Novel glutamine analog

Abstract

Glutamine analogs, compositions containing glutamine analogs and uses thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits of PCT application PCT / China Patent Application Publication No. 2020 / 121114 filed on 15 October 2020; PCT application PCT / China Patent Application Publication No. 2021 / 072111 filed on 15 January 2021; and PCT application PCT / China Patent Application Publication No. 2021 / 076491 filed on 10 February 2021. The entire contents of these applications are incorporated herein by reference.

[0002] This invention relates to novel glutamine analogs, compositions containing glutamine analogs, and their use. [Background technology]

[0003] Glutamine analogs such as 6-diazo-5-oxo-L-norleucine (DON) have been shown to exhibit anticancer activity. However, the occurrence of serious toxicity (e.g., dose-limiting gastrointestinal toxicity such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain) when such glutamine antagonists are administered at therapeutic doses has hindered their clinical development. [Overview of the project] [Problems that the invention aims to solve]

[0004] Previous attempts to mitigate the serious toxicity associated with glutamine antagonists such as DON have been unsuccessful. Therefore, there is a need to develop novel glutamine antagonists that meet clinical needs. [Means for solving the problem]

[0005] In one embodiment, formula I: [ka] (In the formula, Z is OR1 or SR1; R1 is hydrogen, deuterium, halogen, C1-6 alkyl, C1-6 alkoxy, -C3-8 cycloalkyl, -C0-6 alkylene-C3-8 heterocyclyl, -C0-6 alkylene-NH-C0-6 alkyleneC6~ X3 , X2 , X2 , X3 , q , m , RX1 , X2 , m , X1 , X1 , m , p , X1 , X2 , m , m aryl, -C0-6 alkylene-NH-C0-6 alkylene-5-12 member heteroaryl, -C0-6 alkylene-C6~ 10 is selected from the group consisting of aryl and -C0-6 alkylene-5-12 member heteroaryl; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -NH-C3-8 cycloalkyl, carboxyl, -CO-C1-6 alkyl; and each of heteroaryl and heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S; X is hydrogen, deuterium, C1-6 alkyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -O-R X3 , -C(=O)-W-(CR X1 R X2 )​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-GOC(=O)-R8, -C(=O)-W-(CR X1 R X2 ) m -GO-R8, -C(=O)-O-(CR X1 R X2 ) m -OC(=O)-R9, -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m Selected from the group consisting of -G-NR5R5'; W is oxygen, CO, or a bond; m is selected from 1, 2, 3, 4, 5, 6, 7, or 8; p and q are independently selected from 0, 1, or 2, provided that the sum of p and q is 2; R X1 and R X2 These are hydrogen, deuterium, halogens, CN, OH, NH2, C1-6 alkyl, C1-6 alkoxy, C4- 10 Cycloalkyl, -C(=O)-C1~6 alkyl, C5~ 12 Aaryl, -C1~6 alkylene-C5~ 12 Each is independently selected from the group consisting of aryl, -5 to 12-membered heteroaryl, and -C1 to 6 alkylene-5 to 12-membered heteroaryl, and the C1 to 6 alkyl, the C1 to 6 alkoxy, and the C4 10 Cycloalkyl, the C5~ 12 Aryl, the aforementioned -C1~6 alkylene-C5~ 12The aryl, the -5-12 membered heteroaryl, and the -C1-6 alkylene-5-12 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -S-C1-6 alkyl, and carboxyl; and each of the heteroaryl may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; or R X1 and R X2 These, together with the carbon atoms to which they are bonded, form C3~ 10 Carbocycle, C3~ 10 A heterocycline is formed, each heterocycline independently and optionally containing one, two, or three heteroatoms selected from N, O, or S; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6 alkoxy, and C1-6 alkyl; R X3 These include hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, -C(=O)-C1-6 alkyl and -C1-6 alkylene-C5~ 12 Independently selected from the group consisting of aryls, the C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, -C(=O)-C1-6 alkyl and -C1-6 alkylene-C5- 12 Aryls include deuterium, halogen, -OH, oxo, -CN, -C1~6 alkyl, -C1~6 alkoxy, -C3~8 cycloalkyl, -NH2, -NH(C1~6 alkyl), -N(C1~6 alkyl)2, carboxyl, 4~8 membered heterocyclyl. [ka] -C6~ 12It may be optionally substituted with one or more substituents independently selected from the group consisting of aryl, -C(=O)-C1~6alkyl, -NH-C(=O)-C1~6alkyl, -C(=O)-NH2, -C(=O)-NH-C1~6alkyl and -C(=O)-N(C1~6alkyl)2; or R X1 and R X3 These, together with the carbon and oxygen atoms to which they are each bonded, form a 5-12 membered heterocycline, the 5-12 membered heterocycline may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; and each of the heterocyclines may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; R5 and R5' are hydrogen, deuterium, -C1~6 alkyl, -C1~6 alkoxy, -C3~8 cycloalkyl, C5~ 12 Each is independently selected from the group consisting of aryl, 5-12 membered heteroaryl, and 5-12 membered heterocyclyl, and the -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, and C5- 12 The aryl, the 5-12 membered heteroaryl, and the 5-12 membered heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; Each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-6 alkyl, -C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, -C1-6 alkenyl and -C3-8 cycloalkenyl, and the -C1-6 alkyl, the -C3-8 cycloalkyl, the 5-12 membered heterocyclyl ring, the -C1-6 alkenyl and -C3-8 cycloalkenyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; or R6, together with the oxygen atom to which it is bonded, forms a purine or pyrimidine nucleoside; Each of R7 is hydrogen, deuterium, halogen, C1-6 alkyl, C3-8 cycloalkyl, 5-12 member heterocyclyl ring, C1-6 alkenyl, C3-8 cycloalkenyl, C5- 12 Independently selected from the group consisting of aryls and 5-12 membered heteroaryls, the C1-6 alkyl, the C3-8 cycloalkyl, the 5-12 membered heterocyclyl ring, the C1-6 alkenyl, the C3-8 cycloalkenyl, and the C5- 12 The aryl and the 5-12 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; R8 and R9 are C1-6 alkyl, C3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C5- 12 Each is independently selected from the group consisting of aryls and 5-12 member heteroaryls, and the C1-6 alkyls, C3-8 cycloalkyls, monosaccharides, acylated monosaccharides, and C5- 12The aryl and the 5-12 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; G is C5~ 12 It is an aryl or 5-12 member heteroaryl, C5- 12 Aryls and 5-12 membered heteroaryls may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; R3 and R3' are independently selected from the group consisting of hydrogen, deuterium, halogens, C1-6 alkyls, and C1-6 alkoxys, and the C1-6 alkyl and C1-6 alkoxys may be independently and optionally substituted with one or more substituents from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; Y is a bond, oxygen or -(CR Y1 R Y2 ) n -and; n is selected from 1, 2, 3, 4, 5, 6, 7, or 8; R Y1 and R Y2Each of these is independently selected from the group consisting of hydrogen, deuterium, halogens, C1-6 alkyls, and C1-6 alkoxys, and the C1-6 alkyls and C1-6 alkoxys may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyls, -C1-6 alkoxys, -C3-8 cycloalkyls, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyls; R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and the C1-6 alkyl and C1-6 alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; R 10 (The C1-6 alkyl and C1-6 alkoxy atoms are selected from the group consisting of hydrogen, deuterium, halogens, C1-6 alkyl and C1-6 alkoxy atoms, and the C1-6 alkyl and C1-6 alkoxy atoms may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl.) Compounds thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof are provided herein.

[0006] In some embodiments of the present invention concerning compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula IA: [ka] It belongs to them.

[0007] In some embodiments of the present invention concerning compounds of formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula IB: [ka] It belongs to them.

[0008] In some embodiments of the present invention concerning compounds of formulas I, IA, and IB, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R1 is hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, -C3-8 cycloalkyl, -C0-3 alkylene, -C3-8 heterocyclyl, -C0-3 alkylene, -NH-C0-3 alkylene, C6- 10 Aryl, -C0~3 alkylene-NH-C0~3 alkylene-5~12 member heteroaryl, -C0~3 alkylene-C6~ 10 Selected from the group consisting of aryls and -C0-3 alkylene-5-12 membered heteroaryls; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -NH-C3-8 cycloalkyl, -N(C1-6 alkyl)2, carboxyl, and -CO-C1-6 alkyl; and each of the heteroaryls and heterocyclils contains one or two heteroatoms selected from N, O, or S.

[0009] In some embodiments of the present invention concerning compounds of formulas I, IA, and IB, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R1 is hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, -C3-8 cycloalkyl, -C0-3 alkylene, -C3-8 heterocyclyl, -C0-3 alkylene, -NH-C0-3 alkylene, C6- 10 Aryl, -C0~3 alkylene-NH-C0~3 alkylene-5~12 member heteroaryl, -C0~3 alkylene-C6~ 10Selected from the group consisting of aryls and -C0-3 alkylene-5-12 membered heteroaryls; each heteroaryl and heterocyclyl contains one or two heteroatoms selected from N or O; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-6 alkyl), -NH-C3-6 cycloalkyl, -N(C1-3 alkyl)2, carboxyl, and -CO-C1-3 alkyl; each heteroaryl and heterocyclyl contains one or two heteroatoms selected from N or O.

[0010] In some embodiments of the present invention concerning compounds of formulas I, IA, and IB, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R1 is hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, [ka] Selected from the group consisting of; and each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~6 alkyl), -NH-C3~6 cycloalkyl, -N(C1~3 alkyl)2, carboxyl, and -CO-C1~3 alkyl.

[0011] In some embodiments of the present invention concerning compounds of formulas I, IA, and IB, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R1 is hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, [ka] Selected from the group consisting of; and each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, carboxyl, and -CO-tert-butyl.

[0012] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R1 is hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, -CF3, -CH2CF3, -CH(CH3)CF3, -CH(CH3)CH2CF3, -(CH2)2CF3, -(CH2)2-CH(CH3)2, -C(CH3)2CF3, -C(CH3)2CH2CF3, -CN, -CH2CN, -CH(CH3)CN, -CH2CH2CN, -CH(CH3)CH2CN, -C(CH3)2CN, -C(CH3)2CH2CN, -CH2OH, -CH2-O-CH3, -CH2-O-CH2CH3, -CH2-O-CH(CH3)2, [ka] Selected from.

[0013] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is hydrogen, deuterium, C1-6 alkyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3, -C(=O)-W-(CR X1 R X2 ) m -S-R X3 、C(=O)-W-(CR X1 R X2 ) m -SO-R X3 、C(=O)-W-(CR X1 R X2 ) m -SO2-R X3 、-C(=O)-W-(CR X1 R X2 ) m -G、-C(=O)-W-(C RX1 R X2 ) m -NR5R5’、-P(=O)(OR6) p (NHR7) q 、-C(=O)-W-(CR X1 R X2 ) m -G-O-C(=O)-R8、-C(=O)-W-(CR X1 R X2 ) m -G-O-R8、-C(=O)-O-(CR X1 R X2 ) m -O-C(=O)-R9、-C(=O)-O-R7、-C(=O)-W-(CR X1 R X2 ) m -G-O-C(=O)-G and -C(=O)-W-(CR X1 R X2 ) m selected from the group consisting of -G-NR5R5’; W is oxygen, CO or a bond; m is selected from 1, 2 or 3; p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2; R X1 and R X2 are hydrogen, deuterium, halogen, CN, OH, C1-4 alkyl, C1-3 alkoxy, C4-8 cycloalkyl, -C(=O)-C1-3 alkyl, C5- 10 aryl, -C1-3 alkylene-C5- 10Each is independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and -C1-3 alkylene-5-10 membered heteroaryl, and the C1-3 alkyl, the C1-3 alkoxy, the C4-8 cycloalkyl, and the C5- 10 Aryl, the aforementioned -C1~3 alkylene-C5~ 10 The aryl, the 5-10 membered heteroaryl, and the -C1-3 alkylene-5-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -S-C1-6 cycloalkyl, or carboxyl; and each of the heteroaryl may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; or R X1 and R X2 These, together with the carbon atoms to which they are bonded, form a C4-8 carbon ring, a C4-8 membered heterocycline, each of which independently and optionally contains one, two, or three heteroatoms selected from N, O, or S; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6 alkoxy, and C1-6 alkyl; R X3 These include hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C(=O)-C1-3 alkyl and -C1-3 alkylene-C5- 10 Independently selected from the group consisting of aryls, the C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C(=O)-C1-3 alkyl and -C1-3 alkylene-C5- 10 Aryls include deuterium, halogen, -OH, oxo, -CN, -C1~6 alkyl, -C1~6 alkoxy, -C3~8 cycloalkyl, -NH2, -NH(C1~6 alkyl), -N(C1~6 alkyl)2, carboxyl, 4~8 membered heterocyclyl. [ka] -C6~ 12 It may be optionally substituted with one or more substituents independently selected from the group consisting of aryl, -C(=O)-C1~6alkyl, -NH-C(=O)-C1~6alkyl, -C(=O)-NH2, -C(=O)-NH-C1~6alkyl and -C(=O)-N(C1~6alkyl)2; or R X1 and R X3 These, together with the carbon and oxygen atoms to which they are each bonded, form a 5-10 membered heterocycline, the 5-10 membered heterocycline may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; and each of the heterocyclines may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; R5 and R5' are hydrogen, deuterium, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, C5~ 10 Each is independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, and the -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, and C5- 10 It may be optionally substituted with one or more substituents independently selected from the group consisting of aryl, the 5-10 member heteroaryl, the 5-10 member heterocyclyl deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; Each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C1-3 alkenyl and -C3-6 cycloalkenyl, and the -C1-3 alkyl, the -C3-6 cycloalkyl, the 5-10 membered heterocyclyl ring, the -C1-3 alkenyl and -C3-6 cycloalkenyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; or R6, together with the oxygen atom to which it is bonded, forms a purine or pyrimidine nucleoside; Each of R7 is hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5- 10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, the C1-3 alkyl, the C3-6 cycloalkyl, the 5-10 membered heterocyclyl ring, the C1-3 alkenyl, the C3-6 cycloalkenyl, and the C5- 10 The aryl and the 5-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; R8 and R9 are C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5- 10 Each is independently selected from the group consisting of aryls and 5-10 membered heteroaryls, and the C1-3 alkyls, C3-6 cycloalkyls, monosaccharides, acylated monosaccharides, and C5- 10The aryl and the 5-10 membered heteroaryl can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl; or G is C5~ 10 It is an aryl or 5-10 member heteroaryl, C5- 10 Aryls and 5-10 membered heteroaryls may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl.

[0014] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is hydrogen, deuterium, C1-3 alkyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 -C(=O)-W-(CR X1 R X2 ) m -SR X3 , C(=O)-W-(CR X1 R X2 ) m -SO-R X3 , C(=O)-W-(CR X1 R X2 ) m -SO2-R X3 -C(=O)-W-(CR X1 R X2 ) m -G, -C(=O)-W-(C RX1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q -C(=O)-W-(CR X1R X2 ) m -GOC(=O)-R8, -C(=O)-W-(CR X1 R X2 ) m -GO-R8, -C(=O)-O-(CR X1 R X2 ) m -OC(=O)-R9, -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m Selected from the group consisting of -G-NR5R5'; W is oxygen or a bond; m is selected from 1, 2, or 3; p and q are independently selected from 0, 1, or 2, provided that the sum of p and q is 2; R X1 and R X2 These are hydrogen, deuterium, halogens, CN, OH, C1-4 alkyl, C1-3 alkoxy, C4-8 cycloalkyl, -C(=O)-C1-3 alkyl, C5- 10 Aylyl, -C1~3 alkylene-C5~ 10 Each is independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and -C1-3 alkylene-5-10 membered heteroaryl, and the C1-3 alkyl, the C1-3 alkoxy, the C4-8 cycloalkyl, and the C5- 10 Aryl, the aforementioned -C1~3 alkylene-C5~ 10The aryl, the 5-10 membered heteroaryl, and the -C1-3 alkylene-5-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-3 alkyl)2, and -S-C1-3 alkylcarboxyl; and each of the heteroaryl may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; or R X1 and R X2 These, together with the carbon atoms to which they are bonded, form a C4-6 carbon ring, a C4-6 membered heterocycline, and each of the heterocyclines independently and optionally contains one, two, or three heteroatoms selected from N, O, or S; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C1-3 alkoxy, and C1-3 alkyl; R X3 These include hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C(=O)-C1-3 alkyl and -C1-3 alkylene-C5- 10 Independently selected from the group consisting of aryls, the C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -C(=O)-C1-3 alkyl and -C1-3 alkylene-C5- 10 Aryls are deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, -S-C1~3 alkylcarboxyl, 4~6 member heterocyclyl, [ka] -C6~ 10It may be optionally substituted with one or more substituents independently selected from the group consisting of aryl, -C(=O)-C1~3alkyl, -NH-C(=O)-C1~3alkyl, -C(=O)-NH2, -C(=O)-NH-C1~3alkyl, and -C(=O)-N(C1~3alkyl)2; or R X1 and R X3 These, together with the carbon and oxygen atoms to which they are each bonded, form a 5-10 membered heterocycline, the 5-10 membered heterocycline may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl; and each of the heterocyclines may independently optionally contain one, two, or three heteroatoms selected from N, O, or S; R5 and R5' are hydrogen, deuterium, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, C5~ 10 Each is independently selected from the group consisting of aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, and the -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, and C5- 10 The aryl, the 5-10 membered heteroaryl, and the 5-10 membered heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl; Each of R6 is independently selected from the group consisting of hydrogen, deuterium, -C1-3 alkyl, -C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, -C1-3 alkenyl and -C3-6 cycloalkenyl, and the -C1-3 alkyl, the -C3-6 cycloalkyl, the 5-10 membered heterocyclyl ring, the -C1-3 alkenyl and -C3-6 cycloalkenyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl; or R6, together with the oxygen atom to which it is bonded, forms a purine or pyrimidine nucleoside; Each of R7 is hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5- 10 Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, the C1-3 alkyl, the C3-6 cycloalkyl, the 5-10 membered heterocyclyl ring, the C1-3 alkenyl, the C3-6 cycloalkenyl, and the C5- 10 The aryl and the 5-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl; R8 and R9 are C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5- 10 Each is independently selected from the group consisting of aryls and 5-10 membered heteroaryls, and the C1-3 alkyls, C3-6 cycloalkyls, monosaccharides, acylated monosaccharides, and C5- 10The aryl and the 5-10 membered heteroaryl can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl; or G is C5~ 10 It is an aryl or 5-10 member heteroaryl, C5- 10 Aryls and 5-10 membered heteroaryls can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0015] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 -C(=O)-W-(CR X1 R X2 ) m -SR X3 , C(=O)-W-(CR X1 R X2 ) m -SO-R X3 , C(=O)-W-(CR X1 R X2 ) m -SO2-R X3 -C(=O)-W-(CR X1 R X2 ) m -G, -C(=O)-W-(C RX1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q-C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-R8, -C(=O)-W-(CR X1 R X2 ) m -GO-R8, -C(=O)-O-(CR X1 R X2 ) m -OC(=O)-R9, -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m Selected from the group consisting of -G-NR5R5'; W is oxygen or a bond; m is selected from 1, 2, or 3; p and q are independently selected from 0, 1, or 2, provided that the sum of p and q is 2; R X1 and R X2 This includes hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, -CH2-C5 aryl, -CH2-C6 aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C5 aryl, -(CH2)2-C6 aryl, -(CH2)2-C7 aryl, -(CH2)2-C8 aryl, -(CH2)2-C9 aryl, -(CH2)2-C 10Aryl, -(CH2)3-C5 aryl, -(CH2)3-C6 aryl, -(CH2)3-C7 aryl, -(CH2)3-C8 aryl, -(CH2)3-C9 aryl, -(CH2)3-C 10 Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -CH2-5-membered heteroaryl, -CH2-6-membered heteroaryl, -CH2-7-membered heteroaryl, -CH2-8-membered heteroaryl, -CH2-9-membered heteroaryl, -CH2-10-membered heteroaryl, -(CH2)2-5-membered heteroaryl, -(CH2)2-6-membered heteroaryl, -(CH2)2-7-membered heteroaryl, -(CH2)2-8-membered heteroaryl, -(CH2)2-9-membered heteroaryl, -(CH 2) Each is independently selected from the group consisting of 2-10 membered heteroaryls, -(CH2)3-5 membered heteroaryls, -(CH2)3-6 membered heteroaryls, -(CH2)3-7 membered heteroaryls, -(CH2)3-8 membered heteroaryls, -(CH2)3-9 membered heteroaryls and -(CH2)3-10 membered heteroaryls, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, the -CH2-C5 aryl, the -CH2-C6 aryl, the -CH2-C7 aryl, the -CH2-C8 aryl, the -CH2-C9 aryl, the -CH2-C 10 Aryl, the -(CH2)2-C5 aryl, the -(CH2)2-C6 aryl, the -(CH2)2-C7 aryl, the -(CH2)2-C8 aryl, the -(CH2)2-C9 aryl, the -(CH2)2-C 10 Aryl, the -(CH2)3-C5 aryl, the -(CH2)3-C6 aryl, the -(CH2)3-C7 aryl, the -(CH2)3-C8 aryl, the -(CH2)3-C9 aryl, the -(CH2)3-C 10Aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, the 10-membered heteroaryl, the -CH2-5-membered heteroaryl, the -CH2-6-membered heteroaryl, the -CH2-7-membered heteroaryl, the -CH2-8-membered heteroaryl, the -CH2-9-membered heteroaryl, the -CH2-10-membered heteroaryl, the -(CH2)2-5-membered heteroaryl, the -(CH2)2-6-membered heteroaryl, the -(CH2)2-7-membered heteroaryl, the -(CH2)2-8-membered heteroaryl, the -(CH2)2-9-membered heteroaryl, the -(CH2)2-10-membered heteroaryl, the -(CH2)3-5-membered heteroaryl The loaryl, the -(CH2)3-6 membered heteroaryl, the -(CH2)3-7 membered heteroaryl, the -(CH2)3-8 membered heteroaryl, the -(CH2)3-9 membered heteroaryl, and the -(CH2)3-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~6 alkyl), -N(C1~3 alkyl)2, -S-C1~3 alkyl, and carboxyl; and each heteroaryl may independently optionally contain one or two heteroatoms selected from N, O, or S; or R X1 and R X2 These, together with the carbon atoms to which they are bonded, form a 3-membered carbon ring, a 4-membered carbon ring, a 5-membered carbon ring, or a 6-membered carbon ring, a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl, and each of the heterocyclyls independently and optionally contains one or two heteroatoms selected from N or O; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C1-3 alkoxy, and C1-3 alkyl; R X3Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl, - (CH2)3-C5 aryl, -CH2-C6 aryl, -(CH2)2-C6 aryl, -(CH2)3-C6 aryl, -CH2-C7 aryl, -(CH2)2-C7 aryl, -(CH2)3-C7 aryl, -CH2-C8 aryl, -(CH2)2-C8 aryl, -(CH2)3-C8 aryl, -CH2-C9 aryl, -(CH2)2-C9 aryl, -(CH2)3-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C 10 Arial, -(CH2)3-C 10 Independently selected from the group consisting of aryls, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl Reel, the -(CH2)3-C5 aryl, the -CH2-C6 aryl, the -(CH2)2-C6 aryl, the -(CH2)3-C6 aryl, the -CH2-C7 aryl, the -(CH2)2-C7 aryl, the -(CH2)3-C7 aryl, the -CH2-C8 aryl, the -(CH2)2-C8 aryl, the -(CH2)3-C8 aryl, the -CH2-C9 aryl, the -(CH2)2-C9 aryl, the -(CH2)3-C9 aryl, the -CH2-C 10 Aryl, the aforementioned -(CH2)2-C 10 Aryl and -(CH2)3-C 10Aryls are deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, carboxyl, 4~6 member heterocyclyl. [ka] -C6~ 10 It may be optionally substituted with one or more substituents independently selected from the group consisting of aryl, -C(=O)-C1~3alkyl, -NH-C(=O)-C1~3alkyl, -C(=O)-NH2, -C(=O)-NH-C1~3alkyl and -C(=O)-N(C1~3alkyl)2; or R X1 and R X3 These, together with the carbon and oxygen atoms to which they are each bonded, form 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines, and the 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl; and each heterocycline may independently optionally contain one or two heteroatoms selected from N, O, or S; R5 and R5' are hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -C5 aryl, -C6 aryl, -C7 aryl, -C8 aryl, -C9 aryl, C 10Each is independently selected from the group consisting of aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, and 10-membered heterocyclyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, and C 10 The aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, the 10-membered heteroaryl, the 5-membered heterocyclyl, the 6-membered heterocyclyl, the 7-membered heterocyclyl, the 8-membered heterocyclyl, the 9-membered heterocyclyl, and the 10-membered heterocyclyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl; Each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 5-membered heterocyclyl ring, 6-membered heterocyclyl ring, 7-membered heterocyclyl ring, 8-membered heterocyclyl ring, 9-membered heterocyclyl ring, 10-membered heterocyclyl ring, vinyl, allyl, -C3 cycloalkenyl, -C4 cycloalkenyl, -C5 cycloalkenyl, and -C6 cycloalkenyl. Lukyl, the 5-membered heterocyclyl ring, the 6-membered heterocyclyl ring, the 7-membered heterocyclyl ring, the 8-membered heterocyclyl ring, the 9-membered heterocyclyl ring, the 10-membered heterocyclyl ring, the vinyl, the allyl, the -C3 cycloalkenyl, the -C4 cycloalkenyl, the -C5 cycloalkenyl, the -C6 cycloalkenyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl; or R6, together with the oxygen atom to which it is bonded, forms a purine or pyrimidine nucleoside; Each of R7 is hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10Independently selected from the group consisting of aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl, the methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5-membered heterocyclyl ring, 6-membered heterocyclyl ring, 7-membered heterocyclyl ring, 8-membered heterocyclyl ring, 9-membered heterocyclyl ring, 10-membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 The aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, and the 10-membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl; R8 and R9 are C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5- 10 Each is independently selected from the group consisting of aryls and 5-10 membered heteroaryls, and the C1-3 alkyls, C3-6 cycloalkyls, monosaccharides, acylated monosaccharides, and C5- 10 The aryl and the 5-10 membered heteroaryl can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, or carboxyl; or G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10The C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, and C 10 The aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, or the 10-membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0016] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 -C(=O)-W-(CR X1 R X2 ) m -SR X3 , C(=O)-W-(CR X1 R X2 ) m -SO-R X3 , C(=O)-W-(CR X1 R X2 ) m -SO2-R X3 -C(=O)-W-(CR X1 R X2 ) m -G, -C(=O)-W-(C RX1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q -C(=O)-W-(CR X1 R X2 )m -GOC(=O)-R8, -C(=O)-W-(CR X1 R X2 ) m -GO-R8, -C(=O)-O-(CR X1 R X2 ) m -OC(=O)-R9, -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m Selected from the group consisting of -G-NR5R5'; W is oxygen or a bond; m is selected from 1, 2, or 3; p and q are independently selected from 0, 1, or 2, provided that the sum of p and q is 2; R X1 and R X2 This includes hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, -CH2-C5 aryl, -CH2-C6 aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C5 aryl, -(CH2)2-C6 aryl, -(CH2)2-C7 aryl, -(CH2)2-C8 aryl, -(CH2)2-C9 aryl, -(CH2)2-C 10 Aryl, -(CH2)3-C5 aryl, -(CH2)3-C6 aryl, -(CH2)3-C7 aryl, -(CH2)3-C8 aryl, -(CH2)3-C9 aryl, -(CH2)3-C 10Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -CH2-5-membered heteroaryl, -CH2-6-membered heteroaryl, -CH2-7-membered heteroaryl, -CH2-8-membered heteroaryl, -CH2-9-membered heteroaryl, -CH2-10-membered heteroaryl, -(CH2)2-5-membered heteroaryl, -(CH2)2-6-membered heteroaryl, -(CH2)2-7-membered heteroaryl, -(CH2)2-8-membered heteroaryl, -(CH2)2-9-membered heteroaryl, -(CH 2) Each is independently selected from the group consisting of 2-10 membered heteroaryls, -(CH2)3-5 membered heteroaryls, -(CH2)3-6 membered heteroaryls, -(CH2)3-7 membered heteroaryls, -(CH2)3-8 membered heteroaryls, -(CH2)3-9 membered heteroaryls and -(CH2)3-10 membered heteroaryls, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, the -CH2-C5 aryl, the -CH2-C6 aryl, the -CH2-C7 aryl, the -CH2-C8 aryl, the -CH2-C9 aryl, the -CH2-C 10 Aryl, the -(CH2)2-C5 aryl, the -(CH2)2-C6 aryl, the -(CH2)2-C7 aryl, the -(CH2)2-C8 aryl, the -(CH2)2-C9 aryl, the -(CH2)2-C 10 Aryl, the -(CH2)3-C5 aryl, the -(CH2)3-C6 aryl, the -(CH2)3-C7 aryl, the -(CH2)3-C8 aryl, the -(CH2)3-C9 aryl, the -(CH2)3-C 10Aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, the 10-membered heteroaryl, the -CH2-5-membered heteroaryl, the -CH2-6-membered heteroaryl, the -CH2-7-membered heteroaryl, the -CH2-8-membered heteroaryl, the -CH2-9-membered heteroaryl, the -CH2-10-membered heteroaryl, the -(CH2)2-5-membered heteroaryl, the -(CH2)2-6-membered heteroaryl, the -(CH2)2-7-membered heteroaryl, the -(CH2)2-8-membered heteroaryl, the -(CH2)2-9-membered heteroaryl, the -(CH2)2-10-membered heteroaryl, the -(CH2)3-5-membered heteroaryl, the -(CH2)3-6-membered heteroaryl, the -(CH2)3-7-membered heteroaryl, the -(CH2)3-8-membered heteroaryl, the -(CH2)3-9-membered heteroaryl The loaryl and the -(CH2)3-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -S-methyl, and carboxyl; and each heteroaryl may independently optionally contain one or two heteroatoms selected from N, O, or S; or R X1 and R X2These, together with the carbon atoms to which they are bonded, form three-membered carbon rings, four-membered carbon rings, five-membered carbon rings, four-membered heterocyclines, five-membered heterocyclines, and six-membered heterocyclines, and each of the heterocyclines independently and optionally contains one or two heteroatoms selected from N or O; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy; R X3 Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl, - (CH2)3-C5 aryl, -CH2-C6 aryl, -(CH2)2-C6 aryl, -(CH2)3-C6 aryl, -CH2-C7 aryl, -(CH2)2-C7 aryl, -(CH2)3-C7 aryl, -CH2-C8 aryl, -(CH2)2-C8 aryl, -(CH2)3-C8 aryl, -CH2-C9 aryl, -(CH2)2-C9 aryl, -(CH2)3-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C 10 Arial, -(CH2)3-C 10Independently selected from the group consisting of aryls, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl Reel, the -(CH2)3-C5 aryl, the -CH2-C6 aryl, the -(CH2)2-C6 aryl, the -(CH2)3-C6 aryl, the -CH2-C7 aryl, the -(CH2)2-C7 aryl, the -(CH2)3-C7 aryl, the -CH2-C8 aryl, the -(CH2)2-C8 aryl, the -(CH2)3-C8 aryl, the -CH2-C9 aryl, the -(CH2)2-C9 aryl, the -(CH2)3-C9 aryl, the -CH2-C 10 Aryl, the aforementioned -(CH2)2-C 10 Aryl and -(CH2)3-C 10 Aryls are deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, [ka] It may be optionally substituted with one or more substituents independently selected from the group consisting of -C6 aryl, -C(=O)-CH3, -NH-C(=O)-CH3, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-N(CH3)2, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; or R X1 and R X3These, together with the carbon and oxygen atoms to which they are bonded, form 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines, and the 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines contain deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propyl. They may be optionally substituted with one or more substituents independently selected from the group consisting of ropoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; and each heterocyclyl may independently optionally contain one or two heteroatoms selected from N, O, or S; R5 and R5' are hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -C5 aryl, -C6 aryl, -C7 aryl, -C8 aryl, -C9 aryl, C 10 Each is independently selected from the group consisting of aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered heterocyclyl, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, and 10-membered heterocyclyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, and C 10Aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, the 10-membered heteroaryl, the 5-membered heterocyclyl, the 6-membered heterocyclyl, the 7-membered heterocyclyl, the 8-membered heterocyclyl, the 9-membered heterocyclyl, and the 10-membered heterocyclyl are deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethyl It may be optionally substituted with one or more substituents independently selected from the group consisting of toxic, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl; Each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 5-membered heterocyclyl ring, 6-membered heterocyclyl ring, 7-membered heterocyclyl ring, 8-membered heterocyclyl ring, 9-membered heterocyclyl ring, 10-membered heterocyclyl ring, vinyl, allyl, -C3 cycloalkenyl, -C4 cycloalkenyl, -C5 cycloalkenyl, and -C6 cycloalkenyl, and the methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 5-membered heterocyclyl ring, 6-membered heterocyclyl ring, 7-membered heterocyclyl ring, 8-membered heterocyclyl ring, and 9-membered The heterocyclyl ring, the 10-membered heterocyclyl ring, the vinyl, the allyl, the -C3 cycloalkenyl, the -C4 cycloalkenyl, the -C5 cycloalkenyl, and the -C6 cycloalkenyl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl; or R6, together with the oxygen atom to which it is bonded, forms a purine or pyrimidine nucleoside; Each of R7 is hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Independently selected from the group consisting of aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, and 10-membered heteroaryl, the methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5-membered heterocyclyl ring, 6-membered heterocyclyl ring, 7-membered heterocyclyl ring, 8-membered heterocyclyl ring, 9-membered heterocyclyl ring, 10-membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 The aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, and the 10-membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl; R8 and R9 are C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5- 10 Each is independently selected from the group consisting of aryls and 5-10 membered heteroaryls, and the C1-3 alkyls, C3-6 cycloalkyls, monosaccharides, acylated monosaccharides, and C5- 10 The aryl and the 5-10 membered heteroaryl can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; or G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 The C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, and C 10 The aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, or the 10-membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl.

[0017] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is -C(=O)-W-(CR X1 R X2 ) m -OR X3 and; W is a bond; m is either 1 or 2; R X1 and R X2 This includes hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, -CH2-C5 aryl, -CH2-C6 aryl, -CH2-C7 aryl, -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C5 aryl, -(CH2)2-C6 aryl, -(CH2)2-C7 aryl, -(CH2)2-C8 aryl, -(CH2)2-C9 aryl, -(CH2)2-C 10 Aryl, -(CH2)3-C5 aryl, -(CH2)3-C6 aryl, -(CH2)3-C7 aryl, -(CH2)3-C8 aryl, -(CH2)3-C9 aryl, -(CH2)3-C 10Aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, -CH2-5-membered heteroaryl, -CH2-6-membered heteroaryl, -CH2-7-membered heteroaryl, -CH2-8-membered heteroaryl, -CH2-9-membered heteroaryl, -CH2-10-membered heteroaryl, -(CH2)2-5-membered heteroaryl, -(CH2)2-6-membered heteroaryl, -(CH2)2-7-membered heteroaryl, -(CH2)2-8-membered heteroaryl, -(CH2)2-9-membered heteroaryl, -(CH 2) Each is independently selected from the group consisting of 2-10 membered heteroaryls, -(CH2)3-5 membered heteroaryls, -(CH2)3-6 membered heteroaryls, -(CH2)3-7 membered heteroaryls, -(CH2)3-8 membered heteroaryls, -(CH2)3-9 membered heteroaryls and -(CH2)3-10 membered heteroaryls, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, the -CH2-C5 aryl, the -CH2-C6 aryl, the -CH2-C7 aryl, the -CH2-C8 aryl, the -CH2-C9 aryl, the -CH2-C 10 Aryl, the -(CH2)2-C5 aryl, the -(CH2)2-C6 aryl, the -(CH2)2-C7 aryl, the -(CH2)2-C8 aryl, the -(CH2)2-C9 aryl, the -(CH2)2-C 10 Aryl, the -(CH2)3-C5 aryl, the -(CH2)3-C6 aryl, the -(CH2)3-C7 aryl, the -(CH2)3-C8 aryl, the -(CH2)3-C9 aryl, the -(CH2)3-C 10Aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, the 10-membered heteroaryl, the -CH2-5-membered heteroaryl, the -CH2-6-membered heteroaryl, the -CH2-7-membered heteroaryl, the -CH2-8-membered heteroaryl, the -CH2-9-membered heteroaryl, the -CH2-10-membered heteroaryl, the -(CH2)2-5-membered heteroaryl, the -(CH2)2-6-membered heteroaryl, the -(CH2)2-7-membered heteroaryl, the -(CH2)2-8-membered heteroaryl, the -(CH2)2-9-membered heteroaryl, the -(CH2)2-10-membered heteroaryl, the -(CH2)3-5-membered heteroaryl, the -(CH2)3-6-membered heteroaryl, the -(CH2)3-7-membered heteroaryl, the -(CH2)3-8-membered heteroaryl, the -(CH2)3-9-membered heteroaryl The loaryl and the -(CH2)3-10 membered heteroaryl may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -S-methyl, and carboxyl; and each heteroaryl may independently optionally contain one or two heteroatoms selected from N, O, or S; or R X1 and R X2These, together with the carbon atoms to which they are bonded, form 3-membered carbon rings, 4-membered carbon rings, 5-membered carbon rings, 4-membered heterocyclines, 5-membered heterocyclines, and 6-membered heterocyclines, and each of the heterocyclines independently and optionally contains one or two heteroatoms selected from N or O; each of these may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy; or R X3 Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl, - (CH2)3-C5 aryl, -CH2-C6 aryl, -(CH2)2-C6 aryl, -(CH2)3-C6 aryl, -CH2-C7 aryl, -(CH2)2-C7 aryl, -(CH2)3-C7 aryl, -CH2-C8 aryl, -(CH2)2-C8 aryl, -(CH2)3-C8 aryl, -CH2-C9 aryl, -(CH2)2-C9 aryl, -(CH2)3-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C 10 Arial, -(CH2)3-C 10Independently selected from the group consisting of aryls, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-CH2CH2CH3, -C(=O)-CH(CH3)2, -CH2-C5 aryl, -(CH2)2-C5 aryl Reel, the -(CH2)3-C5 aryl, the -CH2-C6 aryl, the -(CH2)2-C6 aryl, the -(CH2)3-C6 aryl, the -CH2-C7 aryl, the -(CH2)2-C7 aryl, the -(CH2)3-C7 aryl, the -CH2-C8 aryl, the -(CH2)2-C8 aryl, the -(CH2)3-C8 aryl, the -CH2-C9 aryl, the -(CH2)2-C9 aryl, the -(CH2)3-C9 aryl, the -CH2-C 10 Aryl, the aforementioned -(CH2)2-C 10 Aryl and -(CH2)3-C 10 Aryls are deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, [ka] It may be optionally substituted with one or more substituents independently selected from the group consisting of -C6 aryl, -C(=O)-CH3, -NH-C(=O)-CH3, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-N(CH3)2, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; or R X1 and R X3These, together with the carbon and oxygen atoms to which they are bonded, form 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines, and the 4-membered heterocyclines, 5-membered heterocyclines, 6-membered heterocyclines, 7-membered heterocyclines, 8-membered heterocyclines, 9-membered heterocyclines, and 10-membered heterocyclines contain deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propyl. They may be optionally substituted with one or more substituents independently selected from the group consisting of ropoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl; and each heterocyclyl may independently optionally contain one or two heteroatoms selected from N, O, or S.

[0018] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is -C(=O)-W-(CR X1 R X2 ) m -OR X3 and; W is a bond; m is either 1 or 2; R X1 and R X2 Hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, -C(=O)-CH3, [ka] Each of these is independently selected from the group consisting of; and each of these is independently and optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NH-methyl, -NH-ethyl, -NH-propyl, -NH-cyclopropyl, -NH-isopropyl, -N(CH3)2, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, or -S-methyl; or R X1 and R X2 Together with the carbon atoms to which they are bonded, [ka] To form; or R X3 This includes hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C(=O)-CH2-CN, -C(=O)-C(CH3)3, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-NH-CH3, -C(=O)-CH2-N(CH3)2, -CH2-C(=O)-CH3, -CH2-C(=O)-NHCH3, -CH2-C(=O)-N(CH3)2, -CH2-NH2, -CH2-NH-CH3, -CH2CH2-OH, -CH2CH2-CN, -CH2-CN, -CH2CH2-C(=O)-NH2, -CH2CH2-C(=O)-NH-CH3, -CH2CH2-NH-C(=O)-CH3, [ka] Independently selected from the group consisting of; or R X1 and R X3 Together with the carbon and oxygen atoms to which they are bonded, [ka] It forms.

[0019] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, X is -C(=O)-CR X1 R X2 -OR X3 and; R X1 and R X2 Hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopentyl, -C(=O)-CH3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, [ka] They are independently selected from the group consisting of; or R X3 These are hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C(=O)-CH2-CN, -C(=O)-C(CH3)3, -C(=O)-CH3, -C(=O)-CH2CH3, [ka] It is independently selected from the group consisting of [the specified elements].

[0020] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R2 is selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyls, -C1-6 alkoxys, -C3-8 cycloalkyls, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyls.

[0021] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R2 is selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0022] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0023] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy are deuterium, F, Cl, Br, I, -OH, oxo, and -C It can be optionally substituted with one or more substituents independently selected from the group consisting of N, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl. Preferably, R2 is selected from hydrogen or deuterium.

[0024] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R3 and R3' are independently selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys can be independently optionally substituted with one or more substituents from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyls, -C1-6 alkoxys, -C3-8 cycloalkyls, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyls.

[0025] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R3 and R3' are independently selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys can be independently optionally substituted with one or more substituents from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0026] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R3 and R3' are independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy may be independently optionally substituted with one or more substituents from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0027] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R3 and R3' are independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, respectively, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy are independently selected from the group consisting of deuterium, F, Cl, Br, I, It may be optionally substituted with one or more substituents from the group consisting of -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2, and carboxyl. Preferably, R3 and R3' are independently selected from hydrogen or deuterium.

[0028] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, Y is combined or -(CR Y1 R Y2 ) n -and; n is selected from 1, 2, or 3; R Y1 and R Y2 Each of these is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl.

[0029] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, Y is combined or -(CR Y1 R Y2 ) n -and; n is selected from 1, 2, or 3; R Y1 and R Y2 Each of these is independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0030] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, Y is combined or -(CR Y1 R Y2 ) n -and; n is selected from 1, 2, or 3; R Y1 and R Y2 Each of the substituents is independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy substituents may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0031] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, Y is combined or -(CR Y1 R Y2 ) n -and; n is selected from 1, 2, or 3; R Y1 and R Y2 Each of these is independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, and -N(CH(CH3)2)2, and carboxyl.

[0032] In some embodiments of the present invention concerning compounds of formulas I, IA, and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, Y is -CH2-.

[0033] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R4 is selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogens, -OH, oxo, -CN, -C1-6 alkyls, -C1-6 alkoxys, -C3-8 cycloalkyls, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyls.

[0034] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R4 is selected from the group consisting of hydrogen, deuterium, halogens, C1-3 alkyls, and C1-3 alkoxys, and the C1-3 alkyls and C1-3 alkoxys may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0035] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0036] In some embodiments of the compounds of formulas I, IA, and IB of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy are deuterium, F, Cl, Br, I, -OH, oxo, and -CN R4 may be optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2 and -N(CH(CH3)2)2, and carboxyl. Preferably, R4 is selected from hydrogen or deuterium.

[0037] In some embodiments of the present invention, compounds of formulas I, IA, and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, R 10 The substituent is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C1-6 alkyl, -C1-6 alkoxy, -C3-8 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, and carboxyl.

[0038] In some embodiments of the present invention, compounds of formulas I, IA, and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, R 10The substituent is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and the C1-3 alkyl and C1-3 alkoxy can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and carboxyl.

[0039] In some embodiments of the present invention, compounds of formulas I, IA, and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, R 10 The substituent is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy can be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1~3 alkyl, -C1~3 alkoxy, -C3~6 cycloalkyl, -NH2, -NH(C1~3 alkyl), -N(C1~3 alkyl)2, and carboxyl.

[0040] In some embodiments of the present invention, compounds of formulas I, IA, and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, R 10R is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, and -N(CH(CH3)2)2, and carboxyl. Preferably, R 10 It is hydrogen or deuterium.

[0041] Formula IC: [ka] (In the formula, Q is O, S, SO or SO2; Z, R X1 , R X2 , R X3 (and m are the same as defined herein) Compounds thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof.

[0042] Formula II: [ka] (In the formula, Z, R X1 , R X2 , R X3 (and m are the same as defined herein) Compounds thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof.

[0043] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, or II, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula III: [ka] (In the formula, R1, R X1 , R X2 , R X3 (and m are the same as defined herein) It belongs to them.

[0044] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, or III, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula IV: [ka] It belongs to them.

[0045] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, or IV, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula V: [ka] It belongs to them.

[0046] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, or IV, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula VI: [ka] It belongs to them.

[0047] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, or IV, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula VII: [ka] It belongs to them.

[0048] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, or IV, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compound is of formula VIII: [ka] (In the formula, R1, R X1 , R X2 , R X3 (and m are the same as defined herein) These are the substances and their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions.

[0049] In some embodiments of the compounds of formula I, IA, IB, IC, II, III, IV, V, VI, VII, or VIII of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, one or more hydrogen atoms are optionally substituted with deuterium.

[0050] In some embodiments of the compounds of formula I, IA, IB, IC, II, III, IV, V, VI, VII, or VIII of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers, and their isotopic substitutions, one or more hydrogens of R1 or RX3 are substituted with deuterium, preferably all hydrogens on one or more methyl groups, methylene groups, or methane groups are substituted with deuterium.

[0051] In some embodiments of the compounds of formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII or VIII of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers and their isotope substitutions, R1 is selected from the group consisting of hydrogen, deuterium, hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy; R X1 and R X2 are each independently selected from the group consisting of hydrogen, deuterium, CN, OH, C1-4 alkyl, C1-3 alkoxy, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-6 alkyl), -N(C1-3 alkyl)2, -S-C1-3 alkyl; or R X3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, each of which may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C1-3 alkyl, -C1-3 alkoxy, -C3-6 cycloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, carboxy, -S-C1-3 alkyl.

[0052] In some embodiments of the compounds of formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII or VIII of the present invention, their pharmaceutically acceptable salts, their stereoisomers, their tautomers and their isotope substitutions, R1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of these is independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy and may be optionally substituted with one or more substituents; R X1 and R X2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, and each of these is independently optionally substituted with deuterium, F, Cl, Br, I, -NH2, -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or R X3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, and each of these may be substituted with deuterium.<00..​​​​​​​​​​​​​​​Hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, [ka] They are independently selected from the group consisting of; or R X3 The compound is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CH2CD3, and -CD2CD3.

[0054] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, IV, V, VI, VII, or VIII, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, R1 is -CD3, -CH2CD3, -CD2CD3, -CD(CD3)2, -CH(CD3)2, [ka] Selected from and deuterated R X3 The option is selected from -CD3, -CH2CD3, and -CD2CD3.

[0055] In some embodiments of the present invention concerning compounds of formula I, IA, IB, IC, II, III, IV, V, VI, VII, or VIII, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, and isotopic substitutions thereof, the compounds are selected from the following:

[0056] [Table 1] TIFF0007837958000031.tif251170TIFF0007837958000032.tif255170TIFF0007837958000033.tif255170 TIFF0007837958000034.tif255168TIFF0007837958000035.tif249170TIFF0007837958000036.tif251170 TIFF0007837958000037.tif254170TIFF0007837958000038.tif251170TIFF0007837958000039.tif255169 TIFF0007837958000040.tif251170TIFF0007837958000041.tif253170TIFF0007837958000042.tif250170 TIFF0007837958000043.tif252170TIFF0007837958000044.tif255169TIFF0007837958000045.tif255170 TIFF0007837958000046.tif255168TIFF0007837958000047.tif255167TIFF0007837958000048.tif251170 TIFF0007837958000049.tif248170TIFF0007837958000050.tif250170TIFF0007837958000051.tif241170 TIFF0007837958000052.tif250170TIFF0007837958000053.tif250170TIFF0007837958000054.tif120170

[0057] Preparation method The compounds of the present invention can be prepared by many methods well known to those skilled in the art of organic synthesis, using the methods described below or variations thereof as understood by those skilled in the art. References cited herein are incorporated herein by reference in their entirety.

[0058] The synthesis methods described below in this specification are intended to illustrate the invention without limiting the subject matter of the invention and the scope of the claimed compounds to these examples. Where the preparation of starting compounds is not described, they may be commercially available or known compounds or may be prepared in the same manner as described herein. Any compound of any of the formulas described herein may be synthesized by referring to the methods described in the following scheme. As shown herein, the final compound is a product having the same structural formula as any of the formulas. It will be understood that any compound of any of the formulas may be prepared by appropriately selecting reagents with appropriate substitutions. Solvents, temperature, pressure and other reaction conditions may be readily selected by those skilled in the art.

[0059] For illustrative purposes, Schemes 1 and 2 illustrate general synthetic methods for preparing the compounds described herein. For a more detailed description of the individual reaction steps, please refer to the Examples section below. Those skilled in the art will understand that the compounds can be synthesized using other synthetic routes. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. [ka] [ka]

[0060] General pathways to the compounds exemplified in the present invention are described in Scheme 1 and Scheme 2, where Z, R X1 , R X2 , R X3 Substituents such as m are functional groups that are defined previously in this text or can be converted to any desired final substituent.

[0061] As shown in Scheme 1 and Scheme 2, iii is obtained by the condensation reaction of acid i and amine ii using an organic base and a condensation reagent. iv can be obtained by the hydrolysis reaction of iii using LiOH, NaOH, etc. Under an organic base and a condensation reagent, iii is obtained as different esters or thioesters by the condensation reaction between iv and an alcohol or a mercaptan.

[0062] Here, the organic base is preferably DIPEA, NMM, 1-methylimidazole, 2,4,6-collidine, etc. The condensation reagent is preferably HATU, TCFH, XtalFluor-E, N,N'-diisopropylcarbodiimide, etc.

[0063] It will be understood that other synthetic routes can also be utilized in the implementation of the present invention.

[0064] In another aspect, a pharmaceutical composition is provided that includes a compound of the present invention, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, and its isotope substitution; and a pharmaceutically acceptable carrier, diluent, or excipient.

[0065] In another aspect, a method of treating a disease or condition is provided, which includes administering to a subject in need of treatment a compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, and its isotope substitution; or its pharmaceutical composition in an amount effective to treat the disease or condition. In yet another aspect, the subject matter of the present disclosure provides the use of a compound, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, and its isotope substitution for treating a disease or condition. In some embodiments, the disease or condition is selected from the group consisting of infectious diseases, cancer, autoimmune diseases, inflammatory diseases, and neurodegenerative diseases or neurological diseases.

[0066] As used herein, “cancer” in a patient means the presence of cells that have characteristics typical of oncogenic cells, such as unrestrained proliferation, loss of specific function, immortality, marked metastatic ability, markedly increased anti-apoptotic activity, rapid growth and proliferation rate, and specific characteristic morphology and cellular markers. In some circumstances, cancer cells take the form of tumors; such cells may be present locally within an animal or may circulate in the bloodstream as independent cells, such as leukemia cells. “Tumor” as used herein means the growth and proliferation of all neoplastic cells, whether malignant or benign, and all precancerous and cancerous cells and tissues. “Solid tumor” as used herein generally refers to an abnormal mass of tissue that does not contain cysts or fluid areas. Solid tumors may be present in the brain, colon, breast, prostate, liver, kidney, lung, esophagus, head and neck, ovaries, cervix, stomach, colon, rectum, bladder, uterus, testes, and pancreas, as non-limiting examples. In some embodiments, after treatment of a solid tumor in the manner disclosed herein, the solid tumor regresses or its growth slows or stops. In other embodiments, the solid tumor is malignant. In some embodiments, the cancer includes stage 0 cancer. In some embodiments, the cancer includes stage I cancer. In some embodiments, the cancer includes stage II cancer. In some embodiments, the cancer includes stage III cancer. In some embodiments, the cancer includes stage IV cancer. In some embodiments, the cancer is refractory and / or metastatic. For example, the cancer may be resistant to treatment by radiotherapy, chemotherapy, or immunotherapy alone.As used herein, cancer includes, but is not limited to, newly diagnosed or recurrent cancers, including acute lymphoblastic leukemia, acute myeloid leukemia, progressive soft tissue sarcoma, brain cancer, metastatic or progressive breast cancer, breast cancer, bronchogenic carcinoma, choriocarcinoma, chronic myeloid leukemia, colon cancer, colorectal cancer, Ewing's sarcoma, gastrointestinal cancer, glioma, glioblastoma multiforme, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, colorectal cancer, leukemia, liver cancer, lung cancer, Lewis lung cancer, lymphoma, malignant fibrous histiocytoma, breast tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, midbrain tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticular sarcoma, sarcoma, small cell lung cancer, solid tumors, gastric cancer, testicular cancer, and uterine cancer.

[0067] In yet another embodiment, a method is provided for treating a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic substitution thereof; or a pharmaceutical composition of the present invention.

[0068] In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma, or head and neck cancer.

[0069] In another embodiment, the use of the compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof and isotopic substitutions thereof; or pharmaceutical compositions of the present invention is provided for the manufacture of agents for treating cancer.

[0070] In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma, or head and neck cancer.

[0071] In some embodiments, the drug is used as a glutamine antagonist.

[0072] As used herein, the term “glutamine antagonist” refers to a glutamine analog that interferes with the glutamine metabolic pathway, for example, inhibiting or blocking a downstream metabolic pathway of glutamine in which glutamine acts as a precursor for one or more non-glutamine compounds. Examples of such metabolic pathways are well known (see, for example, Hensley et al, “Glutamine and cancer: cell biology, physiology, and clinical opportunities” J Clin Invest. 2013;123(9):3678-3684; DeBerardinis et al, “Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer” Oncogene. 2009;29(3):313-324; and Medina et al, “Relevance of glutamine metabolism to tumor cell growth” Mol Cell Biochem. 1992;113(1):1-15). In some contexts, the term glutamine antagonist also includes glutamine analogs that inhibit the uptake of glutamine by cells, thereby reducing its biological activity. This refers to a disease or condition in which glutamine is excessive and / or abnormal.

[0073] In yet another embodiment, compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof and isotopic substitutions thereof, or pharmaceutical compositions of the present invention are provided for therapeutic use.

[0074] In yet another embodiment, compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof and isotopic substitutions thereof, or pharmaceutical compositions of the present invention are provided for use as pharmaceuticals.

[0075] In yet another embodiment, compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof and isotopic substitutions thereof; or pharmaceutical compositions of the present invention are provided for use in the treatment of a disease or condition. In some embodiments, the disease or condition is selected from the group consisting of infectious diseases, cancers, autoimmune diseases, inflammatory diseases and neurodegenerative diseases or neurological disorders.

[0076] In yet another embodiment, compounds of the present invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof and isotopic substitutions thereof; or pharmaceutical compositions of the present invention are provided for use in the treatment of cancer.

[0077] In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma, or head and neck cancer.

[0078] The compounds provided herein, used as active ingredients, are characterized by improved solubility, improved stability, improved safety, improved pKa properties, and high pharmacokinetics. [Brief explanation of the drawing]

[0079] [Figure 1] The plasma stability of the compound after incubation for 4 hours in the presence of dog, monkey, pig, and human plasma is demonstrated. [Figure 2] This shows the changes in body weight after administration of reference compound A and compound 2 in C57BL / 6 mice carrying MC38 tumors. [Figure 3] The antitumor effects of reference compound A and compound 2 in C57BL / 6 mice carrying MC38 tumors are demonstrated. [Figure 4] This shows the changes in body weight after administration of reference compound A and compound 2 to CES1- / - mice carrying MC38 tumors. [Figure 5] The antitumor effects of reference compound A and compound 2 in CES1- / - mice carrying MC38 tumors are demonstrated. [Figure 6]This shows the changes in body weight after administration of compounds 2, 3, 81, 443, and 459 to C57BL / 6 mice carrying MC38 tumors. [Figure 7] The antitumor effects of compounds 2, 3, 81, 443, and 459 in C57BL / 6 mice carrying MC38 tumors are demonstrated. [Modes for carrying out the invention]

[0080] definition As used herein, the term "halogen" means fluoro, chloro, bromo, or iodine unless otherwise specified. Preferred halogen groups include F, Cl, and Br. The terms "halo-C1-6 alkyl," "halo-C2-6 alkenyl," "halo-C2-6 alkynyl," and "halo-C1-6 alkoxy" mean C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkoxy in which one or more (especially 1-3) hydrogen atoms are replaced by halogen atoms, particularly fluorine or chlorine atoms. In some embodiments, fluoroC1-6 alkyl, fluoroC2-6 alkenyl, fluoroC2-6 alkynyl, and fluoroC1-6 alkoxy groups, particularly fluoroC1-3 alkyl, for example CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, and fluoroC1-3 alkoxy groups, for example OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2, or OCH2CF3, with CF3, OCF3, and OCHF2 being the most particularly preferred.

[0081] As used herein, the term "alkyl" includes saturated monovalent hydrocarbon radicals having a linear or cyclic portion, unless otherwise indicated. Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, cyclobutyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl. Similarly, C1-6, as in C1-6 alkyl, is defined as a group having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched configuration.

[0082] The term "alkylene" refers to a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0083] The term "alkenyl" refers to a linear or branched hydrocarbon radical containing one or more double bonds and typically 2 to 20 carbon atoms in length. For example, "C2-6 alkenyl" contains 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-butenyl-1-yl, hepetenyl, and octenyl.

[0084] The term "alkynyl" refers to linear or branched hydrocarbon radicals containing one or more triple bonds and typically 2 to 20 carbon atoms in length. For example, "C2-6 alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, and octynyl.

[0085] The term "alkoxy" radical refers to an oxygen ether formed from the aforementioned alkyl group.

[0086] As used herein, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing a carbocyclic atom, unless otherwise indicated. Preferred aryls are monocyclic or bicyclic 6- to 10-membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0087] The term "heterocyclyl," as used herein, refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms, including monocyclic, bicyclic, bridging, fused, or spirocyclic rings, unless otherwise indicated. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring has 3 to 10 members and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably 1, 2, or 3, are included in this definition. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranil, dioxolanil, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydroxazolyl, tetrahydropyranil, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

[0088] As used herein, the term "heteroaryl" refers to an aromatic ring system containing carbon and at least one heteroatom, unless otherwise indicated. Heteroaryls can be monocyclic or polycyclic, and may or may not be substituted. Monocyclic heteroaryl groups may contain 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups may contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings may contain condensation, spiro, or bridging ring bonds; for example, a bicyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring may contain 8 to 12 ring-member atoms. A monocyclic heteroaryl ring may contain 5 to 8 ring-member atoms (carbon and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridadinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0089] The term "cycloalkyl" refers to substituted or unsubstituted monocyclic, bicyclic, bridging, fused, spirocyclic, and non-aromatic ring systems containing only carbon atoms. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Here, the term "substituted" refers to the above-mentioned groups in which one or more (preferably 1 to 6, more preferably 1 to 3) hydrogen atoms are independently substituted with the same or different substituents. Typical substituents include, but are not limited to, T, C1-6 alkyl, C1-6 alkoxy, and C3- 20 Cycloalkyl, -OR 13 , SR 13 ,=O,=S,-C(O)R 13 ,-C(S)R 13 ,=NR 13 , -C(O)OR 13 , -C(S)OR 13, -NR 13 R 14 -C(O)NR 13 R 14 cyano, nitro, -S(O)2R 13 -OS(O2)OR 13 -OS(O)2R 13 or -OP(O)(OR 13 )(OR 14 ) are listed; where each T is independently a halogen (F, Cl, Br or I), and R 13 and R 14 The substituent is independently selected from -H, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, the substituent is independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, CHF2, methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH3, -SC2H5, formaldehyde group, -C(OCH3), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl. Particularly preferred substituents are -F, -Cl, or -Br.

[0090] As used herein, the term “composition” is intended to encompass products containing specific components in specific amounts and any products obtained directly or indirectly by combining specific components in specific amounts. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and are themselves intended to be included in the present invention. Additionally, some compounds may form solvates (i.e., hydrates) with water or with common organic solvents, and such solvates are also intended to be included within the scope of the present invention.

[0091] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. In pharmaceutical use, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts." pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. pharmaceutically acceptable acidic / anionic salts generally take the form in which the basic nitrogen is protonated with an inorganic or organic acid. Typical organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharic acid, or trifluoroacetic acid. Examples of pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

[0092] The present invention includes, within its scope, prodrugs of the compounds of the present invention. Generally, such prodrugs are functional derivatives of compounds that are readily converted in vivo to the compound of interest. Accordingly, in the treatment methods of the present invention, the term “administer” encompasses treating various disclosed disorders with a compound that is specifically disclosed or a compound that is not specifically disclosed but is converted in vivo to a specific compound after administration to a subject. Conventional procedures for the selection and preparation of appropriate prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

[0093] The definition of a substituent or variable at a specific position within a molecule is intended to be independent of the definition of other positions within that molecule. It is understood that the substituents and substitution patterns of the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and readily synthesizable by known art and methods described herein.

[0094] The present invention comprises compounds described which may contain one or more chiral centers, and thus may give rise to diastereomers and optical isomers. The present invention comprises all such possible diastereomers and racemic mixtures thereof, substantially pure isolated enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0095] The present invention includes all stereoisomers of a compound and its pharmaceutically acceptable salts. Furthermore, it also includes mixtures of stereoisomers and specific isolated stereoisomers. During the process of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0096] In the context of this invention, "stereoisomer" refers to an isomer in which atoms or groups of atoms within a molecule are connected to each other in the same order, but have different spatial arrangements, and includes structural isomers. Configurational isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. This invention includes all possible stereoisomers of a compound.

[0097] The present invention is intended to include all isotopes of the atoms present in the compound of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Hydrogen isotopes are, 1 H (hydrogen), 2 H (deuterium), 3It can be represented as H (tritium). These are generally also represented as D for deuterium and T for tritium. In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. As for carbon isotopes, 13 C and 14 C is one example. The isotope-labeled compounds of the present invention can generally be prepared by the use of a suitable isotope-labeled reagent instead of an unlabeled reagent, by a process similar to the prior art known to those skilled in the art or described herein.

[0098] Where tautomers of a compound exist, unless otherwise specified, the present invention includes all possible tautomers and their pharmaceutically acceptable salts and mixtures thereof.

[0099] When a compound and its pharmaceutically acceptable salts exist in the form of a solvate or polymorph, the present invention includes all possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited as long as it is a pharmaceutically acceptable solvent. For example, water, ethanol, propanol, acetone, etc., can be used.

[0100] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. If the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic and organic bases. If the compound of the present invention is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Since the compounds are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example, at least 60% pure, more preferably at least 75% pure, and particularly at least 98% pure (percentages are by weight).

[0101] The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but in all cases the optimal route depends on the specific host and the nature and severity of the condition to which the active ingredient is administered. The pharmaceutical compositions can be readily provided in unit dosage forms and can be prepared by any method well known in the field of pharmacy.

[0102] In practice, the compounds of the present invention, or their prodrugs, metabolites, or pharmaceutically acceptable salts, can be combined as active ingredients by tightly mixing them with pharmaceutical carriers according to conventional pharmaceutical formulation techniques. The carriers can take a wide variety of forms depending on the desired form of the formulation for administration, e.g., oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention can be provided as individual units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be provided as powders, granules, solutions, suspensions in aqueous liquids, non-aqueous liquids, oil-in-water emulsions, or water-in-oil emulsions. In addition to the above general dosage forms, the compounds or their pharmaceutically acceptable salts can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any compounding method. Generally, such methods include the step of associating the active ingredient with carriers constituting one or more required components. Generally, the compositions are prepared by uniformly and tightly mixing the active ingredient with a liquid carrier, a fine powder solid carrier, or both. The product can then be easily molded into the desired form.

[0103] Accordingly, the pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof. The compound or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0104] The pharmaceutical carriers used may be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers include liquid sugar, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Any convenient pharmaceutical medium may be used when preparing compositions for oral dosage forms. For example, water, glycol, oil, alcohol, flavoring agents, preservatives, colorants, etc., may be used to form oral liquid formulations such as suspensions, elixirs, and solutions; carriers such as starch, sugar, microcrystalline cellulose, diluents, granulators, lubricants, binders, and disintegrants may be used to form oral solid formulations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units for which solid pharmaceutical carriers are used because they are easy to administer. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0105] Tablets containing the composition of the present invention may be prepared by compression or molding with one or more adjuncts or auxiliary agents of the choice. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, mixed with a binder, lubricant, inert diluent, surfactant, or dispersant using a suitable machine, of the choice. Molded tablets may be produced by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine. Each tablet preferably contains about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain about 0.5 mg to about 5 g of the active agent, combined with a suitable and convenient amount of carrier material, which may vary in the range of about 0.05 to about 95 percent of the total composition. Each unit dosage form generally contains approximately 0.01 mg to 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0106] The pharmaceutical compositions of the present invention, suitable for parenteral administration, can be prepared as a solution or suspension of the active compound in water. For example, a suitable surfactant such as hydroxypropyl cellulose may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may be included to prevent harmful microbial growth.

[0107] The pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. Furthermore, the compositions may be in the form of sterile powders for immediate preparation of such sterile injection solutions or dispersions. In either case, the final injection form must be sterile and effectively fluid for easy needle penetration. The pharmaceutical compositions must be stable under manufacturing and storage conditions; therefore, preferably, they should be protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, or suitable mixtures thereof.

[0108] The pharmaceutical compositions of the present invention can be in forms suitable for topical use, such as aerosols, creams, ointments, lotions, and powders. Furthermore, the compositions may be in forms suitable for use in transdermal devices. These formulations can be prepared by conventional process methods using the compounds of the present invention or pharmaceutically acceptable salts thereof. As an example, a cream or ointment may be prepared by mixing a hydrophilic material and water with about 0.05 wt% to about 10 wt% of the compound to produce a cream or ointment with a desired consistency.

[0109] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, wherein the carrier is solid. The mixture is preferably formed into a suppository of a unit dose. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be easily formed by first mixing the composition with a softened or melted carrier, then cooling and molding in a mold.

[0110] In addition to the carrier components described above, the pharmaceutical formulation may optionally contain one or more additional carrier components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, and preservatives (including antioxidants). Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the target of administration. Compositions containing the compound or a pharmaceutically acceptable salt thereof may also be prepared in the form of a powder or liquid concentrate.

[0111] Generally, dose levels of approximately 0.001 mg / kg body weight to approximately 150 mg / kg body weight per day are useful for treating the above conditions, or alternatively, approximately 0.05 mg to approximately 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and conditions of the immune system, and diseases and conditions of the central nervous system (CNS) can be effectively treated by administering approximately 0.001 to 50 mg of the compound per kg of body weight per day, or alternatively, approximately 0.05 mg to approximately 3.5 g of the compound per patient per day.

[0112] However, it is understood that the specific dose level for a particular patient depends on various factors, including age, weight, general health status, sex, diet, administration time, route of administration, excretion rate, drug combinations, and the severity of the specific disease being treated.

[0113] These and other embodiments will become apparent from the following description of the present invention. [Examples]

[0114] The following embodiments are provided to better illustrate the present invention. Unless otherwise indicated, all parts and percentages are by weight, and all temperatures are in Celsius. The following abbreviations are used in the embodiments.

[0115] [Table 2]

[0116] Intermediate A1 [ka] Intermediate A1 was prepared by referring to Compound 3 in Scheme 1 on page 82 of International Publication No. 2017023774.

[0117] The following compounds were synthesized using the procedure described above or the corresponding modification procedure using the starting materials.

[0118] [Table 3]

[0119] Intermediate B1 [ka] Step a: (2S)-methylglycidate (121 mg, 1.185 mmol) was added to a chloroform (3 mL) solution of 7-fluoroindole (308 mg, 2.279 mmol) and ytterbium(III) triflate hydrate (219 mg, 343.119 μmol) under N2 conditions. The mixture was heated to 85°C and stirred for 3 hours. The reaction mixture was cooled to room temperature. The reaction mixture was quenched with Na2CO3 (aqueous solution) (10 mL) and the pH was adjusted to 5-6 with 2 M HCl. The aqueous layer was separated and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography using ethyl hexane (1:2) elution to obtain methyl (2S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxypropanoate (136 mg, 573.292 μmol). MS: m / z 238 (M+H) + .

[0120] Step b: To a solution of methyl (2S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxypropanoate (136 mg, 573.292 μmol) in water (1 mL), LiOH (2 M aqueous solution, 1 mL) was added. The mixture was stirred overnight at room temperature ~ 60°C, citric acid (solid) was added, diluted with water (5 mL), and extracted with EA (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxypropanoic acid (165 mg, 739.247 μmol), which was used in the next step without further purification. MS: m / z (224) + .

[0121] Intermediate B2 [ka] Step a: NaH (217 mg, 9.043 mmol) was added to a solution of indole (302 mg, 2.578 mmol) in DMF (3 mL) over 1 hour in an ice bath. (2S)-methylglycidate (685 mg, 6.710 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with H2O, and the pH was adjusted to 3-4 with citrate. The aqueous layer was extracted with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash with H2O / MeCN (5%-95%) to obtain (S)-2-hydroxy-3-(1H-indole-1-yl)propanoic acid (222 mg, 1.082 mmol). MS: m / z 206 (M+H) + .

[0122] The following compounds were synthesized using the procedure described above or the corresponding modification procedure using the starting materials.

[0123] [Table 4] JPEG0007837958000063.jpg47170

[0124] Intermediate C1 [ka] Step a: To a solution of (S)-(-)-methyl lactate (1099 mg, 10.5567 mmol) and iodoethane (3726 mg, 23.8900 mmol) in diethyl ether (10 mL), Ag2O (4772 mg, 20.5925 mmol) was added under N2. The reaction mixture was stirred overnight at room temperature in the dark. The reaction mixture was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in THF (3 mL), MeOH (3 mL), and H2O (3 mL), and then LiOH (246 mg, 10.2721 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by TLC and the pH was adjusted to 2 with 1N HCl. The reaction mixture was concentrated to 5 mL under reduced pressure. The aqueous layer was extracted with EA (3 × 10 mL). The combined organic layers were washed with a saturated solution of NaCl (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain (S)-2-ethoxypropanoic acid (772 mg, 6.5351 mmol). MS: m / z 119 (M + H) + .

[0125] Intermediate C2 [ka] Step a: Ag2O (4.41 g, 19.0303 mmol) was added to a solution of 2-hydroxy-4-(methylthio)butanoic acid (0.68 g, 4.5274 mmol) and CH3I (3.35 g, 23.6019 mmol) in diethyl ether (10 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (6 mL) and H2O (2 mL), and then NaOH (318 mg, 7.9506 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by TLC and the pH was adjusted to 3 with 1 M HCl. The reaction mixture was concentrated to 5 mL under reduced pressure. The aqueous layer was extracted with EA (3 × 10 mL). The combined organic layers were washed with a saturated solution of NaCl (3 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 2-methoxy-4-(methylthio)butanoic acid (128 mg, 779.4318 μmol). MS: m / z 165 (M + H) + .

[0126] Intermediate C3 [ka] Step a: NaH (55 mg, 2.292 mmol) was added to a solution of 2-hydroxy-3-(1H-indole-3-yl)propanoic acid (152 mg, 740.706 μmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 minutes, then CH3I (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CH3I (358 mg, 2.522 mmol) was added again. The reaction mixture was monitored by LC-MS. The reaction mixture was stirred at 40°C for 3 hours. H2O (5 mL) was added to the reaction mixture and extracted with EA (10 mL). The aqueous layers were combined and purified by flash using H2O / MeCN (0%~100%, 40 min, C18). The product layer was concentrated under reduced pressure to obtain 2-methoxy-3-(1-methyl-1H-indole-3-yl)propanoic acid (119 mg, 510.155 μmol). MS: m / z 234 (M+H) + .

[0127] The following compounds were synthesized using the procedure described above or the corresponding modification procedure using the starting materials.

[0128] [Table 5] JPEG0007837958000068.jpg241170JPEG0007837958000069.jpg255168JPEG0007837958000070.jpg251170JPEG0007837958000071.jpg108170

[0129] Intermediate D1 [ka] Step a: Imidazole (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol) were added to a solution of (S)-2-hydroxy-3-(1H-indole-3-yl)propanoate methyl (2 g, 9.123 mmol) in DCM (20 mL). The mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and the organic extract was collected. The aqueous solution was extracted with DCM (2 × 10 mL). The residue was purified by wet column chromatography using EA / Hex (0-20%). The solution of the product was concentrated under reduced pressure. (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indole-3-yl)propanoate methyl (3099 mg) was obtained. MS: m / z 334 (M+H) + .

[0130] Step b: LiHMDS (10.5 mL, 10.491 mmol) was added to a solution of (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indole-3-yl)propanoate methyl (3.099 g, 9.292 mmol) in THF (30 mL) at -78 °C. The mixture was stirred at -78 °C for 30 minutes. Carbobenzyl oxychloride (4623 mg, 27.100 mmol) was then added dropwise to the mixture at -78 °C. The reaction mixture was stirred at this temperature for 1 hour. The reaction was quenched with saturated aqueous solution, washed with NH4Cl, and the aqueous solution was extracted with EA (2 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL) and de-dried with anhydrous Na2SO4. The organic phase was concentrated under reduced pressure. (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate benzyl (4345 mg) was obtained. MS: m / z 468 (M+H) + .

[0131] Step c: Add tetrabutylammonium fluoride (5 mL) to a solution of (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate benzyl (4.345 g, 9.292 mmol) in THF (30 mL). Stir the mixture overnight at room temperature. Concentrate the reaction mixture under reduced pressure. Purify the residue by flash with EA / Hex (0-60%). Concentrate the product solution under reduced pressure. 3-[(2S)-2-hydroxy-3-methoxy-3-oxopropyl]indole-1-carboxylate benzyl (2.21 g) was obtained. MS: m / z 354 (M+H) + .

[0132] Step d: 3-[(2S)-2-hydroxy-3-methoxy-3-oxopropyl]indole-1-carboxylate benzyl (103 mg, 291.481 μmol) and silver oxide (216 mg, 932.098 μmol) were added to a solution of 4A molecular sieve in CH3I (1 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5 mL), filtered, and the filtrate was concentrated to obtain (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate benzyl (107.088 mg, yield 100.000%). MS: m / z 368 (M+H) + .

[0133] Step e: (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate benzyl (0.107 g, 291.240 μmol) was dissolved in THF (5 mL) and MeOH (5 mL) and NaOH (3 mL, 3 M / L) was added. The mixture was stirred at room temperature for 1 hour. The pH of the reaction mixture was adjusted to 3 with 1 M HCl. The aqueous solution was extracted with EA (2 × 10 mL). The combined organic extracts were washed with brine (3 × 10 mL) and dried with anhydrous Na₂SO₄. The organic phase was concentrated under reduced pressure to obtain (S)-3-(1H-indole-3-yl)-2-methoxypropanoic acid (71 mg). MS: m / z 220 (M + H) + .

[0134] The following compounds were synthesized using intermediate D1 and the modification procedure described above or the corresponding starting material.

[0135] [Table 6] JPEG0007837958000074.jpg108170

[0136] Example 1 (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxypropanamide)-5-isopropyl oxohexanoate (compound 1) [ka] (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanoic acid (0.165 g, 739.247 μmol) and (2S)-2-amino-6-diazo-5-oxohexanoate isopropyl (123 mg, 576.834 μmol) were mixed in a DCM (2 mL) solution to which N,N'-diisopropylcarbodiimide (95 mg, 752.779 μmol), 2,4,6-collidine (115 mg, 949.008 μmol), and ethyl-2-oxime cyanoglycylate (83 mg, 584.044 μmol) were added at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC and concentrated under reduced pressure to obtain isopropyl (2S)-6-diazo-2-[[(2S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxy-propanoyl]amino]-5-oxohexanoate (41.6 mg, 99.422 μmol) by lyophilization. MS:m / z 419(M+H) + , 1 H NMR(400MHz,CDCl3)δ 8.47-8.39(m,1H),7.47(d,J=7.9Hz,1H),7.21-7.19(m,1H),7.16(d,J=7.8Hz,1H),7.0 5(td,J=7.9,4.8Hz,1H),6.93(dd,J=10.8,7.8Hz,1H),5.09(s,1H),5.03(dt,J=12.5,6 .3Hz,1H),4.53-4.45(m,1H),4.43(s,1H),3.29(ddd,J=21.3,14.8,5.4Hz,2H),2.73-2 .60(m,1H),2.43-2.25(m,1H),2.18-1.98(m,2H),1.97-1.80(m,1H),1.30-1.22(m,6H).

[0137] Example 2 (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-isopropyl oxohexanoate (Compound 2) [ka] (S)-2-methoxypropanoic acid (267 mg, 2.565 mmol) and (2S)-2-amino-6-diazo-5-oxohexanoate isopropyl (0.152 g, 712.835 μmol) were dissolved in DMF (5 mL) and N,N'-diisopropylcarbodiimide (327 mg, 2.591 mmol), 2,4,6-collidine (412 mg, 3.400 mmol), and ethyl-2-oxime cyanoglycylate (375 mg, 2.639 mmol) were added at 0°C. The mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 5-100%, 40 min) and concentrated under reduced pressure to obtain (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-isopropyl oxohexanoate (60.2 mg, 201.1211 μmol, readily soluble in water). MS: m / z 300 (M+H) + , 1 H NMR(400MHz,CDCl3)δ 7.22-7.08(m,1H),5.12-5.01(m,1H),4.57(td,J=8.7,4.8Hz,1H),3.77(dt,J=6.7,5.7Hz,1H),3.45( s,3H),2.82-2.58(m,1H),2.50-2.22(m,2H),2.09-1.85(m,1H),1.44-1.35(m,3H),1.31-1.26(m,6H).

[0138] Example 3 (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-methyl oxohexanoate (compound 3) [ka] (S)-2-methoxypropanoic acid (2.06 g, 19.7879 mmol) and (S)-2-amino-6-diazo-5-oxohexanoate methyl (2308 mg, 12.4635 μmol) were dissolved in DMF (5 mL), to which NMM (3.73 g, 36.8770 mmol) and HATU (6.26 g, 16.4637 mmol) were added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-100%, 40 min), concentrated under reduced pressure, and (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate methyl (2.87 g, 10.5799 mmol, readily soluble in water). MS:m / z 272(M+H) + , 1 H NMR(400MHz,CD3OD)δ 5.82(s,1H),4.46(dd,J=8.9,4.8Hz,1H),3.79-3.74(m,1H),3.72(s,3H),3.40( s,3H),2.43(s,2H),2.33-2.15(m,1H),2.08-1.90(m,1H),1.33(d,J=6.7Hz,3H).

[0139] Example 4 (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoic acid (compound 4) [ka] (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate methyl (0.96 g, 3.5389 mmol) was added to a solution of THF (10 mL) with NaOH (176 mg, 4.4003 mmol) in water (5 mL) at 0°C. The mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-80%, 30 min) and concentrated under reduced pressure to obtain (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoic acid (866 mg, 3.3665 mmol, readily soluble in water). MS:m / z 258(M+H) + ,1 H NMR(400MHz,CD3OD)δ 5.82(s,1H),4.27(t,J=5.8Hz,1H),3.72(q,J=6.6Hz,1H),3.40(s,3H),2.4 6-2.27(m,2H),2.28-2.13(m,1H),2.06-1.91(m,1H),1.33(d,J=6.7Hz,3H).

[0140] Example 5 (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indole-3-yl)propanamide)-6-diazo-5-oxohexanoate isopropyl (compound 5) [ka] (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indole-3-yl)-2-hydroxypropanamide)-5-oxohexanoate isopropyl (0.166 g, 396.7325 μmol) was dissolved in DMF (3.5 mL) and pyridine (189 mg, 2.3894 mmol) and acetic anhydride (104 mg, 1.0187 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 2-80%) and concentrated under reduced pressure to obtain (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indole-3-yl)propanamide)-6-diazo-5-oxohexanoate isopropyl (75.2 mg, 163.3196 μmol). MS:m / z 461(M+H) + , 1H NMR(400MHz,CD3OD)δ 7.39(d,J=7.9Hz,1H),7.17(s,1H),6.96(dd,J=13.4,6.4Hz,1H),6.88-6.76(m,1H),5.24(t,J=5.4Hz,1H),4.96(dt,J=12.4,6.3Hz,1H),4. 27(d,J=8.7Hz,1H),3.28(d,J=5.6Hz,2H),2.26-2.13(m,1H),2.10(s,3H),2.05(d,J=10.2Hz,2H),1.88-1.75(m,1H),1.22(t,J=6.8Hz,6H).

[0141] Example 6 (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-ethyl oxohexanoate (compound 6) [ka] (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoic acid (104 mg, 404.2870 μmol) and EtOH (96 mg, 2.0839 mmol) were dissolved in DMF (5 mL), to which NMM (117 mg, 1.1567 mmol) and HATU (237 mg, 623.3081 μmol) were added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-100%, 30 min), concentrated under reduced pressure, and (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate ethyl (0.0332 g, 116.3705 μmol, readily soluble in water). MS:m / z 286(M+H) + , 1 H NMR(400MHz,CD3OD)δ 4.49-4.35(m,1H),4.23-4.13(m,2H),3.83-3.71(m,1H),3.44-3.35(m,3H),2.43( s,2H),2.30-2.15(m,1H),2.08-1.93(m,1H),1.36-1.31(m,3H),1.29-1.24(m,3H).

[0142] The following compounds were synthesized using the procedure described above or the modification procedure of the scheme described above using the corresponding starting materials.

[0143] [Table 7] JPEG0007837958000082.jpg254170JPEG0007837958000083.jpg233170JPEG0007837958000084.jpg247170JPEG0007837958000085.jpg248170JPEG0007837958000086.jpg255165JPEG0007837958000087.jpg242170JPEG0007837958000088.jpg244170JPEG0007837958000089.jpg241170JPEG0007837958000090.jpg252170JPEG0007837958000091.jpg247170JPEG0007837958000092.jpg249170JPEG0007837958000093.jpg246170JPEG0007837958000094.jpg255170JPEG0007837958000095.jpg255165JPEG0007837958000096.jpg228170JPEG0007837958000097.jpg255170JPEG0007837958000098.jpg245170JPEG0007837958000099.jpg250170JPEG0007837958000100.jpg248170JPEG0007837958000101.jpg255170JPEG0007837958000102.jpg236170JPEG0007837958000103.jpg222170JPEG0007837958000104.jpg244170JPEG0007837958000105.jpg255166JPEG0007837958000106.jpg255170JPEG0007837958000107.jpg241170JPEG0007837958000108.jpg244170JPEG0007837958000109.jpg237170JPEG0007837958000110.jpg252170JPEG0007837958000111.jpg239170JPEG0007837958000112.jpg252170JPEG0007837958000113.jpg250170JPEG0007837958000114.jpg255170JPEG0007837958000115.jpg238170JPEG0007837958000116.jpg249170JPEG0007837958000117.jpg248170JPEG0007837958000118.jpg252170JPEG0007837958000119.jpg248170JPEG0007837958000120.jpg244170JPEG0007837958000121.jpg244170JPEG0007837958000122.jpg235170JPEG0007837958000123.jpg242170JPEG0007837958000124.jpg255166JPEG0007837958000125.jpg248170JPEG0007837958000126.jpg255170JPEG0007837958000127.jpg231170JPEG0007837958000128.jpg221170JPEG0007837958000129.jpg220170JPEG0007837958000130.jpg255170JPEG0007837958000131.jpg227170JPEG0007837958000132.jpg248170JPEG0007837958000133.jpg244170JPEG0007837958000134.jpg248170JPEG0007837958000135.jpg251170JPEG0007837958000136.jpg255169JPEG0007837958000137.jpg237170JPEG0007837958000138.jpg255170JPEG0007837958000139.jpg255168JPEG0007837958000140.jpg252170JPEG0007837958000141.jpg236170JPEG0007837958000142.jpg255170JPEG0007837958000143.jpg248170JPEG0007837958000144.jpg238170JPEG0007837958000145.jpg247170JPEG0007837958000146.jpg232170JPEG0007837958000147.jpg240170JPEG0007837958000148.jpg255170JPEG0007837958000149.jpg255170JPEG0007837958000150.jpg231170JPEG0007837958000151.jpg255170JPEG0007837958000152.jpg250170JPEG0007837958000153.jp g251170JPEG0007837958000154.jpg255168JPEG0007837958000155.jpg251170JPEG0007837958000156.jpg 255170JPEG0007837958000157.jpg250170JPEG0007837958000158.jpg245170JPEG0007837958000159.jpg2 33170JPEG0007837958000160.jpg255168JPEG0007837958000161.jpg251170JPEG0007837958000162.jpg24 8170JPEG0007837958000163.jpg228170JPEG0007837958000164.jpg226170JPEG0007837958000165.jpg244 170JPEG0007837958000166.jpg244170JPEG0007837958000167.jpg235170JPEG0007837958000168.jpg2511 70JPEG0007837958000169.jpg224170JPEG0007837958000170.jpg242170JPEG0007837958000171.jpg33170.

[0144] Synthesis of control compounds: Compound 60 (referred to as "Reference Compound A") in International Publication No. 2017023774 was obtained according to the synthesis route and work steps for Compound 60 on page 124 of International Publication No. 2017023774.

[0145] Compound 25 (referred to as "Reference Compound 1") from International Publication No. 2017023774 was obtained according to the synthesis route and work steps for Compound 25 on pages 100-101 of International Publication No. 2017023774.

[0146] Compound 9 (referred to as "Reference Compound 2") in International Publication No. 2017023774 was obtained according to the synthesis route and work steps for Compound 9 on pages 87-88 of International Publication No. 2017023774.

[0147] Compound 47 (referred to as "Reference Compound 3") in International Publication No. 2017023774 was obtained according to the synthetic route and work steps for Compound 47 on pages 115-116 of International Publication No. 2017023774.

[0148] Example 7: Stability in different types of plasma For assays of the plasma stability of different types of compounds, reference compound A, reference compound 1, reference compound 2, compound 2, compound 3, compound 81, compound 443, and compound 459 were provided, as shown below. [ka]

[0149] For metabolic stability, canine, monkey, pig, and human plasma were used. For stability testing, the prodrug (1 μM) was spiked into each solution and incubated in an orbital shaker at 37°C. Two 50 μL aliquots of the mixture were taken, and the reaction was quenched by adding four times the volume of ice-cold acetonitrile spiked with an internal standard (dexamethasone 100 ng / mL). The samples were vortexed for 30 seconds and centrifuged at 15000 g for 5 minutes. 100 μL of the supernatant was diluted with 100 μL of water and transferred to a 0.6 mL plastic tube on a 96-well plate. Prodrug elimination was monitored over time using liquid chromatography and tandem mass spectrometry (LC-MS / MS).

[0150] For LC-MS / MS analysis, the prodrug was analyzed using an ExionLC AD HPLC system connected to a REF Triple Quad5500+ mass spectrometer with an ESI interface, on a Phenomenex Kinetex 5 μm C18 100A (2.1*50) mm UPLC column. The autosampler was temperature-controlled and operated at 4°C. The mobile phase used for chromatographic separation consisted of acetonitrile / water containing 0.1% formic acid, and was operated for 3.5 minutes at a flow rate of 0.6 mL / min using gradient elution. Column effluent was monitored using a TSQ Vantage triple quadrupole mass spectrometer with an electrospray probe set to cationization mode. The sample was introduced to the ionization source through a heated atomizing probe (400°C). Prodrug disappearance was measured from the ratio of the analyte peak area to IS.

[0151] To quantify the residual compounds, the disappearance of the prodrug was measured from the ratio of the analyte's peak area to the IS.

[0152] Figure 1 shows the plasma stability of the compounds after incubation for 4 hours in the presence of dog, monkey, pig, and human plasma. The data shows that reference compounds A, 2, 3, 81, 443, and 459 remained substantially unchanged after 4 hours in the presence of dog, monkey, pig, and human plasma, while only a few of reference compounds 1 and 2 remained in such a state.

[0153] Example 8: Stability of liver microsomes from different species For assays of liver microsome stability in different species, reference compounds A, 1, 2, 3, 81, 443, and 459 were provided.

[0154] For metabolic stability, human, monkey, dog, rat, and mouse microsomes were used. For stability testing, a prodrug (1 μM) was spiked into each microsomal matrix and incubated in an orbital shaker at 37°C. 50 μL aliquots were taken from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction was stopped by adding four times the volume of cold acetonitrile along with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0155] For LC-MS / MS analysis, prodrugs were analyzed using a Waters XSelect HSS T3 C18, 2.5 μm, 2.1 × 30 mm column on an AB Inc (Canada) API4000 instrument with an ESI interface connected to a Shimadzu LC system. The mobile phase used for chromatographic separation consisted of phase A: water (0.1% formic acid); phase B: acetonitrile (0.1% formic acid), and gradient elution was used, operating at a flow rate of 1.0 mL / min for 1.0 minute. The sample was introduced into the ionization source through a heated atomizing probe (500°C). Prodrug disappearance was measured from the ratio of the analyte peak area to IS.

[0156] For data analysis, peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the parent drug residue percentage versus incubation time curve. In vitro half-life (in vitro t 1 / 2 ) was determined from the slope value. In Vitro T 1 / 2 =-(0.693 / k)

[0157] In Vitro T 1 / 2 (minutes) In vitro specific clearance (in vitro CL int The conversion to μL / min / mg protein units was performed using the following formula (average of duplicate measurements).

number

[0158] Table 1 shows the in vitro endogenous clearance of the compounds after incubation for 60 minutes in the presence of human, monkey, dog, rat, and mouse liver microsomes.

[0159] [Table 8]

[0160] Example 9: Examination of the antitumor effect of MC38 syngeneic in C57BL / 6 mice Compounds A, 2, 3, 81, 443, and 459 were provided to demonstrate the antitumor effects of C57BL / 6 mice in the MC38 syngeneic line.

[0161] Animal species: House mouse (Mus musculus); Lineage: C57BL / 6; Age: 6-8 weeks old; Sex: Female.

[0162] MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37°C and 5% CO2. Cells growing in the logarithmic phase were collected and counted for tumor inoculation. Cultured MC38 cells were collected and inoculated in PBS containing 50% Matrigel at a rate of 1 × 10⁶ 7 The cells were resuspended at a density of cells / mL. For tumorigenesis, 1 × 10⁶ cells were placed in 0.1 mL of PBS containing 50% Matrigel in the right flank region of each mouse. 6 The cells were inoculated subcutaneously.

[0163] Average tumor size: 79-118 mm 3 (Average tumor size 96mm) 3Treatment was initiated when the tumor reached a certain level. Each group contained eight tumor-bearing mice. Group 1 was treated with a vehicle (10% DMSO + 90% saline), SC, and QD. Group 2 was treated with reference compound A at 2 μmol / kg, SC, and QD. Group 3 was treated with compound 2 at 2 μmol / kg, SC, and QD. The administration of the test substance in each research group is shown in Table 2 below.

[0164] In vivo efficacy was assessed by absolute tumor growth inhibition rate (TGI), and safety was evaluated by changes in mouse body weight and survival rate.

[0165] [Table 9]

[0166] body weight The results of body weight changes in tumor-bearing mice are shown in Table 3 and Figure 2.

[0167] [Table 10]

[0168] Tumor volume Table 4 and Figure 3 show the results of tumor size for different groups at different time points after tumor inoculation. Table 5 summarizes the tumor growth inhibition rates. The results showed that the other treatment groups exhibited a significant antitumor effect compared to the vehicle group. Statistical analysis of the difference in tumor volume between groups was performed using one-way ANOVA, followed by individual comparisons using Games-Howell post-hoc tests (without assuming equal variances). All data were analyzed using SPSS 22.0 software.

[0169] [Table 11]

[0170] [Table 12]

[0171] Example 10: Examination of the antitumor effect of the MC38 model in CES1c- / - mice. Regarding the antitumor effect of the MC38 model in CES1c- / - mice, reference compound A and compound 2 obtained from Example 2 are provided.

[0172] Animal species: Mus musculus; Strain: C57BL / 6-Ces1 cem1Smoc Age: 6-8 weeks old; Sex: Female. (Shanghai model organism). MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37°C and 5% CO2. Cells growing in the logarithmic growth phase were collected and counted for tumor inoculation. Cultured MC38 cells were collected and inoculated in PBS containing 50% Matrigel at a rate of 1 × 10⁶ 7 The cells were resuspended at a density of cells / mL. For tumorigenesis, 1 × 10⁶ cells were placed in 0.1 mL of PBS containing 50% Matrigel in the right flank region of each mouse. 6 Each dose was administered subcutaneously.

[0173] Average tumor size: 52-132 mm 3 (Average tumor size 95mm) 3 Treatment was initiated when the tumor size reached [a certain level]. Each group contained 5 tumor-bearing mice. Group 1 was treated with vehicle (10% DMSO + 90% saline), SC, and QD (subcutaneous injection, once daily). Group 2 was treated with reference compound A at 2 μmol / kg, SC, and QD. Group 3 was treated with compound 2 at 2 μmol / kg, SC, and QD. The administration of the test substance in each research group is shown in Table 6 below.

[0174] In vivo efficacy was assessed by absolute tumor growth inhibition rate (TGI), and safety was evaluated by changes in mouse body weight and survival rate.

[0175] [Table 13]

[0176] body weight The group treated with reference compound A showed some weight loss, but the groups treated with vehicle and compound 2 were well tolerated by the tumor-bearing mice. The results of weight changes in tumor-bearing mice are shown in Table 7 and Figure 4.

[0177] [Table 14]

[0178] Tumor volume Table 8 and Figure 5 show the results of tumor size for different groups at different time points after tumor inoculation. Table 9 summarizes the tumor growth inhibition rates. The results showed that all treatment groups demonstrated a significant antitumor effect compared to the vehicle group. Statistical analysis of the difference in tumor volume between groups was performed using one-way ANOVA, followed by individual comparisons using Games-Howell post-hoc tests (without assuming equal variances). All data were analyzed using SPSS 22.0 software.

[0179] [Table 15]

[0180] [Table 16]

[0181] Example 11: Examination of the antitumor effect of the MC38 model in C57BL / 6 mice Compounds 2, 3, 81, 443, and 459 were provided to demonstrate their antitumor effects in the MC38 model of C57BL / 6 mice.

[0182] Animal species: House mouse (Mus musculus); Lineage: C57BL / 6; Age: 6-8 weeks old; Sex: Female.

[0183] MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37°C and 5% CO2. Cells growing in the logarithmic phase were collected and counted for tumor inoculation. Cultured MC38 cells were collected and inoculated in PBS containing 50% Matrigel at a rate of 1 × 10⁶ 7 The cells were resuspended at a density of cells / mL. For tumorigenesis, 1 × 10⁶ cells were placed in 0.1 mL of PBS containing 50% Matrigel in the right flank region of each mouse. 6 The cells were inoculated subcutaneously.

[0184] Average tumor size: 82-129 mm 3 (Average tumor size 102 mm) 3 Treatment was initiated when the tumor size reached 5. Each group contained 6 tumor-bearing mice. Group 1 was treated with vehicle (10% DMSO + 90% saline), SC, and QD. Group 2 was treated with compound 2 at 2 μmol / kg, SC, and QD. Group 3 was treated with compound 81 at 2 μmol / kg, SC, and QD. Group 4 was treated with compound 443 at 2 μmol / kg, SC, and QD. Group 5 was treated with compound 459 at 2 μmol / kg, SC, and QD. Group 6 was treated with compound 3 at 2 μmol / kg, SC, and QD. The administration of the test substance in each research group is shown in Table 10 below.

[0185] In vivo efficacy was assessed by absolute tumor growth inhibition rate (TGI), and safety was evaluated by changes in mouse body weight and survival rate.

[0186] [Table 17]

[0187] body weight The results of weight changes in tumor-bearing mice are shown in Table 11 and Figure 6.

[0188] [Table 18]

[0189] Tumor volume Table 12 and Figure 7 show the results of tumor size for different groups at different time points after tumor inoculation. Table 13 summarizes the tumor growth inhibition rates. The results showed that the other treatment groups exhibited a significant antitumor effect compared to the vehicle group. Statistical analysis of the difference in tumor volume between groups was performed using one-way ANOVA, followed by individual comparisons using the Games-Howell post-hoc test (equal variances were not assumed). All data were analyzed using SPSS 22.0 software.

[0190] [Table 19]

[0191] [Table 20]

Claims

1. A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, wherein the compound is (1) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-isopropyl oxohexanoate, (2) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-methyl oxohexanoate, (3) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoic acid, (4) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-ethyl oxohexanoate, (5) (S)-6-diazo-2-(2-methoxyacetamide)-5-isopropyl oxohexanoate, (6) (S)-6-diazo-2-(2-ethoxyacetamide)-5-isopropyl oxohexanoate, (7) (S)-6-diazo-2-((S)-2-hydroxypropanamide)-5-isopropyl oxohexanoate, (8) (S)-6-diazo-2-((S)-2-hydroxy-4-methylpentanamide)-5-isopropyl oxohexanoate, (9) (S)-6-diazo-2-((S)-2-ethoxypropanamide)-5-isopropyl oxohexanoate, (10) (S)-6-diazo-2-((S)-2-isopropoxypropanamide)-5-isopropyl oxohexanoate, (11) (S)-6-diazo-2-(2-hydroxyacetamide)-5-isopropyl oxohexanoate, (12) (S)-6-diazo-2-((S)-2-hydroxybutanamide)-5-isopropyl oxohexanoate, (13) (S)-6-diazo-2-((S)-2-methoxybutanamide)-5-isopropyl oxohexanoate, (14) (S)-6-diazo-2-((S)-2-ethoxybutanamide)-5-isopropyl oxohexanoate, (15) (S)-6-diazo-2-((S)-2-isopropoxybutanamide)-5-isopropyl oxohexanoate, (16) (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-isopropyl oxohexanoate, (17) (S)-6-diazo-2-((S)-2-methoxy-3-methylbutanamide)-5-isopropyl oxohexanoate, (18) (S)-6-diazo-2-((S)-2-ethoxy-3-methylbutanamide)-5-isopropyl oxohexanoate, (19) (S)-6-diazo-2-((S)-2-isopropoxy-3-methylbutanamide)-5-isopropyl oxohexanoate, (20) (S)-6-diazo-2-((2S,3R)-2-hydroxy-3-methylpentanamide)-5-isopropyl oxohexanoate, (21) (S)-6-diazo-2-((2S,3R)-2-methoxy-3-methylpentanamide)-5-isopropyl oxohexanoate, (22) (S)-6-diazo-2-((2S,3R)-2-ethoxy-3-methylpentanamide)-5-isopropyl oxohexanoate, (23) (S)-6-diazo-2-((2S,3R)-2-isopropoxy-3-methylpentanamide)-5-isopropyl oxohexanoate, (24) (S)-6-diazo-2-((S)-2-hydroxypentanamide)-5-isopropyl oxohexanoate, (25) (S)-6-diazo-2-((S)-2-methoxypentanamide)-5-isopropyl oxohexanoate, (26) (S)-6-diazo-2-((S)-2-ethoxypentanamide)-5-isopropyl oxohexanoate, (27) (S)-6-diazo-2-((S)-2-isopropoxypentanamide)-5-isopropyl oxohexanoate, (28) (S)-6-diazo-2-((S)-2-methoxy-4-methylpentanamide)-5-isopropyl oxohexanoate, (29) (S)-6-diazo-2-((S)-2-ethoxy-4-methylpentanamide)-5-isopropyl oxohexanoate, (30) (S)-6-diazo-2-((S)-2-isopropoxy-4-methylpentanamide)-5-isopropyl oxohexanoate, (31) (S)-6-diazo-2-((S)-2-hydroxy-3,3-dimethylbutanamide)-5-isopropyl oxohexanoate, (32) (S)-6-diazo-2-((S)-2-methoxy-3,3-dimethylbutanamide)-5-isopropyl oxohexanoate, (33) (S)-6-diazo-2-((S)-2-ethoxy-3,3-dimethylbutanamide)-5-isopropyl oxohexanoate, (34) (S)-6-diazo-2-((S)-2-isopropoxy-3,3-dimethylbutanamide)-5-isopropyl oxohexanoate, (35) (S)-6-diazo-2-((S)-2-hydroxyhexaneamide)-5-isopropyl oxohexanoate, (36) (S)-6-diazo-2-((S)-2-methoxyhexaneamide)-5-isopropyl oxohexanoate, (37) (S)-6-diazo-2-((S)-2-ethoxyhexanamide)-5-isopropyl oxohexanoate, (38) (S)-6-diazo-2-((S)-2-isopropoxyhexanamide)-5-isopropyl oxohexanoate, (39) (S)-6-diazo-2-(3-methoxy-2-oxopropanamide)-5-isopropyl oxohexanoate, (40) (S)-6-diazo-2-(3-hydroxy-2-oxopropanamide)-5-isopropyl oxohexanoate, (41) (S)-6-diazo-2-(3-hydroxypropanamide)-5-isopropyl oxohexanoate, (42) (S)-6-diazo-2-((S)-3-hydroxybutanamide)-5-isopropyl oxohexanoate, (43) (S)-6-diazo-2-(3-methoxypropanamide)-5-isopropyl oxohexanoate, (44) (S)-6-diazo-2-((S)-3-methoxybutanamide)-5-isopropyl oxohexanoate, (45) (S)-6-diazo-2-((S)-3-hydroxy-2-methylpropanamide)-5-isopropyl oxohexanoate, (46) (S)-6-diazo-2-((S)-3-methoxy-2-methylpropanamide)-5-isopropyl oxohexanoate, (47) (S)-6-diazo-2-((2S,3R)-3-hydroxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (48) (S)-6-diazo-2-((2S,3R)-3-methoxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (49) (S)-6-diazo-2-((2R,3R)-3-hydroxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (50) (S)-6-diazo-2-((2R,3R)-3-methoxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (51) (S)-6-diazo-2-((2R,3S)-3-hydroxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (52) (S)-6-diazo-2-((2R,3S)-3-methoxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (53) (S)-6-diazo-2-((R)-3-hydroxybutanamide)-5-isopropyl oxohexanoate, (54) (S)-6-diazo-2-((2S,3S)-3-hydroxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (55) (S)-6-diazo-2-((2S,3S)-3-methoxy-2-methylbutanamide)-5-isopropyl oxohexanoate, (56) (S)-6-diazo-2-((R)-3-methoxybutanamide)-5-isopropyl oxohexanoate, (57) (S)-6-diazo-2-((R)-3-hydroxy-2-methylpropanamide)-5-isopropyl oxohexanoate, (58) (S)-6-diazo-2-((R)-3-methoxy-2-methylpropanamide)-5-isopropyl oxohexanoate, (59) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate tert-butyl, (60) (S)-6-diazo-2-((R)-2-methoxypropanamide)-5-oxohexanoate tert-butyl, (61) (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-isopropyl oxohexanoate, (62) (S)-6-diazo-2-(2-hydroxy-2-methylpropanamide)-5-isopropyl oxohexanoate, (63) (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-methyl oxohexanoate, (64) (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-methyloxohexanoate, (65) (S)-6-diazo-2-(2-isopropoxyacetamide)-5-methyl oxohexanoate, (66) (S)-6-diazo-2-((S)-2-hydroxypropanamide)-5-oxohexanoic acid, (67) (S)-6-diazo-2-(2-isopropoxyacetamide)-5-isopropyl oxohexanoate, (68) (S)-6-diazo-2-(2-methoxyacetamide)-5-methyl oxohexanoate, (69) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanothioate S-isopropyl, (70) (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-oxohexanoic acid, (71) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-isopropyl oxohexanoate, (72) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanoic acid, (73) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-methyl oxohexanoate, (74) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-ethyl oxohexanoate, (75) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanothioate S-isopropyl, (76) (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamide)-5-isopropyl oxohexanoate, (77) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-methyl-d3 oxohexanoate, (78) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-ethyl-2,2,2-d3 oxohexanoate, (79) (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamide)-5-isopropyl oxohexanoate, (80) (S)-6-diazo-2-(2-(ethoxy-d5)acetamide)-5-isopropyl oxohexanoate, (81) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-ethyl oxohexanoate-d5, (82) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate propane-2-yl-d7, (83) (S)-6-diazo-2-((S)-2-hydroxypropanamide)-5-oxohexanoate propane-2-yl-d7, (84) (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-oxohexanoate propane-2-yl-d7, (85) (S)-6-diazo-2-(2-ethoxyacetamide)-5-oxohexanoate propane-2-yl-d7, (86) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanothio acid S-(propan-2-yl-d7), (87) (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-d7, (88) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-methyl-d3 oxohexanoate, (89) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-ethyl-2,2,2-d3 oxohexanoate, (90) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-ethyl-d5 oxohexanoate, (91) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanoate propane-2-yl-d7, (92) (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamide)-5-oxohexanoate propane-2-yl-d7, (93) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanothio acid S-(propan-2-yl-d7), (94) (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-d7, (95) (S)-6-diazo-2-(2-(ethoxy-d5)acetamide)-5-oxohexanoate propane-2-yl-d7, (96) 6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate-2-d methyl, (97) 6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate-2-d ethyl, (98) 6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate-2-d isopropyl, (99) 6-diazo-2-(2-ethoxyacetamide)-5-oxohexanoate-2-d isopropyl, (100) 6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanothioate-2-dS-isopropyl, (101) 6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-oxohexanoate-2-d isopropyl, (102) 6-diazo-2-((S)-2-hydroxypropanamide)-5-oxohexanoate-2-d isopropyl, (103) 6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-oxohexanoate-2-d isopropyl, (104)(S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (105)(S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamide)-5-propan-2-yl-1,1,1,3,3,3-d6 oxohexanoate (106)(S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanothioic acid S-(propan-2-yl-1,1,1,3,3,3-d6), (107)(S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (108)(S)-6-diazo-2-(2-(ethoxy-d5)acetamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (109)(S)-6-diazo-2-((S)-2-hydroxypropanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (110)(S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (111)(2S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (112)(2S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (113)(2S)-6-diazo-2-((S)-2-(methoxy-d3)propanamide)-5-oxohexanothioate S-(propan-2-yl-1,1,1-d3), (114)(2S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (115)(2S)-6-diazo-2-(2-(ethoxy-d5)acetamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (116)(2S)-6-diazo-2-((S)-2-hydroxypropanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (117)(2S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (118) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (119) (S)-6-diazo-2-(2-ethoxyacetamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (120) (S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanothioic acid S-(propan-2-yl-1,1,1,3,3,3-d6), (121)(S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-1,1,1,3,3,3-d6, (122)(2S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (123)(2S)-6-diazo-2-(2-ethoxyacetamide)-5-oxohexanoate propane-2-yl-1,1,1-d3, (124)(2S)-6-diazo-2-((S)-2-methoxypropanamide)-5-oxohexanothioic acid S-(propan-2-yl-1,1,1-d3), or (125)(2S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamide)-5-oxohexanoate propane-2-yl-1,1,1-d3 A compound, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, or an isotopic substitution thereof, selected from the above. 【Request Item 2】 【Chemistry 1】 Compounds selected from, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or isotopic substitutions thereof. 【Request Item 3】 【Chemistry 2】 A compound that is, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 4, for the manufacture of an agent for treating cancer.

6. The use according to claim 5, wherein the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma, or head and neck cancer.

7. The pharmaceutical composition according to claim 4 for use as a drug.

8. The pharmaceutical composition according to claim 4 for use as a glutamine antagonist.

9. The pharmaceutical composition according to claim 4 for use in the treatment of cancer.

10. The pharmaceutical composition according to claim 9, wherein the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma, or head and neck cancer.

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