Oxadiazole compounds, pharmaceutical compositions containing same and uses thereof

Abstract

JPEG2025513031000120.jpg30108The present application relates to oxadiazole compounds of formula (I), pharmaceutical compositions containing same and their use as HDAC6 inhibitors.

Description

[Technical field]

[0001] The present application relates to oxadiazole compounds, pharmaceutical compositions containing same and their use as HDAC6 inhibitors. [Background technology]

[0002] Histone deacetylases (HDACs) can catalyze the deacetylation of histones or other proteins, and play important roles in various biological processes, mainly by transcriptional inhibition. Human HDACs can be classified into four classes, class I includes HDAC1, HDAC2, HDAC3 and HDAC8, class II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10, class III includes SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7, and class IV includes HDAC11. Class II HDACs can also be classified into IIa subtype (HDAC4, HDAC5, HDAC7 and HDAC9) and IIb subtype (HDAC6 and HDAC10).

[0003] HDAC6 mainly catalyzes the deacetylation of non-histone substrates such as α-tubulin and Hsp90. HDAC6 is involved in the pathological processes of various diseases, including cancer, nervous system diseases, infectious diseases, cardiovascular diseases, and immune and inflammatory-related diseases.

[0004] In the field of oncology therapy, most HDAC inhibitors are broad-spectrum inhibitors that have no selectivity for HDAC subtypes. The side effects of broad-spectrum inhibitors of the HDAC family are closely related to inhibition of class I subtypes (especially inhibition of HDAC1 and HDAC2). Summary of the Invention

[0005] The present application provides oxadiazole compounds that can be used as HDAC6 inhibitors to prevent or treat HDAC6-related diseases. The compounds of the present application have high selectivity for HDAC6, and therefore avoid the side effects of HDAC broad-spectrum inhibitors. In addition, the compounds of the present invention also have better properties, such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (relatively low toxicity (e.g., reduced cardiac toxicity) and / or relatively few side effects), and less likely to cause drug resistance.

[0006] One aspect of the present invention provides a compound or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein said compound has the structure of formula (I): [ka] During the ceremony L is a direct bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 alkynylene-, X is CR 6 or N, Y is CR 4 or N, Z is CR 5 or N, R 1 is H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NRa R b , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b Selected from R 2 and R 3 are each independently H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NR a R b , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O)2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b or R 2 and R 3 together form an oxo group (=O), or R 2 and R 3 are C together with the carbon atoms connected to them. 3-6 Constituting a cyclic hydrocarbon group or a 3- to 10-membered heterocyclyl group, R 4 , R 5 and R 6 are each independently H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NR a R b , -C(=O)OR a , -OR a, -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b Selected from R a and R b are independently H, C each time they appear. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 arylalkyl groups, Each occurrence of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and arylalkyl groups optionally and independently may include halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)Rc , -OC(=O)R c , -OC(=O)NR c R d , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 -R d , -NR c -C(=O)-NR c R d , -C 1-6 Alkylene-OR c , -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d wherein the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and arylalkyl group are further optionally substituted with one or more substituents independently selected from halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, -OC 1-6 Alkyl groups, -O-halogenated C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 substituted with one or more substituents selected from arylalkyl groups; Rc and R d are independently H, C each time they appear. 1-6 Alkyl group, C 3~10 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 The alkyl, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and arylalkyl groups may further optionally and independently be selected from the group consisting of halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 It is substituted with one or more substituents selected from arylalkyl groups.

[0007] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof and one or more pharma- ceutically acceptable carriers, said pharmaceutical composition being preferably a solid, liquid or transdermal formulation.

[0008] Another aspect of the present invention provides use of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for preventing or treating an HDAC6-related disease.

[0009] Another aspect of the present invention provides a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for preventing or treating an HDAC6-related disease.

[0010] Another aspect of the present invention provides a method for preventing or treating an HDAC6-related disease, comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0011] Detailed Description of the Invention definition Unless otherwise defined below, the meaning of all technical and scientific terms used herein is intended to be the same as commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including changes in technology or equivalent technology substitutions that are obvious to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are presented to better explain the present invention.

[0012] The terms "comprise," "include," "have," "contain," or "involve" and other variations thereof herein are inclusive or open-ended and do not exclude other elements or method steps not stated.

[0013] As used herein, the term "alkylene group" refers to a saturated divalent hydrocarbon group, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, such as a methylene group, ethylene group, propylene group, or butylene group.

[0014] As used herein, the term "alkyl group" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, "C 1-6The term "alkyl group" refers to a group that is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogens, in which case the group is referred to as a "haloalkyl group" (e.g., CF 3 , C 2 F 5 , CHF 2 , C.H. 2 F, C.H. 2 CF 3 , C.H. 2 Cl or -CH 2 CH 2 CF 3 "C" refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, or an n-hexyl group). 1-4 The term "alkyl group" refers to a straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0015] As used herein, the term "alkenyl group" refers to a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having two to six carbon atoms ("C 2-6 The alkenyl group refers to, for example, -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain alkenyl groups, the compounds can exist in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene group" refers, for example, to "C2-6 alkenylene group," "C 2-4 Alkenylene groups, etc., specific examples of which are -CH=CH-, -CH 2 CH=CH-, -C(CH 3 )=CH-, a butenylene group, a pentenylene group, a hexenylene group and the like, but are not limited to these.

[0016] As used herein, the term "alkynyl group" refers to a monovalent hydrocarbon group containing one or more triple bonds and preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butanyl, and the like. The alkynyl group is optionally substituted with one or more (e.g., 1 to 3) identical or different substituents. The term "alkynylene group" refers, for example, to "C 2-8 alkynylene group," "C 2-6 alkynylene group," "C 2-4 and corresponding divalent radicals, including "alkynylene radicals." Examples thereof include [ka] and the like, but are not limited to these, the alkynylene groups are optionally substituted with one or more (eg, 1 to 3) identical or different substituents.

[0017] As used herein, the terms "cycloalkylene group", "cycloalkyl group" and "hydrocarbon ring" refer to, for example, a saturated (i.e., "cycloalkylene group" and "cycloalkyl group") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon ring having 3 to 10 (preferably 3 to 8, more preferably 3 to 6) ring carbon atoms, including, but not limited to, (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), (ylidene)cyclopentyl (ring), (ylidene)cyclohexyl (ring), (ylidene)cycloheptyl (ring), (ylidene)cyclooctyl (ring), (ylidene)cyclononyl (ring), (ylidene)cyclohexenyl (ring), and the like.

[0018] As used herein, the term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., or bicyclic, including spiro, fused, or bridged systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decalinyl, etc.)) optionally substituted with one or more (e.g., 1-3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, "C 3-6 The term "cycloalkyl group" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, a cyclopropyl group substituted with a methyl group.

[0019] As used herein, the term "heterocyclyl group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and O, S, S(=O), S(=O) 2 and N.R. a wherein R is a group having one or more (e.g., one, two, three, or four) heteroatoms selected from a is a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6represents an alkyl group, and the heterocyclyl group can be linked to the remainder of the molecule via any one of the carbon atoms or the nitrogen atom (if present). In particular, the 3- to 10-membered heterocyclyl group is a group having 3 to 10 carbon atoms and heteroatoms in the ring, including, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuran, dioxolinyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0020] As used herein, the term "heterocyclyl group" encompasses linked ring structures in which the point of attachment to other groups may be on any ring of the linked ring structure. Thus, heterocyclyl groups of the present invention include heterocycloheterocyclyl groups, heterocyclocycloalkyl groups, monoheterocyclomonoheterocyclyl groups, monoheterocyclomonocyclic alkyl groups, such as 3- to 7-membered (mono)heterocyclo 3- to 7-membered (mono)heterocyclyl groups, 3- to 7-membered (mono)heterocyclo(mono)cycloalkyl groups, 3- to 7-membered (mono)heterocycloC 4-6 Further examples include, but are not limited to, (mono)cycloalkyl groups, such as pyrrolidinocyclopropyl, cyclopentylazacyclopropyl, pyrrolidinocyclobutyl, pyrrolidinopyrrolidinyl, pyrrolidinopiperidinyl, pyrrolidinopiperazinyl, piperidinomorpholinyl, [ka] Further includes, but is not limited to:

[0021] As used herein, the term "heterocyclyl group" includes bridged heterocyclyl groups and spiroheterocyclyl groups.

[0022] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., one, two, three or four) heteroatoms (e.g., oxygen, nitrogen and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly bonded together, such as a 7-10 membered bridged heterocycle, an 8-10 membered bridged heterocycle, a 7-10 membered nitrogen-containing bridged heterocycle, a 7-10 membered oxygen-containing bridged heterocycle, a 7-10 membered sulfur-containing bridged heterocycle, etc. [ka] The above "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.

[0023] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., one, two, three or four) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed by sharing one ring atom between two or more saturated rings, and includes, for example, a 5- to 10-membered spiroheterocycle, a 6- to 10-membered spiroheterocycle, a 6- to 10-membered nitrogen-containing spiroheterocycle, a 6- to 10-membered oxygen-containing spiroheterocycle, a 6- to 10-membered sulfur-containing spiroheterocycle, etc. [ka] The above "nitrogen-containing spiro heterocycle", "oxygen-containing spiro heterocycle", and "sulfur-containing spiro heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6- to 10-membered nitrogen-containing spiro heterocycle" refers to a spiro heterocycle containing a total of 6 to 10 ring atoms, with at least one ring atom being a nitrogen atom.

[0024] As used herein, the term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, "C 6-14The term "aryl group" means an aromatic group, such as a phenyl or naphthyl group, containing 6 to 14 carbon atoms. An aryl group may optionally contain one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 It is substituted with an alkyl group.

[0025] The term "arylalkyl group" preferably refers to an aryl-substituted alkyl group, where the aryl and alkyl are as defined herein. In general, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary arylalkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl groups.

[0026] As used herein, the term "heteroaryl group" or "heteroaryl ring" refers to a monocyclic or polycyclic aromatic group containing one or more homologous or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaryl ring (aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example, 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. Carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (e.g., C=O, S(=O) or S(=O)). 2 (Forming).

[0027] As used herein, the term "5- to 10-membered heteroaryl group" or "5- to 10-membered heteroaryl ring" means a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including a 5- to 10-membered nitrogen-containing heteroaryl group, a 5- to 10-membered sulfur-containing heteroaryl group, a 5- to 6-membered nitrogen-containing heteroaryl group, a 5- to 6-membered oxygen-containing heteroaryl group, a 5- to 6-membered sulfur-containing heteroaryl group, etc. The above "nitrogen-containing heteroaryl group", "oxygen-containing heteroaryl group" and "sulfur-containing heteroaryl group" each optionally contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. Examples thereof include, but are not limited to, a thienyl group, a furyl group, a pyrrolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an isoxazolyl group, an isothiazolyl group, a triazolyl group, a tetrazolyl group, an oxadiazolyl group, a thiadiazolyl group, or the like; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, or the like; and 5- to 10-membered linked ring groups containing these groups.

[0028] As used herein, the term "heteroaryl group" encompasses linked ring structures where the point of attachment to other groups may be on any ring of the linked ring structure. Thus, heteroaryl groups of the present invention include (mono)heteroaryl(mono)heteroaryl groups, (mono)heteroaryl(mono)aryl groups, (mono)heteroaryl(mono)heterocyclyl groups and (mono)heteroaryl(mono)cycloalkyl groups, such as 5-6 membered (mono)heteroaryl 5-6 membered (mono)heteroaryl groups, 5-6 membered (mono)heteroaryl phenyl groups, 5-6 membered (mono)heteroaryl 5-6 membered (mono)heterocyclyl groups or 5-6 membered (mono)heteroaryl C groups. 4-6 Further included are (mono)cycloalkyl groups (e.g., 5- to 6-membered heteroaryl cyclobutyl groups, 5- to 6-membered heteroaryl cyclopentyl groups, or 5- to 6-membered heteroaryl cyclohexyl groups), examples of which include, but are not limited to, indolyl groups, isoindolyl groups, indazolyl groups, benzimidazole groups, quinolinyl groups, isoquinolinyl groups, [ka] These include, but are not limited to:

[0029] As used herein, the term "halogenated" or "halogen" group is defined to include F, Cl, Br, or I.

[0030] The term "alkylthio group," as used herein, means an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio groups include, but are not limited to, methylthio groups, ethylthio groups, tert-butylthio groups, and hexylthio groups.

[0031] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, and optionally including N, O, C=O, S, S=O and S(=O). 2 wherein the nitrogen-containing heterocycle is linked to the remainder of the molecule through a nitrogen atom. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3 to 14 carbon atoms and heteroatoms (wherein at least one is a nitrogen atom) in the ring, and includes, but is not limited to, a 3-membered nitrogen-containing heterocycle (e.g., an aziridinyl group), a 4-membered nitrogen-containing heterocycle (e.g., an azetidinyl group), a 5-membered nitrogen-containing heterocycle (e.g., a pyrrolyl group, a pyrrolidinyl group (pyrrolidine ring), a pyrrolinyl group, a pyrrolidone group, an imidazolyl group, an imidazolidinyl group, an imidazolinyl group, a pyrazolyl group, a pyrazolinyl group), a 6-membered nitrogen-containing heterocycle (e.g., a piperidinyl group (piperidine ring), a morpholinyl group, a thiomorpholinyl group, a piperazinyl group), a 7-membered nitrogen-containing heterocycle, and the like.

[0032] The term "substituted" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with one selected from the indicated group, provided that the replacement does not exceed the normal valence of the designated atom in its current context and that such replacement results in the formation of a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0033] When a substituent is described as "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) can be replaced individually and / or together with any independently selected substituents. When a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) can each be replaced with any independently selected substituent.

[0034] When substituents are described as "independently selected from" a group, each substituent is selected independently of the others. Thus, each substituent may be the same or different as another (other) substituent.

[0035] As used herein, the term "one or more" means one or more than one, where reasonable, for example, two, three, four, five or ten.

[0036] Unless otherwise stated, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent.

[0037] When a bond of a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in that substitutable ring.

[0038] The present invention further includes all pharma- ceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention, except that one or more atoms are replaced by an atom having the same atomic number, but a mass or mass number different from the mass or mass number of the atom predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H), isotopes of carbon (e.g., 11 C. 13 C and 14 C), isotopes of chlorine (e.g. 36 Cl), isotopes of fluorine (e.g. 18 F), isotopes of iodine (e.g. 123 I and 125 I), nitrogen isotopes (e.g., 13 N and 15 N), isotopes of oxygen (e.g. 15 O. 17 O and 18 O), phosphorus isotopes (e.g. 32 P), and isotopes of sulfur (e.g. 35 Certain isotopically labeled compounds of the invention (e.g., those incorporating a radioactive isotope) can be used in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly adapted for this purpose because of their ease of incorporation and ease of detection. 11 C. 18 F, 15 O and 13 Substitution with N) can be used to probe substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying routes and / or examples and preparations, by substituting the appropriate isotopically labeled reagents for the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the invention include those in which the solvent of crystallization can be isotopically substituted, e.g., D 2O, acetone-d 6 or DMSO-d 6 Includes.

[0039] It should also be understood that some compounds of the present invention can exist in free form for treatment, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly or indirectly provide the compound of the present invention or its metabolites or residues after administration to a patient in need thereof.Therefore, in the present specification, when referring to "compounds of the present invention", it is meant to include the above-mentioned various derivative forms of the compound.

[0040] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base salts thereof.

[0041] For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, 2002. Methods for preparing pharma- ceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0042] As used herein, the term "ester" refers to an ester derived from a compound of the respective general formula of this application, including physiologically hydrolyzable esters (wherein the compound of the invention is hydrolyzed under physiological conditions to release the compound in the form of a free acid or alcohol). The compound of the invention may itself be an ester.

[0043] The compounds of the present invention can exist in the form of solvates, preferably hydrates, in which the compounds of the present invention contain polar solvents, in particular, for example, water, methanol or ethanol, which are constituents of the crystal lattice of said compounds. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0044] Further included within the scope of this invention are metabolites of the compounds of this invention, i.e., substances formed in vivo upon administration of the compounds of this invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic degradation, etc. of the administered compound. Thus, the invention includes metabolic products of the compounds of this invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0045] The present invention further includes within its scope prodrugs of the compounds of the present invention, where some derivatives of the compounds of the present invention, which may or may not themselves have less pharmacological activity, can be converted, for example by hydrolysis, to the compounds of the present invention having the desired activity when administered into or on the body. Typically, such prodrugs are functional derivatives of the above compounds that are easily converted in vivo to the desired therapeutically active compound. For further information on the use of prodrugs, reference can be made to "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing the appropriate functional groups present in the compounds of the present invention with some moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0046] The present invention also encompasses the compounds of the present invention that contain protective groups. In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups in any related molecules, thereby forming chemically protected forms of the compounds of the present invention. This can be achieved by conventional protective groups, such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973, and TW Greene & PG M Huts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protective groups can be removed at a suitable subsequent stage using methods known in the art.

[0047] As used herein, the term "about" refers to within ±10%, preferably within ±5%, and more preferably within ±2% of the stated value.

[0048] compound In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of Formula (I): [ka] During the ceremony L is a direct bond, -C 1-6 Alkylene-, -C 2-6 Alkenylene- and -C 2-6 alkynylene-, X is CR 6 or N, Y is CR 4 or N, Z is CR 5 or N, R 1 is H, halogen, -OH, -NH2 , -CN, -NO 2 , C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NR a R b , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b Selected from R 2 and R 3 are each independently H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NR a R b , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b or R 2 and R 3 together form an oxo group (=O), or R 2 and R 3 are C together with the carbon atoms connected to them. 3-6 Constituting a cyclic hydrocarbon group or a 3- to 10-membered heterocyclyl group, R 4 , R 5 and R 6 are each independently H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R a , -OC(=O)R a , -OC(=O)NR a R b , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b and -OC 1-6 Alkylene-NR a R b Selected from R a and R b are independently H, C each time they appear. 1-6 Alkyl group, C 3-10 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 arylalkyl groups, Each occurrence of the above alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and arylalkyl groups optionally and independently may include halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, C 6-12 Arylalkyl groups, -C(=O)R c , -OC(=O)R c , -OC(=O)NR c R d , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 -R d , -NR c -C(=O)-NR c R d , -C 1-6 Alkylene-OR c , -C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R dwherein the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and arylalkyl group are further optionally substituted with one or more substituents independently selected from halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, -OC 1-6 Alkyl groups, -O-halogenated C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 substituted with one or more substituents selected from arylalkyl groups; R c and R d are independently H, C each time they appear. 1-6 Alkyl group, C 3~10 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 The alkyl, cyclic hydrocarbon, heterocyclyl, aryl, heteroaryl and arylalkyl groups may further optionally and independently be selected from the group consisting of halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl groups, halogenated C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups and C 6-12 It is substituted with one or more substituents selected from arylalkyl groups.

[0049] In a preferred embodiment, the present invention provides a compound or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein said compound has the structure of Formula (II) or Formula (III): [ka] During the ceremony, L' is -C 1-6 alkylene-, the alkylene group optionally being independently selected from -OH, -C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 aryl group and 5-14 membered heteroaryl group, preferably said alkylene group is optionally substituted with one or more substituents independently selected from -OH, cyclopropyl group and phenyl group optionally substituted with one or more halogens; The remaining groups are as defined herein.

[0050] In some embodiments, the present invention provides a compound of Formula (I), Formula (II) or Formula (III) or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein L is a direct bond or -C 1-6 alkylene-, where the alkylene groups are optionally, independently, —OH, —OCH 3 , C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 The alkyl group, the cyclic hydrocarbon group, the heterocyclyl group, the aryl group and the heteroaryl group are each optionally substituted with one or more substituents selected from the group consisting of halogen or C 1-6 It is substituted with an alkyl group.

[0051] In a preferred embodiment, L is a direct bond, a methylene group, or an ethylene group, wherein the methylene and ethylene groups are optionally, independently, —OH, —OCH 3 , methyl, cyclopropyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl, optionally further substituted with one or more halogen and / or methyl groups; In the most preferred embodiment, L is a direct bond, -CH 2 -, [ka] It is.

[0052] In some embodiments, the present invention provides a compound of Formula (I), Formula (II) or Formula (III) or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein X, Y, and Z are each independently CH, CF, or N.

[0053] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1 is C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 selected from an aryl group and a 5- to 14-membered heteroaryl group; The alkyl, cyclic hydrocarbon, heterocyclyl, aryl and heteroaryl groups each optionally and independently include halogen, -OH, -CN, C 1-6 Alkyl group, C 3-6 Cyclic hydrocarbon groups, 3-10 membered heterocyclyl groups, C 6-10 Aryl groups, 5-14 membered heteroaryl groups, -C(=O)R c , -OC(=O)R c , -C(=O)ORc , -OR c , -S(=O) 2 R c , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 -R d and -NR c -C(=O)-NR c R d The alkyl, cyclic hydrocarbon, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from, independently, halogen (e.g., fluorine), -OH, =O, C 1-6 Alkyl groups (e.g. methyl groups), halogenated C 1-6 Alkyl groups (e.g. trifluoromethyl groups), -OC 1-6 Alkyl groups (e.g., methoxy groups) and -O-halogenated C 1-6 It is substituted with one or more substituents selected from alkyl groups (eg, trifluoromethoxy groups).

[0054] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R c and R d are independently H, C each time they appear. 1-6 Alkyl groups (e.g., methyl, ethyl, tert-butyl), C 3-10 Cyclic hydrocarbon groups (e.g., cyclopropyl groups), 3- to 10-membered heterocyclyl groups (e.g., pyrrolidinyl groups, morpholinyl groups, or piperidinyl groups, optionally substituted with F), C 6-10aryl groups (e.g., phenyl groups optionally substituted with F) and 5-14 membered heteroaryl groups (e.g., pyridyl groups), wherein the alkyl groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups and heteroaryl groups are further optionally and independently selected from halogen (e.g., F), -OH, halogenated C 1-6 Alkyl groups (e.g. trifluoromethyl groups) and C 3-6 It is substituted with one or more substituents selected from cyclic hydrocarbon groups (eg, cyclopropyl groups).

[0055] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1 is selected from methyl, cyclopropyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl and imidazopyridyl, each of which is optionally and independently selected from -F, -Cl, -OH, -CN, -NH 2 , -CH 3 , -CF 3 , -CH 2 CF 2 CF 3 , -NHCH 2 CF 3 , [ka] is substituted with one or more substituents selected from

[0056] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1 has the following structure: [ka] During the ceremony, U and V are each independently CR 8e R 8f , N.R. 8g or O, R 8a , R 8b , R 8c , R 8d , R 8e , R 8f and R 8g are each independently H or halogen (e.g., F); and R 9 -OR c , -NR c -C(=O)R d , -NR c R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 -R d , -NR c -C(=O)-NR c R d , -OC(=O)R c It is.

[0057] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 1 is a methyl group, [ka] [ka] Selected from.

[0058] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 2 and R3 is H or C 1-6 an alkyl group, preferably H or a methyl group, or R 2 and R 3 together form an oxo group (=O), or R 2 and R 3 are C together with the carbon atoms connected to them. 3-6 It constitutes a cyclic hydrocarbon group, preferably a cyclopropyl group.

[0059] In some embodiments, the present invention provides a compound of Formula (I), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 4 , R 5 and R 6 are each independently H or halogen, preferably R 4 , R 5 and R 6 are each independently H or F.

[0060] The present invention encompasses compounds obtained by any combination of the various embodiments.

[0061] In a preferred embodiment, the present invention provides a compound or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein said compound is selected from: [Table 1-1]

[0062] [Table 1-2]

[0063] [Table 1-3]

[0064] [Table 1-4]

[0065] [Table 1-5]

[0066] [Table 1-6]

[0067] [Table 1-7]

[0068] [Table 1-8]

[0069] [Table 1-9]

[0070] [Table 1-10]

[0071] Pharmaceutical compositions and methods of treatment In some embodiments, the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof and one or more pharma- ceutically acceptable carriers, preferably a solid formulation, a liquid formulation or a transdermal formulation.

[0072] In some embodiments, the present invention provides use of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for preventing or treating an HDAC6-related disease.

[0073] In some embodiments, the present invention provides a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for preventing or treating an HDAC6-related disease.

[0074] In some embodiments, the present invention provides a method for preventing or treating an HDAC6-related disease, comprising administering an effective amount of a compound of the present invention or a pharma- ceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention to an individual in need thereof.

[0075] The above HDAC6-related diseases include cancer or proliferative diseases (e.g., lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, multiple myeloma, and solid tumors), Wilson's disease, spinocerebellar ataxia, prion disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, spinal amyotrophic lateral sclerosis, and Lewy body dementia. dementia, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, psoriasis, inflammatory bowel disease, chronic inflammatory lung disease, eczema, asthma, ischemia / reperfusion injury, ulcerative colitis, acute respiratory distress syndrome, psoriatic arthritis, infectious arthritis, progressive chronic arthritis, osteoarthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, neutral granulocytopenia, ulcerative colitis, Crohn's disease disease, host versus graft disease, graft versus host disease, allograft rejection, chronic thyroiditis, Graves' disease, scleroderma, diabetes mellitus, active hepatitis, primary biliary cirrhosis, myasthenia gravis, multiple sclerosis (MS), systemic lupus erythematosus, atopic dermatitis, contact dermatitis, skin sunburn, chronic renal insufficiency, Stevens-Johnson syndrome, idiopathic seborrheic dermatitis, sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, mid-pulmonary interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis insufficiency, pulmonary dysfunction syndrome, emphysema, pulmonary fibrosis or silicoemphysema.

[0076] As used herein, a "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, or vehicle suitable for administration with a therapeutic agent and for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment.

[0077] Unless otherwise explained, as used herein, the term "treatment" means reversing, alleviating, inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such disease or condition, or preventing such disease or condition, or one or more symptoms of such disease or condition.

[0078] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include human individuals (referred to as patients) suffering from a disease (e.g., a disease described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or farm animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0079] In another embodiment, a pharmaceutical composition of the invention may further comprise one or more additional therapeutic or prophylactic agents.

[0080] Manufacturing method In some embodiments, the compounds of the present application are synthesized by the following reaction route: [ka] wherein R is halogen and each remaining group is as defined herein.

[0081] [ka] where R is a halogen, PG is an amino protecting group, and R10 is -C(=O)R d , -C(=O)OR d , -S(=O) 2 -R d , C(=O)-NR c R d and each remaining group is as defined herein.

[0082] [ka] wherein R is halogen and each remaining group is as defined herein.

[0083] [ka] where R is a halogen, PG is an amino protecting group, and R 10 is -C(=O)R d , -C(=O)OR d , -S(=O) 2 -R d , C(=O)-NR c R d and each remaining group is as defined herein.

[0084] [ka] wherein each group is as defined herein.

[0085] [ka] where PG is an amino protecting group and R 10 is -C(=O)R d , -C(=O)OR d , -S(=O) 2 -R d , C(=O)-NR c R d and each remaining group is as defined herein. EXAMPLES

[0086] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0087] The abbreviations in the present invention have the following meanings: [Table 2]

[0088] Example 1: (Compound 1) [ka]

[0089] Step 1: (Compound 1b) Compound 1a (5 g, 36.72 mmol) was dissolved in chlorosulfonic acid (17.11 g, 146.88 mmol) and stirred at 120° C. under nitrogen gas protection for 4 h, when LC-MS showed the reaction was complete. The reaction was slowly poured into crushed ice, and the resulting solid was filtered and dried under vacuum to give white solid 1b (7.3 g, 75%).

[0090] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 7.8, 2.0 Hz, 1H), 7.29 (d, J =7.8 Hz, 1H), 2.61 (s, 3H).

[0091] Step 2: (Compound 1c) Compound 1b (6.3 g, 26.85 mmol) was dissolved in oxalyl chloride (30 g, 236.35 mmol) and stirred at 70° C. for 2 h under nitrogen gas protection. The reaction was shown to be complete by TLC, quenched with methanol, excess oxalyl chloride was removed under reduced pressure, the residue was dissolved in dichloromethane (20 mL), cooled to 0° C., and methanol (10 mL) was slowly added dropwise. After the addition, stirring was continued at 0° C. for 2 h, and the reaction was shown to be complete by TLC. The reaction was concentrated and purified by column chromatography to give a white solid 1c (5.5 g, 82%).

[0092] 1 HNMR (400MHz, CDCl 3 ) δ 8.76 (d, J = 1.8Hz, 1H), 8.30 (dd, J = 7.9, 1.8Hz, 1H), 7.57 (d, J = 8.0Hz, 1H), 4.01 (s, 3H), 2.90 (s, 3H).

[0093] Step 3: (Compound 1d) Compound 1c (2 g, 8.04 mmol), N-bromosuccinimide (1.57 g, 8.84 mmol) and azobisisobutyronitrile (132.02 mg, 0.80 mmol) were added to carbon tetrachloride (30 mL). The reaction was stirred at 80° C. for 8 h under nitrogen gas protection. The reaction was monitored by TLC, diluted with ethyl acetate (100 mL) and water (30 mL), and the separated organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give colorless oil 1d (1.6 g, 35%).

[0094] 1 HNMR (400MHz, CDCl 3 ) δ 8.80 - 8.76 (m, 1H), 8.41 (dd, J = 8.1, 1.8Hz, 1H), 7.90 (d, J = 8.1Hz, 1H), 5.06 (s, 2H), 4.03 (s, 3H).

[0095] Step 4: (Compound 1e) Compound 1d (1.6 g, 2.78 mmol), 1d' (0.6 g, 2.78 mmol) and sodium carbonate (0.69 g, 5.56 mmol) were added to a mixture of acetonitrile (30 mL) and water (6 mL). The reaction mixture was stirred at 25° C. for 30 minutes, heated to 80° C., stirred for 4 hours, diluted with ethyl acetate (60 mL) and water (20 mL), and the separated organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain colorless oil 1e (1.02 g, 86%).

[0096] ESI m / z [M+H] + = 425.1 1 HNMR (400 MHz, DMSO-d 6 ) δ 8.24 (d, J = 9.2Hz, 2H), 7.81 (d, J = 8.0Hz, 1H), 6.72 (d, J = 9.2Hz, 1H), 4.79 (d, J = 15.2Hz, 1H), 4.58 (d, J = 15.1Hz, 1H), 3.92 (s, 3H), 3.55-3.41 (m, 2H), 1.88-1.66 (m, 5H), 1.51 (d, J = 12.1Hz, 1H), 1.27 (d, J = 9.6Hz, 2H), 1.10 (s, 9H).

[0097] Step 5: (Compound 1f) Compound 1e (500 mg, 1.18 mmol) and hydrazine hydrate (2.06 g, 32.92 mmol, 80%) were added to methanol (6 mL). The reaction was stirred in a sealed tube at 80° C. for 2 h. LC-MS showed the reaction was complete, and the excess methanol was removed under reduced pressure, filtered, and dried in vacuum to give a white solid 1f (495 mg, 99%).

[0098] ESI m / z [M+H] + = 425.2.

[0099] Step 6: (Compound 20) Compound 1f (495 mg, 1.17 mmol), triethylamine (0.53 g, 5.23 mmol) and difluoroacetic anhydride (0.45 g, 2.57 mmol) were added to dichloromethane (20 mL). The reaction was stirred at 25° C. for 16 h. LC-MS showed the reaction was complete, and it was concentrated and purified by column chromatography to give 20 (330 mg, 58%) as a white solid.

[0100] ESI m / z [M+H] + = 485.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d, J = 1.5 Hz, 1H), 8.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.93 (d, J =8.1 Hz, 1H), 7.59 (t, J = 51.3 Hz, 1H), 6.76 (d, J = 9.1 Hz, 1H), 4.83 (d, J = 15.2 Hz, 1H), 4.62 (d, J =15.2 Hz, 1H), 3.54 - 3.41 (m, 2H), 1.84 (d, J = 11.8 Hz, 2H), 1.73 (d, J = 17.5 Hz, 3H), 1.52 (q, J = 12.3, 11.5 Hz, 1H), 1.31 (d, J = 12.2 Hz, 2H), 1.12 (s, 9H).

[0101] Step 7: (Compound 108) Compound 20 (150 mg, 0.31 mmol) was dissolved in 4 M hydrogen chloride in ethyl acetate (20 mL). The reaction was stirred at 25° C. for 2 h, when LC-MS showed the reaction to be complete and concentrated to give 108 (130 mg, 100%) as a white solid.

[0102] ESI m / z [M+H] + = 385.1, 1 H NMR (400 MHz, DMSO-d 6) δ 8.40 (d, J = 1.5 Hz, 1H), 8.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 51.3 Hz, 1H), 6.76 (d, J = 9.1 Hz, 1H), 4.83 (d, J = 15.2 Hz, 1H), 4.62 (d, J =15.2 Hz, 1H), 3.47 (dtd, J = 21.6, 10.8, 5.2 Hz, 2H), 1.84 (d, J = 11.5 Hz, 2H), 1.73 (d, J = 17.5 Hz, 3H), 1.52 (d, J = 12.2 Hz, 1H), 1.31 (d, J = 12.6 Hz, 2H).

[0103] Step 8: (Compound 1) Compound 108 (65 mg, 0.15 mmol), difluoropropionic acid (20 mg, 0.18 mmol), N,N-diisopropylethylamine (39 mg, 0.3 mmol) and HATU (74 mg, 0.20 mmol) were added to N,N-dimethylformamide (3 mL). The reaction was stirred at 25° C. for 2 h. LC-MS showed the reaction was complete, and it was diluted with ethyl acetate (40 mL) and water (15 mL). The separated organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give a white solid 1 (26 mg, 36%).

[0104] ESI m / z [M+H] + = 477.1, 1 H NMR (400 MHz, DMSO-d 6) δ 7.97 (d, J = 9.3 Hz, 1H), 7.77 (d, J = 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.6 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 51.3 Hz, 1H), 4.14 - 3.91 (m, 2H), 3.36 - 3.21 (m, 1H), 3.01 (td, J = 11.0, 4.2 Hz, 1H), 1.28 - 1.03 (m, 6H), 0.87 (t, J = 19.4 Hz, 3H), 0.71 (d, J = 11.2 Hz, 2H).

[0105] Example 2: (Compound 2) [ka] To a solution of compound 108 (71 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.11 g, 0.85 mmol) in N,N-dimethylformamide (3 mL) was added difluoroacetic anhydride (59 mg, 0.34 mmol) at 25° C., and the mixture was stirred for 1 h after completion of the addition. When the reaction was shown to be complete by TLC, it was diluted with ethyl acetate (40 mL) and water (15 mL), and the separated organic phase was washed with saturated brine (15 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a white solid 2 (36.2 mg, 46%).

[0106] ESI m / z [M+H] + = 463.0, 1 H NMR (400 MHz, DMSO-d 6) δ 8.76 (d, J = 9.3 Hz, 1H), 8.44-8.31 (m, 2H), 7.92 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 6.03 (t, J = 53.8 Hz, 1H), 4.76 -4.62 (m, 2H), 3.99-3.87 (m, 1H), 3.61 (td, J =10.8, 4.5 Hz, 1H), 1.94-1.57 (m, 6H), 1.32 (d, J = 25.9 Hz, 2H).

[0107] Example 3: (Compound 3) [ka] Compound 108 (200 mg, 0.48 mmol) was dissolved in dichloromethane (4 mL) and N,N-diisopropylethylamine (156.27 mg, 0.50 mmol) and pentafluoropropionic anhydride (189.21 mg, 1.46 mmol) were added. The reaction was stirred at 10° C. for 14 hours. When the reaction was complete by LCMS, it was poured into water, extracted with dichloromethane, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give a white solid 3 (23 mg, 9%).

[0108] ESI m / z [MH] - = 529.1, 1 H NMR (400 MHz, DMSO-d 6) δ 9.44 (d, J = 9.1 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H), 8.35 (dd, J = 8.1, 1.6 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 51.3 Hz, 1H), 4.69 (d, J = 15.4 Hz, 1H), 4.56 (d, J = 15.4 Hz, 1H), 4.09 - 3.90 (m, 1H), 3.63 (td, J = 11.0, 4.2 Hz, 1H), 1.78 (ddd, J = 33.3, 16.2, 6.8Hz, 6H), 1.34 (d, J = 9.4 Hz, 2H).

[0109] Example 4: (Compound 4) [ka] Compound 108 (200 mg, 0.48 mmol) was dissolved in dichloromethane (4 mL) and N,N-diisopropylethylamine (186.11 mg, 1.44 mmol) and cyclopropylsulfonyl chloride (80.98 mg, 0.58 mmol) were added. The reaction was stirred at 10° C. for 14 hours. After completion by LCMS, the reaction was poured into water, extracted with dichloromethane, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep plate to give a white solid 4 (27 mg, 12%).

[0110] ESI m / z [MH] - = 487.2, 1 H NMR (400 MHz, DMSO-d 6) δ 8.41 (d, J = 1.5 Hz, 1H), 8.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 51.3 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H), 4.71 (d, J = 2.5 Hz, 2H), 3.52 - 3.37 (m, 2H), 2.18 (d, J = 12.9 Hz, 1H), 1.92 (d, J = 12.6 Hz, 1H), 1.72 (q, J = 13.2, 12.2 Hz, 3H), 1.58 - 1.44 (m, 1H), 1.37 - 1.22 (m, 3H), 0.92 - 0.75 (m, 4H).

[0111] Example 5: (Compound 6) [ka]

[0112] Step 1 (Compound 6b) Compound 6a (1 g, 3.41 mmol) was dissolved in acetonitrile (20 mL), and diisopropylethylamine (1.1 g, 8.53 mmol) and compound 1d' (730 mg, 3.41 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then stirred at 80°C overnight. The reaction solution was washed with water, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain compound 6b (1.2 g, 82%).

[0113] Step 2 to Step 5 (Compound 6) With reference to steps 5 to 8 of the synthesis route of Example 1, compound 6b was used instead of 1e in step 5, and difluoroacetic acid was used instead of difluoropropionic acid in step 8, to obtain a white solid 6.

[0114] ESI m / z [M+H] + = 477.0, 1 H NMR (400 MHz, CDCl 3) δ 8.54 (s, 1H), 8.50 (d, J=8.0 Hz, 1 H), 8.17 (d, J=8.0 Hz, 1 H), 6.89 (t, J=51.6 Hz, 1 H), 6.29 (d, J=8.4 Hz, 1 H), 5.61 (t, J=54.4 Hz, 1 H),4.62-4.60 (m, 1 H), 3.77-3.74 (m,1 H), 2.50-2.41 (m, 1 H), 2.22-2.16 (m, 1 H), 2.04-2.01 (m, 1 H), 1.93-1.87 (m, 1 H), 1.81-1.78 (m, 1H), 1.47-1.40 (m, 1 H), 1.37-1.28 (m, 2 H).

[0115] Example 6: (Compound 7) [ka]

[0116] 1.(Compound 7b) A solution of compound 7a (5.0 g, 23.6 mmol) and 4,4-dimethylcyclohexanone (5.9 g, 47.2 mmol) in methanol (100 mL) was stirred at room temperature for 1 h. The mixture was cooled to 0° C., sodium borohydride (3.6 g, 94.3 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried and concentrated, and then stirred with hydrogen chloride (4 M in dioxane, 20 mL) for 1 h. After filtration, the filter cake was dissolved in water, neutralized with sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried and concentrated to give pale yellow oil 7b (5 g, 66%).

[0117] 1 H NMR (400 MHz, CDCl 3) δ 7.21-7.12 (m, 10H), 4.01 (d, J= 7.2 Hz, 1H), 3.84 (d, J= 7.6 Hz,1H), 2.23-2.16 (m, 1H), 2.04 (s, 3H), 1.74-1.64 (m, 1H), 1.531.45 (m, 1H), 1.28-1.21 (m, 3H), 1.17-0.96 (m, 3H), 0.82 (d, J= 14.4 Hz, 6H).

[0118] 2.(Compound 7c) Compound 7b (3.6 g, 11.1 mmol), N-Boc-Op-toluenesulfonylhydroxylamine (16.0 g, 55.7 mmol), sodium bicarbonate (23.4 g, 278.7 mmol) and benzoic acid (6.8 g, 55.7 mmol) were added to chloroform (200 mL). Stirred at room temperature for 1 hour, cyclohexenone (16.0 g, 167.2 mmol) was added and stirred at room temperature overnight. The reaction was quenched by adding water and extracted with dichloromethane. The organic phase was dried and concentrated, and after separation by column chromatography, yellow oil 7c (8.5 g, 64%) was obtained.

[0119] 1 H NMR (400 MHz, CDCl 3 ) δ 3.10-3.05 (m, 1H), 2.89 (d, J= 5.6 Hz, 1H), 2.54-2.46 (m, 1H), 2.27-2.19 (m, 1H), 2.10-1.91 (m, 2H), 1.83-1.74 (m, 1H), 1.68-1.60 (m, 1H), 1.45 (s, 9H).

[0120] 3.(Compound 7d) To a solution of compound 7c (2.5 g, 11.8 mmol) in dichloromethane (30 mL) was added DAST (12.3 g, 59.2 mmol) at 0° C. The mixture was stirred at room temperature for 16 hours, poured into ice water, and extracted with dichloromethane. The organic phase was dried and concentrated, and after separation by column chromatography, yellow oil 7d (5.0 g, 63%) was obtained.

[0121] 1 H NMR (400 MHz, CDCl 3 ) δ 2.88-2.81 (m, 2H), 1.99-1.64 (m, 4H), 1.62-1.55 (m, 2H), 1.45 (s, 9H).

[0122] 4.(Compound 7e) A solution of compound 7e (5.0 g, 21.5 mmol) in methanol / ammonia (100 mL) was stirred at room temperature for 3 days. The reaction solution was directly concentrated and separated by column chromatography to give a white solid 7e (1.8 g, 33%).

[0123] ESI m / z [M+H] + = 251.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.89 (d, J=9.6 Hz, 1H), 3.50-3.35 (m, 1H), 2.62-2.53 (m, 1H), 2.06-1.93 (m, 1H), 1.85-1.59 (m, 3 H), 1.48 (s, 2H), 1.39 (s, 9H), 1.36-1.15 (m, 2H).

[0124] 5.(Compound 7) Following the synthesis route of compound 1 in Example 1, compound 7e was used in place of 1d' to obtain a white solid 7.

[0125] ESI m / z [M+H] + = 512.9, 1 H NMR (400 MHz, CDCl 3) δ 8.50 (s, 1H), 8.38 (d, J=7.6 Hz, 1 H), 7.43 (d, J=8.4 Hz, 1 H), 7.06-6.78 (m, 2 H), 4.69 (d, J=14.4 Hz, 1 H), 4.50 (d, J=14.0 Hz, 1 1.56 (t, J=18.8 Hz, 3H).

[0126] Example 7: (Compound 10) [ka]

[0127] 1.(Compound 10a) HATU (0.3 g, 0.8 mmol) and N,N-diisopropylethylamine (0.31 g, 2.4 mmol) were added to a solution of 7e (0.2 g, 0.8 mmol) in DMF (1 mL). The mixture was stirred at 25° C. for 30 minutes, and difluoropropionic acid (0.11 g, 0.96 mmol) was further added, followed by stirring at 20° C. for 16 hours. Water was added to precipitate a solid, which was then filtered to obtain a white solid 10a (0.2 g, 73%).

[0128] ESI m / z [M+H] + = 343.1.

[0129] 2.(Compound 10b) To a solution of compound 10a (150 mg, 0.44 mmol) in dioxane (5 mL), a solution of hydrogen chloride in dioxane (1 mL, 4 M) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was directly concentrated to give yellow oil 10b (0.1 g, 94%).

[0130] ESI m / z [M+H] + = 243.1.

[0131] 5.(Compound 10) Following the synthesis route of compound 20 in Example 1, compound 10b was used instead of 1d' in step 4 to give white solid 10.

[0132] ESI m / z [MH] - = 511.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (d, J = 9.2 Hz, 1H), 8.48 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 8.1, 1.6 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 4.88 - 4.73 (m, 2H), 4.30 - 4.19 (m, 1H), 4.18 -4.04 (m, 1H), 2.25 (s, 1H), 2.02 - 1.83 (m, 3H), 1.54 (d, J = 13.9 Hz, 2H), 1.38 (d, J = 19.2 Hz, 3H).

[0133] Example 8: (Compound 21) [ka] Following the synthesis route of compound 20 in Example 1, (1R,2R)-2-aminocyclohexan-1-ol was used in place of 1d′ in step 4 to give white solid 21.

[0134] ESI m / z [MH] - = 384.1, 1 H NMR (400 MHz, DMSO-d 6) δ 8.40 - 8.33 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 51.3 Hz, 1H), 4.84 (d, J = 5.0 Hz, 1H), 4.72 - 4.59 (m, 2H), 3.59 - 3.49 (m, 2H), 1.94 (dd, J = 27.5, 11.9 Hz, 2H), 1.65 (d, J = 15.7 Hz, 2H), 1.37 - 1.14 (m, 4H).

[0135] Example 9: (Compound 24) [ka] Following the synthesis method of compound 4 in Example 4, methylsulfonyl chloride was used instead of cyclopropylsulfonyl chloride to obtain a white solid 24.

[0136] ESI m / z [M+H] + = 463.2, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.72 (s, 2H), 3.52 - 3.39 (m, 2H), 2.84 (s, 3H), 2.17 - 2.06 (m, 1H), 1.99 - 1.63 (m, 4H), 1.47 (dd, J = 18.2, 7.6 Hz, 1H), 1.31 (q, J = 16.0, 13.4 Hz, 2H).

[0137] Example 10: (Compound 39) [ka] With reference to the synthesis method of compound 1 in Example 1, methyl 3-fluoro-4-methylbenzoate was used in place of p-methylbenzoic acid in step 1 to obtain a white solid 39.

[0138] ESI m / z [M+H] + = 494.9, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (d, J=9.6 Hz, 1 H), 8.30 (d,J=0.8 Hz, 1 H), 8.25-8.22 (m, 1 H), 7.56 (d, J=51.2 Hz, 1 H), 4.77-4.66 (m, 2 H), 3.96-3.93 (m, 1 H), 3.65-3.61 (m, 1 H), 1.86-1.70 (m, 6 H), 1.54-1.44 (m, 3 H), 1.34-1.23 (m, 2 H).

[0139] Example 11: (Compound 40) [ka] With reference to the synthesis method of compound 1 in Example 1, methyl 3-fluoro-4-methylbenzoate was used instead of p-methylbenzoic acid in step 1, and difluoroacetic acid was used instead of difluoropropionic acid in step 8, to obtain a white solid 40.

[0140] ESI m / z [M+H 2 O] + = 498.0, 1 H NMR (400 MHz, DMSO-d 6) δ 8.73 (d, J=9.2 Hz, 1 H), 8.29 (d, J=0.8 Hz, 1 H), 8.23 ​​(d, J=9.2 Hz, 1 H), 7.57 (d, J=51.2 Hz, 1 H), 6.00 (d, J=53.6 Hz, 1 H),4.78-4.67 (m, 2 H), 3.98-3.93 (m, 1 H), 3.61-3.55 (m, 1 H), 1.87-1.63 (m, 6 H), 1.35-1.23 (m, 2 H).

[0141] Example 12: (Compound 47) [ka] Following the synthesis method of compound 20 in Example 1, (3R,4R)-4-amino-3-hydroxytetrahydropyran was used instead of 1d′ in step 4 to give white solid 47.

[0142] ESI m / z [M+H] + = 387.9, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 8.38-8.36 (m, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 7.70-7.44 (m, 1 H), 5.23 (d, J=5.2 Hz, 1 H), 4.77 (d, J=15.6 Hz, 1 H), 4.65 (d, J=15.6 Hz, 1 H), 3.91-3.82 (m, 2 H), 3.69-3.57 (m, 2 H), 3.42-3.34 (m, 1 H), 3.15-3.09 (m, 1 H), 1.94-1.90 (m, 2 H).

[0143] Example 13: (Compound 49) [ka] Following the synthesis method of compound 20 in Example 1, (3R,4R)-3-amino-4-hydroxytetrahydropyran was used instead of 1d′ in step 4 to give white solid 49.

[0144] ESI m / z [M+H] + = 387.9, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 8.38-8.36 (m, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 7.70-7.44 (m, 1 H), 5.23 (d, J=5.2 Hz, 1 H), 4.77 (d, J=15.6 Hz, 1 H), 4.65 (d, J=15.6 Hz, 1 H), 3.91-3.82 (m, 2 H), 3.69-3.57 (m, 2 H), 3.42-3.34 (m, 1 H), 3.15-3.09 (m, 1 H), 1.94-1.90 (m, 2 H).

[0145] Example 14: (Compound 55) [ka] A white solid 55 was obtained by synthesizing compound 2 in Example 2 using trifluoroacetic anhydride instead of difluoroacetic anhydride.

[0146] ESI m / z [MH] - = 479.2, 1 H NMR (400 MHz, DMSO-d 6) δ 9.36 (d, J = 9.1 Hz, 1H), 8.46 - 8.33 (m, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 4.73 (d, J = 15.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.03 - 3.90 (m,1H), 3.69 - 3.59 (m, 1H), 1.82 (d, J = 17.0 Hz, 4H), 1.73 (d, J = 11.0 Hz, 2H), 1.36 (d, J = 10.4 Hz, 2H).

[0147] Example 15: (Compound 60) [ka] The synthesis method of compound 20 in Example 1 was followed. 3-Chlorobenzylamine was used instead of 1d' to obtain a white solid 60.

[0148] ESI m / z [MH] - = 410.0, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 8.1, 1.6 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.75 - 7.45 (m, 5H), 4.54 (s, 2H), 4.53 (s, 2H).

[0149] Example 16: (Compound 61) [ka] The synthesis method of compound 1 in Example 1 was followed. 7e was used instead of 1d' in step 4, and difluoroacetic acid was used instead of difluoropropionic acid in step 8 to give white solid 61.

[0150] ESI m / z [M+H] + = 499.1,1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (d, J = 9.7 Hz, 1H), 8.44 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 6.19 (t, J = 53.7 Hz, 1H), 4.78 (d, J = 15.6 Hz, 1H), 4.74 - 4.62 (m, 1H), 4.57 (d, J = 15.5 Hz, 1H), 3.77 (td, J = 11.7, 3.9 Hz, 1H), 2.26 - 1.99 (m, 3H), 1.87 (d, J = 13.1 Hz, 2H), 1.64 - 1.48 (m, 1H).

[0151] Example 17: (Compound 62) [ka] To a solution of compound 108 (100 mg, 0.65 mol) in acetonitrile (2 mL), N,N-diisopropylethylamine (100 mg, 0.78 mmol) and 2,2,2-trifluoroethyl triflate (91 mg, 0.39 mmol) were added with stirring at 25° C., and the mixture was reacted for 16 hours at 80° C. The reaction solution was subjected to reverse phase column chromatography to obtain a white solid 62 (50 mg, 41%).

[0152] ESI m / z [M+H] + = 467.2, 1 H NMR (400 MHz, DMSO-d 6) δ 8.45 (d, J = 1.5 Hz, 1H), 8.40 (dd, J = 8.1, 1.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 4.75 - 4.61 (m, 2H), 3.48 (t, J = 9.0 Hz, 1H), 3.28 (s, 1H), 2.79 - 2.66 (m, 1H), 2.48 - 2.34 (m, 1H), 2.14- 2.02 (m, 1H), 1.91 (d, J = 11.6 Hz, 1H), 1.72 (s, 3H), 1.38 (d, J = 12.2 Hz, 1H), 1.23 (d, J = 9.4 Hz, 1H), 1.03 (d, J = 6.4 Hz, 1H).

[0153] Example 18: (Compounds 70i-A, 70i-B, 70i-BA, 70i-BB) [ka]

[0154] 1.(Compound 70c) At -78°C, n-butyllithium (16.8mL, 1.5M in THF) was added to a solution of compound 70a (2.34g, 25.25mmol) in tetrahydrofuran (40mL) and stirred at this temperature for 1 hour. Next, a solution of compound 70b (3.46g, 25.25mmol) in tetrahydrofuran (20mL) was slowly added dropwise. The mixture was stirred at this temperature for 3 hours, warmed to room temperature, and then stirred overnight. The reaction was quenched with dilute hydrochloric acid, extracted with dichloromethane, concentrated, and separated by column chromatography to obtain white solid compound 70c (2.0g, 40%).

[0155] 2.(Compound 70d) Compound 70c (1.94 g, 9.78 mmol) was added to hydrochloric acid (6 M, 20 mL) at 0° C., and an aqueous solution (5 mL) of sodium nitrite (1.69 g, 24.5 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane, concentrated, and separated by column chromatography to obtain a yellow solid 70d (1.51 g, 68%).

[0156] 3.(Compound 70e) Sodium borohydride (304 mg, 8 mmol) was added to a solution of compound 70d (1.51 g, 6.68 mmol) in methanol (40 mL) at 0° C. The mixture was stirred for 2 h. It was washed with water, extracted with dichloromethane, and concentrated to give a yellow solid 70e (1.5 g, 98%).

[0157] 4.(Compound 70f-P1, 70f-P2) A solution of compound 70e (1.5 g, 6.5 mmol) and Pd / C (750 mg, 10%) in methanol (200 mL) was stirred at 70° C. under hydrogen atmosphere (4.0 MPa) for 2 days. After filtration, the filtrate was separated by column chromatography to give yellow oils 70f-P1 (400 mg, 27%) and 70f-P2 (400 mg, 27%).

[0158] 70f-P1: 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.51-8.47 (m, 2 H), 7.79-7.68 (m, 2 H), 7.46 (d, J=10.4 Hz, 1 H), 4.79 (d, J=10.4 Hz, 1 H), 7.26-7.20 (m, 2 H), 5.47 (s, 1 H), 4.91 (d, J=4.8 Hz, 1 H), 4.25 (d, J=5.2 Hz, 1 H), 1.94 (s, 2 H).

[0159] 70f-P2: 1 H NMR (400 MHz, DMSO-d 6): δ 8.48-8.41 (m, 2 H), 7.68-7.59 (m, 2 H), 7.23-7.15 (m, 4 H), 5.46 (s, 1 H), 4.79 (d, J=6.0 Hz, 1 H), 4.19 (d, J=6.4 Hz, 1 H), 2.04 (s, 2H).

[0160] 5.(Compound 70i-A) The synthesis route of compound 20 in Example 1 was followed. Compound 70f-P1 was used instead of 1d' to obtain white solid 70i-A, which was racemic.

[0161] ESI m / z [M+H] + = 485.9, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51-8.47 (m, 2 H), 8.35-8.33 (m, 2 H), 7.93 (d, J=8.4 Hz, 1 H), 7.70-7.43 (m, 4 H), 7.24-7.18 (m, 3 H), 5.96 (d, J=5.6 Hz, 1 H), 5.61-5.58 (m, 1 H), 5.44 (d, J=6.0 Hz, 1 H), 5.14-5.01 (m, 2 H).

[0162] 6.(Compound 70i-B) The synthesis route of compound 20 in Example 1 was followed. Compound 70f-P2 was used instead of 1d' to obtain white solid 70i-B, which was racemic.

[0163] ESI m / z [M+H] + = 485.9, 1 H NMR (400 MHz, DMSO-d 6) δ 8.58 (d, J=4.0 Hz, 1 H), 8.38 (d,J=4.4 Hz, 1 H), 8.30-8.28 (m, 1 H), 8.24 (s, 1 H), 7.89 (d, J=8.4 Hz, 1 H), 7.80-7.74 (m, 2 H), 7.66-7.40 (m, 3 H), 7.37-7.31 (m, 1 H), 7.22-7.19 (m, 1 H), 6.99 (d, J=6.0 Hz, 1 H), 5.47-5.44 (m, 1 H), 5.18 (d, J=8.4 Hz, 1 H), 5.14-5.02 (m, 2H).

[0164] 7.(Compound 70i-BA, 70i-BB) Compound 70i-B (240 mg, 0.49 mmol) underwent chiral resolution (column: IC, mobile phase: Hex / EtOH / TFA50 / 50 / 0.3, flow rate: 25 mL / min, detection wavelength: 254 nM) to give white solid compound 70i-BA (retention time: 21.264 min, 50 mg, 21%) and compound 70i-BB (retention time: 29.823 min, 50 mg, 21%), both of which were chirally pure compounds.

[0165] 70i-BA: ESI m / z [M+H] + = 486.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1 H), 8.40 (s, 1 H), 8.29 (d, J=8.0 Hz, 1 H), 8.25 (s, 1 H), 7.89(d, J=8.4 Hz, 1 H), 7.80-7.74(m, 2 H), 7.66-7.63(m, 1 H), 7.53-7.41(m, 2 H), 7.33(m, 1 H), 7.23(m, 1 H), 6.03(s, 1 H), 5.47 (d, J=7.2 Hz, 1 H), 5.19-5.00 (m, 3 H).

[0166] 70i-BB: ESI m / z [M+H] + = 485.9.1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (d, J=4.0 Hz, 1 H), 8.38 (d, J=4.4 Hz, 1 H), 8.30-8.28 (m, 1 H), 8.25 (s, 1 H), 7.89(d, J=8.0 Hz, 1 H), 7.80-7.75(m, 2 H), 7.66-7.41(m, 3 H), 7.34-7.31(m, 1 H), 7.23-7.20(m, 1 H), 6.01(s, 1 H), 5.46(d, J=8.0 Hz, 1 H), 5.20-5.02 (m, 3 H).

[0167] Example 19: (Compound 72) [ka]

[0168] 1.(Compound 72b) Compound 72a (1 g, 6.21 mmol), 4-bromo-1-methyl-1H-pyrazole (1.98 g, 6.21 mmol), potassium carbonate (2.57 g, 18.6 mmol) and 1,1'-bisdiphenylphosphineferrocenedichloropalladium (0.55 g, 0.75 mmol) were added to a mixture of dioxane (5 mL) and water (1 mL) and reacted for 16 hours under stirring at 80° C. The reaction solution was poured into water, extracted with dichloromethane, concentrated and purified by column chromatography to obtain white solid 72b (900 mg, 53%).

[0169] ESI m / z [M+H] + = 274.1.

[0170] 2.(Compound 72c) Compound 72b (500 mg, 2.12 mmol) was added to a dichloromethane (5 mL) solution, and trifluoroacetic acid (2 mL) was added while stirring, and the mixture was reacted for 2 hours. The reaction solution was concentrated to give yellow oil 72c (300 mg, 95%).

[0171] 3.(Compound 72) The synthesis route of compound 20 in Example 1 was followed. Compound 72c was used instead of 1d', and a white solid 72 was synthesized via a three-step reaction.

[0172] ESI m / z [M+H] + = 444.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 - 8.57 (m, 1H), 8.46 (dd,J = 8.1, 1.6 Hz, 1H), 8.06 (s, 1H), 7.91 (d,J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.77 - 7.61 (m, 3H), 7.54 (td,J = 7.6, 1.4 Hz, 1H), 7.43 (td,J = 7.6, 1.6 Hz, 1H), 4.83 (s, 2H), 3.81 (s, 3H).

[0173] Example 20: (Compounds 79i, 79i-A, 79i-B) [ka]

[0174] 1.(Compound 79c) A mixture of compound 79a (2 g, 16.6 mmol), sodium tert-butoxide (3.8 g, 39.6 mmol) and XPhosPd-G3 (1.41 g, 1.66 mmol) in toluene (20 mL) was stirred under nitrogen gas protection for 30 min, and compound 79b (3.8 g, 18.2 mmol) was further added and reacted at 130° C. in a microwave for 30 min or more. Washed with water, extracted with ethyl acetate, concentrated the organic phase and separated by column chromatography to give brown solid 79c (1.05 g, 32%).

[0175] ESI m / z [M+H] + = 201.0.

[0176] 2.(Compound 79f) 79f was synthesized through a three-step reaction using 79c instead of 70c according to the synthesis route of 70f in Example 18. The mixture of 79f was used in the next reaction without separating the isomers of 79f.

[0177] 3. (Compound 79i, 79i-A, 79i-B) Refer to the synthesis conditions of compound 70i-A in Example 18, use 79f instead of 70f-P1, synthesize mixture 79i through three-step reaction, and undergo chiral separation (column: IBN, mobile phase: Hex / EtOH50 / 50, flow rate: 25mL / min, detection wavelength: 254nM) to obtain white solid 79i-A (isomer A, retention time: 15.494 min) and 79i-B (isomer B, retention time: 18.437 min), both of which are chiral pure compounds, and simultaneously obtain two other isomers 79i-C (retention time: 29.632 min) and 79i-D (retention time: 35.885 min) with low yields by separation.

[0178] 79i-A (isomer A):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (s, 1 H), 8.32(d, J=8.0 Hz, 1 H), 7.84(d, J=8.4 Hz, 1 H), 7.72 (s, 1 H), 7.69-7.44(m, 2 H), 7.35-7.33(m, 2 H), 7.28-7.25(m, 2 H), 7.19-7.18(m, 1 H), 6.01(d, J=4.8 Hz, 1 H), 5.25-5.23(m, 1 H), 4.98(d, J=4.0 Hz, 1 H), 4.89(d, J=16.0 Hz, 1 H), 4.37 (d, J=16.4 Hz, 1 H), 3.74 (s, 3 H).

[0179] 79i-B (isomer B):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6) δ 8.38 (s, 1 H), 8.33-8.31(m, 1 H), 7.84(d, J=8.4 Hz, 1 H), 7.72 (s, 1 H), 7.69-7.44(m, 2 H), 7.35-7.34(m, 2 H), 7.28-7.25(m, 2 H), 7.19-7.18(m, 1 H), 6.02(d, J=4.4 Hz, 1 H), 5.26-5.23(m, 1 H), 4.98(d, J=4.4 Hz, 1 H), 4.89(d, J=16.0 Hz, 1 H), 4.37(d, J=16.0 Hz, 1 H), 3.74 (s, 3 H).

[0180] Example 21: (Compounds 84j-A, 84j-B, 84j-AA, 84j-AB) [ka]

[0181] 1.(Compound 84b) Compound 84a (1.0 g, 9.3 mmol) in methanol (7 mL) was slowly added to a solution (14 mL) of tert-butyl carbamate (1.09 g, 9.3 mmol) and sodium p-toluenesulfonate (2.5 g, 14.0 mmol), and the mixture was stirred at room temperature for half an hour, and formic acid (0.72 mL) was further added. After stirring at room temperature for 3 days, the reaction solution was directly filtered, and the filter cake was washed with water and dried to obtain white solid 84b (1.7 g, 50%).

[0182] 2.(Compound 84e) Triethylamine (7.1 g, 70.3 mmol) was added to a solution of compound 84c (125 mg, 4.47 mmol), compound 84b (1.7 g, 4.7 mmol) and compound 84d (226 mg, 0.89 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred for 16 hours under nitrogen gas protection at 60° C. The reaction solution was cooled to 0° C., treated with saturated ammonium chloride, extracted with ethyl acetate, dried over sodium sulfate, and separated by column chromatography to give white solid 84e (1.05 g, 70%).

[0183] ESI m / z [M+H] + = 332.1.

[0184] 3.(Compound 84f) Sodium borohydride (253 mg, 6.67 mmol) was slowly added to a solution of compound 84e (1.84 g, 5.55 mmol) in methanol (40 mL) and stirred at 0° C. for 1 hour. A small amount of water was added to quench the excess sodium borohydride, and the reaction solution was directly concentrated and separated by column chromatography to give yellow solid 84f (1.75 g, 94%).

[0185] ESI m / z [M+H] + = 334.1.

[0186] 4.(Compound 84g) To a solution of compound 84f (750 mg, 2.25 mmol) in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was slowly added and stirred at room temperature for 1 hour. The reaction solution was directly concentrated to give yellow oil 84g (781 mg, trifluoroacetate salt).

[0187] ESI m / z [M+H] + = 234.1.

[0188] 5. (Compounds 84j-A, 84j-B) The synthesis route of compound 20 in Example 1 was followed. Compound 84g was used instead of 1d' to finally synthesize 84j, and the diastereomers were separated by reverse phase fractionation to obtain white solids 84j-A and 84j-B.

[0189] 84j-A (isomer A):ESI m / z [M+H] + = 504.0. 1 H NMR (400 MHz, DMSO-d 6) δ 8.60 (d, J=4.0 Hz, 1 H), 8.36 (s, 1 H), 8.30-8.28 (m, 1 H), 8.25 (s, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.72-7.70 (m, 2 H), 7.66-7.36 (m, 2 H), 7.34-7.32 (m, 1 H), 6.03 (d, J=6.0 Hz, 1 H), 5.52-5.48 (m, 1 H), 5.12 (d, J=8.8 Hz, 1 H), 5.09-4.98 (m, 2H).

[0190] 84j-B (isomer B):ESI m / z [M+H] + = 503.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53-8.47 (m, 2 H), 8.35-8.33 (m, 2 H), 7.93-7.91 (m, 1 H), 7.71-7.43 (m, 4 H), 7.27-7.21 (m, 2 H), 6.08 (d, J=5.2 Hz, 1 H), 5.67-5.64 (m, 1 H), 5.38 (d, J=5.6 Hz, 1 H), 5.10-4.99 (m, 2 H).

[0191] 6. (Compounds 84j-AA, 84j-AB) Compound 84j-A (100 mg) underwent chiral resolution (column: IC, mobile phase: Hex / EtOH / TFA40 / 60 / 0.3, flow rate: 25 mL / min, detection wavelength: 254 nM) to give white solid compound 84j-AA (retention time: 15.293 min, 30 mg, 30%) and compound 84j-AB (retention time: 21.500 min, 30 mg, 30%), both of which were chirally pure compounds.

[0192] 84j-AA (isomer AA):ESI m / z [M+H] + = 504.0. 1 H NMR (400 MHz, DMSO-d 6) δ 8.60 (d, J=4.0 Hz, 1 H), 8.36 (s, 1 H), 8.30-8.28 (m, 1 H), 8.25 (s, 1 H), 7.88 (d, J=8.0 Hz, 1 H), 7.82-7.77 (m, 1 H), 7.72-7.70 (m, 2 H), 7.66-7.41 (m, 2 H), 7.35-7.32 (m, 1 H), 6.03 (d, J=6.0 Hz, 1 H), 5.52-5.48 (m, 1 H), 5.11 (d, J=8.4 Hz, 1 H), 5.09-4.98 (m, 2H).

[0193] 84j-AB (isomer AB):ESI m / z [M+H] + = 504.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.60 (d, J=4.0 Hz, 1 H), 8.36 (s, 1 H), 8.30-8.28 (m, 1 H), 8.25 (s, 1 H), 7.89 (d, J=8.0 Hz, 1 H), 7.82-7.78 (m, 1 H), 7.72-7.70 (m, 2 H), 7.66-7.41 (m, 2 H), 7.35-7.32 (m, 1 H), 6.03 (d, J=6.0 Hz, 1 H), 5.52-5.48 (m, 1 H), 5.13-4.98 (m, 3 H).

[0194] Example 22: (Compounds 88j-A, 88j-B, 88j-AA, 88j-AB) [ka]

[0195] 1. (Compounds 88j-A, 88j-B) The synthesis route of compound 84j in Example 21 was followed. Compound 5-fluoropyridine-2-carbaldehyde was used instead of 84a, and the diastereomers were finally separated by reverse phase fractionation to obtain white solids 88j-A and 88j-B.

[0196] 88j-A (Isomer A): ESI m / z [M+H] + = 521.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, J = 3.2 Hz, 1 H), 8.37 (d, J = 1.6 Hz, 1 H), 8.31 - 8.29 (m, 1 H), 8.26 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.77 - 7.70 (m, 3 H), 7.67 - 7.41(m, 2 H), 6.02 (d, J = 5.6 Hz, 1 H), 5.49 - 5.45 (m, 1 H), 5.17 (d, J = 8.8 Hz, 1 H), 5.07 - 4.96 (m, 2 H).

[0197] 88j-B (Isomer B): ESI m / z [M+H] + = 522.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d, J = 3.2 Hz, 1 H), 8.47 (d, J = 2.8 Hz, 1 H), 8.36 - 8.34 (m, 2 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.69 - 7.43 (m, 4 H), 7.35 - 7.32 (m, 1 H), 6.10 (d, J = 5.2 Hz, 1 H), 5.62 - 5.59 (m, 1 H), 5.42 (d, J = 6.0 Hz, 1 H), 5.09 - 4.99 (m, 2 H).

[0198] 2. (Compound 88j-A-A, 88j-A-B) Compound 88j-A (100 mg) was subjected to chiral resolution (column: IC, mobile phase: Hex / EtOH / TFA 40 / 60 / 0.3, flow rate: 25 mL / min, detection wavelength: 254 nM). White solid compounds 88j-A-A (retention time: 10.727 minutes, 30 mg, 30%) and 88j-A-B (retention time: 17.608 minutes, 20 mg, 20%) were obtained, both of which were chiral pure compounds.

[0199] 88j-AA (isomer AA):ESI m / z [M+H] + = 521.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, J=2.8 Hz, 1 H), 8.37 (d, J=1.6 Hz, 1 H), 8.31-8.29 (m, 1 H), 8.25 (s, 1 H), 7.88 (d, J=8.4 Hz, 1 H), 7.76-7.69 (m, 3 H), 7.66-7.41(m, 2 H), 6.01 (d, J=5.6 Hz, 1 H), 5.48-5.44 (m, 1 H), 5.16 (d, J=8.4 Hz, 1 H), 5.06-4.95 (m, 2 H).

[0200] 88j-AB (isomer AB):ESI m / z [M+H] + = 521.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d, J=2.4 Hz, 1 H), 8.37 (s, 1 H), 8.31-8.29 (m, 1 H), 8.25 (s, 1 H), 7.88 (d, J=8.0 Hz, 1 H), 7.76-7.69 (m, 3 H), 7.66-7.41(m, 2 H), 6.02 (d, J=6.0 Hz, 1 H), 5.48-5.44 (m, 1 H), 5.17 (d, J=8.4 Hz, 1 H), 5.06-4.95 (m, 2 H).

[0201] Example 23: (Compound 92) [ka] A white solid 92 was obtained by synthesizing compound 4 in Example 4 using methyl chloroformate instead of cyclopropylsulfonyl chloride.

[0202] ESI m / z [M+H] + = 443.1. 1H NMR (400 MHz, DMSO-d 6 ) δ 8.38-8.34 (m, 2H), 7.98 (d, J = 4Hz, 1H), 7.57 (t, 1H), 7.03 (d, J = 4.2Hz, 1H), 4.68 (s, 1H), 3.50-3.45 (m, 2H) 3.31 (s, 3H), 1.89-1.70 (m, 5H), 1.51-1.49 (m, 1H), 1.28-1.24 (m, 2H).

[0203] Example 24: (Compound 93) [ka] A white solid 93 was obtained by synthesizing compound 4 in Example 4 using dimethylcarbamoyl chloride instead of cyclopropylsulfonyl chloride.

[0204] ESI m / z [M+H] + = 456.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37-8.33 (m, 2H), 7.87 (d, J=4Hz, 1H), 7.57 (t, 1H), 5.99 (d, J=3.6Hz, 1H), 4.65 (s, 1H), 3.76-3.73 (m, 1H), 3.57-3.56 (m, 1H), 2.63 (s, 6H), 1.85-1.70 (m, 5H), 1.55-1.52(m, 1H), 1.30-1.24 (m, 2H).

[0205] Example 25: (Compound 94) [ka] A white solid 94 was obtained by synthesizing compound 4 in Example 4 using methylcarbamoyl chloride instead of cyclopropylsulfonyl chloride.

[0206] ESI m / z [M+H] + = 442.1.1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39-8.35 (m, 2H), 7.91 (d, J=8Hz, 1H), 7.59 (t, 1H), 5.77 (d, J=12Hz, 1H), 4.64 (d, J=5.2Hz, 1H), 4.71 (dd, J=10Hz, 2H), 3.76-3.73 (m, 1H), 3.45-3.37 (m, 1H), 2.39 (d, J=6Hz, 3H), 1.91-1.88 (m, 2H), 1.75-1.72 (m, 3H), 1.34-1.30 (m, 3H).

[0207] Example 26: (Compounds 95j-A, 95j-B, 95j-BA, 95j-BB) [ka]

[0208] 1. (Compounds 95j-A, 95j-B) Refer to the synthesis route of compound 84j in Example 21. 95j was finally synthesized using 1-methylpyrazole-4-carbaldehyde instead of 84a and 84c, and the diastereomers were separated by reverse phase fractionation to obtain white solids 95j-A and 95j-B.

[0209] 95j-A (isomer A):ESI m / z [M+H] + = 492.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1 H), 8.34 (dd, J 1 =1.2 Hz, J 2=8.0 Hz, 1 H), 7.73 (d, J=8.0 Hz, 1 H), 7.70 (s, 1 H), 7.60 (s, 1 H), 7.56 (s, 1 H), 7.46 (s, 1 H), 7.36-7.10 (m, 1 H), 5.52 (d, J=6.0 Hz, 1 H), 5.04 (d, J=6.0 Hz, 1 H), 4.83 (d, J=6.0 Hz, 1 H), 4.45 (d, J=15.6 Hz, 1 H), 3.81 (s, 6 H).

[0210] 95j-B (isomer B):ESI m / z [M+H] + = 492.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1 H), 8.34 (dd, J 1 =1.2 Hz, J 2 =8.0 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d, J=8.0 Hz, 1 H), 7.64 (s, 1 H), 7.49 (s, 1 H), 7.36 (s, 1 H), 7.35-7.10 (m, 1 H), 5.34 (d, J=5.2 Hz, 1 H), 5.03 (d, J=5.2 Hz, 1 H), 4.77 (d, J=5.2 Hz, 1 H), 4.39 (d, J=15.6 Hz, 1 H), 3.84 (s, 3 H), 3.79 (s, 3 H).

[0211] 2. (Compounds 95j-BA, 95j-BB) Compound 95j-B (40 mg) underwent chiral resolution (column: IE, mobile phase: MeOH / EtOH50 / 50, flow rate: 25 mL / min, detection wavelength: 214 nM) to give white solid compound 95j-BA (retention time: 12.459 min, 20 mg, 50%) and compound 95j-BB (retention time: 15.560 min, 20 mg, 50%), both of which were chirally pure compounds.

[0212] 95j-BA (isomer BA):ESI m / z [M+H]+ = 492.0. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1 H), 8.34 (dd, J 1 =1.6 Hz, J 2 =8.4 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.49 (s, 1 H), 7.36 (s, 1 H), 7.35 - 7.10 (m, 1 H), 5.34 (d, J = 4.8 Hz, 1 H), 5.04 (d, J = 4.8 Hz, 1 H), 4.80 (d, J = 4.8 Hz, 1 H), 4.39 (d, J = 15.6 Hz, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H).

[0213] 95j-B-B (isomer B-B): ESI m / z [M+H] + = 492.0. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1 H), 8.34 (dd, J 1 =1.6 Hz, J 2 =8.4 Hz, 1 H), 7.78 (s, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.64 (s, 1 H), 7.49 (s, 1 H), 7.36 (s, 1 H), 7.35 - 7.10 (m, 1 H), 5.34 (d, J = 4.8 Hz, 1 H), 5.03 (d, J = 4.8 Hz, 1 H), 4.78 (d, J = 4.8 Hz, 1 H), 4.40 (d, J = 15.6 Hz, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H).

[0214] Example 27: (Compound 99j-A, 99j-B, 99j-A-A, 99j-A-B)

Chem.

[0215] 1. (Compounds 99j-A, 99j-B) The synthesis route of compound 84j in Example 21 was followed. 2-Pyrazineformaldehyde was used instead of 84a and 84c, and finally the diastereomers were separated by reverse phase fractionation to obtain white solids 99j-A and 99j-B.

[0216] 99j-A (isomer A):ESI m / z [M+H] + = 488.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92 (s, 1 H), 8.83 (d, J=1.2 Hz, 1 H), 8.70 (s, 1 H), 8.63 (d, J=2.4 Hz, 1 H), 8.52-8.48 (m, 2 H), 8.32-8.30 (m, 1 H), 8.26 (s, 1 H), 7.88 (d, J=8.4 Hz, 1 H), 7.66-7.41 (m, 1 H), 6.24 (d, J=5.6 Hz, 1 H), 5.54-5.50 (m, 1 H), 5.36 (d, J=9.2 Hz, 1 H), 5.03 (s, 2 H).

[0217] 99j-B (isomer B):ESI m / z [M+H] + = 488.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (s, J=1.2 Hz, 1 H), 8.64 (d, J=1.2 Hz, 1 H), 8.59-8.50 (m, 4 H), 8.37-8.35 (m, 2 H), 7.93 (d, J=8.4 Hz, 1 H), 7.68-7.43 (m, 1 H), 6.39 (d, J=5.2 Hz, 1 H), 5.73-5.70 (m, 1 H), 5.56 (d, J=5.6 Hz, 1 H), 5.15-5.05 (s, 2 H).

[0218] 2. (Compounds 99j-AA and 99j-AB) Compound 99j-A (100 mg) was subjected to chiral resolution (column: IH, mobile phase: MeOH / EtOH / TFA50 / 50 / 0.3, flow rate: 25 mL / min, detection wavelength: 254 nM) to give white solid compound 99j-AA (retention time: 8.371 min, 35 mg, 35%) and compound 99j-AB (retention time: 11.741 min, 35 mg, 35%), both of which were chirally pure compounds.

[0219] 99j-AA (isomer AA):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92 (d, J=1.2 Hz, 1 H), 8.83 (d, J=1.2 Hz, 1 H), 8.70 (s, 1 H), 8.63 (d, J=2.4 Hz, 1 H), 8.52-8.48 (m, 2 H), 8.32-8.26 (m, 2 H), 7.88 (d, J=8.0 Hz, 1 H), 7.66-7.41 (m, 1 H), 6.24 (d, J=6.0 Hz, 1 H), 5.54-5.51 (m, 1 H), 5.36 (d, J=9.2 Hz, 1 H), 5.03 (s, 2 H).

[0220] 99j-AB (isomer AB):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.93 (s, 1 H), 8.83 (d, J=0.8 Hz, 1 H), 8.70 (d, J=2.0 Hz, 1 H), 8.63 (d, J=2.4 Hz, 1 H), 8.52-8.48 (m, 2 H), 8.32-8.26 (m, 2 H), 7.88 (d, J=8.4 Hz, 1 H), 7.66-7.41 (m, 1 H), 6.25 (d, J=6.0 Hz, 1 H), 5.55-5.51 (m, 1 H), 5.36 (d, J=9.2 Hz, 1 H), 5.04 (s, 2 H).

[0221] Example 28: (Compounds 103j-A, 103j-B, 103j-C, 103j-D) [ka] Refer to the synthesis route of compound 84j in Example 21. Instead of 84a and 84c, 2-pyrimidineformaldehyde was used, and the finally obtained mixture 103j was subjected to chiral resolution (column: IBN, mobile phase: MeOH / DCM90 / 10, flow rate: 25 mL / min, detection wavelength: 254 nM) to obtain white solid compound 103j-A (retention time: 9.214 min), compound 103j-B (retention time: 12.041 min), compound 103j-C (retention time: 13.807 min) and compound 103j-D (retention time: 18.648 min), all of which were chiral pure compounds.

[0222] 103j-A (isomer A):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78-8.75 (m, 4 H), 8.36-8.34 (m, 1 H), 8.31 (s, 1 H), 7.97 (d, J=8.4 Hz, 1 H), 7.68-7.43 (m, 1 H), 7.41-7.36 (m, 2 H), 5.94 (d, J=4.8 Hz, 1 H), 5.73-5.71 (m, 1 H), 5.53-5.48 (m, 2 H), 5.14 (d, J=16.4 Hz, 1 H).

[0223] 103j-B (isomer B):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6) δ 8.82-8.76 (m, 4 H), 8.32-8.30 (m, 1 H), 8.25 (s, 1 H), 7.94 (d, J=8.0 Hz, 1 H), 7.67-7.38 (m, 3 H), 5.86 (d, J=6.0 Hz, 1 H), 5.51-5.42 (m, 2 H), 5.33 (d, J=16.0 Hz, 1 H), 5.06 (d, J=15.6 Hz, 1 H).

[0224] 103j-C(isomer C):ESI m / z [M+H] + = 487.9. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82-8.77 (m, 4 H), 8.31 (d, J=8.4 Hz, 1 H), 8.25 (s, 1 H), 7.94 (d, J=8.0 Hz, 1 H), 7.67-7.38 (m, 3 H), 5.86 (d, J=6.4 Hz, 1 H), 5.51-5.42 (m, 2 H), 5.33 (d, J=16.0 Hz, 1 H), 5.06 (d, J=15.6 Hz, 1 H).

[0225] 103j-D (isomeric form D):ESI m / z [M+H] + = 488.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78-8.75 (m, 4 H), 8.36-8.34 (m, 1 H), 8.31 (s, 1 H), 7.97 (d, J=8.0 Hz, 1 H), 7.68-7.43 (m, 1 H), 7.41-7.36 (m, 2 H), 5.95 (d, J=4.8 Hz, 1 H), 5.73-5.71 (m, 1 H), 5.53-5.47 (m, 2 H), 5.13 (d, J=16.4 Hz, 1 H).

[0226] Example 29: (Compound 107)

change

[0227] ESI m / z [MH] - = 387.1. 1 H NMR (400 MHz, Methanol-d 4 ) δ 8.56 (s, 1H), 8.47 (dd, J = 8.1, 1.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.29 (t, J = 51.6 Hz, 1H), 4.75 (d, J = 15.0 Hz, 1H), 4.63 (d, J = 14.9 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 3.92 (dt, J = 12.2, 3.2 Hz, 1H), 3.69 (ddd, J = 12.3, 10.0, 2.8 Hz, 1H), 3.55 - 3.36 (m, 4H), 3.22 - 2.95 (m, 2H).

[0228] Example 30: (Compound 109) [ka] To a mixture of cyclopropylamine (500 mg, 8.76 mmol) and triethylamine (2.66 g, 26.28 mmol) in toluene (3 mL) and water (2 mL), triphosgene (0.91 g, 3.07 mmol) was added at 0° C. and stirred for 2 hours. The upper toluene layer was removed and added to a solution of compound 108 (200 mg, 0.52 mmol) and triethylamine (130 mg, 1.3 mmol) in N,N-dimethylformamide (2 mL), and stirred for 2 hours. The reaction solution was washed with water and separated by reverse phase column chromatography to obtain white solid 109 (30 mg, 12%).

[0229] ESI m / z [M+H] + = 468.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.41 (d, J = 1.5 Hz, 1H), 8.37 (dd, J = 8.1, 1.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 6.08 (s, 1H), 5.75 (d, J = 9.1 Hz, 1H), 4.80 (d, J = 15.5 Hz, 1H), 4.66 (d, J= 15.5 Hz, 1H), 3.73 (d, J = 11.1 Hz, 1H), 3.52 (t, J = 10.2 Hz, 1H), 2.23 (dd, J = 7.0, 4.0Hz, 1H), 2.09 - 1.99 (m, 1H), 1.92 (d, J = 13.1 Hz, 2H), 1.75 (d, J = 11.0 Hz, 2H), 1.48 (d, J = 11.7 Hz, 2H), 0.46 (dt, J = 12.4, 7.5 Hz, 2H), 0.24 (dd, J = 10.0, 5.0 Hz, 1H), 0.18 - 0.08 (m, 1H).

[0230] Example 31: (Compound 110) [ka] The synthesis method of compound 109 in Example 30 was repeated except that cyclopropylmethylamine was used instead of cyclopropylamine to obtain a white solid 110. ESI m / z [M+H] + = 482.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.44 - 8.20 (m, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 51.3 Hz, 1H), 5.85 - 5.68 (m, 2H), 4.78 (d, J = 15.4 Hz, 1H), 4.62 (d, J = 15.5 Hz, 1H), 3.79 - 3.59 (m, 1H), 2.69 (td, J = 6.3, 4.7 Hz, 2H), 1.88 (d, J = 11.7 Hz, 2H), 1.71 (q, J = 12.0, 10.9 Hz, 3H), 1.45 - 1.19 (m, 4H), 0.64 - 0.53 (m, 1H), 0.10 (ddd, J = 9.8, 4.7, 2.7 Hz, 2H), -0.09 (dd, J = 4.8, 1.9 Hz, 2H).

[0231] Example 32: (Compound 111) [ka] A white solid 111 was obtained by synthesizing compound 109 in Example 30 using trifluoroethylamine instead of cyclopropylamine.

[0232] ESI m / z [M+H] + = 510.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.41 (s, 1H), 8.38 (dd, J = 8.1, 1.6 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.62 (t, J = 51.3 Hz, 1H), 6.44 (t, J = 6.5 Hz, 1H), 6.13 (d, J = 9.3 Hz, 1H), 4.82 - 4.64 (m, 2H), 3.85 - 3.73 (m, 1H), 3.72 - 3.62 (m, 2H), 3.47 (dt, J = 11.1, 5.7 Hz, 1H), 1.99 - 1.88 (m, 2H), 1.76 (t, J = 12.3 Hz, 3H), 1.50 - 1.30 (m, 3H).

[0233] Example 33: (Compound 112) [ka] A white solid 112 was obtained by synthesizing compound 109 in Example 30 using tetrahydropyrrole instead of cyclopropylamine.

[0234] ESI m / z [M+H] + = 482.3. 1 H NMR (400 MHz, DMSO-d 6) δ 8.40 (d, J = 1.5 Hz, 1H), 8.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 5.81 (d, J = 9.0 Hz, 1H), 4.70 (q, J = 15.6 Hz, 2H), 3.75 (t, J =11.9 Hz, 1H), 3.59 (td, J = 11.1, 10.7, 3.8 Hz, 1H), 3.12 (dt, J = 9.4, 6.1 Hz, 2H), 3.01 (dt, J = 9.4, 6.3 Hz, 2H), 1.87 (t, J = 10.4 Hz, 2H), 1.74 (q, J = 11.3, 10.1 Hz, 3H), 1.69 - 1.62 (m, 4H), 1.56 (d, J = 12.2Hz, 1H), 1.33 (t, J = 10.5 Hz, 2H).

[0235] Example 34: (Compound 113) [ka] A white solid 113 was obtained by synthesizing compound 109 in Example 30 using morpholine instead of cyclopropylamine.

[0236] ESI m / z [M+H] + = 498.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.60 - 8.30 (m, 2H), 7.82 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 51.6 Hz, 1H), 6.28 (d, J = 8.9 Hz, 1H), 4.73 - 4.60 (m, 2H), 3.98 - 3.80 (m, 1H), 3.63 (td, J = 11.2, 4.1 Hz, 1H), 3.51 - 3.36 (m, 4H), 3.23 (t, J = 5.0 Hz, 4H), 2.01 (d, J = 13.8 Hz, 2H), 1.93 - 1.70 (m, 3H), 1.48 (q, J = 13.8, 13.2 Hz, 3H).

[0237] Example 35: (Compound 114) [ka] To a solution of cyclopropyl carboxylic acid (20 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was added diisopropylethylamine (90 mg, 0.70 mmol) and HATU (90 mg, 0.24 mmol). The mixture was stirred at room temperature for 30 minutes, and then compound 108 (100 mg, 0.26 mmol) was added and stirred overnight. The reaction mixture was filtered and separated by reverse phase column chromatography to give white solid 114 (30 mg, 28%).

[0238] ESI m / z [M+H] + = 453.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.44-8.31 (m, 2H), 7.98 (d, J = 9.4 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 4.80-4.53 (m, 2H), 4.00-3.82 (m, 1H), 3.49 (dd, J = 11.3, 3.8 Hz, 1H),1.98-1.82 (m, 2H), 1.82-1.67 (m, 3H), 1.59-1.21 (m, 4H), 0.54 (dddd, J = 20.3, 10.0, 7.3, 3.3Hz, 2H), 0.46-0.32 (m, 1H), 0.20 (ddt, J = 9.8, 7.2, 3.9 Hz, 1H).

[0239] Example 36: (Compound 118) [ka] Following the synthesis method of Example 21, 118a was used in place of 84a, and 118c was used in place of 84c to obtain 118.

[0240] ESI m / z [M+H] + = 506.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 8.35 (dd, J = 8.1, 1.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 13.3 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.41 (dd, J = 8.5, 5.5 Hz, 2H), 7.11 (t, J = 8.8 Hz,2H), 6.09 (d, J = 4.9 Hz, 1H), 5.26 (t, J = 5.1 Hz, 1H), 5.06 - 4.83 (m, 2H), 4.40 (d, J = 16.2 Hz, 1H), 3.79 (s, 3H).

[0241] Example 37: (Compound 116) [ka] The synthesis method of compound 2 in Example 2 was followed. Trifluoromethanesulfonic anhydride was used instead of difluoroacetic anhydride to obtain a white solid 116.

[0242] ESI m / z [M+H] + = 515.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (d, J = 9.1 Hz, 1H), 8.46 - 8.33 (m, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 51.3 Hz, 1H), 4.73 (d, J = 15.5 Hz, 1H), 4.63 (d, J = 15.4 Hz, 1H), 4.03 - 3.90 (m,1H), 3.69 - 3.59 (m, 1H), 1.82 (d, J = 17.0 Hz, 4H), 1.73 (d, J = 11.0 Hz, 2H), 1.36 (d, J = 10.4 Hz, 2H).

[0243] Example 38: (Compound 117) [ka] Following the synthesis method of compound 72 in Example 19, 2-bromopyridine was used instead of 4-bromo-1-methyl-1H-pyrazole in step 1 to obtain white solid 117.

[0244] ESI m / z [M+H] + = 441.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.60 (d, J = 4.9 Hz, 1H), 8.47 (d, J = 1.4 Hz, 1H), 8.41 (dd, J = 8.1, 1.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.80 - 7.74 (m, 4H), 7.69 - 7.64 (m, 2H), 7.54 (d, J = 51.2 Hz, 1H), 7.32 (ddd, J = 6.7, 4.8, 1.7 Hz, 1H), 4.98 (s, 2H).

[0245] Example 39: (Compound 14) [ka]

[0246] 1.(Compound 14e) Following the synthesis method of compound 108 in Example 1, 14a was used instead of 1d', and a white solid 14e was synthesized via four reaction steps.

[0247] 2.(Compound 14) Following the synthesis method of compound 2 in Example 2, compound 14e was used instead of compound 108 to obtain white solid 14.

[0248] ESI m / z [MH] - = 463.2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (s, 1H), 8.47 (dd, J = 8.1, 1.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 51.7 Hz, 1H), 5.95 (td, J = 54.0, 3.3 Hz, 1H), 4.66 (s, 2H), 4.43 (dt, J = 10.5, 5.5 Hz, 1H), 4.13 - 4.05 (m, 2H), 3.89 - 3.77 (m, 2H), 3.65 - 3.58 (m, 1H), 2.05 (ddd, J = 18.9, 12.2, 6.6 Hz, 3H).

[0249] Example 40: (Compound 13) [ka]

[0250] 1.(Compound 13a) To a solution (2 mL) of compound 14a (200 mg, 0.92 mmol) in dichloromethane was added diisopropylethylamine (360 mg, 2.76 mmol). The mixture was stirred for 5 minutes, and difluoroacetic anhydride (240 mg, 1.38 mmol) was added dropwise at 0° C. and stirred for 2 hours. The reaction mixture was treated with water, extracted with ethyl acetate, and concentrated to obtain colorless oil 13a (250 mg, 91%).

[0251] ESI m / z [M+H] + = 295.1.

[0252] 2.(Compound 13b) To a solution of compound 13a (250 mg, 0.85 mmol) in dichloromethane was added a solution of hydrogen chloride in dioxane (1 mL, 4 M). The mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to give colorless oil 13b (150 mg, 90%).

[0253] ESI m / z [M+H] + = 195.1.

[0254] 3.(Compound 13) The synthesis method of compound 20 in Example 1 was followed. 13b was used instead of 1d' to obtain white solid 13.

[0255] ESI m / z [MH] - = 463.2. 1 H NMR (400 MHz, Methanol-d 4) δ 8.54 (s, 1H), 8.47 (dd, J = 8.1, 1.6 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.32 (t, J = 51.7 Hz, 1H), 5.95 (td, J = 54.0, 3.3 Hz, 1H), 4.66 (s, 2H), 4.43 (dt, J = 10.5, 5.5 Hz, 1H), 4.13 - 4.05 (m, 2H), 3.89 - 3.77 (m, 2H), 3.65 - 3.58 (m, 1H), 2.05 (ddd, J = 18.9, 12.2, 6.6 Hz, 3H).

[0256] Example 41: (Compound 65) [ka] A white solid 65 was obtained by synthesizing compound 114 in Example 35 using compound 14e instead of compound 108 and 1-trifluoromethylcyclopropyl-1-formic acid instead of cyclopropylformic acid.

[0257] ESI m / z [M+H] + = 521.2. 1 H NMR (400 MHz, DMSO-d 6) δ 8.45 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.59 (t, J = 51.3 Hz, 1H), 4.77 - 4.63 (m, 2H), 4.25 (dq, J = 10.2, 5.3 Hz, 1H), 3.87 (ddd, J = 14.5, 10.6, 4.0 Hz, 2H), 3.75 - 3.59 (m, 2H), 3.46 (d, J = 10.3Hz, 1H), 2.06 - 1.85 (m, 1H), 1.81 (dd, J = 13.5, 4.6 Hz, 1H), 1.41 - 1.32 (m, 1H), 1.19 - 1.12 (m, 1H), 1.08 (ddd, J = 10.4, 8.7, 6.4 Hz, 2H).

[0258] Example 42: (Compound 66) [ka] With reference to the synthesis method of compound 2 in Example 2, compound 14e was used instead of compound 108, and pentafluoropropionic anhydride was used instead of difluoroacetic anhydride, to obtain white solid 66.

[0259] ESI m / z [M+H] + = 533.0. 1 H NMR (400 MHz, DMSO-d 6) δ 9.63 (s, 1H), 8.46 (s, 1H), 8.40 (dd, J = 8.1, 1.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 102.6 Hz, 1H), 7.60 (s, 1H), 4.80 - 4.62 (m, 2H), 4.36 (s, 1H), 3.91 (dd, J = 10.2, 4.6 Hz, 2H), 3.84 - 3.67 (m, 2H), 3.50 (t, J = 11.7 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.89 (d, J = 10.9 Hz, 1H).

[0260] Example 43: (Compound 119) [ka] The synthesis method of compound 72 in Example 19 was repeated except that 4-bromo-1-fluorobenzene was used instead of 4-bromo-1-methyl-1H-pyrazole in step 1 to obtain white solid 119. ESI m / z[MH] - =456.2 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d, J = 1.5 Hz, 1H), 8.38 (dd, J = 8.1, 1.6 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.73 - 7.48 (m, 6H), 7.24 - 7.18 (m, 2H), 4.66 (s, 2H).

[0261] Example 44: (Compound 120) [ka] Following the synthesis method of compound 72 in Example 19, 3-bromo-1-fluorobenzene was used instead of 4-bromo-1-methyl-1H-pyrazole in step 1 to obtain white solid 120.

[0262] 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 1.5 Hz, 1H), 8.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.67 - 7.47 (m, 4H), 7.44 - 7.37 (m, 3H), 7.18 (tdd, J = 9.2, 4.0, 2.2 Hz, 1H), 4.68 (s, 2H).

[0263] Example 45: (Compound 121) [ka] The synthesis of compound 72 in Example 19 was repeated except that 5-bromo-1,3-difluorobenzene was used instead of 4-bromo-1-methyl-1H-pyrazole in step 1 to obtain white solid 121.

[0264] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (d, J = 1.5 Hz, 1H), 8.41 (dd, J = 8.1, 1.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.75 - 7.46 (m, 4H), 7.33 - 7.26 (m, 2H), 7.23 (tt, J = 9.4, 2.4 Hz, 1H), 4.78 (s, 2H).

[0265] Example 46: (Compound 63) [ka]

[0266] 1.(Compound 63b) Compound 63a (5 g, 27.75 mmol), cuprous bromide (4.78 g, 33.3 mmol) and acetonitrile (100 mL) were added to a reaction flask. The temperature was lowered to 0° C. and tert-butyl nitrite (7.73 g, 74.93 mmol) was added dropwise. The mixture was stirred at room temperature for 2 days. LCMS showed the reaction was complete. The reaction was concentrated and passed through a silica gel column (dichloromethane / ethyl acetate: 20-50%) to give off-white solid product 63b (5 g, 73.83%). MS m / z [M+H] + : 244.0.

[0267] 2.(Compound 63c) A reaction flask was charged with compound 63b (1.5 g, 6.15 mmol), azobisisobutyronitrile (0.1 g, 0.62 mmol), N-bromosuccinimide (1.09 g, 6.15 mmol) and dichloroethane (20 mL). The temperature was raised to 80 °C and stirred overnight. LCMS showed the reaction was complete. The reaction was concentrated and purified by silica gel column (dichloromethane / ethyl acetate: 30-80%) to give yellow oily product 63c (1.2 g, 60.46%). MS m / z [M+H] + : 323.8.

[0268] 3.(Compound 63d) Compound 63c (1.2 g, 4.03 mmol), compound 1d' (1 g, 4.67 mmol) and acetonitrile (20 mL) were added to the reaction flask. The mixture was stirred at room temperature for 5 hours, and LCMS showed the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (30 mL x 2), separated, washed with water, washed with saturated saline, dried over sodium sulfate, concentrated and purified by silica gel column (dichloromethane / ethyl acetate: 50-90%) to give rice white product 63d (1 g, yield: 54.44%). MS m / z [M+H] + : 456.2.

[0269] 4.(Compound 63e) Compound 63d (1 g, 2.19 mmol), benzylthiol (0.5 g, 4.03 mmol), N,N-diisopropylethylamine (0.8 g, 6.19 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.13 g, 0.22 mmol), tris(dibenzylideneacetone)dipalladium (0.20 g, 0.22 mmol) and dioxane (20 mL) were added to a reaction flask. After purging with nitrogen gas three times, the mixture was heated to 106 °C and stirred for 16 h. LCMS showed the reaction was complete. The reaction was purified by silica gel column (dichloromethane / ethyl acetate: 50-90%) to give rice white product 63e (400 mg, yield: 36.53%). MS m / z [M+H] + : 500.3.

[0270] 5.(Compound 63f) Compound 63e (400 mg, 0.80 mmol), N-chlorosuccinimide (1070 mg, 8 mmol), acetic acid (3 mL) and water (1 mL) were added to a reaction flask. The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL x 2), separated, washed with water, washed with saturated saline, concentrated and separated by silica gel column (ethyl acetate / dichloromethane: 30-80%) to give rice white product 63f (300 mg, yield: 85.26%). MS m / z [M-100] + : 340.1.

[0271] 6.(Compound 63g) A reaction flask was charged with compound 63f (300 mg, 0.68 mmol), hydrazine hydrate (0.5 mL) and ethanol (5 mL). The temperature was raised to 80° C. and stirred for 2 h. LCMS showed the reaction was complete. The reaction was concentrated to give crude product 63g, which was used directly in the next step (0.3 g, yield: 100%). MS m / z [M-100] + : 326.1.

[0272] 7.(Compound 63h) Compound 63g (300 mg, 0.71 mmol), triethylamine (220 mg, 2.17 mmol) and dichloromethane (5 mL) were added to a reaction flask. Difluoroacetic anhydride (250 mg, 1.44 mmol) was added dropwise at 0° C. and stirred for 2 h. LCMS showed the reaction was complete. The reaction was concentrated to give pale yellow product 63h (0.3 g, yield: 84.51%). MS m / z [M-100] + : 404.2.

[0273] 8.(Compound 63i) Compound 63h (300 mg, 0.60 mmol), p-toluenesulfonyl chloride (140 mg, 0.72 mmol), triethylamine (180 mg, 1.80 mmol) and acetonitrile (5 mL) were added to a reaction flask at 0° C. and stirred at 25° C. for 2 h. LCMS showed the reaction was complete. Water (20 mL) was added to the reaction solution, which was extracted with dichloromethane (30 mL×2), separated, washed with water, concentrated and purified by silica gel column (ethyl acetate / dichloromethane: 40-90%) to give yellow product 63i (0.1 g, yield: 34.57%). MS m / z [M-100] + : 386.1.

[0274] 9.(Compound 63j) Compound 63i (100 mg, 0.21 mmol) and dichloromethane (2 mL) were added to a reaction flask. Trifluoroacetic acid (0.2 mL) was added dropwise at 0° C. and stirred at room temperature for 1 h. LCMS showed the reaction was complete. Water (10 mL) was added to the reaction solution, the pH was adjusted to 7-9 with saturated aqueous sodium carbonate, extracted with dichloromethane (30 mL×2), separated, washed with water, dried over sodium sulfate, filtered, and concentrated to give white product 63j (60 mg, yield: 75.59%). MS m / z [M+H] + : 386.1.

[0275] 10.(Compound 63) Compound 2,2-difluoropropionic acid (400 mg, 3.63 mmol), 1 drop of DMF and dichloromethane (3 mL) were added to a reaction flask. Thionyl chloride (450 mg, 3.78 mmol) was slowly added dropwise and stirred at 0° C. for 2 hours to obtain a 2,2-difluoropropionyl chloride solution.

[0276] In a separate reaction flask, compound 63j (60 mg, 0.16 mmol), potassium carbonate (100 mg, 0.72 mmol), DCM (3 mL) and water (1 mL) were added. The above 2,2-difluoropropionyl chloride solution was added dropwise at 0° C. and stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction was concentrated and purified by reverse phase column (acetonitrile / 0.05% formic acid in water: 30-60%) to give white solid product 63 (19.2 mg, yield: 25.83%, purity: 96.92%). MS m / z [M+H] + : 478.1.

[0277] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.51 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 9.2 Hz, 1H), 7.63 (t, J = 51.2 Hz, 1H), 4.90 - 4.68 (m, 2H), 4.05 - 3.90 (m, 1H), 3.77 - 3.65 (m, 1H), 1.91 -1.70 (m, 6H), 1.53 (t, J = 19.5 Hz, 3H), 1.36 (s, 2H).

[0278] Example 47: (Compound 145) [ka] A reaction flask was charged with pentafluoropropionic acid (20 mg, 0.12 mmol), N,N-diisopropylethylamine (30 mg, 0.23 mmol), HATU (44 mg, 0.12 mmol) and DMF (2 mL). After stirring at room temperature for half an hour, compound 63j (30 mg, 0.078 mmol) was added and stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The reaction was purified by reverse phase column (acetonitrile / 0.05% formic acid in water: 50-70%) to give white solid product 145 (2 mg, yield: 4.83%). MS m / z [MH] + :530.2.

[0279] 1 H NMR (400 MHz, Methanol-d 4 ) δ 9.55 (d, J = 2.0 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 7.30 (t, J = 51.6 Hz, 1H), 4.78 (d, J = 16.2 Hz, 2H), 4.15 (td, J = 11.2, 4.4 Hz, 1H), 3.81 (dt, J = 13.0, 6.6 Hz, 1H), 2.16- 1.84 (m, 6H), 1.50 (q, J = 11.6, 11.1 Hz, 2H).

[0280] Example 48: (Compound 18) [ka] Compound 63j (30 mg, 0.078 mmol), N,N-diisopropylethylamine (30 mg, 0.039 mmol) and DCM (3 mL) were added to a reaction flask. Difluoroacetic anhydride (16 mg, 0.094 mmol) was added dropwise at 0 °C and stirred at room temperature for 1 h. LCMS showed the reaction was complete. The reaction was concentrated and purified by reverse phase column (acetonitrile / 0.05% formic acid aqueous solution: 30-60%) to give white solid product 18 (16.6 mg, yield: 46.02%, purity: 100%). MS m / z [M+H] + : 464.2.

[0281] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.51 (d, J = 1.9 Hz, 1H), 9.02 (d, J = 1.9 Hz, 1H), 8.79 (d, J = 9.2 Hz, 1H), 7.63 (t, J = 51.2 Hz, 1H), 6.03 (t, J = 53.8 Hz, 1H), 4.78 (q, J = 16.1 Hz, 2H), 3.99 (d, J = 10.4Hz, 1H), 3.66 (td, J = 10.4, 5.5 Hz, 1H), 2.02 - 1.77 (m, 4H), 1.77 - 1.62 (m, 2H), 1.38 (d, J = 9.7 Hz, 2H).

[0282] Example 49: (Compound 159) [ka]

[0283] 1.(Compound 159a) Compound 63c (200 mg, 0.62 mmol), cyclopentanamine (60 mg, 0.64 mmol), potassium carbonate (260 mg, 1.86 mmol) and acetonitrile (2 mL) were added to a reaction flask. The mixture was stirred at room temperature for 3 hours, and LCMS showed the reaction was complete. Water (30 mL) was added to the reaction mixture, which was then extracted with dichloromethane (30 mL x 2), separated, washed with water, washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give yellow oily product 159a (0.1 g, yield: 49.35%). MS m / z [M+H] + : 327.0.

[0284] 2.(Compound 159b) Compound 159a (0.1 g, 0.31 mmol), benzylthiol (0.06 g, 0.46 mmol), N,N-diisopropylethylamine (0.12 g, 0.93 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0.04 g, 0.06 mmol), tris(dibenzylideneacetone)dipalladium (0.03 g, 0.03 mmol) and dioxane (3 mL) were added to a reaction flask. After purging with nitrogen gas three times, the temperature was raised to 108 °C and stirred for 16 h. LCMS showed the reaction was complete. The reaction solution was purified by silica gel column (dichloromethane / ethyl acetate: 50-90%) to give rice white product 159b (50 mg, yield: 44.16%). MS m / z [M+H] + : 371.2.

[0285] 3.(Compound 159c) Compound 159b (50 mg, 0.13 mmol), N-chlorosuccinimide (170 mg, 1.3 mmol), acetic acid (3 mL) and water (1 mL) were added to a reaction flask. The mixture was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. Water (20 mL) was added to the reaction mixture, and the pH was adjusted to 7-8 with saturated sodium carbonate solution. The mixture was extracted with dichloromethane (30 mL x 2), separated, washed with water, washed with saturated saline, concentrated and purified by silica gel column (ethyl acetate / dichloromethane: 30-80%) to give yellow oily product 159c (20 mg, yield: 47.75%). MS m / z [M+H] + : 311.1.

[0286] 4. (Compound 159d) Compound 159c (20 mg, 0.064 mmol), hydrazine hydrate (0.1 mL) and ethanol (2 mL) were added to a reaction flask. The temperature was raised to 80° C. and stirred for 2 h. LCMS showed the reaction was complete. The reaction was concentrated to give crude product 159d (19 mg, 100% yield) which was used directly in the next reaction. MS m / z [M+H] + : 297.1.

[0287] 5.(Compound 159e) Compound 159d (10 mg, 0.034 mmol), triethylamine (10 mg, 0.099 mmol) and dichloromethane (2 mL) were added to a reaction flask. Difluoroacetic anhydride (12 mg, 0.069 mmol) was added dropwise at 0° C. and stirred for 2 hours. LCMS showed the reaction was complete. The reaction was concentrated to give pale yellow product 159e (10 mg, yield: 79.3%). MS m / z [M+H] + : 375.1.

[0288] 6.(Compound 159) Compound 159e (10 mg, 0.027 mmol), p-toluenesulfonyl chloride (3 mg, 0.032 mmol), triethylamine (8 mg, 0.081 mmol) and acetonitrile (2 mL) were added to a reaction flask at 0° C. and stirred at 25° C. for 2 h. LCMS showed the reaction was complete. The reaction was filtered and purified by reverse phase column to give off-white solid product 159 (2.6 mg, yield: 27.31%).

[0289] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.54 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 7.29 (t, J = 51.6 Hz, 1H), 4.65 (s, 2H), 4.00 (q, J = 7.6 Hz, 1H), 2.12 (s, 2H), 2.02 - 1.81 (m, 4H), 1.73 (dd, J = 7.3, 4.4Hz, 2H).

[0290] Example 50: (Compound 122) [ka] The synthesis of compound 72 in Example 19 was repeated except that 2-bromo-6-trifluoromethylpyridine was used in place of 4-bromo-1-methyl-1H-pyrazole in step 1 to obtain white solid 122.

[0291] 1H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (d, J = 8.4 Hz, 2H), 8.12 (t, J = 7.8 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.87 - 7.81 (m, 3H), 7.75 - 7.46 (m, 3H), 5.18 (s, 2H).

[0292] Biological testing Experimental example 1. The inhibitory activity of the compounds of the present application against HDAC6 was evaluated by enzyme activity experiments.

[0293] HDAC6 (Abcam), test compounds, and 20 μM substrate solution (Ac-GAK(Ac)-AMC) were added to a 384-well plate, incubated at 37°C for 30 min, 1 μM Trypsin and 10 μM TSA were added, incubated at room temperature for 15 min, excited at 360 nm, and the fluorescence emission intensity at 455 nm was detected. The inhibition rate at each concentration was calculated, and the IC was calculated using GraphPad Prism 7.0 software. 50 was fitted.

[0294] The experimental results obtained are shown in Table 1. [Table 3]

[0295] Experimental example 2. The inhibitory activity of the compounds of the present application against HDAC1 to 5 and 7 to 11 was evaluated by enzyme activity experiments.

[0296] Different isoforms of HDAC proteins (purchased from BPS), test compounds, and substrate solutions (purchased from BPS) with concentrations of 2.5 to 40 μM were added to a 384-well plate, incubated at 37°C for 30 min, 1 μM Trypsin and 10 μM TSA were added, incubated at room temperature for 15 min, excited at 360 nm, and the fluorescence emission intensity at 455 nm was detected. The inhibition rate at each concentration was calculated, and the IC was calculated using GraphPad Prism 7.0 software. 50 was fitted.

[0297] The experimental results obtained are shown in Tables 2 and 3. [Table 4]

[0298] [Table 5]

[0299] Experimental Example 3. Testing α-Tublin Acetylation Levels A375 / HCT116 / HCC827 cells in the logarithmic growth phase were harvested, digested with pancreatin cell digestion solution, centrifuged, counted, and seeded at the appropriate cell density in a 96-well plate (30,000 cells / well) at 100 μL / well, and the surrounding area was water-sealed with an appropriate amount of PBS. The next day, different concentrations of compounds were administered to the cells (initial concentration 100 μM, 5-fold dilution, 9 concentration gradients were set), and after 6 h, the medium was aspirated and washed twice with 100 μL of PBST. The cells were then fixed with 4% paraformaldehyde and incubated at room temperature for 20 min. The fixative was discarded and the cells were washed with PBST. 150 μL of a dedicated blocking solution (containing 1% Triton-100) was added to each well, blocked at room temperature for 2 h, and excess blocking solution was washed off with PBS. The α-tubulin (DM1A) mouse mAb and acetyl-α-tubulin (Lys40) (D20G3) XP rabbit mAb were diluted at a ratio of 1:2000 using blocking solution containing 0.033% Triton-100, added to a 96-well plate, and incubated overnight at 4°C. A blank control group was also set up. The next day, the plate was washed twice with PBST, and the secondary antibody, anti-mouse IgG (H+L) (DyLight) was incubated at a ratio of 1:2000 using blocking solution containing 0.033% Triton-100. TM 680 conjugate) and anti-rabbit IgG (H+L) (DyLight TM 800 complex) was diluted and added to a 96-well plate and incubated at room temperature for 2 h. After washing twice with PBST and once with PBS, the fluorescent signals at 700 nm and 800 nm were detected using a Li-COR Odyssey dual-color near-infrared laser imager, respectively.

[0300] The experimental results obtained are shown in Table 4. [Table 6]

[0301] [Table 7]

[0302] Experimental Example 4. Stability test The phase 1 metabolic stability of pending compounds was evaluated in liver microsomes from CD-1 mice (MLM), Sprague-Dawley rats (RLM), beagle dogs (DLM), cynomolgus monkeys (CLM) and humans (HLM).

[0303] Testing system: Animal and human liver microsomes used in the test system were purchased from Xenotech, Corning or other quality suppliers and stored in a refrigerator below -60°C prior to use.

[0304] A brief introduction to the experiment: The samples and control compounds were incubated with animal and human liver microsomes at 37±1°C for a set period of time, with a maximum incubation time of 60 min. At the designated time points, samples were removed and the reaction was stopped with acetonitrile or other organic solvents containing an internal standard. After centrifugation, the resulting supernatant was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0305] Testing Method: 1. Buffer Preparation 73.21 g of potassium dihydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate were dissolved in 4000 mL of ultrapure water. The pH value of the solution was adjusted to between 7.40±0.10 with 10% phosphoric acid or 1 M potassium hydroxide to a final concentration of 100 mM.

[0306] 2. Preparation of Working Fluid The sample powder was prepared into a stock solution of a given concentration in DMSO or other organic solvent and then further diluted with the appropriate organic solvent.

[0307] The control compounds testosterone, diclofenac and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in the appropriate organic solvent.

[0308] 3. Preparation of Liver Microsome Solution Microsomes of each species were diluted to a working concentration of 2× with 100 mM potassium phosphate buffer, and the final concentration of microsomes in the reaction system was 0.5 mg / mL.

[0309] 4. Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regenerating system Appropriate amounts of nicotinamide adenine phosphate dinucleotide (NADP) and isocitrate (ISO) powders were weighed, dissolved in magnesium chloride solution, and mixed uniformly by shaking. Appropriate amounts of isocitrate dehydrogenase (IDH) were added and mixed uniformly by gently inverting the mixture. The final concentrations in the reaction system were 1 mM NADP, 1 mM magnesium chloride, 6 mM ISO, and 1 unit / mL IDH, respectively.

[0310] 5. Preparation of Stop Solution A stop solution was prepared using acetonitrile or other organic solvent containing an internal standard (tolbutamide or other appropriate compound). The prepared stop solution was stored in a refrigerator at 2-8 °C.

[0311] 6. Incubation Process Incubations were completed in 96-well plates. Eight incubation plates were prepared, designated T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The corresponding reaction time points for the first six plates were 0, 5, 15, 30, 45, and 60 minutes, respectively. No sample or control compound was added to the Blank60 plate, and it was sampled after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer was incubated for 60 minutes instead of NADPH regenerating system solution. All condition samples were in triplicate.

[0312] After mixing the microsomes with the sample or control compound, the incubation plates Blank60, T5, T15, T30, T45 and T60, except for T0 and NCF60, were pre-incubated in a water bath at 37°C for about 10 minutes. The stop solution was added to the incubation plate T0, followed by the NADPH regenerating system working solution, and 98μL of potassium phosphate buffer was added to each sample well of the incubation plate NCF60 to start the reaction. After the pre-incubation of the incubation plates Blank60, T5, T15, T30, T45 and T60 was completed, 98μL of the NADPH regenerating system working solution was added to each sample well to start the reaction. The reaction temperature was 37±1°C, the final reaction volume was 200μL, and the reaction system contained 0.5mg / mL microsomes, 1.0μM substrate, 1mM NADP, 6mM ISO and 1unit / mL IDH.

[0313] At 5, 15, 30, 45 and 60 minutes, respectively, the reaction was terminated by adding cold stop solution containing an internal standard to the reaction plate.

[0314] After completion of the reaction, all reaction plates were shaken uniformly and centrifuged at 3220×g for 20 minutes at 4° C. The supernatant was diluted at a certain ratio and then subjected to LC-MS / MS analysis.

[0315] Sample analysis Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) without standard curves and quality control samples. Semiquantitative measurements were performed using the ratio of the analyte peak area to the internal standard peak area. Retention times of the analytes and internal standards, chromatogram acquisition, and chromatogram integration were processed using the software Analyst (Sciex, Framingham, Massachusetts, USA).

[0316] The CV of the internal standard peak areas in each matrix in each analytical batch should be within 20%.

[0317] Data analysis The ratio of the compound to the internal standard peak area in the following formula was converted into a residual rate to determine the in vitro elimination rate constant ke of the compound.

[0318]

number

number

[0319] CL (liver) =(CL int(liver) ×Q h ) / (CL int(liver) +Q h ) The parameters in the formula are given in the table below. [Table 8]

[0320] [Table 9]

[0321] Experimental Example 5. Pharmacokinetics test in mice In this example, the pharmacokinetic behavior of the compound in BALB / c mice was examined following administration by intravenous injection (IV) and oral gavage (PO).

[0322] On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. Three mice were included in each group. For each compound, two groups were tested: one group was administered a single dose intravenously, and the other group was administered a single dose by oral gavage. Whole blood samples were collected at the designated time points (0.25, 0.5, 1, 2, 4, 8, and 24 h after administration) by retro-orbital blood collection. After collection, the blood samples were immediately transferred to tagged commercial sample tubes containing K2-EDTA (0.85-1.15 mg) and then centrifuged (3200 × g, 4 °C, 10 min) and plasma was collected. The plasma was transferred to pre-cooled centrifuge tubes, flash frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60 °C or lower until LC-MS / MS analysis was performed.

[0323] Plasma concentrations were measured using LC-MS / MS. The plasma drug concentration data of compounds 1 and 2 were processed with a non-compartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The linear-logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.

[0324] The experimental results obtained are shown in Table 6. [Table 10]

[0325] [Table 11-1] [Table 11-2]

[0326] Experimental Example 6. Pharmacokinetics test in rats In this example, the pharmacokinetic behavior of the compound in SD rats was examined after administration by intravenous injection (IV) and oral gavage (PO).

[0327] On the day of administration, the rats were weighed and the dose volume was calculated. Three rats were included in each group. For each compound, two groups were tested: one group was administered a single dose intravenously, and the other group was administered a single dose by oral gavage. Whole blood samples were collected at the designated time points (0.25, 0.5, 1, 2, 4, 8, and 24 h after administration) by jugular vein blood collection. After collection, the blood samples were immediately transferred to tagged commercial sample tubes containing K2-EDTA (0.85-1.15 mg) and then centrifuged (3200 × g, 4 °C, 10 min) and plasma was collected. The plasma was transferred to pre-cooled centrifuge tubes, flash frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60 °C or lower until LC-MS / MS analysis was performed.

[0328] Plasma concentrations were measured using an LC-MS / MS method. The plasma drug concentration data of the compounds were processed with a noncompartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The linear-logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.

[0329] Experimental Example 7. Mouse brain-blood drug concentration ratio On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. Nine mice per group were administered a single dose of the compound by intravenous injection (IV) and oral gavage (PO). Whole blood samples were collected at the designated time points by retro-orbital blood collection. After collection, the blood samples were immediately transferred to tagged commercial sample tubes containing K2-EDTA (0.85-1.15 mg) and then centrifuged (3200×g, 4°C, 10 min) and plasma was collected. The plasma was transferred to pre-cooled centrifuge tubes, flash frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or lower until LC-MS / MS analysis was performed. 20 μL of plasma samples or brain tissue homogenates were taken and added to 80 μL of internal standard solution (50 ng / mL propafenone in acetonitrile), the plate was sealed at 165°C with a film seal, shaken for 10 min with a microoscillator (maximum oscillation speed), centrifuged at 4000 rpm for 20 min with a low-speed tabletop centrifuge, 10 μL of the supernatant was removed and added to 90 μL of acetonitrile, vortexed, and the plate was sealed at 165°C with a film seal, and 1 μL of the supernatant was removed after vortexing for LC-MS / MS analysis. The plasma drug concentration data of the compounds were processed with a non-compartmental model using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. The linear-logarithmic trapezoidal method was used to calculate the relevant pharmacokinetic parameters.

[0330] Data processing: Mouse brain blood drug concentration ratio at the same time point = brain tissue drug concentration / plasma drug concentration [Table 12]

[0331] Experimental Example 8. hERG Inhibition Test HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at a culture temperature of 37°C and CO 2 The concentration of TrypLE was set to 5%. TM After digestion with Express, centrifugation was performed to reduce the cell density to 2 x 106 After adjusting to cells / mL, the cells were gently mixed for 15-20 min on a room temperature equilibrated shaker and subjected to patch clamp testing in the instrument. The prepared cell medium was replaced with extracellular solution. Intracellular and extracellular solutions were aspirated from the liquid pool and added to the intracellular pool, cell and test substance pool of the QPlate chip, respectively. Whole-cell patch clamp recorded the voltage stimulation of whole-cell hERG potassium current, and the test data were collected and stored by Qpatch. Compounds were started at 30 μM and diluted 3-fold, and six concentration points were set, with each drug concentration administered twice for at least 5 minutes. The current detected by each cell in compound-free extracellular solution was detected independently and repeated twice using at least two cells at each concentration as an autologous control group. All electrophysiological tests were performed at room temperature.

[0332] The data were analyzed by first normalizing the currents to each drug concentration and the blank control currents.

number

number

number

[0333] Experimental Example 9. Cytochrome oxidase P450 inhibition test 1) Preparation of buffer solutions: 100 mM K-Buffer: Mix 9.5 mL of stock solution A with 40.5 mL of stock solution B, adjust the total volume to 500 mL with ultrapure water, and add KOH or H 3 PO 4 The buffer was titrated to pH 7.4 with

[0334] Ingredient A (1M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water Stock solution B (1M potassium dihydrogen phosphate): 174.2 g potassium dihydrogen phosphate in 1 L water

[0335] 2) Preparation of test specimen The test article powder was prepared as a stock solution at a fixed concentration in DMSO or other organic solvent and then further diluted with the appropriate organic solvent.

[0336] 3) In vitro incubation The in vitro incubation system of liver microsomes for CYP450 enzyme metabolic phenotype research is a biochemical reaction in which redox coenzymes and enzyme-specific selective inhibitors are added to the prepared liver microsomes under conditions simulating physiological temperature and physiological environment.

[0337] 4) Detection of prototype drugs or metabolites The concentrations of the prototype drugs or their metabolites in the incubation solutions were measured using LC-MS / MS.

[0338] Experimental Example 10. Human, rat, and mouse plasma protein binding experiments (1) Preparation of solutions: 0.05 M sodium phosphate and 0.07 M NaCl buffer solutions, a control compound (final concentrations of warfarin and quinidine in the system were both 1 μM) and an administration solution (final concentration 1 μM) were prepared.

[0339] (2) Dialysis membrane pretreatment: First, the membrane was immersed in distilled water for 60 minutes, then a 20% (v / v) ethanol solution (diluted with distilled water) was added, and the membrane was left immersed for 20 minutes until the start of the test. Before use, the membrane was washed twice with distilled water to remove excess ethanol.

[0340] (3) Plasma pretreatment: 1) Thaw human, rat, and mouse plasma at room temperature, and after thawing, centrifuge at room temperature for 5 minutes at a speed of up to 2000 × g, and reserve the supernatant (fiber precipitation occurs due to freezing and thawing of plasma, so the plasma samples were stored at room temperature for the remaining tests); 2) Detect the pH value of the plasma and add a small amount of solid powder NaH 2 PO 4 The pH was adjusted to 7.4±0.02 by adding

[0341] (4) Control group and test group: 100 μL of plasma solution containing a positive control or a compound to be measured was added to the donor of the equilibrium dialysis device, and 100 μL of blank buffer solution was added to the receiver.

[0342] (5) The equilibrium dialysis apparatus was incubated at 37°C and 100 rpm for 5 hours.

[0343] (6) Control group and test group T 0 Sample preparation: 25 μL of plasma solution containing the positive control or the compound to be measured was taken and supplemented with 25 μL of blank buffer.

[0344] (7) After incubating the control and test groups for 5 hours, 25 μL of the dosing end sample was taken and supplemented with 25 μL of blank buffer, and 25 μL of the receiving end sample was taken and supplemented with 25 μL of blank plasma.

[0345] (8) All samples were added to 200 μL of acetonitrile containing the internal standard, and the samples were vortexed and shaken for 10 minutes, then centrifuged at 4000 rpm for 10 minutes. The prepared samples were subjected to UPLC-MS / MS analysis. Note: The internal standard was 40 ng / mL tolbutamide.

[0346] (9) Data processing T 0 Calculate the plasma protein binding rate of the compound to be measured by detecting the sample, the donor end and the acceptor end samples after 5 hours of equilibrium dialysis, and calculate according to the following formula: Binding rate% = 100 × ([administration end] 5h - [reception end] 5h) / [administration end] 5h

[0347] Experimental Example 11. Detection of contaminant mutagenicity The test strains used in this mutagenicity test were Salmonella typhimurium auxotrophic strains TA98 and TA100. The test was performed in 6-well plates in the presence or absence of S9 metabolic activation system, with a solvent control group (DMSO) and a positive control group, with two parallel wells for each treatment group. The compounds were set at 5 concentrations within the range of 62.5-1000.0 μg / well (concentrations equivalent to 312.5-5000.0 μg / dish in the standard Ames test). The plates were incubated at 37°C for 48-72 hours, and then the bacterial toxicity of each well was detected and the number of mutant colonies in each well was counted. If the number of revertant colonies in the pending compound group was more than twice the number of spontaneous revertant colonies in the solvent control group, and there was reproducibility and dose-dependence, the test substance was considered to have positive mutagenicity against the test strain.

[0348] In this study, dimethyl sulfoxide (DMSO) was used to dissolve the test substance and was used as the negative control (solvent) in this study. In the group without S9 (-S9), 2-nitrofluorene and sodium azide were used as positive controls for TA98 and TA100, respectively, and in the S9 group (+S9), 2-aminofluorene was used as a positive control for TA98 and TA100.

[0349] [Table 13]

[0350] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the above description. Such modifications are also intended to be included within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony L is a direct bond, -C １－６ Alkylene-, -C ２－６ Alkenylene- and -C ２－６ Selected from alkynylene, X is CR ６ or N, Y is CR ４ or N, Z is CR ５ or N, R １ is H, halogen, -OH, -NH ２ , -CN, -NO ２ , C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－６ cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ arylalkyl group, -C(=O)R ａ , -OC(=O)R ａ , -OC(=O)NR ａ R ｂ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ -C(=O)-NR ａ R ｂ , -C １－６ alkylene-OR ａ , -C １－６ alkylene-NR ａ R ｂ and -O-C １－６ alkylene-NR ａ R ｂ selected from, R ２ and R ３ are each independently H, halogen, -OH, -NH ２ , -CN, -NO ２ , C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－６ cyclic hydrocarbon group, 3- to 10-membered heterocyclyl group, C ６－１０ aryl group, 5- to 14-membered heteroaryl group, C ６－１２ arylalkyl group, -C(=O)R ａ , -OC(=O)R ａ , -OC(=O)NR ａ R ｂ , -C(=O)OR ａ , -OR ａ , -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ａ R ｂ , -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C(=O)OR ｂ , -NR ａ -S(=O) ２ -R ｂ , -NR ａ , -NR ａ R ｂ , -C １－６ alkylene-OR ａ , -C １－６ alkylene-NR ａ R ｂ and -O-C １－６ alkylene-NR ａ R ｂ selected from, or R ２ and R ３ together form an oxo group (=O), or R ２ and R ３ together with the carbon atom to which they are attached form C ３－６ Constituting a cyclic hydrocarbon group or a 3- to 10-membered heterocyclyl group, R ４ , R ５ and R ６ These are H, halogen, -OH, and -NH, respectively, independently. ２ -CN, -NO ２ , C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group, C ６－１２ Arylalkyl groups, -C(=O)R ａ -OC(=O)R ａ , -OC(=O)NR ａ R ｂ , -C (=O) OR ａ , -OR ａ ,-SR ａ , -S(=O)R ａ , -S (=O) ２ R ａ , -S (=O) ２ NR ａ R ｂ , -NR ａ R ｂ , -C(=O)NR ａ R ｂ , -NR ａ -C(=O)R ｂ , -NR ａ -C (=O) OR ｂ , -NR ａ -S (=O) ２ -R ｂ , -NR ａ -C(=O)-NR ａ R ｂ , -C １－６ Alkylene-OR ａ , -C １－６ Alkylene-NR ａ R ｂ and -O-C １－６ Alkylene-NR ａ R ｂ Selected from, R ａ and R ｂ Each time they appear, H and C appear independently. １－６ alkyl group, C ３－１０ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group and C ６－１２ Selected from arylalkyl groups, Each of the alkyl groups, alkylene groups, alkenyl groups, alkenylene groups, alkynyl groups, alkynylene groups, cyclic hydrocarbon groups, heterocyclyl groups, aryl groups, heteroaryl groups, and arylalkyl groups is, each time it appears, optionally and independently associated with a halogen, -OH, =O, or -NH. ２ -CN, -NO ２ , C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group, C ６－１２ Arylalkyl groups, -C(=O)R ｃ -OC(=O)R ｃ , -OC(=O)NR ｃ R ｄ , -C (=O) OR ｃ , -OR ｃ ,-SR ｃ , -S(=O)R ｃ , -S (=O) ２ R ｃ , -S (=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -C(=O)NR ｃ R ｄ , -NR ｃ -C(=O)R ｄ , -NR ｃ -C (=O) OR ｄ , -NR ｃ -S (=O) ２ -R ｄ , -NR ｃ -C(=O)-NR ｃ R ｄ , -C １－６ Alkylene-OR ｃ , -C １－６ Alkylene-NR ｃ R ｄ and -O-C １－６ Alkylene-NR ｃ R ｄ Substituting with one or more substituents selected from, wherein the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group and arylalkyl group are further optionally and independently a halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH ２ -CN, -NO ２ , C １－６ Alkyl alkyl groups, halogenated C １－６ Alkyl alkyl group, -OC １－６ Alkyl alkyl groups, -O-halogenated C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group and C ６－１２ The alkyl group is substituted with one or more substituents selected from arylalkyl groups, preferably the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group, and arylalkyl group are further optionally and independently a halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH ２ -CN, -NO ２ , C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group and C ６－１２ Substituted with one or more substituents selected from arylalkyl groups, R ｃ and R ｄ Each time they appear, H and C appear independently. １－６ alkyl group, C ３～１０ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group and C ６－１２ Selected from arylalkyl groups, the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, heteroaryl group, and arylalkyl group may be further optionally and independently a halogen, -OH, =O, -C(=O)O-tert-butyl group, -NH ２ -CN, -NO ２ , C １－６ Alkyl alkyl groups, halogenated C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 membered heteroaryl group and C ６－１２ [Substituted with one or more substituents selected from arylalkyl groups] Compounds having the structure of the same, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, crystalline polymorphs, solvates, metabolites, isotope-labeled compounds, or prodrugs thereof.

2. L is a direct bond or -C １－６ The alkylene group is -OH, -OCH, where the alkylene group is optionally and independently -OH, -OCH ３ , C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ The alkyl group is substituted with one or more substituents selected from aryl groups and 5- to 14-membered heteroaryl groups, and the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, and heteroaryl group are further optionally substituted with one or more halogens or C １－６ Substituted with an alkyl group, Preferably, L is directly bonded or -C １－６ Alkylene-, where the alkylene group is optionally and independently -OH, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ The cyclic hydrocarbon group, heterocyclyl group, aryl group, and heteroaryl group are further optionally substituted with one or more halogens or carbon atoms. １－６ Substituted with an alkyl group, Preferably, L is a directly bonded methylene group or ethylene group, where the methylene group and ethylene group can be optionally and independently -OH and -OCH. ３ , substituted with one or more substituents selected from methyl, cyclopropyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, and pyridadinyl groups, and said group is optionally further substituted with one or more halogens and / or methyl groups, Preferably, L is a direct bond, a methylene group, or an ethylene group, where the methylene group and the ethylene group are optionally and independently substituted with one or more substituents selected from -OH, a cyclopropyl group, a phenyl group, a pyrazolyl group, and a pyridyl group, and the group is optionally further substituted with one or more halogens and / or methyl groups. Preferably, L is directly bonded, -CH ２ - 【Chemistry 2】 And, Preferably, L is directly bonded, -CH ２ - 【Transformation 3】 That is, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

3. X, Y, and Z are each independently CH, CF, or N. The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

4. R １ C １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Selected from aryl groups and 5-14 membered heteroaryl groups, The alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, and heteroaryl group can each be optionally and independently a halogen, -OH, -CN, or C. １－６ alkyl group, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ Aryl group, 5-14 member heteroaryl group, -C(=O)R ｃ -OC(=O)R ｃ , -C (=O) OR ｃ , -OR ｃ , -S (=O) ２ R ｃ , -NR ｃ R ｄ , -C(=O)NR ｃ R ｄ , -NR ｃ -C(=O)R ｄ , -NR ｃ -C (=O) OR ｄ , -NR ｃ -S (=O) ２ -R ｄ and -NR ｃ -C(=O)-NR ｃ R ｄ The alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, and heteroaryl group are further optionally and independently substituted with halogens (e.g., fluorine), -OH, =O, and C. １－６ Alkyl groups (e.g., methyl group), halogenated C １－６ Alkyl group (e.g., trifluoromethyl group), -OC １－６ Alkyl groups (e.g., methoxy group) and -O-halogenated C １－６ The alkyl group is substituted with one or more substituents selected from alkyl groups (e.g., trifluoromethoxy group), preferably the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group and heteroaryl group are further optionally and independently substituted with halogens (e.g., fluorine), -OH, =O, C １－６ Substituted with one or more substituents selected from alkyl groups (e.g., methyl groups), The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

5. R ｃ and R ｄ Each time they appear, H and C appear independently. １－６ Alkyl groups (e.g., methyl group, ethyl group, tert-butyl group), C ３－１０ Cyclic hydrocarbon group (e.g., cyclopropyl group), 3-10 membered heterocyclyl group (e.g., optionally substituted with F pyrrolidinyl group, morpholinyl group or piperidinyl group, preferably optionally substituted with F piperidinyl group), C ６－１０ The alkyl group is selected from aryl groups (phenyl groups optionally substituted with F) and 5- to 14-membered heteroaryl groups (e.g., pyridyl groups), and the alkyl group, cyclic hydrocarbon group, heterocyclyl group, aryl group, and heteroaryl group are further optionally and independently replaced with a halogen (e.g., F), -OH, or halogenated C １－６ Alkyl groups (e.g., trifluoromethyl group) and C ３－６ Substituted with one or more substituents selected from cyclic hydrocarbon groups (e.g., cyclopropyl groups), The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

6. R １ The group is selected from methyl, cyclopropyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrazolyl, pyridyl, pyrimidinyl, pyridadinyl, and imidazopyridyl groups, and each of these groups is optionally and independently selected as -F, -Cl, -OH, -CN, -NH ２ ien-CH ３ , -CF ３ ien-CH ２ CF ２ CF ３ , - NHCH ２ CF ３ , 【Chemistry 4】 Substituted with one or more substituents selected from, Preferably, R １ The group is selected from methyl, cyclohexyl, tetrahydropyrrolyl, tetrahydropyranyl, piperidinyl, morpholinyl, phenyl, pyrazolyl, pyridyl, and imidazopyridyl groups, and each of these groups is optionally and independently selected as -F, -Cl, -OH, -CN, and -CH ３ , -CF ３ ien-CH ２ CF ２ CF ３ , - NHCH ２ CF ３ , 【Transformation 5】 Substituted with one or more substituents selected from, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

7. R １ It has the following structure: 【Transformation 6】 During the ceremony, U and V are each independently CR ８ｅ R ８ｆ , NR ８ｇ or O, R ８ａ , R ８ｂ , R ８ｃ , R ８ｄ , R ８ｅ , R ８ｆ and R ８ｇ Each is independently H or a halogen (e.g., F), and R ９ is, -OR ｃ , -NR ｃ -C(=O)R ｄ , -NR ｃ R ｄ , -NR ｃ -C (=O) OR ｄ , -NR ｃ -S (=O) ２ -R ｄ , -NR ｃ -C(=O)-NR ｃ R ｄ or -OC(=O)R ｃ That is, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

8. R １ is a methyl group, 【Transformation 7】 【Transformation 8】 Selected from, Preferably, R １ is a methyl group, 【Chemistry 9】 【Chemistry 10】 Selected from, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

9. R ２ and R ３ is H or C １－６ Alkyl group, preferably H or methyl group, or R ２ and R ３ They together form an oxo group (=O), or R ２ and R ３ C ３－６ Constituting a cyclic hydrocarbon group, preferably a cyclopropyl group, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

10. R ４ , R ５ and R ６ Each is independently H or halogen, preferably R ４ , R ５ and R ６ These are, independently, H or F. The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

11. The compound has the structure of formula (II) or formula (III), 【Chemistry 11】 During the ceremony, L' is -C １－６ The alkylene group is -OH, and the alkylene group can be optionally and independently -OH, C ３－６ Cyclic hydrocarbon group, 3-10 membered heterocyclyl group, C ６－１０ The alkylene group is substituted with one or more substituents selected from aryl groups and 5- to 14-membered heteroaryl groups, preferably the alkylene group is optionally and independently substituted with one or more substituents selected from -OH, cyclopropyl groups and phenyl groups optionally substituted with one or more halogens. The remaining units are as defined in claim 1. The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

12. The aforementioned compound, Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Selected from, The compound described in claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound, or prodrug thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, crystalline polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers, wherein the pharmaceutical composition is preferably a solid formulation, a liquid formulation or a transdermal formulation.

14. The pharmaceutical composition according to claim 13 for preventing or treating HDAC6-related diseases.

15. The aforementioned HDAC6-related diseases include cancer or proliferative disorders (e.g., lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary kidney cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, multiple myeloma, and solid tumors), Wilson's disease, spinocerebellar ataxia, prion diseases, Parkinson's disease, and Huntington's disease. Amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease, Alexander's disease, alcoholic liver disease, cystic fibrosis, Pick's disease, spinal muscular atrophy or Lewy body dementia, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, psoriasis, inflammatory bowel disease, chronic inflammatory lung disease, eczema, asthma, ischemia / reperfusion injury, ulcerative colitis, acute respiratory distress syndrome, psoriatic arthritis, infectious arthritis, progressive chronic arthritis Osteoarthritis, osteoarthritis, traumatic arthritis, gouty arthritis, Rayleigh syndrome, polychondritis, acute synovitis and spondylitis, glomerulonephritis, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, neutral granulocytopenia, ulcerative colitis, Crohn's disease, host-versus-graft disease, graft-versus-host disease, allogeneic transplant rejection, chronic thyroiditis, Graves' disease, scleroderma, diabetes mellitus, active hepatitis, primary biliary cirrhosis, myasthenia gravis, polychondritis Selected from: sclerosing syndrome (MS), systemic lupus erythematosus, atopic dermatitis, contact dermatitis, sunburn, chronic renal failure, Stevenson-Johnson syndrome, idiopathic liporrhea, sarcoidosis, Guillain-Barré syndrome, uveitis, conjunctivitis, keratoconjunctivitis, otitis media, periodontal disease, interstitial fibrosis, asthma, bronchitis, rhinitis, sinusitis, pneumoconiosis, pulmonary dysfunction syndrome, emphysema, pulmonary fibrosis, or silicosis. The pharmaceutical composition according to claim 14.

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