogen-substituted C 1-6 alkyl; and R5 is nitro or halogen.

[0043] In some embodiments, R4 is halogen; 1-6 Alkoxy, preferably methoxy; or C 1-6 Alkyl, preferably methyl; and R5 is nitro.

[0044] In some embodiments, R4 is halogen; methoxy; or methyl; and R5 is nitro, cyano, or chloro.

[0045] In some embodiments, R4 is halogen, such as F, Cl or Br, and R5 is nitro.

[0046] In some further embodiments, R4 is methoxy; difluoromethoxy; trifluoromethoxy, and R5 is nitro, cyano or chloro.

[0047] R1, R4 and R5

[0048] In some embodiments,

[0049] R4 is hydrogen, halogen (e.g., F, Cl or Br), CN, C 1-6 Alkyl (e.g., C 1-4 Alkyl, further for example, methyl) or C 1-6 Alkoxy (eg, methoxy), the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution,

[0050] R5 is nitro, CN or halogen;

[0051] L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl;

[0052] L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy;

[0053] L3 is a single bond, -O-, -S-, -NR c - or -C(O)-; wherein R c is hydrogen or C 1-6 alkyl;

[0054] R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl or heterocyclic; wherein the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with R b Replaced, and the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace;

[0055] in

[0056] R b It is halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 3-6 Each of the cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to three substituents selected from the group consisting of cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Alkyl-S-, C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclyl;

[0057] R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0058] in

[0059] R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0060] R e Halogen, C 1-6 Alkyl, C 1-6Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0061] R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0062] In some embodiments, if L3 is a single bond, and L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Any of the alkynylene groups, then R1 is not C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Any of the alkynyl groups.

[0063] In some further embodiments, R4 is halogen (eg, Cl) or C 1-6 In some even further embodiments, R4 is Cl. In some even further embodiments, R4 is methoxy or ethoxy.

[0064] In some embodiments,

[0065] R4 is hydroxy or halogen (e.g., F, Cl or Br),

[0066] R5 is a halogenated C 1-6 Alkyl (e.g., trifluoromethyl) or SO2-R 5a , where R 5a It is hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0067] L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl;

[0068] L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy;

[0069] R1 is hydrogen, cyano, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR b 、-SR b 、-SOR b 、-SO2R b 、-NR b R c 、-C(O)R b 、-C(O)OR b 、-C(O)NR b R c 、-OC(O)NR b R c or -NR b C(O)R c , each of which is as defined in formula (I).

[0070] In some embodiments,

[0071] R4 is hydrogen, halogen (e.g., F, Cl or Br), nitro, CN, C 1-6 Alkyl (e.g., C 1-4 Alkyl, further for example, methyl) or C 1-6 Alkoxy (eg, methoxy), the C1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution,

[0072] R5 is nitro, CN or halogen;

[0073] L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl;

[0074] L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy;

[0075] R1 is hydrogen, cyano, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR b 、-SR b 、-SOR b 、-SO2R b 、-NR b R c 、-C(O)R b 、-C(O)OR b 、-C(O)NR b R c 、-OC(O)NR b R c or -NR b C(O)R c , wherein the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace;

[0076] in

[0077] R b and R c are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6Each of the alkynyl groups is unsubstituted or substituted with R b Replaced, and the C 3-8 Each of the cycloalkyl, phenyl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d Substitution; wherein R b is cyano, halogen, hydroxyl, C 1-6 Alkoxy, phenyl, heteroaryl or heterocyclyl, wherein each of the phenyl, heteroaryl or heterocyclyl is unsubstituted or replaced by R d replace;

[0078] R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0079] in

[0080] R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0081] R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0082] R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0083] -L1-L2-L3-R1

[0084] -L1-L2-L3-R1 wherein L1 is a single bond, L2 is a single bond, L3 is a single bond, -O- or -S-, and R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-8 Cycloalkyl

[0085] In some embodiments, L1 is a single bond, L2 is a single bond, L3 is a single bond, -O- or -S-, and R1 is C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-8 Cycloalkyl; each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkoxy or phenyl, the phenyl being unsubstituted or substituted by halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 In other embodiments, R1 is methyl, ethyl, isopropyl, propyl, tert-butyl, ethynyl or vinyl.

[0086] In some embodiments, L1 is a single bond, L2 is a single bond, L3 is a single bond, and R1 is C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in other embodiments, R1 is methyl, ethyl, isopropyl, propyl, tert-butyl, ethynyl or vinyl.

[0087] In some embodiments, L1 is a single bond, L2 is a single bond, L3 is -O- or -S-, and R1 is C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in other embodiments, R1 is methyl, ethyl, isopropyl, propyl, tert-butyl, ethynyl or vinyl.

[0088] In some embodiments, L1 is a single bond, L2 is a single bond, L3 is a single bond, and R1 is C 3-8 Cycloalkyl, the C 3-8 Cycloalkyl is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted.

[0089] -L1-L2-L3-R1 where L1 is -NR a -

[0090] R a

[0091] In some embodiments, R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 In some embodiments, R a It is C 1-6 In some embodiments, R a It is C1-4 In some embodiments, R a It is methyl or ethyl.

[0092] (a) -L1-L2-L3-R1 wherein L1 is NR as defined above a , L2 is C 1-6 Alkylene, L3 is a single bond, and R1 is Aryl

[0093] In some embodiments, L2 is unsubstituted or halogen-substituted C 1-6 Alkylene, preferably C 1-3 alkylene, for example, methylene, and R1 is aryl, wherein the aryl is unsubstituted or substituted by R d replace,

[0094] Where R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, C 3-8 Cycloalkyl, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NR m R n 、-C(O)NR m R n 、-C(O)R m 、-C(O)OR m , phenyl, heteroaryl or heterocyclic, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0095] R m , R n and R p are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl, heterocyclic, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution,

[0096] in

[0097] R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclic, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0098] R f Halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution.

[0099] In some embodiments, R1 is phenyl, wherein the phenyl is unsubstituted or substituted with R as defined above. d In some further embodiments, R d Selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NRm R n or phenyl, pyridyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, pyridyl, piperidyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino groups is unsubstituted or replaced by R f Substitution, where R m , R n and R p are independently hydrogen or C 1-6 Alkyl, where R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyrazolyl or morpholino, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; R f Halogen, C 1-6 Alkyl or hydroxyl C 1-6 Alkyl-; and R e1 and R e2 are independently hydrogen or C 1-6 alkyl.

[0100] In some embodiments, R1 is aryl, for example, phenyl, which is unsubstituted or substituted with one or two or three substituents selected from the group consisting of chloro, fluoro, bromo, phenyl, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, dimethylamino, 3- (Hydroxymethyl)pyridin-2-yl, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, pyrimidin-4-yl, morpholino, 2,2,2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl)methoxy, (1-methyl-1H-pyrazol-4-yl)methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, or acetamido.

[0101] (b) -L1-L2-L3-R1 wherein L1 is NR as defined above a , L2 is C 1-6 Alkylene, L3 is a single bond, and R1 is C 3-8 Cycloalkyl, heteroaryl or heterocyclic

[0102] In some embodiments, L2 is unsubstituted or halogen-substituted C 1-6 Alkylene, preferably C 1-3 alkylene, for example, methylene, and R1 is heteroaryl or heterocyclic, wherein each of the heteroaryl or heterocyclic is unsubstituted or replaced by R d replace,

[0103] R d is cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, -NR m R n , phenyl, heteroaryl or heterocyclic group, wherein the phenyl, heteroaryl or heterocyclic group is unsubstituted or replaced by R f Substitution, where R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; wherein R f Halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution.

[0104] In some embodiments, R1 is heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is pyridyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinolinyl, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or replaced by R as defined above. d In some further embodiments, R d is cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, -NR m R n ; phenyl, heteroaryl, heterocyclic; halogen or C 1-6 Alkyl substituted phenyl; halogen or C 1-6 alkyl-substituted heteroaryl; or halogen or C 1-6 Alkyl-substituted heterocyclic group, wherein R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or heterocyclic.

[0105] In some embodiments, R1 is heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazinyl (e.g., pyrazin-2-yl, pyrazin-4-yl), dihydrobenzofuranyl (e.g., dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl), indazolyl (e.g., 1H-indazol-6-yl), benzodioxinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxin-6-yl), isoquinolinyl (e.g., isoquinolin-6-yl), triazol-4-yl (e.g., 1 1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-3-yl), imidazolyl (e.g., 1H-imidazolyl), isoxazolyl (e.g., isoxazol-5-yl), oxazolyl (e.g., oxazol-2-yl), thiazolyl (e.g., thiazol-2-yl) or triazolyl (e.g., 1H-1,2,3-triazol-4-yl or 1H-1,2,4-triazol-3-yl), each of which is unsubstituted or substituted with chloro, fluoro, hydroxy, methyl, cyano, oxo, methoxy, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), pyridin-4-yl, phenyl or NR m R n Substitution, where R m and R n are independently hydrogen, C 1-6 alkyl or triazolyl (eg, 1H-1,2,3-triazol-4-yl).

[0106] (c) -L1-L2-L3-R1 wherein L1 is NR as defined above a , L2 is C 1-6 Alkylene, and L3 is -O-, -S-, - SO-, -SO2-, -NR c -、-C(O)-、C(O)O-、-C(O)NR c -、-OC(O)NR c -、-C(O)ONR c -or-NR c C(O)-, and R1 It is hydrogen, C 1-6 Alkyl, phenyl or naphthyl, heteroaryl or heterocyclic

[0107] In some embodiments, L2 is unsubstituted or halogen-substituted C 1-6 Alkylene, preferably C 1-3 Alkylene, e.g., methylene;

[0108] Where R1 is C 1-6 alkyl, phenyl or naphthyl, heteroaryl or heterocyclic, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl or heteroaryl or heterocyclic group is unsubstituted or replaced by R d replace,

[0109] R b It is halogen, cyano, hydroxyl, C 1-6 Alkoxy, phenyl, heteroaryl or heterocyclyl;

[0110] R d is cyano, halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy C1-6 Alkyl-, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, phenyl, heterocyclic, heteroaryl, -SF5, -NR m C(O)NR n R p NR m R n 、-C(O)NR n R n 、-NR m C(O)R n 、-C(O)R m or-C(O)OR m wherein each of the heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted, where R m and R n are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0111] In some embodiments, R1 is C 1-6 alkyl, phenyl or naphthyl, or a heteroaryl selected from the group consisting of pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl); pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl); benzo[d]imidazolyl (e.g., benzo[d]imidazolyl-4-yl); indazolyl (e.g., indazol-4-yl); or heterocyclyl (e.g., dihydropyridinyl or azetidinyl), wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl or heteroaryl or heterocyclic group is unsubstituted or replaced by R d Substitution, where R b is halogen, cyano, hydroxyl or C 1-6 Alkoxy; R d Halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, phenyl, heterocyclyl (eg, azetidinyl), heteroaryl (eg, pyridinyl, pyrazolyl, pyridinyl, pyrazinyl), NR m R n 、-C(O)NR m Rn or -NR m C(O)R n wherein each of the heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted by halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy substituted, where R m and R n are independently hydrogen or C 1-4 alkyl.

[0112] (d) -L1-L2-L3-R1 wherein L1 is NR as defined above a , L2 is C 2-6 Alkenylene or C 2-6 Alkyne, and L3 It is a single bond, -O-, -S-, -SO-, -SO2-, -NR c -、-C(O)-、C(O)O-、-C(O)NR c -、-OC(O)NR c -or-NR c C(O)-, and R1 is hydrogen, C 1-6 Alkyl, phenyl or naphthyl, heteroaryl or heterocyclic

[0113] In some embodiments, L2 is unsubstituted or halogen-substituted C 2-6 Alkyne or C 2-6 In some embodiments, R1 is selected from hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, heteroaryl, heterocyclyl or aryl, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b Replaced, and the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d Substitution, where R b It is halogen, cyano, hydroxyl, C 1-6 alkoxy, phenyl, heteroaryl or heterocyclyl; and R d It is cyano, C 1-6 Alkyl, halogen, oxo, -OR m or -NR m R n , where R m and R n are independently hydrogen, C 1-6 Alkyl or phenyl, where R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or phenyl.

[0114] In some embodiments, L2-L3-R1 is ethynyl, prop-2-ynyl, but-2-ynyl, but-3-yn-2-yl, pent-2-ynyl, pent-2-ynyl, pent-3-ynyl, pent-3-yn-2-yl, pent-3-ynyl, hex-2-ynyl, each of which is unsubstituted or substituted with one or two halogens, C 1-6 Alkyl or hydroxy substituted or C3-8 Cycloalkyl, heteroaryl, heterocyclyl, aryl and -NR m R n Substitution, where R m and R n are independently hydrogen, C 1-6 alkyl or phenyl, and wherein the C 3-8 Each of the cycloalkyl, heteroaryl, heterocyclyl or aryl groups is unsubstituted or replaced by C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, oxo, halogen, di-C 1-6 Alkylamino, C 1-6 substituted with alkylamino or amino; preferably L2-L3-R1 is ethynyl, prop-2-ynyl, but-2-ynyl, but-3-yn-2-yl, pent-2-ynyl, pent-2-ynyl, pent-3-ynyl, pent-3-yn-2-yl, pent-3-ynyl, hex-2-ynyl, each of which is unsubstituted or substituted with fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hydroxy, 1-hydroxy The cyclopropyl group may be substituted with a cyclopropyl group, a 1-methyl-1H-pyrazol-4-yl group, a 1-methyl-2-oxo-1,2-dihydropyridin-3-yl group, a 1-methyl-2-oxopiperidin-3-yl group, a 2-chlorophenyl group, a 2-cyanophenyl group, a 2-fluorophenyl group, a 2-hydroxyphenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a pyridin-3-yl group, a pyridin-4-yl group, an o-tolyl group, a phenyl group, a pyrazin-2-yl group, a pyridin-2-yl group or a dimethylamino group.

[0115] (e) -L1-L2-L3-R1 wherein L1 is NR as defined above a , L2 is a single bond, L3 is a single bond or -O-, -S-, - NR c -、C(O)NR c - or -SO2-, and R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heteroaryl, heterocyclic or aryl

[0116] In some embodiments, L3 is a single bond, and R1 is heteroaryl, heterocyclyl, aryl, or C 3-8 Cycloalkyl, each of which is unsubstituted or substituted as defined in formula (I). In some embodiments, L3 is -O-, -S-, -NR c -、C(O)NR c - or -SO2-, and R1 is hydrogen, C 1-6 Alkyl or phenyl, the C 1-6 The alkyl or phenyl group is unsubstituted or substituted as defined in formula (I).

[0117] In some embodiments, L3 is a single bond or -O-, -S-, -NR c -、C(O)NR c - or -SO2-, and R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heteroaryl, heterocyclyl or aryl; wherein the C 1-6 The alkyl group is unsubstituted or replaced by Rb substituted, and heteroaryl, heterocyclic, aryl or C 3-8 Each of the cycloalkyl groups is unsubstituted or substituted by R d replace,

[0118] in

[0119] R d It is cyano, C 1-6 Alkyl, halogen, heteroaryl, heterocyclyl, oxo, -C(O)NR m R n NR m R n 、-OR m or -NR m C(O)NR n R p , where R m , R n and R p are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution;

[0120] R b is cyano, halogen, hydroxyl, C 3-6 Cycloalkyl or phenyl.

[0121] In some embodiments, R1 is methyl, ethyl, isopropyl, propyl, butyl, isobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, cyanomethyl, or cyclopropylmethyl.

[0122] In some embodiments, R1 is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), triazolyl (e.g., 4H-1,2,4-triazol-3-yl), oxazolyl, isoxazolyl (e.g., isoxazol-3-yl, isoxazol-5-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-5-yl), pyrazolyl, benzisoxazol-3-yl (e.g., benzo[c]isoxazol-3-yl), triazolopyridin-3-yl, triazolooxazinyl, tetratriazolopyridin-3-yl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazolo[4 ,3-a]pyridin-3-yl), dihydrotriazolooxazinyl (e.g., 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl, 6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl) or isoquinolinyl (i.e., isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl), each of which is unsubstituted or substituted with one or two or three substituents selected from the group consisting of: C 1-6 Alkyl, halogen, heteroaryl, oxo, -C(O)NR m R n NR m R n 、-OR m 、-NR m C(O)R n or -NR m C(O)NR n R p , preferably fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, phenyl, pyridyl, methylureido, acetylamino, amino, oxo and phenoxy; R1 is -OR b or -SR b , where R b It is C 1-6 Alkyl or phenyl, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl group is unsubstituted or replaced by R d Substitution, where R b is halogen or hydroxyl, and R d is halogen, hydroxyl and C 1-6 Alkyl; or R1 is C 1-6 Alkylamino, di-C 1-6 Alkylamino, N-phenylamino or NC 1-6 Alkyl-N-phenylamino, the phenyl group is unsubstituted or substituted by one or two selected from halogen and C 1-6 or R1 is C(O)NRb R c or-SO2R b , where R b and R c Each is hydrogen or C 1-6 alkyl; or R1 is carbamoyl (ie, NH2C(O)-) or methylsulfonyl (CH3SO2-).

[0123] In some embodiments, R1 is pyridin-3-yl, 3,4-dimethylisoxazol-5-yl, 3-methyl-4-phenylisoxazol-5-yl, 4-methyl-3-(pyridin-2-yl)isoxazol-5-yl, 4-methyl-3-phenylisoxazol-5-yl), 4-methyl-4H-1,2,4-triazol-3-yl), 4-methyl-6-(methylureido)pyridin-3-yl, 4-methyl-6-acetylaminopyridin-3-yl, 4-methyl-6-aminopyridin-3-yl, 4-methylisoxazol-3-yl, 4-methylisoxazol-5-yl, 4-methylpyridin-3-yl. -yl, 4-methylpyrimidin-5-yl, 4-phenylisoxazol-5-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl, 5-fluoro-4-methylpyridin-3-yl, 5-methyl-2-oxo-1,2-dihydropyridin-4-yl, 5-phenoxypyridin-3-yl, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-yl, 6,8-dihydro-5H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl or benzo[c]isoxazol-3-yl.

[0124] In some embodiments, the compound is a compound of formula (II)

[0125]

[0126] R2 and R3 are both hydrogen;

[0127] R4 is hydrogen, hydroxyl, halogen, nitro, CN, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution,

[0128] R5 is nitro, CN or halogen;

[0129] R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl;

[0130] L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy;

[0131] L3 is a single bond, -O-, -S-, -NR c - or -C(O)-; wherein R c is hydrogen or C 1-6 alkyl;

[0132] R1 is aryl, heteroaryl, heterocyclic, wherein the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace;

[0133] in

[0134] R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0135] in

[0136] R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0137] R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0138] R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

[0139] In some further embodiments, each variable in formula (II), including the moiety L2-L3-R1 in formula (II) has all the definitions as defined in formula (I).

[0140] In some embodiments, R4 is hydrogen; halogen; hydroxy; unsubstituted or substituted with halogen, hydroxy or C 1-6 Alkoxy substituted C 1-6 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substituted C 1-6 Alkyl-S-; unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted C 1-6 Alkyl; C 2-6 Alkenyl; or C 2-6 Alkynyl.

[0141] In some embodiments, R4 is unsubstituted or substituted with halogen, hydroxyl or C 1-4 Alkoxy substituted C 1-4 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-4 Alkoxy substituted C 1-4 Alkyl-S-; unsubstituted or substituted by halogen, hydroxyl, C 1-4 Alkoxy or C 1-4 Alkyl-S-substituted C 1-4 Alkyl; C 2-4 Alkenyl; or C 2-4 Alkynyl.

[0142] In some embodiments, R4 is unsubstituted or substituted with halogen, hydroxyl or C 1-2 Alkoxy substituted C 1-2 Alkoxy; unsubstituted or substituted by halogen, hydroxy or C 1-2 Alkoxy substituted C 1-2 Alkyl-S-; or unsubstituted or substituted with halogen, hydroxyl, C 1-2 Alkoxy or C 1-2 Alkyl-S-substituted C 1-2 alkyl.

[0143] In some embodiments, R4 is nitro, cyano, hydrogen, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, vinyl, ethynyl, fluorine, chlorine, bromine or iodine. In some embodiments, R4 is methoxy, fluorine, chlorine, methyl or trifluoromethoxy.

[0144] In some embodiments, R5 is nitro, fluoro, chloro, or cyano.

[0145] In some embodiments, Ra It is C 1-6 In some further embodiments, R a It is methyl or ethyl.

[0146] In some embodiments, L2 is unsubstituted or substituted with halogen or hydroxy. 1-6 In some embodiments, L2 is an unsubstituted C 1-6 Alkylene.

[0147] In some embodiments, L3 is a single bond, -O-, -S-, -NR c - or -C(O)-; wherein R c is hydrogen or C 1-6 In some further embodiments, L3 is a single bond or -O-.

[0148] In some embodiments, R1 is phenyl or heteroaryl, each of which is unsubstituted or replaced by R d replace,

[0149] Where R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, C 3-8 Cycloalkyl, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NR m R n 、-C(O)NR m R n 、-C(O)R m 、-C(O)OR m , phenyl, heteroaryl or heterocyclic, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace,

[0150] R m , R n and R p are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution,

[0151] in

[0152] R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclic, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0153] R f Halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution.

[0154] In some embodiments, R1 is phenyl, wherein the phenyl is unsubstituted or substituted with R as defined above. d In some further embodiments, R d Selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Alkyl-S-, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NR m R n or phenyl, pyridyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, pyridyl, piperidyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino groups is unsubstituted or replaced by R f Substitution, where R m , R n and R p are independently hydrogen or C 1-6 Alkyl, where R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyrazolyl or morpholino, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; R f Halogen, C 1-6 Alkyl or hydroxyl C 1-6 Alkyl-; and R e1 and R e2 are independently hydrogen or C 1-6 alkyl.

[0155] In some embodiments, R1 is phenyl, which is unsubstituted or substituted with one or two or three substituents selected from the group consisting of chloro, fluoro, bromo, phenyl, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, dimethylamino, 3-(hydroxy)- methyl)pyridin-2-yl, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, pyrimidin-4-yl, morpholino, 2,2,2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl)methoxy, (1-methyl-1H-pyrazol-4-yl)methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, or acetamido. In some further embodiments, R1 is phenyl, which is unsubstituted or substituted with one or two or three substituents selected from the group consisting of chloro, fluoro, bromo, phenyl, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, or thiazol-2-ylamino.

[0156] In some embodiments, R1 is heteroaryl, which is pyridyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinolinyl, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or replaced by R as defined above. d In some further embodiments, R d is cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, -NR m R n ; phenyl, heteroaryl, heterocyclic; halogen or C 1-6 Alkyl substituted phenyl; halogen or C 1-6 alkyl-substituted heteroaryl; or halogen or C 1-6 Alkyl-substituted heterocyclic group, wherein R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or heterocyclic.

[0157] In some embodiments, R1 is heteroaryl, which is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrazinyl (e.g., pyrazin-2-yl, pyrazin-4-yl), dihydrobenzofuranyl (e.g., dihydrobenzofuran-6-yl, dihydrobenzofuran-5-yl), indazolyl (e.g., 1H-indazol-6-yl), benzodioxinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxin-6-yl), isoquinolinyl (e.g., isoquinolin-6-yl), triazol-4-yl (e.g., 1H-1,2 , 3-triazol-4-yl, 1H-1,2,4-triazol-3-yl), imidazolyl (e.g., 1H-imidazol-4-yl), isoxazolyl (e.g., isoxazol-5-yl), oxazolyl (e.g., oxazol-2-yl), thiazolyl (e.g., thiazol-2-yl) or triazolyl (e.g., 1H-1,2,3-triazol-4-yl or 1H-1,2,4-triazol-3-yl), each of which is unsubstituted or replaced by chloro, fluoro, hydroxy, methyl, cyano, oxo, methoxy, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), pyridin-4-yl, phenyl or NR m R n Substitution, where R m and R n are independently hydrogen, C 1-6 alkyl or triazolyl (eg, 1H-1,2,3-triazol-4-yl).

[0158] In some embodiments, disclosed herein are compounds selected from Examples 1 to 672.

[0159] The inventors of the present invention have found that the FTO inhibitors of the present invention have comparable or improved FTO inhibition and improved FTO inhibition selectivity relative to COMT inhibition due to the following structural modifications:

[0160] (1) The compounds of the present invention produce improved FTO inhibition selectivity relative to COMT inhibition by adjusting the left portion of the compound (i.e., R4 on the benzene ring);

[0161] (2) The compounds of the present invention produce comparable or improved FTO inhibition by adjusting the L1-L2-L3-R1 attached to the carbonyl group, especially when L1 is -NR a -, and L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, L3 is a single bond or -O-, and R1 is an aryl group (such as phenyl or heteroaryl);

[0162] (3) Different electron-withdrawing groups as R5 can also adjust the selectivity and / or FTO inhibition activity of the compounds of the present invention; and

[0163] (4) For the compound, wherein L1 is -NR a -, the R a The non-hydrogen definition of can enhance the FTO inhibition activity of the compounds of the present invention.

[0164] In one aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0165] In one aspect, the present invention provides a method for inhibiting FTO or a method for treating diseases associated with excessive FTO activity (including obesity, obesity-related diseases and Alzheimer's disease). Specifically, the present invention discloses a method for inhibiting weight gain in a subject; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration or Alzheimer's disease; or treating damage or promoting wound healing or tissue regeneration, the method comprising administering an effective amount of a compound disclosed herein to a subject in need thereof.

[0166] In one aspect, provided herein is the use of a compound disclosed herein in the manufacture of a medicament for: inhibiting weight gain; or promoting weight loss; or lowering serum LDL, cholesterol, LDL-c or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration or Alzheimer's disease; or treating injuries or promoting wound healing or tissue regeneration.

[0167] In one aspect, provided herein is any one of the compounds disclosed herein for use in: inhibiting weight gain; or promoting weight loss; or lowering serum LDL, cholesterol, LDL-c or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration or Alzheimer's disease; or treating injuries or promoting wound healing or tissue regeneration.

[0168] In some embodiments regarding the above methods or uses, the above methods or uses are characterized by FTO inhibition. DETAILED DESCRIPTION

[0169] definition

[0170] The following terms have the indicated meanings throughout this specification:

[0171] As used herein, including the appended claims, singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0172] Unless the context clearly dictates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0173] The term "alkyl" refers to a hydrocarbon group selected from a straight chain saturated hydrocarbon group and a branched chain saturated hydrocarbon group, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl, 2-propyl or isopropyl, 1-butyl or n-butyl, 2-methyl-1-propyl or isobutyl, 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. The alkyl group may be optionally substituted or deuterium-enriched, for example, -CD3 (methyl-d3), -CD2CD3 (ethyl-d5), and the like.

[0174] The term "alkylene" refers to a divalent alkyl group as defined herein. For example, methylene refers to -CH2-.

[0175] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0176] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine and iodine). Examples of haloalkyl groups include halo C 1-8 Alkyl, halogenated C 1-6 Alkyl or halogenated C 1-4 Alkyl, but not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3 and the like.

[0177] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1-6 Alkoxy or C 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0178] The term "alkoxy-alkyl-" refers to an alkyl group as defined above that is further substituted with an alkoxy group as defined above. 1-6 Alkoxy-C 1-6 Examples of alkyl-) include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl or propoxymethyl, and the like.

[0179] The term "amino" refers to -NH2. The term "alkylamino" refers to -NH(alkyl). The term "dialkylamino" refers to -N(alkyl)2.

[0180] The term "alkenyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl.

[0181] The term "alkenylene" refers to a divalent alkenyl group as defined herein.

[0182] The term "alkynyl" herein refers to a hydrocarbon group selected from a straight chain hydrocarbon group and a branched hydrocarbon group, which contains at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkynyl groups (e.g., C2-6 alkynyl) include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl.

[0183] The term "alkynylene" refers to a divalent alkynyl group as defined herein.

[0184] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused cycloalkyl groups, bridged cycloalkyl groups, or spirocycloalkyl groups.

[0185] For example, cycloalkyl can include 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5 or 3 to 4) carbon atoms.Even further for example, cycloalkyl can be selected from the monocyclic group including 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms.The example of monocyclic cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.Specifically, saturated monocyclic cycloalkyl (for example, C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, a cycloalkyl group is a monocyclic ring (abbreviated as C 3-6 Cycloalkyl) includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The example of bicyclic cycloalkyl includes those with 7 to 12 ring atoms, which are arranged as fused bicyclic selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, or bridged bicyclic selected from bicyclic [2.2.1] heptane, bicyclic [2.2.2] octane and bicyclic [3.2.2] nonane. Other examples of bicyclic cycloalkyl include those arranged as bicyclic selected from [5,6] and [6,6] ring systems. In some embodiments, cycloalkyl also includes at least one double bond or at least one triple bond.

[0186] The term "deuterated" in deuterated analogs is used herein to modify a chemical structure or an organic group or radical in which one or more carbon-bound hydrogens are replaced by one or more deuteriums, such as "deuterated-alkyl", "deuterated-cycloalkyl", "deuterated-heterocycloalkyl", "deuterated-aryl", "deuterated-morpholinyl", etc. For example, the term "deuterated-alkyl" defined above refers to an alkyl group as defined herein in which at least one carbon-bound hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bound to deuterium; and it is possible for a carbon atom to be bound to more than one deuterium; it is also possible for more than one carbon atom in an alkyl group to be bound to deuterium.

[0187] The term "aryl", used alone or in combination with other terms, refers to a group selected from:

[0188] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0189] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl; and

[0190] - a tricyclic ring system, such as a 10- to 15-membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0191] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0192] The term "heteroaryl" herein refers to a group selected from:

[0193] - a 5-, 6- or 7-membered aromatic monocyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, selected from nitrogen (N), sulfur (S) and oxygen (O), the remaining ring atoms being carbon;

[0194] - a 7- to 12-membered bicyclic ring containing at least one heteroatom, e.g., 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0195] - an 11- to 14-membered tricyclic ring containing at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, which heteroatoms are selected from nitrogen, oxygen or optionally oxidized sulfur (as one or more ring members), the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0196] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not greater than 1. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in one or more rings of the heteroaryl group may be oxidized to form N-oxides.

[0197] As used herein, the term "optionally oxidized sulfur" refers to S, SO or SO2.

[0198] The terms "aromatic heterocycle" and "heteroaryl" are used interchangeably in the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9 or 10 ring members, wherein 1, 2, 3 or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S) and oxygen (O), and the remaining ring members are carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring, which is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0199] Examples of heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (as numbered starting from the attachment position designated as priority 1), pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl) ), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazine, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl or 1, 3,4-triazolyl), quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thio hetero-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0200] "Heterocyclyl", "heterocycle" or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, the remaining ring members being carbon, including monocyclic, fused, bridged and spirocyclic rings, i.e. including monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl and fused heterocyclyl.

[0201] Exemplary monocyclic 4- to 9-membered heterocyclic groups include, but are not limited to (as numbered from the attachment position designated as priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridine-1-yl, yl, aziridine-2-yl, azoctan-1-yl, azoctan-2-yl, azoctan-3-yl, azoctan-4-yl, azoctan-5-yl, thioethanethiyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridine, tetrahydropyridinyl, thiomorpholinyl, thiooxanyl, piperazinyl, homopiperazinyl, homopiperidinyl yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathiazyl, 1,4-dioxepanyl, 1,4-oxathiazyl, 1,4-oxathiazyl, 1,4-dithiazyl, 1,4-thiazazepanyl, and 1,4-diazepanyl, 1,4-dithiazyl, 1,4-thiazazepanyl. 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinyl, or 1,1-dioxo-thiomorpholinyl.

[0202] Compounds disclosed herein may contain asymmetric centers, and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound, which are non-superimposable mirror images of each other. In the case where compounds disclosed herein have two or more asymmetric centers, they may exist as diastereomers in addition. Enantiomers and diastereomers belong to a wider range of stereoisomer categories. It is intended to include all these possible stereoisomers of substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically mentioned, a reference to an isomer is applicable to any possible isomer. Whenever isomer composition is not specified, all possible isomers are included.

[0203] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0204] When the compounds disclosed herein contain disubstituted cyclohexyl or cyclobutyl, the substituents found on the cyclohexyl or cyclobutyl ring can be formed in cis and trans configurations. The cis configuration means that the two substituents are found on the upper side of the 2 substituent positions on the carbon, while the trans configuration means that they are on the opposite side.

[0205] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter separated) to the desired uniformity by techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reverse phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and equipment; small scale analytical; simulated moving bed ("SMB") and preparative thin or thick layer chromatography; and small scale thin layer and flash chromatography techniques. Those skilled in the art will apply the technique most likely to achieve the desired separation.

[0206] "Diastereomers" refer to stereoisomers of compounds with two or more chiral centers, but they are not mirror images of each other. Diastereoisomer mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the respective diastereomers into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0207] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolving racemic mixtures using optically active resolving agents using methods such as diastereoisomer formation [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH, et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): p. 283-302]. Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) forming ionic diastereomeric salts with chiral compounds and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereoisomers and converting to pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: Wainer, Irving W. ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0208] "Pharmaceutically acceptable salts" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and with a reasonable benefit / risk ratio commensurate. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base.

[0209] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. In contrast, if the product is a free base, an addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0210] As defined herein, "pharmaceutically acceptable salts thereof" include salts of at least one compound of formula (I) and salts of stereoisomers of compounds of formula (I), such as enantiomeric salts and / or diastereomeric salts.

[0211] When applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids, the terms "administration", "administering", "treating" and "treatment" refer to the contact of an exogenous agent, therapeutic agent, diagnostic agent or composition with the animal, human, subject, cell, tissue, organ or biological fluid. Treatment of cells encompasses contact of an agent with the cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic agent, a binding compound or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

[0212] The term "effective amount" or "therapeutically effective amount" refers to the following amount of an active ingredient (such as a compound), which is sufficient to affect such treatment of such a disease, disorder or symptom when the compound is administered to a subject to treat a disease or at least one clinical symptom of a disease or condition. The "therapeutically effective amount" may vary with the following: the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given example, the appropriate amount is clear to those skilled in the art, or can be determined by routine experiments. In some embodiments, a "therapeutically effective amount" is at least one compound disclosed herein and / or at least one of its stereoisomers and / or at least one of its pharmaceutically acceptable salts effective for "treating" (as defined above) the amount of a disease or disorder of a subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of a combination object used to effectively treat a disease, disorder or condition.

[0213] Throughout the specification and the claims that follow, unless the context requires otherwise, the term "comprises" and variations such as "comprising" are intended to specify the presence of the features that follow, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprising" may be replaced by the terms "containing", "including" or sometimes "having".

[0214] Throughout the specification and the claims that follow, the term "Cn-m" indicates a range including endpoints, where n and m are integers and represent the number of carbons. Examples include C1-8, C1-6, etc.

[0215] The expression "unsubstituted or substituted", for example, "unsubstituted or substituted R d "Substituted" means that such groups are unsubstituted or replaced with at least one substituent (e.g., R d ) is replaced. Regarding “replaced by…”, for example, “replaced by R d "Substituted" means that if the number of substituents is not indicated, the group is generally replaced by at least one substituent (e.g., 1 to 4, 1 to 3, 1 or 2, or 1 substituent) (e.g., selected from R d ) provided that it complies with the valence theory.

[0216] The expression "selectivity of FTO inhibition relative to COMT inhibition" refers to the degree of inhibition of FTO by a compound relative to inhibition of COMT. Thus, improved selectivity of FTO inhibition relative to COMT inhibition means that the compound exhibits FTO inhibition activity that is stronger than COMT inhibition activity. It is expected that the compounds of the present invention exhibit comparable or improved FTO inhibition and do not exhibit observable COMT inhibition.

[0217] Example

[0218] Unless otherwise specifically indicated, reagents and solvents were obtained from commercial sources (eg, Sigma-Aldrich, Alfa, Sinopharm Chemical Reagent Co. (SCRC) or others).

[0219] As used herein, the symbols and conventions used in the methods, schemes, and examples, whether or not a particular abbreviation is explicitly defined, are consistent with those used in the contemporary scientific literature (e.g., Journal of the American Chemical Society or the Journal of Biological Chemistry).

[0220] Specifically, but not limiting, the following abbreviations may be used in the examples and throughout the specification:

[0221]

[0222]

[0223] For intermediates or for final compounds, the following examples are for illustration only. However, the present invention should not be limited thereto.

[0224] Intermediate B-1: 3-Chloro-4-hydroxy-5-nitrobenzoic acid

[0225]

[0226] To a solution of 3-chloro-4-hydroxybenzoic acid (20 g, 116.28 mmol) in HOAc (100 mL) was added HNO3 (10 mL) dropwise at 0°C for 30 min. The mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water (200 mL). The precipitate was filtered and the filter cake was washed with water. The yellow solid was collected and dried to give the desired product (16 g, yield: 64%). MS [MH] - , the calculated value for C7H4ClNO5 is 216.6, and the measured value is 216.6

[0227] Intermediate B-2: 3-Fluoro-4-hydroxy-5-nitrobenzoic acid

[0228]

[0229] In a 250 ml flask, HNO3 (10 mL) was added to a solution of 1-ethyl-1H-imidazole (1 g, 6.41 mmol) in HOAc (10 ml) at 0 ° C for 15 min. The solution was then warmed to room temperature and stirred for 5 h. The reactants were quenched with ice water. The precipitate was filtered and dried to give 3-fluoro-4-hydroxy-5-nitrobenzoic acid (720 mg, yield: 56%) as a yellow solid. MS [MH] - , the calculated value for C7H4FNO5 is 200, and the measured value is 200.

[0230] Intermediate B-3: 4-Hydroxy-2-methoxy-5-nitrobenzoic acid

[0231]

[0232] To a solution of 4-hydroxy-2-methoxybenzoic acid (1 g, 6.0 mmol) in HOAc (20 mL) was added HNO3 (0.5 mL) dropwise at 0°C for 30 min. The mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water (20 mL). The precipitate was filtered and the filter cake was washed with water. The yellow solid was collected and dried to give the desired product (1.0 g, yield: 81.2%). MS [MH] - , the calculated value for C8H7NO6 is 211.9, and the measured value is 211.9

[0233] Intermediate B-4: 4-Hydroxy-3-methoxy-5-nitrobenzoic acid

[0234]

[0235] Step 1: Synthesis of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (2)

[0236] To a solution of methyl 4-hydroxy-3-methoxybenzoate (1.0 g, 5.49 mmol) in HOAc (10 mL) was added HNO3 (0.5 mL) dropwise at 0°C for 30 min. The mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water (10 mL). The precipitate was filtered and the filter cake was washed with water. The yellow solid was collected and dried to give the desired product (900 mg, 72.3%). MS [MH] - , the calculated value for C9H9NO6 is 225.9, and the measured value is 225.9.

[0237] Step 2: Synthesis of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (B-4)

[0238] To a mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (900 mg, 3.96 mmol) in MeOH / H2O (10 mL / 5 mL) was added NaOH (633 mg, 15.84 mmol). The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and then acidified to pH 3-4 with aqueous HCl. The precipitate was filtered. The filter cake was collected and dried to give the desired product (700 mg, 83.0%). MS [MH] - , the calculated value for C8H7NO6 is 211.9, and the measured value is 211.9.

[0239] Intermediate B-5: 4-Hydroxy-3-methyl-5-nitrobenzoic acid

[0240]

[0241] To a solution of 4-hydroxy-3-methylbenzoic acid (3 g, 19.7 mmol) in HOAc (30 mL) was added HNO3 (1.6 g) dropwise at 0°C for 30 min. The mixture was stirred at room temperature for 1 h. The reaction was quenched with ice water (30 mL). The precipitate was filtered and the filter cake was washed with water. The yellow solid was collected and dried to give the desired product (2 g, 51.5%). MS [MH] - , the calculated value for C8H7NO5 is 196.1, and the measured value is 196.1.

[0242] Intermediate B-6: 3-Bromo-4-hydroxy-5-methoxybenzoic acid

[0243]

[0244] Step 1: 4-Hydroxy-3-methoxybenzoic acid (2)

[0245] To a mixture of methyl 4-hydroxy-3-methoxybenzoate (900 mg, 4.94 mmol) in MeOH / H2O (20 mL / 10 mL) was added NaOH (989 mg, 24.72 mmol). The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and then acidified to pH 3-4 with aqueous HCl. The precipitate was filtered. The filter cake was collected and dried to give the desired product (750 mg, 90.4%). MS [MH] - , the calculated value for C8H8O4 is 167.1, and the measured value is 167.1.

[0246] Step 2: Synthesis of 3-bromo-4-hydroxy-5-methoxybenzoic acid (B-6)

[0247] To a solution of 4-hydroxy-3-methoxybenzoic acid (650 mg, 3.87 mmol) in DMF (10 mL) was added NBS (1.38 g, 7.74 mmol) at 0°C. The mixture was stirred at room temperature for 60 min. The mixture was quenched with ice and extracted with EA (50 mL*3). The organic phases were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 7) to give the product (450 mg, 47.1%). MS [MH] - , the calculated value for C8H7BrO4 is 246.5, and the measured value is 246.5

[0248] Intermediate B-7: 3-Cyano-4-hydroxy-5-methoxybenzoic acid

[0249]

[0250] To a solution of 3-bromo-4-hydroxy-5-methoxybenzoic acid (400 mg, 1.62 mmol) in DMF (10 mL) was added CuCN (173.0 mg, 1.94 mmol) at 0°C. The mixture was heated to 150°C and stirred overnight at said temperature. The mixture was quenched by ice and extracted with EA (50 mL*3). The organic phases were combined and dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 7) to give the product (300 mg, 96.1%). MS [MH] - , the calculated value for C9H7NO4 is 192.1, and the measured value is 192.1.

[0251] Intermediate B-8: 3,5-dicyano-4-hydroxybenzoic acid

[0252]

[0253] Step 1: Synthesis of methyl 3,5-dicyano-4-hydroxybenzoate (2)

[0254] A solution of methyl 4-hydroxy-3,5-diiodobenzoate (800.0 mg, 1.98 mmol) and CuCN (193.8 mg, 2.18 mmol) in DMF (10 mL) was stirred at 150 ° C for 8 h. The reactant was then quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a crude product. Further purification by column chromatography (silica gel, PE / EA=3 / 2) provided the desired product (350.0 mg, 87.5%). MS [M+H] + The calculated value for C10H6N2O3 is 203.2, and the measured value is 203.2.

[0255] Step 2: Synthesis of 3,5-dicyano-4-hydroxybenzoic acid (B-8)

[0256] A solution of methyl 3,5-dicyano-4-hydroxybenzoate (350.0 mg, 1.73 mmol), LiOH (207.6 mg, 8.65 mmol) in THF / H2O (10 ml / 2 mL) was stirred at room temperature for 5 h. 1N HCl (5 mL) and water (20 mL) were added to the mixture. The mixture was extracted with ethyl acetate (100 mL x 3), and the extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=3 / 2) provided the desired product (120.0 mg, 36.9%). MS [MH] ＝ The calculated value for C9H4N2O3 is 187.1, and the measured value is 187.1.

[0257] Intermediate B-9: 3-Cyano-4-hydroxybenzoic acid

[0258]

[0259] Step 1: Synthesis of methyl 3-cyano-4-hydroxybenzoate (2)

[0260] CuCN (360 mg, 4.0 mmol) was added to a solution of 4-hydroxy-3-iodobenzoic acid methyl ester (556 mg, 2.0 mmol) in DMF (10 mL). The mixture was stirred at 150 ° C overnight. The mixture was cooled to room temperature. The reactant was quenched with water and extracted with EA. The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. Further purified by preparative TLC to obtain a solid (305 mg, crude product) as the desired product. MS [MH] - , the calculated value for C9H7NO3 is 176.0, and the measured value is 176.0.

[0261] Step 2: Synthesis of 3-cyano-4-hydroxybenzoic acid (B-9)

[0262] To a solution of methyl 3-cyano-4-hydroxybenzoate (177 mg, 1.0 mmol) in THF / H2O (10 mL / 10 mL) was added NaOH (160 mg, 4.0 mmol). The reactant was stirred at room temperature for 6 h. The mixture was acidified to pH 5-6 with concentrated HCl and extracted with DCM (150 mL*3). The extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the product (155 mg, 95.0%). MS [MH] - , the calculated value for C8H5NO3 is 161.9, and the measured value is 161.9

[0263] Intermediate B-10: 3-Cyano-4-hydroxy-5-methylbenzoic acid

[0264]

[0265] Step 1: Synthesis of methyl 3-bromo-4-hydroxy-5-methylbenzoate (2)

[0266] NBS (1.9 g, 10.84 mmol) was added to a solution of methyl 4-hydroxy-3-methylbenzoate (900 mg, 5.42 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 2 h. The reactant was quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to obtain a crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 1) provided the desired product (1 g, 75.7%). MS [M+H] + The calculated value for C9H9BrO3 is 246.1 and the measured value is 246.1.

[0267] Step 2: Synthesis of methyl 3-cyano-4-hydroxy-5-methylbenzoate (3)

[0268] CuCN (399.6 mg, 4.49 mmol) was added to a solution of methyl 3-bromo-4-hydroxy-5-methylbenzoate (1 g, 4.08 mmol) in DMF (20 mL). The mixture was heated to 150 ° C and stirred overnight. The mixture was cooled to room temperature. Water and EA were added to the mixture extracted with EA and removed in vacuo. Further purification by preparative TLC gave a solid (300.0 mg, crude) as the desired product. MS [M+H] + The calculated value for C10H9NO3 is 192.1 and the measured value is 192.1.

[0269] Step 3: Synthesis of 3-cyano-4-hydroxy-5-methylbenzoic acid (B-10)

[0270] To a solution of methyl 3-cyano-4-hydroxy-5-methylbenzoate (300 mg, 1.57 mol) in THF / H2O (10 mL / 2 mL) was added NaOH (314.1 mg, 7.85 mol). The reactant was stirred at 70 ° C overnight. 1N HCl (15 mL) and water (30 mL) were added. The mixture was extracted with ethyl acetate (20 mL x 3). The extracts were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give a crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 5) provided the desired product (200 mg, 71.9%). MS [MH] - The calculated value for C9H7NO3 is 176.4, and the measured value is 176.4.

[0271] Intermediate B-11: 3-Chloro-5-fluoro-4-hydroxybenzoic acid

[0272]

[0273] To a solution of 3-fluoro-4-hydroxybenzoic acid (500 mg, 3.2 mmol) in chloroform (50 mL) was added sulfuryl chloride (1.1 g, 8.0 mmol). The reactor was degassed with nitrogen. The mixture was stirred at 70 ° C under a nitrogen atmosphere overnight. The reactant was quenched with water (20 ML) and extracted with DCM (150 mL * 3). The extracts were combined, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to give the product (413 mg, 68%). MS [MH] - , the calculated value for C7H4ClFO3 is 189.0, and the measured value is 189.0

[0274] Intermediate B-12: 3-Chloro-5-cyano-4-hydroxybenzoic acid

[0275]

[0276] Step 1: Synthesis of methyl 3-chloro-5-cyano-4-hydroxybenzoate (2)

[0277] At 0°C, N-chlorosuccinimide (2.26 g, 16.9 mmol) was added to a mixture of 3-cyano-4-hydroxybenzoate (3.0 g, 16.9 mmol) in DMF (30 mL) and stirred. The solution was then stirred at room temperature for 60 min. The mixture was quenched with ice and extracted with EA (50 mL*3). The combined extracts were dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 6) to give the product (2.9 g, 81.0%). MS[M+H] + The calculated value for C9H6ClNO3 is 212.6, and the measured value is 212.6.

[0278] Step 2: Synthesis of 3-chloro-5-cyano-4-hydroxybenzoic acid (B-12)

[0279] To a mixture of 3-chloro-5-cyano-4-hydroxybenzoate (2.9 g, 13.74 mmol) in MeOH / H2O (20 mL / 10 mL) was added NaOH (550 mg, 13.74 mmol) at room temperature. The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and acidified to pH 3-4 with concentrated HCl, the precipitate was filtered and dried to give the desired product (2.3 g, 84.9%). MS [MH] - , the calculated value for C8H4ClNO3 is 196.6, and the measured value is 196.6

[0280] Intermediate B-13: 3-Bromo-4-hydroxy-5-nitrobenzoic acid

[0281]

[0282] NBS (486 mg, 2.73 mmol) was added to a solution of 4-hydroxy-3-nitrobenzoic acid (500 mg, 2.73 mmol) in DCM (4 mL) / HOAc (4 mL) / sulfuric acid (0.08 mL). The mixture was stirred at room temperature overnight, then warmed to 60 ° C and stirred for 4 h. The solution was concentrated in vacuo and diluted with water (15 mL). The precipitate was filtered and dried to give the desired product (450 mg, 63%). MS [MH] +, the calculated value for C7H4BrNO5 is 262, and the measured value is 262

[0283] Intermediate B-14: 3-Fluoro-4-methoxy-5-(trifluoromethyl)benzoic acid

[0284]

[0285] Step 1: Synthesis of methyl 3-fluoro-4-methoxy-5-(trifluoromethyl)benzoate (2)

[0286] A solution of 5-bromo-1-fluoro-2-methoxy-3-(trifluoromethyl)benzene (5 g, 18.3 mmol), Pd(dppf)Cl2 (1.5 g, 1.8 mmol) and Et3N (5.5 g, 54.9 mmol) in MeOH (60 mL) was stirred at 120°C under CO for 16 h. The solvent was removed in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=5 / 1) afforded the desired product (3.2 g, 69%). MS [MH] + , for C 10 The calculated value of H8F4O3 is 253.0, and the measured value is 253.0.

[0287] Step 2: Synthesis of 3-fluoro-4-methoxy-5-(trifluoromethyl)benzoic acid (B-14)

[0288] NaOH (1.5 g, 13.53 mmol) was added to a solution of methyl 3-fluoro-4-methoxy-5-(trifluoromethyl)benzoate (3.2 g, 12.7 mmol) in water (20 mL) and THF (20 mL). The mixture was stirred at room temperature overnight. The reaction was diluted with 1N HCl (15 mL). The mixture was filtered and the filter cake was dried to give the crude product (1.4 g, 46%). MS [MH] - , the calculated value for C9H6F4O3 is 237.0, and the measured value is 237.0

[0289] Intermediate B-15: Synthesis of 3-cyano-5-fluoro-4-hydroxybenzoic acid

[0290]

[0291] Step 1: Synthesis of 5-bromo-3-fluoro-2-hydroxybenzonitrile (2)

[0292] NBS (1.33 g, 7.45 mmol) was added to a solution of 3-fluoro-2-hydroxybenzonitrile (1.021 g, 7.45 mmol) in anhydrous MeCN (20 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. Aqueous NaHCO3 solution and ether were added to the residue. The aqueous phase was adjusted to pH 2, extracted with ether, and the extract was concentrated in vacuo to provide the desired product (1.67 g, crude). MS [MH] - , the calculated value for C7H3BrFNO is 214.0, and the measured value is 214.0.

[0293] Step 2: Synthesis of methyl 3-cyano-5-fluoro-4-hydroxybenzoate (3)

[0294] A solution of 5-bromo-3-fluoro-2-hydroxybenzonitrile (1.586 g, 7.34 mmol), Pd(dppf)Cl2 (600 mg, 0.73 mmol) and Et3N (2.303 g, 22.76 mmol) in MeOH (20 mL) was stirred at 120°C under CO for 16 h. The solvent was removed in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=5 / 1) afforded the desired product (880 mg, 61%). MS [MH] - , the calculated value for C9H6FNO3 is 194.0, and the measured value is 194.0.

[0295] Step 3: Synthesis of 3-cyano-5-fluoro-4-hydroxybenzoic acid (B-15)

[0296] NaOH (541 mg, 13.53 mmol) was added to a solution of methyl 3-cyano-5-fluoro-4-hydroxybenzoate (880 mg, 4.51 mmol) in water (10 mL) and THF (10 mL). The mixture was stirred at room temperature overnight. The reactant was diluted by 1N HCl (15 mL). The mixture was filtered. The solid was dried to give a solid (750 mg, crude) as a crude product. MS [MH] - , the calculated value for C8H4FNO3 is 180.0, and the measured value is 180.0

[0297] Intermediate B-16: 3,4-dimethoxy-5-nitrobenzoic acid

[0298]

[0299] Step 1: Synthesis of methyl 3,4-dimethoxy-5-nitrobenzoate (2)

[0300] To a mixture of methyl 4-hydroxy-3-methoxy-5-nitrobenzoate (10.0 g, 44.1 mmol) in acetone (150 mL) was added dimethyl sulfate (8.3 g, 66.1 mmol) and K2CO3 (9.1 g, 66.1 mmol). The mixture was warmed to 65°C and stirred overnight at this temperature. The reactants were cooled and quenched with ice water (50 mL) and extracted with EA (200 mL*3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=2 / 1) to give the product (5.0 g, 47%). MS [MH] + , for C 10 H 11 The calculated value of NO6 is 242.1 and the measured value is 242.1.

[0301] Step 2: Synthesis of 3,4-dimethoxy-5-nitrobenzoic acid (B-16)

[0302] To a mixture of methyl 3,4-dimethoxy-5-nitrobenzoate (5.0 g, 20.7 mmol) in THF / H2O (30 mL / 30 mL) was added LiOH (2.6 g, 62.2 mmol). The reaction was stirred at room temperature for 6 h. The mixture was acidified to pH about 5-6 by HCl, extracted by DCM (150 mL*3), and dried over Na2SO4 to give the product (3.0 g, 65.0%). MS [MH] - , the calculated value for C9H9NO6 is 226.0, and the measured value is 226.0

[0303] Intermediate B-17: 4-Hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid

[0304]

[0305] Step 1: Synthesis of 2-methoxy-6-(trifluoromethyl)phenol (2)

[0306] At -78 ° C, n-butyl lithium (102 mL, 255.5 mmol) and N, N, N', N'-tetramethylethylenediamine (45 mL, 298 mmol) are added to anhydrous THF (250 mL). 1-methoxy-3-(trifluoromethyl) benzene (50 g, 285 mmol) is added dropwise. The reaction mixture is stirred at -78 ° C for 15 min, then allowed to warm to room temperature and stirred for 10 min. The reaction mixture is cooled to -78 ° C, and trimethyl borate (80.5 mL, 710 mmol) is added dropwise slowly, and the reaction mixture is stirred at -78 ° C for 15 min, then allowed to warm to room temperature and stirred for 20 h. 7N NH3 / MeOH (100 mL) is added and the solvent is removed in vacuo. The residue is dissolved in formic acid (100 mL), and the mixture is cooled to 0 ° C, and hydrogen peroxide (30 mL, 342.5 mmol) is then added. The solution was warmed to room temperature and stirred for 2h. The product was extracted with EtOAc (3x 250mL), and the combined organic matter was then oscillated with NaOH (2x 250mL). The aqueous phase was acidified with 1M HCl and the product was extracted with DCM (2x150mL). The organic layer was washed with brine (2x 150mL), dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (silica gel, PE / EA=2 / 1) to obtain 2-methoxy-6-(trifluoromethyl)phenol (2) (38g, 70%) as a colorless oil. MS [MH] - , the calculated value for C8H7F3O2 is 191.0, and the measured value is 191.0.

[0307] Step 2: Synthesis of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3)

[0308] A mixture of 2-methoxy-6-(trifluoromethyl)phenol (36g, 187.2mmol) and hexamethylenetetramine (25.92g, 43.2mmol) in TFA (300mL) was stirred at reflux for 3h. The solvent was removed in vacuo and the residue was dissolved in 1M HCl (280mL). The product was extracted with DCM (3x 250mL), and the combined organic phase was washed with brine (2x250mL). The solvent was then removed in vacuo. The residue was purified by silica gel chromatography (silica gel, PE / EA=1 / 1) to obtain 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (3) (18g, 43%) as a white solid. MS[M+H] + , the calculated value for C9H7F3O3 is 221.1, and the measured value is 221.1.

[0309] Step 3: Synthesis of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (B-17)

[0310] A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (18 g, 81.76 mmol) and potassium monopersulfate (Oxone) (60 g, 98.11 mmol) in DMF (300 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (600 mL) and the solution was washed with 1M HCl (600 mL) and brine (4 x 600 mL) in sequence. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (silica gel, MeOH / DCM=1 / 15) to obtain 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (8 g, 41%) as a white solid. MS [MH] - , the calculated value for C9H7F3O4 is 235.0, and the measured value is 235.0.

[0311] Intermediate B-18: 5-Chloro-2-fluoro-4-hydroxybenzoic acid

[0312]

[0313] NaOH (294.1 mg, 7.35 mmol) was added to a solution of 5-chloro-2-fluoro-4-hydroxybenzoic acid methyl ester (300.0 mg, 1.47 mmol) in water (10 mL) and THF (10 mL). The mixture was stirred at 70 ° C overnight. The reaction mixture was acidified with 1N HCl (15 mL). The mixture was extracted with DCM (100 mL × 3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to obtain a crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 5) provided the desired product (250.0 mg, 89.6%). MS [MH] - The calculated value for C7H4ClFO3 is 189.2, and the measured value is 189.2.

[0314] Intermediate B-19: 4-Hydroxy-3-methoxy-5-(methylsulfonyl)benzoic acid

[0315]

[0316] Step 1: Synthesis of methyl 3-bromo-4-hydroxy-5-methoxybenzoate (2)

[0317] To a mixture of methyl 4-hydroxy-3-methoxybenzoate (3 g, 16.5 mmol) and TsOH (2.8 g, 16.5 mmol) in MeCN (100 mL) was added NBS (2.9 g, 16.5 mmol). The mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (2.6 g, 60%). MS [MH] - , the calculated value for C9H9BrO4 is 258.9, and the measured value is 258.9.

[0318] Step 2: Synthesis of methyl 4-hydroxy-3-methoxy-5-(methylsulfonyl)benzoate (3)

[0319] L-Valine (540 mg, 4.6 mmol) and CuI (440 mg, 2.3 mmol) were added to a mixture of methyl 3-bromo-4-hydroxy-5-methoxybenzoate (2 g, 7.7 mmol) and sodium methanesulfinate (6.3 g, 61.3 mmol) in DMSO (60 mL). The solution was stirred at 110 ° C for 16 h. The reactants were quenched with ice water (100 mL). The mixture was extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (700 mg, 35%). MS [MH] - , for C 10 H 12 The calculated value of O6S is 258.9 and the measured value is 258.9.

[0320] Step 3: Synthesis of 4-hydroxy-3-methoxy-5-(methylsulfonyl)benzoic acid (B-19)

[0321] To a mixture of 4-hydroxy-3-methoxy-5-(methylsulfonyl)benzoate (700 mg, 2.7 mmol) in MeOH / H2O (20 mL / 10 mL) was added NaOH (430.5 mg, 10.8 mmol). The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and acidified to pH 5-6 with 1N HCl. The precipitate was filtered and dried to give the desired product (569.6 mg, 86%). MS [MH] - , for C9H 10 The calculated value of O6S is 245.0, and the measured value is 245.0

[0322] Intermediate B-20: 4-methoxy-3-(methylsulfonyl)benzoic acid

[0323]

[0324] Step 1: (2-methoxy-5-(methoxycarbonyl)phenyl)boronic acid (2)

[0325] A mixture of methyl 3-bromo-4-methoxybenzoate (3 g, 12.2 mmol), boronic acid (911 mg, 14.7 mmol), Pd(dppf)Cl2 (993 mg, 1.2 mmol) and KOAc (2.4 g, 24.4 mmol) in dioxane (100 mL) was stirred at 100 ° C under nitrogen for 8 h. The reaction was quenched with water (20 ML) and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (1.7 g, 68%). MS [MH] - , for C9H 11 The calculated value of BO5 is 208.9 and the measured value is 208.9.

[0326] Step 2: Synthesis of methyl 4-methoxy-3-(methylsulfonyl)benzoate (3)

[0327] K2CO3 (1.1 g, 8.1 mmol) and Cu(OAc)2 (486 mg, 2.4 mmol) were added to a mixture of (2-methoxy-5-(methoxycarbonyl)phenyl)boronic acid (1.7 g, 8.1 mmol) and sodium methanesulfinate (6.6 g, 64.8 mmol) in DMSO (60 mL). The mixture was stirred at 110°C for 16 h. The reactants were quenched with ice water (100 mL) and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the product (691 mg, 35%). MS[MH] + , for C 10 H 12 The calculated value of O5S is 242.9 and the measured value is 242.9.

[0328] Step 3: Synthesis of 4-methoxy-3-(methylsulfonyl)benzoic acid (B-20)

[0329] To a mixture of methyl 4-methoxy-3-(methylsulfonyl)benzoate (690 mg, 2.8 mmol) in MeOH / H2O (20 mL / 10 mL) was added NaOH (452 ​​mg, 11.3 mmol). The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and acidified to pH 5-6 with 1N HCl. The precipitate was filtered and dried to give the desired product (559 mg, 86%). MS [MH] - , for C9H 10 The calculated value of O5S is 229.0 and the measured value is 229.0

[0330] Intermediate B-21: 3,4-dimethoxy-5-(methylsulfonyl)benzoic acid

[0331]

[0332] Step 1: Synthesis of 3-bromo-4,5-dimethoxybenzoic acid (2)

[0333] Methyl 3-bromo-4,5-dimethoxybenzaldehyde (10 g, 40.8 mmol) was added to 6% KMnO4 aqueous solution (20 mL) at 0°C. The mixture was stirred at 0°C for 8 h. Additional water (20 mL) was added. The mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (10.1 g, 95%). MS [MH] - , the calculated value for C9H9BrO4 is 258.9, and the measured value is 258.9.

[0334] Step 2: Synthesis of methyl 3-bromo-4,5-dimethoxybenzoate (3)

[0335] A mixture of methyl 3-bromo-4,5-dimethoxybenzoic acid (10 g, 40.8 mmol) and sulfuric acid (one drop) in MeOH (20 mL) was stirred at 70 ° C for 8 h. The reactant was evaporated. The residue was washed with water (20 mL) and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (8.4 g, 80%). MS [MH] + , for C 10 H 11 The calculated value of BrO4 is 274.9 and the measured value is 274.9.

[0336] Step 3: Synthesis of methyl 3,4-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (4)

[0337] A mixture of methyl 3-bromo-4-methoxybenzoate (8 g, 29.1 mmol), bis(pinacolato)diboron (8.9 mg, 34.9 mmol), Pd(dppf)Cl2 (2.3 mg, 2.9 mmol) and KOAc (5.7 g, 58.2 mmol) in dioxane (200 mL) was stirred at 100°C for 8 h. The reaction mixture was washed with water (20 ML) and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (4.5 g, 48%). MS [MH] + , for C 16 H 23 The calculated value of BO6 is 323.1 and the measured value is 323.1.

[0338] Step 4: Synthesis of methyl 3,4-dimethoxy-5-(methylsulfonyl)benzoate (5)

[0339] K2CO3 (642 mg, 4.7 mmol) and Cu(OAc)2 (280 mg, 1.4 mmol) were added to a mixture of methyl 3,4-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.5 g, 4.7 mmol) and sodium methanesulfinate (3.8 g, 37.3 mmol) in DMSO (60 mL). The mixture was stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature, washed with ice water (100 mL), and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the product (213 mg, 25%). MS[MH] + , for C 11 H 14 The calculated value of O6S is 274.9 and the measured value is 274.9.

[0340] Step 5: Synthesis of 3,4-dimethoxy-5-(methylsulfonyl)benzoic acid (B-21)

[0341] To a mixture of methyl 3,4-dimethoxy-5-(methylsulfonyl)benzoate (200 mg, 0.7 mmol) in MeOH / H2O (20 mL / 10 mL) was added NaOH (117 mg, 2.9 mmol). The reaction was stirred at 70°C overnight. The mixture was cooled to room temperature and acidified to pH 5-6 with 1N HCl. The precipitate was filtered and dried to give the desired product (152 mg, 80%). MS [MH] - , for C 10 H 12 The calculated value of O6S is 259.0, and the measured value is 259.0

[0342] Intermediate B-22: 4-Hydroxy-3-nitro-5-(trifluoromethoxy)benzoic acid

[0343]

[0344] Step 1: Synthesis of 4-hydroxy-3-(trifluoromethoxy)benzoic acid (2)

[0345] A mixture of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (1.0 g, 4.85 mmol) in acetone (10 mL) was stirred at 0°C. Jones reagent (0.25 mL, 2.5 M / L) was added to the mixture and stirred at 0°C for 10 min. The reactants were stirred at room temperature for 1 h. The reactants were quenched by isopropanol, extracted with EA (20 mL*3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=20 / 80, 0.1% TFA, 2 times) to give a crude product (900 mg, 83.6%). MS [MH]-, calculated for C8H5F3O4 was 221.1, and found was 221.1.

[0346] Step 2: Synthesis of 4-hydroxy-3-nitro-5-(trifluoromethoxy)benzoic acid (B-22)

[0347] A mixture of 4-hydroxy-3-(trifluoromethoxy)benzaldehyde (400 mg, 1.80 mmol) in AcOH (10 mL) was stirred at 10 ° C. HNO3 (0.2 mL) was added to the mixture and stirred at 10 ° C for 10 min. The reactants were stirred at room temperature for 16 h. The reactants were quenched with ice water (20 ML), extracted with EA (20 mL * 3), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to obtain a crude product (150 mg, 30.9%). MS [MH]-, the calculated value for C8H4F3NO6 was 266.0, and the found value was 266.0

[0348] Intermediate B-23: 3-(Difluoromethoxy)-4-hydroxy-5-nitrobenzoic acid

[0349]

[0350] Step 1: Synthesis of methyl 4-(benzyloxy)-3-(difluoromethoxy)benzoate (2)

[0351] To a solution of methyl 4-(benzyloxy)-3-hydroxybenzoate (2 g, 7.75 mmol) and sodium 2-bromo-2,2-difluoroacetate (2.9 g, 19.38 mmol) in DMF (20 mL) was added K2CO3 (1.3 g, 9.3 mmol). After stirring at 70 ° C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (PE / EA=2 / 1) to give the product (1 g, 42%). MS [MH] +, calculated for C16H14F2O4 was 309.2, and found to be 309.2.

[0352] Step 2: Synthesis of methyl 3-(difluoromethoxy)-4-hydroxybenzoate (3)

[0353] A solution of methyl 4-(benzyloxy)-3-(difluoromethoxy)benzoate (1 g, 3.25 mmol) and Pd / C (300 mg) in MeOH (30 mL) was stirred at room temperature for 3 h under H2. The reaction solution was filtered to remove Pd / C and removed in vacuo to obtain a crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 1) provided the desired product (650 mg, 92%). MS [MH] +, calculated for C9H8F2O4 was 219.2, and found was 219.2.

[0354] Step 3: Synthesis of methyl 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoate (4)

[0355] At 0°C, HNO3 (282 mg, 4.47 mmol) was added to a solution of compound 3 (650 mg, 2.98 mmol) in AcOH (8 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with water (20 mL) and extracted with EA (100 mL x 3), dried over Na2SO4, and concentrated to dryness in vacuo to obtain the desired product (600 mg, 77%). MS [MH] +, calculated for C9H7F2NO6 was 264.2, found to be 264.2.

[0356] Step 4: Synthesis of 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoic acid (5)

[0357] To a solution of methyl 3-(difluoromethoxy)-4-hydroxy-5-nitrobenzoate (600 mg, 2.28 mmol) in THF / H2O (10 / 10 mL) was added LiOH (239.54 mg, 5.70 mmol) at 0°C. After addition, the reactant was warmed to room temperature and stirred for 2 h. The mixture was neutralized with hydrochloric acid, extracted with EA (100 mL x 3), dried over Na2SO4, and concentrated to dryness in vacuo to give the desired product (550 mg, 97%). MS [MH]+, calculated for C8H5F2NO6 was 250.2, found to be 250.2.

[0358] Preparation of Intermediate A series amides by general procedure for the synthesis of Intermediates A-1 and A-2

[0359]

[0360] Intermediate A-1: ​​2-cyano-N,N-diethylacetamide (A-1)

[0361]

[0362] To a mixture of diethylamine (1.0 g, 13.70 mmol) in DCM (20 mL) was added 2-cyanoacetic acid (1.28 g, 15.07 mmol), T3P (13.07 g, 20.55 mmol) and DIEA (5.3 g, 41.1 mmol). The reactants were stirred at room temperature for 16 h. The reaction mixture was washed with ice water (50 ML) and extracted with EA (50 mL*3). The combined extracts were dried over anhydrous Na2SO4 and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=3 / 1) to give the product (900 mg, 46.9%). MS [M+H]+ , the calculated value for C7H12N2O is 141.2, and the measured value is 141.2.

[0363] Intermediate A-2: 2-Cyano-N-methyl-N-(2-phenoxyethyl)acetamide

[0364]

[0365] A solution of N-methyl-2-phenoxyethyl-1-amine (1.51 g, 10.03 mmol), 2-cyanoacetic acid (853 mg, 10.03 mmol), HATU (2.59 g, 20.05 mmol) and DIEA (7.62 g, 20.05 mmol) in DCM (30 mL) was stirred at room temperature for 5 h, and then the solution was washed with water (30 mL). The mixture was extracted with ethyl acetate (25 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=10 / 1) provided the desired product (1.5 g, 68%). MS [MH] + , the calculated value for C12H14N2O2 is 219, and the measured value is 219.

[0366] By using the same procedure as for the preparation of intermediates A-1 and A-2 in Scheme 1, substituting the appropriate amine, this can afford the corresponding intermediate A amides. Of the amines, those that are not commercially available need to be synthesized in the laboratory.

[0367] Synthesis of N-ethyl-3-(2-methoxyphenyl)propan-1-amine

[0368]

[0369] Step 1: Synthesis of N-ethyl-3-(2-methoxyphenyl)propionamide

[0370] To a mixture of 3-(2-methoxyphenyl)propanoic acid (1.0 g, 5.56 mmol) in DCM (20 mL) was added ethylamine (250 mg, 5.56 mmol), T3P (5.3 g, 8.34 mmol) and DIEA (2.15 g, 16.68 mmol). The reactants were stirred at room temperature for 16 h. The reaction mixture was washed with ice water (50 ML) and extracted with EA (50 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 2) to give the product (1.0 g, 87.0%). MS[M+H] + , the calculated value for C12H17NO2 is 208.2, and the measured value is 208.2.

[0371] Step 2: Synthesis of N-ethyl-3-(2-methoxyphenyl)propan-1-amine

[0372] To a mixture of N-ethyl-3-(2-methoxyphenyl)propionamide (1.0 g, 4.83 mmol) in THF (30 mL) was added BH3-THF (9.66 mL) at -78°C. The reactants were stirred at room temperature for 2 h. The reactants were quenched with ice water (50 ML). The mixture was extracted with DCM (50 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 5) to give the product (720 mg, 77.3%). MS[M+H] + , the calculated value for C12H19NO is 194.3, and the measured value is 194.3

[0373] Synthesis of 2-(3-(Methylamino)propyl)benzonitrile

[0374]

[0375] Prepared as described for N-ethyl-3-(2-methoxyphenyl)propan-1-amine, but using 3-(2-cyanophenyl)propionic acid instead of 3-(2-methoxyphenyl)propionic acid. MS [M+H]+, calculated for C11H14N2, 175.2, found 175.2

[0376] Synthesis of 3-(2-chlorophenyl)-N-ethylpropan-1-amine

[0377]

[0378] Prepared as described for N-ethyl-3-(2-methoxyphenyl)propan-1-amine but using 3-(2-chlorophenyl)propanoic acid instead of 3-(2-methoxyphenyl)propanoic acid. MS [MH] + , the calculated value for C11H16ClN is 198, and the measured value is 198

[0379] Synthesis of 1-(3-fluoro-[1,1'-biphenyl]-4-yl)-N-methylmethanamine

[0380]

[0381] Step 1: Synthesis of 3-fluoro-[1,1'-biphenyl]-4-carbaldehyde

[0382] A solution of (3-fluoro-4-formylphenyl)boronic acid (1 g, 5.95 mmol), bromobenzene (928 mg, 5.95 mmol), Na2CO3 (946 mg, 8.93 mmol) and Pd(PPh3)4 (347 mg, 0.30 mmol) in water (5 mL), THF (5 mL) and 1,2-dimethoxyethane (10 mL) was stirred at 90 ° C for 16 h. The solution was washed with water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=10 / 1) provided the desired product (900 mg, 75.6%). MS[M+H] + , the calculated value for C13H9FO is 201.2, and the measured value is 201.2.

[0383] Step 2: Synthesis of 1-(3-fluoro-[1,1'-biphenyl]-4-yl)-N-methylmethanamine

[0384] NaBH(OAc)3 (1.07 g, 5.03 mmol) was added to a solution of 3-fluoro-[1,1'-biphenyl]-4-carbaldehyde (900 mg, 4.19 mmol) and methylamine (4.19 mL, 8.38 mmol) in DCE (10 mL). The mixture was stirred at room temperature for 5 h, and the solution was then quenched with 1N NaOH (10 mL). The mixture was extracted with DCM (30 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=5 / 1) provided the desired product (800 mg, 88.9%). MS[M+H] + , the calculated value for C14H14FN is 216.3, and the measured value is 216.3

[0385] Synthesis of 1-(4-fluoro-[1,1'-biphenyl]-3-yl)-N-methylmethanamine

[0386]

[0387] Prepared as described for 1-(3-fluoro-[1,1'-biphenyl]-4-yl)-N-methylmethanamine but using (4-fluoro-3-formylphenyl)boronic acid instead of (3-fluoro-4-formylphenyl)boronic acid MS [MH] + , the calculated value for C14H14FN is 216, and the measured value is 216

[0388] Synthesis of 1-(2-fluoro-4-(pyridin-3-yl)phenyl)-N-methylmethanamine

[0389]

[0390] Prepared as described for 1-(3-fluoro-[1,1'-biphenyl]-4-yl)-N-methylmethanamine, but using 3-bromopyridine instead of bromobenzene. MS [MH] + , the calculated value for C14H14FN is 216, the found value is 216MS[M+H] + , the calculated value for C13H13FN2 is 217.3, and the measured value is 217.3

[0391] Synthesis of 1-(2-fluoro-5-(pyrimidin-4-yl)phenyl)-N-methylmethanamine

[0392]

[0393] Prepared as described for 1-(4-fluoro-[1,1'-biphenyl]-3-yl)-N-methylmethanamine, but using 4-chloropyrimidine instead of bromobenzene. MS [MH] + , for C 12 H 12 The calculated value of FN3 is 217.9 and the measured value is 217.9.

[0394] Synthesis of 2-methyl-6-((methylamino)methyl)phenol

[0395]

[0396] At room temperature, NaBH (OAc) 3 (1.87 g, 8.82 mmol) was added to a solution of 2-hydroxy-3-methylbenzaldehyde (1 g, 7.35 mmol) and methylamine (7.35 mL, 14.7 mmol) in DCE (20 mL), stirred for 5 h, and then the solution was washed with 1 N NaOH (20 mL). The mixture was extracted with DCM (20 mL x 3). The combined extracts were dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=6 / 1) provided the desired product (1.0 g, 90.1%). MS [M+H] + , the calculated value for C9H13NO is 152.2, and the measured value is 152.2.

[0397] The following analogous amines were synthesized in a similar manner starting from the corresponding aldehydes or ketones and characterized.

[0398]

[0399]

[0400] Synthesis of 1-(7-Fluoroisoquinolin-6-yl)-N-methylmethanamine

[0401]

[0402] Step 1: Synthesis of 7-fluoroisoquinoline-6-carbonitrile

[0403] CuCN (6.0 g, 66.4 mmol) was added to a solution of 6-bromo-7-fluoroisoquinoline (10 g, 44.2 mmol) in DMF (100 mL). The mixture was stirred at 150° C. overnight. The reaction mixture was washed with water and extracted with EA. The solvent of the combined extracts was removed in vacuo. Further purification by preparative TLC gave a solid (7.4 g, 97%) as the desired product. MS [MH] + , for C 10 The calculated value of H5FN3 is 173.0 and the measured value is 173.0.

[0404] Step 2: Synthesis of tert-butyl ((7-fluoroisoquinolin-6-yl)methyl)carbamate

[0405] A mixture of 7-fluoroisoquinoline-6-carbonitrile (7.4 g, 43.0 mmol), (Boc)2O (18.7 g, 86.0 mmol), NiCl 6H2O (1.0 g, 4.3 mmol), NaBH4 (11.4 g, 301.0 mmol) in MeOH (100 mL) was stirred at 25 °C overnight. The reactant was quenched with water (20 mL). The mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (1.9 g, 16%). MS [MH] + , for C 15 H 17 The calculated value of FN2O2 is 276.9 and the measured value is 276.9.

[0406] Step 3: Synthesis of tert-butyl ((7-fluoroisoquinolin-6-yl)methyl)(methyl)carbamate

[0407] At -20 ° C, NaH (0.3 g, 13.0 mmol) was added to a mixture of tert-butyl ((7-fluoroisoquinolin-6-yl)methyl)carbamate (1.8 g, 6.5 mmol) in THF (50 mL). The mixture was stirred at 20 ° C under a nitrogen atmosphere for 30 min. Iodomethane (0.4 mL, 6.5 mmol) was then added and the mixture was stirred overnight. The mixture was acidified to pH 5-6 with 1N HCl and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the product (1.8 g, 96%). MS [MH] + , for C 16 H 19 The calculated value of FN2O2 is 290.9 and the measured value is 290.9.

[0408] Step 4: Synthesis of 1-(7-fluoroisoquinolin-6-yl)-N-methylmethanamine

[0409] A mixture of tert-butyl ((7-fluoroisoquinolin-6-yl)methyl)(methyl)carbamate (1.8 g, 6.2 mmol) in dioxane (60 mL) was stirred at 0°C. Conc. HCl (drops) was added. The mixture was stirred for 16 h. The reactant was quenched with ice water (50 mL). The mixture was extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (500 mg, 45%). MS [MH] + , for C 11 H 11 The calculated value of FN2 is 190.9, and the measured value is 190.9

[0410] Synthesis of 1-(2-Fluoro-3,5-dimethylphenyl)-N-methylmethylamine

[0411]

[0412] Step 1: Synthesis of 2-fluoro-3,5-dimethylbenzaldehyde

[0413] A solution of 1-bromo-2-fluoro-3,5-dimethylbenzene (2 g, 9.9 mmol) in THF (20 mL) was cooled to -78 ° C, and then n-butyl lithium (9.9 mL, 9.9 mmol) was added to the above solution. The mixture was stirred at -78 ° C for 1 h. DMF (73 mg, 9.9 mmol) was added to the above solution. The mixture was stirred at 25 ° C for 1 h. The reactants were quenched with 1N HCl (2 mL) and water (15 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give a crude product (1.2 g, 80%). MS [M+H] + , the calculated value for C9H9FO is 153.2, and the measured value is 153.2.

[0414] Step 2: Synthesis of 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine

[0415] NaBH4(OAc)3(2.0 g, 9.47 mmol) was added to a solution of 2-fluoro-3,5-dimethylbenzaldehyde (1.2 g, 7.89 mmol) and methylamine (7.89 mL, 15.78 mmol) in DCE (40 mL). The mixture was stirred at room temperature for 5 h, and the reactant was then quenched with 1 N NaOH (10 mL). The mixture was extracted with DCM (30 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give a crude product. Further purification by column chromatography (silica gel, PE / EA=3 / 1) provided the desired product (1.0 g, 75.8%). MS[M+H] + , the calculated value for C10H14FN is 168.2, and the measured value is 168.2

[0416] Synthesis of 1-(2,4-difluoro-5-methylphenyl)-N-methylmethylamine

[0417]

[0418] Prepared as described above for 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine, but using 1-bromo-2,4-difluoro-5-methylbenzene instead of 1-bromo-2-fluoro-3,5-dimethylbenzene. MS [M+H] + , the calculated value for C9H11F2N is 172.2, and the measured value is 172.2

[0419] Synthesis of 1-(3-Fluoro-6-methylpyridin-2-yl)-N-methylmethylamine

[0420]

[0421] Prepared as described above for 1-(2-fluoro-3,5-dimethylphenyl)-N-methylmethanamine, but using 2-bromo-3-fluoro-6-methylpyridine instead of 1-bromo-2-fluoro-3,5-dimethylbenzene. MS [M+H] + , the calculated value for C8H11FN2 is 155.1, and the measured value is 155.1.

[0422] Synthesis of 2-(2-chlorophenoxy)-N-ethyleth-1-amine

[0423]

[0424] Step 1: Synthesis of tert-butyl (2-(2-chlorophenoxy)ethyl)carbamate

[0425] At 0°C, NaH (187.5mg, 7.8mmol) was added to a solution of 2-chlorophenol (1.0g, 7.8mmol) in anhydrous THF (25mL). The mixture was stirred at 0°C for 30min. (2-bromoethyl) tert-butyl carbamate (1.7g, 7.8mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15min, then allowed to warm to room temperature and stirred overnight. The reactant was quenched with water (30mL). The mixture was extracted with EtOAc (200mL x 3). The combined extracts were dried over Na2SO4 and filtered. The solvent was removed in vacuo to obtain tert-butyl (2-(2-chlorophenoxy)ethyl)carbamate (1.1g, 52%). MS [MH] + , for C 13 H 18 The calculated value of ClNO3 is 272.1 and the measured value is 272.1.

[0426] Step 2: Synthesis of tert-butyl (2-(2-chlorophenoxy)ethyl)(ethyl)carbamate

[0427] At -20 ° C, NaH (0.2 g, 8.1 mmol) was added to a mixture of tert-butyl (2-(2-chlorophenoxy)ethyl)carbamate (1.1 g, 4.1 mmol) in THF (50 mL). The solution was stirred at -20 ° C under N2 atmosphere for 30 min. Subsequently, iodoethane (0.6 g, 4.1 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was acidified to pH 5-6 with 1N HCl and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the product (1.0 g, 83%). MS [MH] +, for C 15 H 22 The calculated value of ClNO3 is 299.9 and the measured value is 299.9.

[0428] Step 3: Synthesis of 2-(2-chlorophenoxy)-N-ethylethan-1-amine

[0429] A mixture of tert-butyl (2-(2-chlorophenoxy)ethyl)(ethyl)carbamate (900 mg, 3.0 mmol) and TFA (0.5 mL) in DCM (20 mL) was stirred at 25 °C overnight. The reaction was evaporated to give the product (500 mg, 83%). MS [MH] - , for C 10 H 14 The calculated value of ClNO was 199.9 and the measured value was 199.9.

[0430] Synthesis of N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine

[0431]

[0432] Step 1: Synthesis of tert-butyl ethyl (2-(pyrimidin-2-yloxy)ethyl)carbamate (2)

[0433] At 0°C, NaH (194mg, 4.86mmol) was added to a solution of tert-butyl ethyl (2-hydroxyethyl) carbamate (1.1g, 5.81mmol) in anhydrous THF (15mL). The mixture was stirred at 0°C for 30min. 2-chloropyrimidine (497mg, 4.34mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15min, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with water (30mL). The mixture was extracted with EtOAc (20mL x 3). The combined extracts were dried over Na2SO4 and filtered. The solvent of the filtrate was removed in vacuo to obtain tert-butyl ethyl (2-(pyrimidin-2-yloxy)ethyl) carbamate (1.6g, crude product). MS [MH] + , the calculated value for C13H21N3O3 is 268, and the measured value is 268.

[0434] Step 2: Synthesis of N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine (3)

[0435] A solution of tert-butyl ethyl (2-(pyrimidin-2-yloxy)ethyl)carbamate (1.6 g, 5.98 mmol) in HCl / dioxane (15 mL) was stirred at room temperature for 3 h. The mixture was evaporated in vacuo to give N-ethyl-2-(pyrimidin-2-yloxy)ethan-1-amine (1.1 g, crude) as a yellow solid. MS [MH] + , the calculated value for C8H13N3O is 168, and the measured value is 168.

[0436] Synthesis of 3-(2-chlorophenyl)-N-methylprop-2-yn-1-amine

[0437]

[0438] To a mixture of N-methylprop-2-yn-1-amine (1 g, 14.5 mmol) in dioxane (40 mL) was added 1-chloro-2-iodobenzene (3.4 g, 14.5 mmol), PdCl2(PPh3)2 (0.2 g, 0.3 mmol) and CuI (28 mg, 0.14 mmol). The reactants were stirred at 0°C for 22 h. The reaction mixture was washed with ice water (30 ML) and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 3) to give the product (2.1 g, 80.6%). MS[M+H] - , for C 10 H 10 The calculated value of ClNO is 180.1 and the measured value is 180.1.

[0439] Synthesis of N-methylbut-2-yn-1-amine

[0440]

[0441] Methylamine methanol (2.86 g, 15.0 mmol) was added to a mixture of 1-bromobut-2-yne (1.0 g, 7.5 mmol) in MeOH (20 mL). The mixture was stirred at 25 ° C for 16 h. The reactant was quenched with ice water (30 ML). The mixture was acidified to pH 7-8 with aqueous Na2CO3 solution and extracted with EA (20 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the product (500 mg, 80%). MS [M+H] + , the calculated value for C5H9N is 84.1, and the measured value is 84.1.

[0442] Synthesis of N-methyl-2-phenylethan-1-amine

[0443]

[0444] A solution of (2-bromoethyl)benzene (2.5 g, 13.5 mmol) and MeNH2 (30 mL, 135.1 mmol) in EtOH (50 mL) was stirred at 80 °C for 16 h, and then the solution was concentrated in vacuo. The residue was dissolved in DCM (3 mL) and PE (30 mL). The mixture was filtered. The filter cake was collected and dried to give the desired product (875 mg, 48%). MS [MH] + , for C9H 13 The calculated value of N is 136.1, and the measured value is 136.1

[0445] Synthesis of 2-(Methylamino)-N-phenylacetamide

[0446]

[0447] Prepared as described for N-methyl-2-phenylethan-1-amine above, but using 2-bromo-N-phenylacetamide instead of (2-bromoethyl)benzene. MS [MH] + , for C9H 12 The calculated value of N2O is 165.1, and the measured value is 165.1

[0448] Synthesis of N-methyl-1-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methanamine

[0449]

[0450] Step 1: Synthesis of 4-azidopyridine

[0451] NaOH (1M) was added to a solution of 4-bromopyridine (5.0 g, 25.71 mmol) in H2O (40 mL) to adjust the pH to 6-7. EtOH (20 mL) and sodium azide (2.5 g, 38.57 mmol) were added. The mixture was stirred at 100°C overnight. The mixture was cooled to room temperature and acidified to pH 3-4 with 1N HCl. The mixture was washed with water and extracted with EA. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (PE / EA=2 / 1) to give the product (2.56 g, 82.9%). MS [M+H] + , the calculated value for C5H4N4 is 121.1, and the measured value is 121.1.

[0452] Step 2: Synthesis of 1-(pyridin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde

[0453] To a mixture of 4-azidopyridine (2.0 g, 16.65 mmol) in THF / H2O (20 mL / 20 mL), 3,3-diethoxyprop-1-yne (2.1 mg, 16.65 mmol), CuSO45H2O (4.2 g, 16.65 mmol) and sodium ascorbate (3.3 g, 16.65 mmol) were added. The mixture was then warmed to 55°C and stirred overnight. The reactants were quenched with ice water (20 mL). The mixture was extracted with DCM (20 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the product (1.27 g, 43.9%). MS[M+H] + , the calculated value for C8H6N4O is 175.1, and the measured value is 175.1.

[0454] Step 3: Synthesis of N-methyl-1-(1-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)methanamine

[0455] To a mixture of 1-(pyridin-4-yl)-1H-1,2,3-triazole-4-carbaldehyde (300 mg, 1.72 mmol) in MeOH (10 mL) was added methylamine hydrochloride (116.1 mg, 1.72 mmol), NaBH3CN (108 mg, 1.72 mmol) and ZnCl2 (234 mg, 1.72 mmol), and the mixture was then warmed to 50°C and stirred for 6 hours. The reactants were quenched with ice water (20 mL). The mixture was adjusted to pH 7-8 with aqueous Na2CO3 solution and extracted with EA (20 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the product (250 mg, 76.9%). MS[M+H] + , the calculated value for C9H11N5 is 190.1, and the measured value is 190.1.

[0456] Synthesis of N-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)methanamine

[0457]

[0458] Prepared as described for N-methyl-1-(1-methyl-1H-1,2,3-triazol-4-yl)methanamine but using iodomethane instead of 4-bromopyridine. MS [MH]+ , for C5H 10 The calculated value of N4 is 127.1 and the measured value is 127.1.

[0459] The following provides experimental procedures for compounds of the invention.

[0460]

[0461] Example 1: (Z)-3-(3-chloro-4-hydroxy-5-nitrophenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide

[0462]

[0463] A mixture of 3-chloro-4-hydroxy-5-nitrobenzoic acid (100 mg, 0.46 mmol) in SOCl2 (10 mL) was heated to 80 ° C for 2 hours. It was then concentrated in vacuo to obtain an acyl chloride. A solution of 2-cyano-N, N-diethylacetamide (64.4 mg, 0.46 mmol) in THF (10 mL) was stirred at 0 ° C under N2 atmosphere for 10 min, followed by the addition of NaH (27.6 mg, 0.69 mmol). The mixture was stirred for 1 hour. Acid chloride was added to the reaction mixture. The solution was warmed to room temperature and stirred overnight. The mixture was acidified to pH 3-4 with 1N HCl and extracted with DCM (30 mL * 3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=1 / 1, 0.1% TFA) to obtain the product (20 mg, 12.8%). MS[M+H] + The calculated value for C14H14ClN3O5 is 338.1 and the measured value is 337.8. 1 H NMR(400MHz,DMSO-d6)δ8.353(s,1H),8.210(s,1H),3.574(s,4H),1.208(s,6H)

[0464] Examples 2-4 were synthesized in similar manner to those of Example 1, generally following Scheme 2 starting from the appropriate intermediate A.

[0465]

[0466] Example 5: (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-phenoxyethyl)acrylamide

[0467]

[0468] A solution of 3,4-dihydroxy-5-nitrobenzoic acid (155mg, 0.78mmol) in SOCl2 (10mL) was stirred at 80°C for 2h, and then concentrated in vacuo to obtain acyl chloride. At 0°C, NaH (78mg, 1.95mmol) was added to a solution of 2-cyano-N-methyl-N-(2-phenoxyethyl) acetamide (170mg, 0.78mmol) in THF (15mL). The solution was stirred for 1h, and then acyl chloride was added. The mixture was stirred at 0°C for 1h, and then overnight at room temperature. The reaction mixture was washed with 1NHCl (5mL) and water (15mL). The mixture was extracted with ethyl acetate (20mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to obtain a crude product. Further purification by preparative HPLC (0.05% TFA; ACN-H2O) gave (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-phenoxyethyl)acrylamide (25 mg, 8%). 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.83(s,1H),7.47(s,1H),7.29(t,J=7. 8Hz, 2H), 6.95 (dd, J = 13.2, 6.2Hz, 3H), 4.22 (s, 2H), 3.92 (s, 2H), 3.25 (s, 3H). MS[MH] - , the calculated value for C19H17N3O7 is 397.7, and the measured value is 397.7.

[0469] Examples 6-9 were synthesized in similar manner to those of Example 5, generally following Scheme 2 starting from the appropriate intermediate B.

[0470]

[0471]

[0472] The following compounds were synthesized in a similar manner to those of Examples 1 and 5, generally following Scheme 2 starting from the appropriate intermediate A or B.

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518] Example 456: (Z)-2-cyano-N-cyclopropyl-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methylacrylamide:

[0519]

[0520] A mixture of (Z)-2-cyano-N-cyclopropyl-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methylacrylamide (140 mg, 0.4 mmol) in DCM (20 mL) was stirred at -10 ° C for 15 min. Then BBr3 (0.1 mL) was added to the above mixture. The mixture was warmed to room temperature and stirred overnight. The reactants were quenched with ice, and the mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give the product (23 mg, HPLC: 98.4%). MS [MH] - , for C14 H 13 The calculated value of N3O6 is 318.1, and the measured value is 318.1. 1 H NMR (400MHz, DMSO) δ7.83 (s, 1H), 7.52 (s, 1H), 2.98 (s, 3H), 2.46 (t, J = 4.0Hz, 1H), 0.92 (s, 4H).

[0521] The following examples were synthesized in a similar manner as above.

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Example 632: (Z)-2-Cyano-N,N-diethyl-3-(3-fluoro-4-hydroxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide

[0542]

[0543] Step 1: Synthesis of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide

[0544] The solution of 3-fluoro-4-methoxy-5-(trifluoromethyl)benzoic acid (150mg, 0.6mmol) in SOCl2(20mL) was stirred at 80°C for 2h, then concentrated in vacuo to obtain acyl chlorides. At 0°C, NaH (30mg, 1.2mmol) was added to a solution of 2-cyano-N, N-diethylacetamide (84mg, 0.6mmol) in THF (15mL). The mixture was stirred for 1h, then acyl chlorides were added. The mixture was stirred at 0°C for 1h, then at room temperature overnight. The mixture was washed with 1N HCl (15mL) and water (20mL). The mixture was extracted with ethyl acetate (20mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to obtain a crude product. Further purification by preparative HPLC (0.05% TFA; ACN-H2O) gave (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (150 mg, 66%). MS [MH] - , for C 16 H 16 The calculated value of F4N2O3 is 359.0, and the measured value is 359.0.

[0545] Step 2: Synthesis of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-hydroxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (Example 632)

[0546] A mixture of (Z)-2-cyano-N,N-diethyl-3-(3-fluoro-4-methoxy-5-(trifluoromethyl)phenyl)-3-hydroxyacrylamide (150 mg, 0.4 mmol) in DCM (20 mL) was stirred at -10 ° C for 15 min. BBr3 (0.1 mL) was then added to the above mixture. The reaction mixture was warmed to room temperature and stirred overnight. The reactants were quenched with ice. The mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated to dryness in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give the product (70 mg, HPLC: 96.3%). MS [MH] - , for C 15 H 14 The calculated value of F4N2O3 is 344.8, and the measured value is 344.8. 1 H NMR (400MHz, DMSO-d6) δ12.04(s,1H),7.99(d,J=12.0Hz,1H),7.87(s,1H),3.56(d,J=8.0Hz,4H),1.2(s,6H).

[0547] Example 633: (Z)-2-Cyano-3-(2,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide

[0548]

[0549] Step 1: Synthesis of (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4-hydroxy-2-methoxy-5-nitrophenyl)acrylamide

[0550] The mixture of methyl 4-hydroxy-2-methoxy-5-nitrobenzoic acid (1.0g, 4.7mmol) in SOCl2 (40mL) is heated to 80°C for 2 hours. It is then concentrated in a vacuum to obtain acyl chlorides. A solution of 2-cyano-N, N-diethylacetamide (657mg, 4.7mmol) in THF (20mL) is stirred for 10min at -78°C under N2 atmosphere, followed by the addition of LiHMDS (0.7mL, 11.8mmol). The mixture is stirred for 1 hour. Acyl chlorides are added to the reaction mixture. The mixture is warmed to room temperature and stirred overnight. The mixture is acidified to pH 5-6 with 1N HCl and extracted with DCM (200mL*3). The combined extracts are dried over anhydrous Na2SO4, filtered and concentrated in a vacuum. The residue was purified by preparative HPLC (H2O / MeCN=45 / 55, 0.1% TFA, 2 times) to give a crude product (1.0 mg, 68%). MS [MH] + , for C 15 H 17 The calculated value of N3O6 is 334.1, and the measured value is 334.1.

[0551] Step 2: Synthesis of (Z)-2-cyano-3-(2,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide (Example 633)

[0552] A mixture of (Z)-2-cyano-N,N-diethyl-3-hydroxy-3-(4-hydroxy-2-methoxy-5-nitrophenyl)acrylamide (100 mg, 0.3 mmol) in DCM (20 mL) was stirred at -10 ° C for 15 min. Then BBr3 (0.3 mL) was added to the above mixture. The reaction mixture was warmed to room temperature and stirred overnight. The reactants were quenched with ice. The mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give the product (32 mg, HPLC: 99.8%). MS [MH] - , for C 14 H 15 The calculated value of N3O6 is 319.8, and the measured value is 319.8. 1HNMR(400MHz,DMSO-d6)δ11.93(s,1H),8.35(s,1H),7.72(s,2H),6.96(s,1H),3.39( d, J=16.0Hz, 2H), 3.19 (t, J=8.0Hz, 2H), 1.13 (t, J=8.0Hz, 3H), 1.06 (t, J=8.0Hz, 3H).

[0553] Examples 634 and 635: tert-Butyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acrylamide (Example 634) and (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acrylamide (Example 635)

[0554]

[0555] Step 1: Synthesis of N-(but-2-yn-1-yl)-2-cyano-N-methylacetamide

[0556] To a solution of 2-(methylamino)-N-phenylacetamide (1.2 mg, 7.3 mmol) and 2-cyanoacetic acid (622 mg, 7.3 mmol) in DCM (50 mL) was added T3P (3.5 g, 11.0 mmol) and DIEA (2.8 g, 22.0 mmol). The flask was degassed with nitrogen. The mixture was stirred at 25 ° C for 8 h. The reaction mixture was washed with water (20 mL) and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=2 / 3) to give the product (450 mg, 27%). MS [MH] + , for C 12 H 13 The calculated value of N3O2 is 231.9 and the measured value is 231.9.

[0557] Step 2: Synthesis of 2-cyano-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acetamide

[0558] A mixture of N-(but-2-yn-1-yl)-2-cyano-N-methylacetamide (450 mg, 1.9 mmol), (Boc)2O (637 mg, 2.9 mmol), 4-dimethylaminopyridine (356 mg, 2.9 mmol), Et3N (13.0 g, 129.1 mmol) in DCM (100 mL) was stirred at 25°C overnight. The reaction mixture was washed with water (20 mL) and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM / MeOH=30 / 1) to give the product (350 g, 54%). MS [MH] + , for C 17 H 21 The calculated value of N3O4 is 331.9, and the measured value is 331.9.

[0559] Step 3: Synthesis of tert-butyl (N-(2-cyanoacetyl)-N-methylglycyl)(phenyl)carbamate

[0560] The mixture of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (234mg, 1.1mmol) in SOCl (50mL) is heated to 80 ℃, continues 2 hours.Then it is concentrated in vacuo to obtain acyl chloride.A solution of 2-cyano-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acetamide (350mg, 1.1mmol) in THF (30mL) is stirred at -78 ℃ under N2 atmosphere for 10min, then LiHMDS (2.6mL, 2.6mmol) is added.The mixture is stirred for 1 hour.Acyl chloride is added in the reaction mixture.The solution is warmed to room temperature, and stirred overnight.The mixture is acidified to pH 5-6 with 1N HCl, extracted with DCM (150mL*3).The combined extracts are dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=55 / 45, 0.1% TFA, 2 times) to give the product (250 mg, 45%). MS [MH] - , for C 25 H 26 The calculated value of N4O9 is 525.1 and the measured value is 525.1.

[0561] Step 4: Synthesis of tert-butyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acrylamide (Example 634)

[0562] A mixture of tert-butyl (N-(2-cyanoacetyl)-N-methylglycyl)(phenyl)carbamate (150 mg, 0.3 mmol), TFA (0.5 mL) in DCM (20 mL) was stirred at 25 °C overnight. The mixture was evaporated to give the product (100 mg, 83%). MS [MH] - , for C 20 H 18 The calculated value of N4O7 is 424.9 and the measured value is 424.9. 1 HNMR(400MHz,DMSO-d6)δ10.19(s,1H),8.00(s,1H),7.58(s,1H),7.34(s,2H),7. 31(t,J=4.0Hz,2H),7.06(t,J=8.0Hz,1H),4.39(s,2H),3.93(s,3H),3.29(s,3H).

[0563] Step 5: Synthesis of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxy-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acrylamide (Example 635)

[0564] A mixture of (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-N-methyl-N-(2-oxo-2-(phenylamino)ethyl)acrylamide (100 mg, 0.3 mmol) in DCM (20 mL) was stirred at -10 ° C for 15 min. BBr3 (0.1 mL) was then added to the above mixture. The mixture was warmed to room temperature and stirred overnight. The mixture was washed with ice water and extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give the product (1 mg, HPLC: 86.6%). MS [MH] - , for C 19 H 16 The calculated value of N4O7 is 410.9 and the measured value is 410.9. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),7.84(s,2H),7.55(s,2H),7.45(s,1H),7.28(s,1H),7.04(t,J=4.0Hz,1H),4.32(s,2H),3.21(s,3H).

[0565] The following examples were synthesized in a similar manner to above, generally following Scheme 2 starting from the appropriate intermediate C (wherein L1 is a single bond).

[0566] Example 636: (Z)-5-(2-Cyano-3-cyclopropyl-1-hydroxy-3-oxoprop-1-en-1-yl)-2-hydroxybenzonitrile

[0567]

[0568] The mixture of 3-cyano-4-hydroxybenzoic acid (200mg, 1.23mmol) in SOCl2 (20mL) is heated to 80°C for 2 hours. Then it is concentrated to dryness in a vacuum and the residue is used for the next step. A solution of 3-cyclopropyl-3-oxopropionitrile (134mg, 1.23mmol) in THF (20mL) is stirred for 10min at -78°C under N2 atmosphere, and after adding LiHMDS (1.23mL, 1,23mmol), it is stirred for another 1 hour. The above concentrated acyl chloride is added to the reaction mixture, warmed to room temperature, and stirred overnight. After the reaction is completed, the mixture is acidified to pH about 5-6 by HCl and extracted with DCM (20mL*3). The combined extracts are dried over anhydrous Na2SO4, filtered and concentrated in a vacuum. The residue was purified by preparative HPLC (H2O / MeCN=4 / 5, 0.1% TFA, 2 times) to give the product (16.9 mg, HPLC: 98.9%). MS [MH] - , the calculated value for C14H10N2O3 is 253.0, and the measured value is 253.0. 1 H NMR (400MHz, DMSO-d6) δ8.245 (d, J = 4.0 Hz, 1H), 8.10-8.08 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 2.45-2.42 (m, 1H), 1.28-1.21 (m, 4H).

[0569] Examples 637 and 638: (Z)-2-(Cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylonitrile (Example 637) and (Z)-2-(Cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylonitrile (Example 638)

[0570]

[0571] Step 1: Synthesis of (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylonitrile (Example 637)

[0572] By 4-hydroxy-3-methoxy-5-nitrobenzoic acid (977mg, 4.6mmol) in SOCl2 (100mL) in the mixture is heated to 80 ℃, continues 2 hours.Then it is concentrated in a vacuum to obtain acyl chlorides.A solution of 3-cyclopropyl-3-oxopropionitrile (500mg, 4.6mmol) in THF (50mL) is stirred at -78 ℃ under N2 atmosphere for 10min, then LiHMDS (11.5mL, 11.5mmol) is added.The mixture is stirred for 1 hour.The above acyl chlorides are added in the reaction mixture.The mixture is warmed to room temperature, and stirred overnight.The mixture is acidified to pH 5-6 with 1N HCl, extracted with DCM (200mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give a crude product (100 mg, HPLC: 99%). MS [MH] + , for C 14 H 12 The calculated value of N2O6 is 305.1, and the measured value is 305.1. 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.77(s,1H),3.95(s,3H),2.44-2.48(m,1H),1.23-1.30(m,4H).

[0573] Step 2: Synthesis of (Z)-2-(cyclopropanecarbonyl)-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylonitrile (Example 638)

[0574] By 4-hydroxy-3-methoxy-5-nitrobenzoic acid (92mg, 0.5mmol) in SOCl2 (10mL) in the mixture is heated to 80 ℃, continues 2 hours.Then it is concentrated in a vacuum to obtain acyl chlorides.A solution of 3-cyclopropyl-3-oxopropionitrile (50mg, 0.5mmol) in THF (10mL) is stirred for 10min at -78 ℃ under N2 atmosphere, then LiHMDS (0.1mL, 0.1mmol) is added.The solution is stirred for 1 hour.The above acyl chlorides are added in the reaction mixture.The mixture is warmed to room temperature, and stirred overnight.The mixture is acidified to pH 5-6 with 1N HCl, extracted with DCM (200mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and the residue was purified by preparative HPLC (H2O / MeCN=40 / 60, 0.1% TFA, 2 times) to give the crude product (7 mg, HPLC: 98%). MS [MH] + , for C13 H 10 The calculated value of N2O6 is 291.1 and the measured value is 291.1. 1 H NMR (400MHz, DMSO) δ8.26 (s, 1H), 7.66 (s, 1H), 2.38-2.44 (m, 1H), 1.20 (d, J = 4.0Hz, 4H).

[0575] Examples 639 and 640: Ethyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Example 639) and Ethyl (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacrylate (Example 640)

[0576]

[0577] Step 1: Synthesis of (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Example 639)

[0578] 3,4-dihydroxy-5-nitrobenzoic acid (18.5g, 86.79mmol) in SOCl2 (200mL) solution was stirred at 80 ° C for 4h, then concentrated in a vacuum to obtain acyl chloride. At 0 ° C, NaH (7.64g, 190.94mmol) was added to a solution of ethyl 2-cyanoacetate (9.82g, 86.79mmol) in THF (150mL) and stirred for 1h, then acyl chloride was added to the above solution. The mixture was stirred at 0 ° C for 1h, then stirred at room temperature overnight. The reaction mixture was diluted with 1NHCl (150mL) and water (200mL). The mixture was extracted with ethyl acetate (200mL × 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in a vacuum to obtain a crude product. Further purification by column chromatography (silica gel, PE / EA=2 / 1) provided (Z)-ethyl 2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (15 g, 56%). MS [MH] - , the calculated value for C13H12N2O7 is 307, and the measured value is 307. 1 H NMR (400MHz, DMSO-d6) δ7.94(s,1H),7.65(s,1H),4.26(s,2H),3.93(s,3H),1.25(s,3H).

[0579] Step 2: Synthesis of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyethyl acrylate (Example 640)

[0580] To a solution of (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)ethyl acrylate (100 mg, 0.32 mmol) in DCM (10 mL) was added BBr3 (0.1 mL) at -5°C. The reaction mixture was stirred at room temperature overnight. The mixture was cooled to -5°C and washed with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give a crude product. Further purification was performed by preparative HPLC (0.05% TFA; ACN-H2O) to give (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyethyl acrylate (35 mg, 37%). MS [MH] - , the calculated value for C12H10N2O7 is 294.8, and the measured value is 294.8. 1 H NMR (400MHz, DMSO-d6) δ10.85(s,1H),7.84(s,1H),7.49(s,1H),4.26(s,2H),1.25(t,J=4.0Hz,3H).

[0581] Example 641: 5-Chloro-2-fluorobenzyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate

[0582]

[0583] Step 1: Synthesis of 5-chloro-2-fluorobenzyl 2-cyanoacetate (C-3)

[0584] A mixture of methyl (5-chloro-2-fluorophenyl) methanol (500 mg, 3.1 mmol), 2-cyanoacetic acid (395 mg, 4.7 mmol) and PPh3 (1.2 g, 4.7 mmol) in DCM (50 mL) was stirred at 0 ° C for 10 min. Then DIAD (949 mg, 4.7 mmol) was added to the above mixture. The reactants were warmed to room temperature and stirred overnight. The mixture was quenched with ice and extracted with DCM (200 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA=1 / 1) to obtain the product (380 mg, 53%). MS [M+H] - , for C 10 The calculated value for H7ClFNO2 is 228.0, and the found value is 228.0.

[0585] Step 2: Synthesis of 5-chloro-2-fluorobenzyl (Z)-2-cyano-3-hydroxy-3-(4-hydroxy-3-methoxy-5-nitrophenyl)acrylate (Example 641)

[0586] By methyl 4-hydroxy-3-methoxy-5-nitrobenzoic acid (94mg, 0.4mmol) in SOCl (20mL) mixture is heated to 80 ℃, continues 2 hours.Then it is concentrated in a vacuum to obtain acyl chlorides.Solution of 5-chloro-2-fluorobenzyl 2-cyanoacetate (100mg, 0.4mmol) in THF (20mL) is stirred for 10min at -78 ℃ under N atmosphere, then bis (trimethylsilyl) lithium amide (1.1mL, 1.1mmol) is added.The mixture is stirred for 1 hour.The above acyl chlorides are added in the reaction mixture.The mixture is warmed to room temperature, and stirred overnight.The mixture is acidified to pH 5-6 with 1N HCl, extracted with DCM (200mL*3).The extract merged is through anhydrous Na SO Dry, filter and concentrate in a vacuum. The residue was purified by preparative HPLC (H2O / MeCN=45 / 55, 0.1% TFA, 2 times) to give the product (60 mg, HPLC: 100%). MS [MH] + , for C 18 H 12 The calculated value of ClFN2O7 is 423.1 and the measured value is 423.1. 1 H NMR (400MHz, DMSO-d6) δ7.70 (s, 1H), 7.44-7.48 (m, 3H), 7.29 (t, J = 8.0Hz, 1H), 5.15 (s, 2H), 3.87 (s, 3H).

[0587] The following analogous compounds were obtained by generally following Scheme 2 starting from the appropriate intermediates B and C:

[0588]

[0589]

[0590]

[0591] Example 657: (Z)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide

[0592]

[0593] Step 1: Synthesis of 2-cyano-N-ethyl-N-(2-hydroxyethyl)acetamide (A-3)

[0594] A solution of 2-(ethylamino)ethan-1-ol (2.1 g, 23.51 mmol), 2-cyanoacetic acid (2 g, 23.51 mmol), HATU (10.73 g, 28.21 mmol) and DIPEA (3.64 g, 28.21 mmol) in DCM (30 mL) was stirred at room temperature for 5 h, and then the solution was washed with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 1) provided the desired product (814 mg, 22%). MS [MH] + , the calculated value for C7H12N2O2 is 155, and the measured value is 155.

[0595] Step 2: Synthesis of 2-cyano-N-ethyl-N-(2-((tetrahydro-2H-pyran-2-yl)-(A-4)

[0596] A solution of 3,4-dihydro-2H-pyran (526 mg, 6.25 mmol), 2-cyano-N-ethyl-N-(2-hydroxyethyl)acetamide (814 mg, 5.21 mmol), pyridinium p-toluenesulfonate (1.96 g, 7.82 mmol) in DCM (10 mL) was stirred at 40 ° C for 5 h, and then concentrated in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=2 / 1) provided the desired product (430 mg, 34%). MS [MH] + , the calculated value for C12H20N2O3 is 241, and the measured value is 241.

[0597] Step 3: Synthesis of (Z)-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acrylamide (2)

[0598] A solution of 3,4-dimethoxy-5-nitrobenzoic acid (407 mg, 1.79 mmol) in SOCl2 (10 mL) was stirred at 80 ° C for 2 h, and then it was concentrated in vacuo to give the acid chloride. At 0 ° C, NaH (179 mg, 4.47 mmol) was added to a solution of 2-cyano-N-ethyl-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acetamide (430 mg, 1.79 mmol) in THF (15 mL). The mixture was stirred for 1 h, and then the acid chloride was added to the above solution. The mixture was stirred at 0 ° C for 1 h, and then stirred at room temperature overnight. The mixture was washed with 1N HCl (5 mL) and water (15 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product (11 mg, crude). MS [MH] - , the calculated value for C21H27N3O8 is 448, and the measured value is 448.

[0599] Step 4: Synthesis of (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide (Example 657)

[0600] To a solution of (Z)-2-cyano-3-(3,4-dimethoxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)acrylamide (11 mg, 0.024 mmol) in DCM (10 mL) was added BBr (0.01 mL) at -5 °C. The reaction mixture was stirred overnight at room temperature in a tube. The mixture was cooled to -5 °C and washed with water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product. Further purification was performed by preparative HPLC (0.05% TFA; ACN-H2O) to give (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-ethyl-3-hydroxy-N-(2-hydroxyethyl)acrylamide (4 mg, 49%). MS[MH] - , the calculated value for C14H15N3O7 is 336, and the measured value is 336.

[0601] Example 658: (Z)-N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine

[0602]

[0603] Step 1: Synthesis of N-(2-cyanoacetyl)-N-methylglycine methyl ester

[0604] To a solution of N-methylglycine hydrochloride (1.0 g, 7.2 mmol) and 2-cyanoacetic acid (0.6 g, 7.2 mmol) was added T3P (3.4 g, 10.8 mmol) and DIEA (2.8 g, 21.6 mmol). The flask was degassed with nitrogen. The mixture was stirred at 25 ° C for 8 h. The reaction mixture was washed with water (20 ML) and extracted with DCM (150 mL * 3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 2 / 3) to give the product (710 mg, 58%). MS [MH] + , for C7H 10 The calculated value of N2O3 is 171.1 and the measured value is 171.1.

[0605] Step 2: Synthesis of (Z)-N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine methyl ester

[0606] The mixture of 3,4-dihydroxy-5-nitrobenzoic acid (200mg, 1.0mmol) in SOCl2 (10mL) is heated to 80 ° C for 2 hours. Then it is concentrated in vacuo to obtain acyl chloride. A solution of N-(2-cyanoacetyl)-N-methylglycine ester (170mg, 1.0mmol) in THF (20mL) is stirred for 10min at -78 ° C under N2 atmosphere, and LiHMDS (1.5mL, 1.5mmol) is subsequently added. The mixture is stirred for 1 hour. The above acyl chloride is added to the reaction mixture. The mixture is warmed to room temperature and stirred overnight. The mixture is acidified to pH 5-6 with 1N HCl and extracted with DCM (50mL*3). The combined extracts are dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=55 / 45, 0.1% TFA, 3 times) to give a crude product (100 mg, 28.6%). MS [MH] - , the calculated value for C14H13N3O8 is 350.1, and the measured value is 350.1.

[0607] Step 3: Synthesis of (Z)-N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine (Example 658)

[0608] To a mixture of (Z)-N-(2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-3-hydroxyacryloyl)-N-methylglycine methyl ester (100 mg, 0.29 mmol) in THF / H2O (10 mL / 10 mL) was added LiOH (17 mg, 0.58 mmol). The reactants were stirred at room temperature for 6 h. The mixture was acidified to pH 5-6 with 1N HCl and extracted with DCM (20 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the product (80 mg, 82.5%). MS [MH] - , the calculated value for C13H11N3O8 is 336.1, and the measured value is 336.1.

[0609] Example 659: (Z)-2-Cyano-3-(3,5-dichloro-4-hydroxyphenyl)-3-hydroxy-N-(2-((2-methoxyethyl)amino)-2-oxoethyl)-N-methylacrylamide

[0610]

[0611] To a mixture of 2-methoxyeth-1-amine (22 mg, 0.3 mmol) in DCM (30 mL) was added (Z)-N-(2-cyano-3-(3,5-dichloro-4-hydroxyphenyl)-3-hydroxyacryloyl)-N-methylglycine (100 mg, 0.3 mmol), T3P (138 mg, 0.43 mmol) and DIEA (112 g, 0.87 mmol). The reactants were stirred at room temperature for 16 h. The reactants were quenched with ice water (20 ML). The mixture was extracted with DCM (150 mL*3). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (H2O / MeCN=60 / 40, 0.1% TFA, 3 times) to give the product (59 mg, HPLC: 99.4%). MS [MH] + , for C 16 H 17 The calculated value of Cl2N3O5 is 399.9 and the measured value is 399.9. 1 H NMR (400MHz, DMSO-d6) δ8.31(s,1H),7.82(s,2H),4.12(s,2H),3.35-3.37(t,J=4.0Hz,2H),3.27(s,2H),3.17(s,3H),3.14(s,3H).

[0612] Examples 660 and 661: (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid methyl ester (Example 660) and (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (Example 661)

[0613]

[0614] Step 1: Synthesis of (Z)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide

[0615] A solution of 3-bromo-4-hydroxy-5-methoxybenzoic acid (1.4 g, 5.67 mmol) in SOCl2 (20 mL) was stirred at 80 ° C for 2 h, and then concentrated in vacuo to obtain the acid chloride. At 0 ° C, NaH (567 mg, 14.17 mmol) was added to a solution of 2-cyano-N, N-diethylacetamide (794 mg, 5.67 mmol) in THF (15 mL). The mixture was stirred for 1 h, and then the acid chloride was added to the above solution. The mixture was stirred at 0 ° C for 1 h, and then stirred at room temperature overnight. The reaction mixture was washed with 1N HCl (15 mL) and water (30 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to obtain a crude product (410 mg, crude product). MS [MH] - , the calculated values ​​for C15H17BrN2O4 are 367 and 369, and the measured values ​​are 367 and 369.

[0616] Step 2: Synthesis of methyl (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2-hydroxy-3-methoxybenzoate

[0617] A solution of (Z)-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-2-cyano-N,N-diethyl-3-hydroxyacrylamide (500 mg, 1.35 mmol), Et3N (274 mg, 2.71 mmol) and Pd(dppf)Cl2 (99 mg, 0.14 mmol) in MeOH (10 mL) was stirred at 120°C for 4 h under CO. The mixture was washed with water and extracted with EA. The solvent of the combined extracts was removed in vacuo to give the crude product. Further purification by column chromatography (silica gel, PE / EA=1 / 1) provided the desired product (60 mg, 13%). MS [MH] -, the calculated value for C17H20N2O6 is 347, and the measured value is 347.

[0618] Step 3: Synthesis of (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid methyl ester (Example 660)

[0619] At -5 ° C, to (Z) -5- (2-cyano -3- (diethylamino) -1- hydroxy -3- oxo -1- alkene -1-yl) -2-hydroxy -3- methoxybenzoic acid methyl ester (60mg, 0.17mmol) in DCM (10mL) solution, add BBr (0.1mL). The reaction mixture was stirred overnight at room temperature in a tube. The mixture was cooled to -5 ° C, and washed with water (15mL). The mixture was extracted with ethyl acetate (10mL × 2). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to obtain a crude product. Further purification was carried out by preparative HPLC (0.05% TFA; ACN-H2O) to obtain (Z) -5- (2-cyano -3- (diethylamino) -1- hydroxy -3- oxo -1- alkene -1-yl) -2,3- dihydroxybenzoic acid methyl ester (27mg, 47%). 1 H NMR (400MHz, DMSO-d6) δ10.790(s,1H),10.095(s,1H),7.782(s,1H),7.481(s,1H),3.916(s,3H),3.564(d,J=6.8Hz,4H),1.208(t,J=6.8Hz,6H). MS[MH] - , the calculated value for C16H18N2O6 is 333, and the measured value is 333.

[0620] Step 4: Synthesis of (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (Example 661)

[0621] At 0 ° C, NaOH (5 mg, 0.12 mmol) was added to a solution of (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxo-prop-1-ene-1-yl)-2,3-dihydroxybenzoic acid methyl ester (20 mg, 0.060 mmol) in THF / water (10 mL / 10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to -5 ° C and washed with 1N HCl (5 mL). The mixture was extracted with ethyl acetate (10 mL × 2). The combined extracts were dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to obtain a crude product. Further purification by preparative HPLC (0.05% TFA; ACN-H2O) gave (Z)-5-(2-cyano-3-(diethylamino)-1-hydroxy-3-oxoprop-1-en-1-yl)-2,3-dihydroxybenzoic acid (7 mg, 36%). 1 H NMR (400MHz, DMSO) δ9.795 (s, 1H), 7.837 (s, 1H), 7.431 (s, 1H), 3.565 (d, J = 6.8Hz, 4H), 1.210 (t, J = 6.8Hz, 6H). MS[MH] - , the calculated value for C15H16N2O6 is 319, and the measured value is 319.

[0622] Biological assays

[0623] FTO inhibition assay (enzyme inhibition).The inhibition assay was adapted from a publication on the Maz-F coupled FTO demethylase activity assay (Chem Commun. 2017 Nov 30; 53(96): 12930-12933. doi: 10.1039 / c7cc07699a). The FTO-catalyzed demethylase activity was measured in a 10 μl reaction system containing 20 mM HEPES buffer (pH 7.5), 20 μM a-KG, 10 μM (NH4)2Fe(SO4)2, 1.5 mM L-ascorbic acid, 2 μM m6A-containing DRNA (5'-FAM-d(CAT)r(GG-m6A-CA)d(TATGT)-BHQ1-3'), and 0.15 μM FTO protein. The reaction system was incubated at 32°C for 45 min. An aliquot of MazF (40ul 1×Maz-F+10ul reactant / well) was added to each well above to a final concentration of 50nM, and the reaction system was incubated at 37°C for 25min. MazF only cuts non-methylated DRNA (-ACA-), allowing specific detection of the methylation state of DRNA. Maz-F easily cuts DRNA and eventually releases 5'-FAM, emitting a strong fluorescence signal near 535nm (485nm excitation-535 emission).

[0624] COMT inhibition assay. The inhibition of COMT by compound was measured in the reaction kinetic model. The test compound was diluted to the desired concentration with assay buffer. The COMT enzyme was also diluted with assay buffer. Then 5 μL of the diluted test article, 5 μL of the diluted COMT and 5 μL of esculetin were added to the plate and incubated for 5 min at 37°C, sealed with TopSeal-A 384 transparent glue (PE). Then 5 μL of AdoMet were added to the plate. The reaction system contained 1U COMT enzyme, test compound, 4 μM of esculetin, 0.6mM AdoMet, 50mM K3PO4 and 10mM MgCl2. The plate was read using a kinetic model (excitation at 360nm and emission at 460nm). Inhibition was calculated from the slope.

[0625]

[0626]

[0627]

[0628] Ref1 compound has The structure of Ref2 is: structure.

[0629] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clear understanding, it is obvious to those skilled in the art that some minor changes and modifications may be implemented. Therefore, the description and example should not be interpreted as limiting the scope of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a deuterated analog thereof, L1 is -NR a - or a single bond, where R a It is C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Each of the alkoxy groups is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted; L2 is C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkyne or a single bond, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy; L3 is a single bond, -O-, -S-, -SO-, -SO2-, -NR c -, -C(O)-, -C(O)O-, -C(O)NR c -、-OC(O)NR c -、-C(O)ONR c -、-C(O)N(R c )O-、-OC(O)NR c -or-NR c C(O)-; where R c It is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halo C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 alkyl, phenyl, phenylalkyl-, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; R1 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, aryl, heteroaryl, heterocyclic group, wherein the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with R b Replaced, and the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace; in R b It is halogen, cyano, hydroxyl, C 1-6 Alkoxy, -NR m C(O)NR n R p , -NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 3-6 Each of the cycloalkyl, phenyl, heteroaryl or heterocyclyl is unsubstituted or substituted with one to three substituents selected from the group consisting of cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 3-6 Cycloalkyl, phenyl, heteroaryl or heterocyclyl; R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace, in R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; Where R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R2 is hydrogen, halogen, cyano, C 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy; R3 is hydrogen, halogen, cyano, C 1-6 Alkyl, hydroxyl or C 1-6 Alkoxy; R4 is cyano; hydrogen; halogen; hydroxyl; C 1-6 Alkoxy; C 1-6 Alkyl-S-; nitro (-NO2); or -SF5, the C 1-6 Alkoxy or C 1-6 Each of the alkyl-S- is unsubstituted or substituted with halogen, hydroxyl or C 1-6 Alkoxy substituted; or C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Each of the alkynyl groups is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkoxy or C 1-6 Alkyl-S-substituted; R5 is hydrogen, nitro (-NO2), cyano, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, -C(O)OR 5a 、-SO2-R 5a or -SF5, where R 5a It is hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; Provided that if L1, L2, and L3 are each a single bond, then R1 is not hydrogen; There is a further proviso that the compound is not (Z)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-3-hydroxyacrylamide.

2. The compound according to claim 1, wherein R4 is hydrogen; cyano; nitro; -SF5; halogen; hydroxyl; C 1-6 Alkoxy; Halogenated C 1-6 Alkoxy or C 1-6 alkyl.

3. The compound according to claim 1 or claim 2, wherein R4 is cyano, nitro, hydrogen, methyl, ethyl, hydroxymethyl, methoxymethyl, methylthiomethyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, methylthio, trifluoromethylthio, vinyl, ethynyl, fluorine, chlorine, bromine or iodine.

4. The compound according to claim 3, wherein R5 is nitro, cyano, fluorine, chlorine, bromine, trifluoromethyl, ethynyl, vinyl, methoxycarbonyl, carboxyl, -SF5 or methylsulfonyl.

5. The compound according to claim 1, wherein R4 is halogen; methoxy; difluoromethoxy; trifluoromethoxy or methyl; and R5 is nitro, cyano or halogen.

6. The compound according to claim 1, wherein R4 is hydrogen, halogen, nitro, CN, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution, R5 is nitro, CN or halogen; L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl; L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy; L3 is a single bond or -O-; R1 is aryl, heteroaryl, heterocyclic, C 3-8 Cycloalkyl, wherein the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace; in R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n 、-C(O)R m 、-C(O)OR m , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or replaced by R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace, in R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

7. The compound according to claim 6, wherein R4 is halogen, methoxy, difluoromethoxy, trifluoromethoxy or ethoxy.

8. The compound according to claim 1, wherein R4 is hydroxy or halogen, R5 is a halogenated C 1-6 Alkyl or SO2-R 5a , where R 5a It is hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl; L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy; L3 is a single bond or -O-; R1 is aryl or heteroaryl as defined in claim 1; or R4 is hydrogen, halogen, nitro, CN, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution, R5 is nitro, CN or halogen; L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 alkyl; L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy; R1 is aryl or heteroaryl as defined in claim 1.

9. The compound according to claim 1, wherein L1 is a single bond, L2 is a single bond, L3 is a single bond, -O- or -S-, and R1 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-8 Cycloalkyl; each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkoxy or phenyl, the phenyl being unsubstituted or substituted by halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-S- or cyano substituted.

10. The compound according to claim 1, wherein L1 is -NR a -, where R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or hydroxy C 1-6 Alkyl; preferably C 1-4 Alkyl; more preferably methyl or ethyl; (a) L2 is C 1-6 Alkylene, C 2-6 Alkynyl or C 2-6 Alkynyl, each of which is unsubstituted or substituted by halogen, and L3 is a single bond, R1 is aryl, heteroaryl, heterocyclic or C 3-8 Cycloalkyl, wherein the aryl, heteroaryl, heterocyclic or C 3-8 Cycloalkyl is unsubstituted or substituted by R d replace, Where R d Selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -SF5, C 3-8 Cycloalkyl, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NR m R n 、-C(O)NR m R n 、-C(O)R m 、-C(O)OR m , phenyl, heteroaryl or heterocyclic, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace, R m , R n and R p are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution, in R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclic, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R f Halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution; (b) L2 is C 1-6 Alkylene, C 2-6 Alkenyl or C 2-6 Alkynyl, each of which is unsubstituted or substituted by halogen; L3 is -O-, -S-, -SO-, -SO2-, -NR c -、-C(O)-、C(O)O-、-C(O)NR c -、-OC(O)NR c -、-C(O)ONR c -or-NR c C(O)-, and R1 is hydrogen, C 1-6 alkyl, phenyl or naphthyl, heteroaryl or heterocyclic; wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl or heteroaryl or heterocyclic group is unsubstituted or replaced by R d replace, Where R b It is halogen, cyano, hydroxyl, C 1-6 alkoxy, phenyl, heteroaryl or heterocyclyl; and R d is cyano, halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, phenyl, heterocyclic, heteroaryl, -SF5, -NR m C(O)NR n R p 、-C(O)R m 、-C(O)OR m NR m R n 、-C(O)NR n R n 、-NR m C(O)R n 、-C(O)R m or-C(O)OR m wherein each of the heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted, where R m and R n are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 Alkyl; or (c) L2 is a single bond, L3 is a single bond or -O-, -S-, -NR c -、C(O)NR c - or -SO2-, and R1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heteroaryl, heterocyclyl or aryl, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and heteroaryl, heterocyclic, aryl or C 3-8 Each of the cycloalkyl groups is unsubstituted or substituted by R d Replace, where R d It is cyano, C 1-6 Alkyl, halogen, heteroaryl, heterocyclic group, oxo, -C(O)R m 、-C(O)OR m 、-C(O)NR m R n NR m R n 、-OR m or -NR m C(O)NR n R p , where R m , R n and R p are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; and R b is cyano, halogen, hydroxyl, C 3-6 Cycloalkyl or phenyl.

11. The compound according to claim 10, wherein L2 is C 1-6 Alkylene; L3 is a single bond or -O- ； R1 is phenyl, wherein the phenyl is unsubstituted or substituted by R d Substitution, where R d Selected from cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -NR m C(O)NR n R p 、-NR m C(O)R n 、-NR m R n 、-C(O)R m 、-C(O)OR m or phenyl, pyridyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or R e and each of the phenyl, pyridyl, piperidyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl or morpholino groups is unsubstituted or replaced by R f Substitution, where R m , R n and R p are independently hydrogen or C 1-6 Alkyl, where R e Is halogen, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , phenyl, pyridinyl, piperidinyl, piperazinyl, azetidinyl, pyrazinyl, pyrimidinyl, pyrazolyl or morpholino, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy substituted; R f Halogen, C 1-6 Alkyl or hydroxyl C 1-6 Alkyl-; and R e1 and R e2 are independently hydrogen or C 1-6 alkyl.

12. The compound according to claim 11, wherein R1 is phenyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of chlorine, fluorine, bromine, phenyl, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, tert-butyl, cyano, methylureido, hydroxymethyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, methoxymethyl, methylthio, ethynyl, vinyl, thiazol-2-ylamino, 1-methyl-1H-pyrazol-4-ylamino, dimethylamino, 3-(hydroxymethyl)pyridine -2-yl, 4-(4-methylpiperazin-1-yl)piperidin-1-yl, 4-methylpiperazin-1-yl, pyridin-3-yl, azetidin-1-yl, pyrazin-2-yl, 1-methylpiperidin-4-yl, pyrimidin-4-yl, morpholino, 2,2,2-trifluoroethoxy, trifluoromethoxy, difluoromethoxy, trifluoromethyl, trifluoromethoxymethyl, (1-methylpiperidin-4-yl)methoxy, (1-methyl-1H-pyrazol-4-yl)methyl, aminocarbonylmethyl, methylaminocarbonylmethyl, or acetamido.

13. The compound according to claim 10, wherein L2 is C 1-6 alkylene, L3 is a single bond, and R1 is a heteroaryl or heterocyclic group, wherein each of the heteroaryl or heterocyclic groups is unsubstituted or replaced by R d replace, R d is cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, -NR m R n , phenyl, heteroaryl or heterocyclic group, wherein the phenyl, heteroaryl or heterocyclic group is unsubstituted or replaced by R f Substitution, where R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substituted; wherein R f Halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy substitution.

14. The compound according to claim 13, wherein R1 is heteroaryl or heterocyclyl, wherein the heteroaryl or heterocyclyl is pyridyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinolinyl, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or replaced by R as defined above. d In some further embodiments, R d is cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, -NR m R n ; phenyl, heteroaryl, heterocyclic; halogen or C 1-6 Alkyl substituted phenyl; halogen or C 1-6 alkyl-substituted heteroaryl; or halogen or C 1-6 Alkyl-substituted heterocyclic group, wherein R m and R n are independently hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl or heterocyclic.

15. The compound according to claim 13, wherein R1 is heteroaryl or heterocyclic, wherein the heteroaryl or heterocyclic is pyridyl, pyrazinyl, dihydrobenzofuranyl, indazolyl, benzodioxinyl, dihydrobenzodioxinyl, isoquinolinyl, triazol-4-yl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or triazolyl, each of which is unsubstituted or substituted with chloro, fluoro, hydroxy, methyl, cyano, oxo, methoxy, tetrahydropyranyl, pyridin-4-yl, phenyl or NR m R n Substitution, where R m and R n are independently hydrogen, C 1-6 Alkyl or triazolyl.

16. The compound according to claim 10, wherein L2 is C 1-6 Alkylene, the C 1-6 Alkylene is unsubstituted or substituted by halogen, and L3 is -O-, -S-, -SO- or -SO2-, Where R1 is hydrogen, C 1-6 alkyl, phenyl or naphthyl or a heteroaryl selected from pyridyl, pyrimidinyl, benzo[d]imidazolyl, indazolyl or a heterocyclic group, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl group is unsubstituted or replaced by R d Substitution, where R b is halogen, cyano, hydroxyl or C 1-6 Alkoxy; R d Halogen, C 1-6 Alkyl, oxo, C 1-6 Alkoxy C 1-6 Alkyl-, hydroxyl C 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, phenyl, heterocyclic, heteroaryl, NR m R n 、-C(O)NR m R n or -NR m C(O)R n wherein each of the heterocyclyl, heteroaryl or phenyl is unsubstituted or substituted by halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy substituted, where R m and R n are independently hydrogen or C 1-4 alkyl.

17. The compound according to claim 10, wherein L2 is a single bond; L3 is a single bond or -O-, -S-, -NR c -、C(O)NR c - or -SO2-; R1 is pyridyl, triazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrazolyl, benzisoxazol-3-yl, triazolopyridin-3-yl, triazolooxazinyl, tetratriazolopyridin-3-yl, dihydrotriazolooxazinyl, each of which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: C 1-6 Alkyl, halogen, heteroaryl, oxo, -C(O)NR m R n NR m R n 、-OR m or -NR m C(O)NR n R p , preferably fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, phenyl, pyridyl, methylureido, acetylamino, amino, oxo and phenoxy; or R1 is C 1-6 Alkyl or phenyl, wherein the C 1-6 The alkyl group is unsubstituted or replaced by R b substituted, and the phenyl group is unsubstituted or replaced by R d Substitution, where R b is halogen or hydroxyl, and R d is halogen, hydroxyl and C 1-6 alkyl.

18. The compound according to claim 1, which is a compound of formula (II) R2 and R3 are both hydrogen; R4 is hydrogen, hydroxyl, halogen, nitro, CN, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or substituted by halogen, hydroxy or C 1-6 Alkoxy substitution, R5 is nitro, CN or halogen; R a It is C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxyl C 1-6 alkyl; L2 is C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, wherein the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Each of the alkynylene groups is unsubstituted or substituted with halogen or hydroxy; L3 is a single bond, -O-, -S-, -NR c - or -C(O)-; wherein R c is hydrogen or C 1-6 alkyl; R1 is aryl, heteroaryl, heterocyclic, wherein the C 3-8 Each of the cycloalkyl, aryl, heteroaryl or heterocyclyl groups is unsubstituted or replaced by R d replace; in R d Selected from cyano, halogen, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-S-, -NR m C(O)NR n R p 、-NR m C(O)R n 、-C(O)NR m R n 、-NR m R n , C 3-8 Cycloalkyl, phenyl, heteroaryl or heterocyclic group, wherein the C 1-6 Alkyl or C 1-6 Alkoxy is unsubstituted or R e and each of the phenyl, heteroaryl or heterocyclic radical is unsubstituted or replaced by R f replace, in R m , R n and R p are independently hydrogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl-, phenyl-C 1-6 Alkyl-, heteroaryl-C 1-6 Alkyl-, heterocyclyl-C 1-6 alkyl-, heterocyclyl, heteroaryl, phenyl or naphthyl, each of which is unsubstituted or substituted by halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; R e Halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkoxy, hydroxy, -C(O)NR e1 R e2 、-NR e1 C(O)R e2 、-C(O)R e1 、-OR e1 、-SR e1 、-NR e1 R e2 , heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; wherein R e1 and R e2 are independently hydrogen, C 1-6 Alkyl or halogenated C 1-6 alkyl; R f Halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Hydroxyl, Hydroxyl C 1-6 Alkyl-, C 1-6 Alkoxy-C 1-6 Alkyl-, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-S-, heterocyclyl, heteroaryl or phenyl, each of which is unsubstituted or substituted by halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy.

19. The compound of claim 1, wherein the compound is selected from Examples 1 to 672.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

21. A method for inhibiting weight gain in a subject; or promoting weight loss; or reducing serum LDL, cholesterol, LDL-c or triglycerides; or treating obesity or obesity-related diseases (especially obesity-related diabetes, hyperglycemia, diabetic nephropathy, hyperlipidemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease), macular degeneration or Alzheimer's disease; or treating injuries or promoting wound healing or tissue regeneration, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 19.

22. The method of claim 21, wherein the method is characterized by FTO inhibition.

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