Glutamine analogs

Abstract

The present invention relates to a glutamine analogue, a composition containing the glutamine analogue and use thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of PCT Application No. PCT / CN2020 / 121114, filed on October 15, 2020, PCT Application No. PCT / CN2021 / 072111, filed on January 15, 2021, and PCT Application No. PCT / CN2021 / 076491, filed on February 10, 2021. The entire contents of these applications are incorporated herein by reference. Technical Field

[0003] The present invention relates to a novel glutamine analogue, a pharmaceutical composition comprising the glutamine analogue, and applications thereof. Technical Background

[0004] Glutamine antagonists, such as 6-diazo-5-oxo-L-norleucine (DON), have demonstrated anticancer activity. However, their clinical development has been hampered by the development of severe toxicities (e.g., dose-limiting GI toxicities, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain) when administered at therapeutic doses.

[0005] Previous attempts to mitigate the severe toxicities associated with glutamine antagonists such as DON have been unsuccessful. Therefore, the development of new glutamine antagonists is needed to meet clinical needs. Summary of the Invention

[0006] In one aspect, the present invention provides a compound as shown in Formula I, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof.

[0007]

[0008] in,

[0009] Z is OR1 or SR1; each R1 is independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -C 0-6 Alkylene-C 3-8 Heterocyclic group, -C 0-6 Alkylene-NH-C 0-6 Alkylene C 6-10 Aryl, -C 0-6 Alkylene-NH-C 0-6 Alkylene-5-12 membered heteroaryl, -C 0-6 Alkylene-C 6-10 Aryl and -C 0-6The group consisting of alkylene-5-12 membered heteroaryl; wherein each heteroaryl and heterocyclic group contains 1, 2 or 3 heteroatoms selected from N, O or S; and each of said R1 is arbitrarily substituted by one or more substituents, said substituents being independently selected from the group consisting of: deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -NH-C 3-8 Cycloalkyl, carboxyl and -CO-C 1-6 alkyl;

[0010] X is selected from the group consisting of hydrogen, deuterium, C 1-6 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 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 RX2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m -G-NR5R5';

[0011] W is O, CO, or a bond;

[0012] m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0013] p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;

[0014] R X1 and R X2 are independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 4-10 Cycloalkyl, -C(=O)-C 1-6 Alkyl, C 5-12 Aryl, –C 1-6 Alkylene-C 5-12 Aryl, -5-12 membered heteroaryl and -

[0015] C 1-6 Alkylene-5-12 membered heteroaryl; wherein said C 1-6 Alkyl, the C 1-6 Alkoxy, the C 4-10 Cycloalkyl, the C 5-12 Aryl, the –C 1-6 Alkylene-C 5-12 aryl, the -5-12 membered heteroaryl and the -C 1-6 Alkylene-5-12 membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -SC 1-6 alkyl, carboxyl; and each heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] or R X1 and R X2 Together with the carbon atom to which they are attached, they form C 3-10 Carbocyclic group, C 3-10-membered heterocyclic group, and each heterocyclic group independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each carbocyclic group or heterocyclic group may be optionally substituted by one or more substituents independently selected from the group consisting of: deuterium, halogen, -NH2, -CN, -OH,

[0017] -NO2, carbonyl, =O, oxo, carboxyl, C 1-6 Alkoxy, C 1-6 alkyl;

[0018] R X3 independently selected from the group consisting of hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl and -C 1-6 Alkylene-C 5-12 Aryl, wherein the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 3-8 Cycloalkyl,

[0019] -C(=O)-C 1-6 Alkyl and the -C 1-6 Alkylene-C 5-12 Aryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl, 4-8 membered heterocyclic group, -C 6-12 Aryl,

[0020] -C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 Alkyl)2;

[0021] or R X1 and R X3 Together with the carbon atom and oxygen atom to which they are attached, they form a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 wherein each heterocyclic group independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0022] Each R5 and R5' is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, C 5-12 aryl, 5-12 membered heteroaryl, and 5-12 membered heterocyclyl, and the -C 1-6 Alkyl, the -C 1-6 Alkoxy, the -C 3-8 Cycloalkyl, the C 5-12 The aryl group, the 5-12 membered heteroaryl group, the 5-12 membered heterocyclic group, may be optionally substituted with one or more substituents, the substituents being independently selected from the group consisting of: deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0023] Each R6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, 5-12 membered heterocyclic group, -C 1-6 Alkenyl, and -C 3-8 Cycloalkenyl, wherein the -C 1-6 Alkyl, the -C 3-8 Cycloalkyl, the 5-12 membered heterocyclic group, the -C 1-6 Alkenyl and the -C 3-8 Cycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0024] Or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;

[0025] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, 5-12 membered heterocyclic group, C 1-6 Alkenyl, C 3-8 Cycloalkenyl, C 5-12 Aryl, and 5-12 membered heteroaryl, wherein the C 1-6 Alkyl, the C 3-8 Cycloalkyl, the 5-12 membered heterocyclic group, the C 1-6 Alkenyl, the C 3-8 Cycloalkenyl, the C 5-12 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, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0026] Each of R8 and R9 is independently selected from the group consisting of: C 1-6 Alkyl, C 3-8 Cycloalkyl, monosaccharide, acylated monosaccharide, C 5-12 Aryl and 5-12 membered heteroaryl, and the C 1-6 Alkyl, the C 3-8 Cycloalkyl, the monosaccharide, the acylated monosaccharide, the C 5-12 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, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0027] G is C 5-12 Aryl or 5-12 membered heteroaryl, wherein C 5-12 Aryl and 5-12 membered heteroaryl groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6alkyl)2, carboxyl;

[0028] R2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, and the C 1-6 Alkyl and the C 1-6 The alkoxy group may be optionally replaced by one or more independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl) 2, carboxyl substituent substitution;

[0029] Each R3 and R3' is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl, and C 1-6 Alkoxy, and the C 1-6 Alkyl and the C 1-6 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0030] Y is a bond, O or -(CR Y1 R Y2 ) n -;

[0031] n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0032] Each R Y1 and R Y2 independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl, and C 1-6 Alkoxy, and the C 1-6 Alkyl and the C 1-6 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6alkyl)2, carboxyl;

[0033] R4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, and the C 1-6 Alkyl and the C 1-6 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0034] R 10 Selected from the group consisting of: hydrogen, deuterium, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, and the C 1-6 Alkyl and the C 1-6 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, carboxyl.

[0035] In some embodiments of Formula I, the compound is a compound represented by Formula IA, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope thereof:

[0036]

[0037] In some embodiments of Formula I, the compound is a compound of Formula IB, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope thereof:

[0038]

[0039] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, -C 3-8 Cycloalkyl, -C 0-3Alkylene-C 3-8 Heterocyclic group, -C 0-3 Alkylene-NH-C 0-3 Alkylene C 6-10 Aryl, -C 0-3 Alkylene-NH-C 0-3 Alkylene-5-12 membered heteroaryl, -C 0-3 Alkylene-C 6-10 Aryl and -C 0-3 Alkylene-5-12 membered heteroaryl; each heteroaryl and heterocyclic group contains 1 or 2 heteroatoms selected from N, O or S; and each R1 is arbitrarily substituted with one or more substituents independently selected from the group consisting of: deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -NH-C 3-8 Cycloalkyl, -N(C 1-6 Alkyl)2, carboxyl, -CO-C 1-6 alkyl.

[0040] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, -C 3-8 Cycloalkyl, -C 0-3 Alkylene-C 3-8 Heterocyclic group, -C 0-3 Alkylene-NH-C 0-3 Alkylene C 6-10 Aryl, -C 0-3 Alkylene-NH-C 0-3 Alkylene-5-12 membered heteroaryl, -C 0-3 Alkylene-C 6-10 Aryl and -C 0-3 Alkylene-5-12 membered heteroaryl; and each heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and each R1 may be optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -NH-C 3-6 Cycloalkyl, -N(C 1-3Alkyl)2, carboxyl, -CO-C 1-3 alkyl.

[0041] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0042] R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,

[0043] and each R1 is arbitrarily substituted by one or more substituents independently selected from the group consisting of deuterium, F,

[0044] Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -NH-C 3-6

[0045] Cycloalkyl, -N(C 1-3 Alkyl)2, carboxyl, -CO-C 1-3 alkyl.

[0046] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic substitutions, wherein R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, and each R1 is arbitrarily substituted by 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, isopropyloxy, -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.

[0047] In some embodiments, the compounds of Formula I, IA, and IB, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein R1 is selected from 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,

[0048] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0049] X is selected from the group consisting of hydrogen, deuterium, C 1-6 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-(CR X1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q 、-C(=O)-W-(CRX1 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 -G-NR5R5';

[0050] W is O, CO, or a bond;

[0051] m is selected from 1, 2 or 3;

[0052] p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;

[0053] Each R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 1-3 Alkoxy, C 4-8 Cycloalkyl, -C(=O)-C 1-3 Alkyl, C 5-10 Aryl, -C 1-3 Alkylene-C 5-10 Aryl, 5-10 membered heteroaryl, and -C 1-3 Alkylene-5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 1-3 Alkoxy, the C 4-8 Cycloalkyl, the C 5-10 Aryl, the -C 1-3 Alkylene-C 5-10 Aryl, the 5-10 membered heteroaryl and the -C 1-3 Alkylene-5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6Alkyl)2, -SC 1-6 alkyl, or carboxyl; and each heteroaryl group independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0054] or R X1 and R X2 Together with the carbon atom to which they are attached, they form C 4-8 Carbon ring, C 4-8 each heterocyclic group optionally containing 1, 2 or 3 heteroatoms selected from N, O or S; each carbocyclic or heterocyclic group may be optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C 1-6 Alkoxy, C 1-6 alkyl;

[0055] R X3 independently selected from the group consisting of hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -C(=O)-C 1-3 Alkyl and -C 1-3 Alkylene-C 5-10 Aryl, wherein the C 1-3 Alkyl, the C 1-3 Alkoxy, the C 3-6 Cycloalkyl, the -C(=O)-C 1-3 Alkyl and the -C 1-3 Alkylene-C 5-10 Aryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl, 4-8 membered heterocyclic group, -C 6-12 Aryl, -C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl and -C(=O)-N(C 1-6 Alkyl)2;

[0056] or R X1 and R X3Together with the carbon atom and oxygen atom to which they are attached, they form a 5-10 membered heterocyclic group, which may be optionally substituted by one or more independently selected from deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 or carboxyl substituents; and each heterocyclic group independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0057] Each R5 and R5' is independently selected from the group consisting of hydrogen, deuterium, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, C 5-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic group, the -C 1-3 Alkyl, -C 1-3 Alkoxy, the -C 3-6 Cycloalkyl, the C 5-10 The aryl group, the 5-10 membered heteroaryl group, the 5-10 membered heterocyclic group, may be optionally substituted with one or more substituents, the substituents being independently selected from the group consisting of: deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0058] Each R6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-3 Alkyl, -C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, -C 1-3 Alkenyl and -C 3-6 Cycloalkenyl, and the -C 1-3 Alkyl, the -C 3-6 Cycloalkyl, the 5-10 membered heterocyclic group, the -C 1-3 Alkenyl and the -C 3-6 Cycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0059] or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;

[0060] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 1-3 Alkenyl, C 3-6 Cycloalkenyl, C 5-10 Aryl and 5-10 membered heteroaryl, the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the 5-10 membered heterocyclic group, the C 1-3 Alkenyl, the C 3-6 Cycloalkenyl, the C 5-10 The aryl group and the 5-10 membered heteroaryl group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl;

[0061] Each of R8 and R9 is independently selected from the group consisting of: C 1-3 Alkyl, C 3-6 Cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 Aryl and 5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the monosaccharide, the acylated monosaccharide, the C 5-10 The aryl group and the 5-10 membered heteroaryl group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, carboxyl; or

[0062] G is C 5-10 Aryl or 5-10 membered heteroaryl, wherein C 5-10 Aryl and 5-10 membered heteroaryl groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 alkyl,

[0063] -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, carboxyl.

[0064] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0065] X is selected from the group consisting of hydrogen, deuterium, C 1-3 Alkyl, –C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 、

[0066] -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 、

[0067] -C(=O)-W-(CR X1 R X2 ) m -G, -C(=O)-W-(CR X1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q 、

[0068] -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,

[0069] -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m -G-NR5R5';

[0070] W is O or a bond;

[0071] m is selected from 1, 2 or 3;

[0072] p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;

[0073] Each R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 1-3 Alkoxy,

[0074] C 4-8 Cycloalkyl, -C(=O)-C 1-3 Alkyl, C 5-10 Aryl, –C 1-3 Alkylene-C 5-10 Aryl, 5-10 membered heteroaryl and –C 1-3 Alkylene-5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 1-3 Alkoxy, the C 4-8 Cycloalkyl, the C 5-10 Aryl, the –C 1-3 Alkylene-C 5-10 aryl, the 5-10 membered heteroaryl and the -C 1-3 Alkylene-5-10 membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH,

[0075] Oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-3 Alkyl)2, -SC 1-3 alkyl, carboxyl; and each heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0076] or R X1 and R X2Together with the carbon atom to which they are attached, they form C 4-6 Carbon ring, C 4-6 The heterocyclic group is a ring system, wherein each heterocyclic group independently contains 1, 2 or 3 heteroatoms selected from N, O or S; each ring system may be optionally substituted by one or more substituents independently selected from the group consisting of: deuterium, halogen, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C 1-3 Alkoxy, C 1-3 alkyl;

[0077] R X3 The radicals are independently selected from the group consisting of hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, -C(=O)-C 1-3 Alkyl and -C 1-3 Alkylene-C 5-10 Aryl, wherein the C 1-3 Alkyl, the C 1-3 Alkoxy, the C 3-6 Cycloalkyl, the -C(=O)-C 1-3 Alkyl and the -C 1-3 Alkylene-C 5-10 Aryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl, 4-6 membered heterocyclic group, -C 6-10 Aryl, -C(=O)-C 1-3 Alkyl, -NH-C(=O)-C 1-3 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-3 Alkyl, -C(=O)-N(C 1-3 Alkyl)2;

[0078] or R X1 and R X3 Together with the carbon atom and oxygen atom to which they are commonly attached, they form a 5-10 membered heterocyclic group, wherein the 5-10 membered heterocyclic group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 and each heterocyclic group independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each R5 and R5' are independently selected from the group consisting of: hydrogen, deuterium, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, C 5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic group, and the -C 1-3 Alkyl, -C 1-3 Alkoxy, the -C 3-6 Cycloalkyl, the C 5-10 The aryl group, the 5-10 membered heteroaryl group, the 5-10 membered heterocyclic group, may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl;

[0079] Each R6 is independently selected from the group consisting of hydrogen, deuterium, -C 1-3 Alkyl, -C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, -C 1-3 Alkenyl and -C 3-6 Cycloalkenyl, and the -C 1-3 Alkyl, the -C 3-6 Cycloalkyl, the 5-10 membered heterocyclic group, the -C 1-3 Alkenyl and the -C 3-6 Cycloalkenyl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl;

[0080] or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;

[0081] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl, C 3-6Cycloalkyl, 5-10 membered heterocyclic group, C 1-3 Alkenyl, C 3-6 Cycloalkenyl, C 5-10 Aryl and 5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the 5-10 membered heterocyclic group, the C 1-3 Alkenyl, the C 3-6 Cycloalkenyl, the C 5-10 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl) 2, carboxyl; each R8 and R9 are independently selected from the group consisting of: C 1-3 Alkyl, C 3-6 Cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 Aryl and 5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the monosaccharide, the acylated monosaccharide, the C 5-10 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl; or

[0082] G is C 5-10 Aryl or 5-10 membered heteroaryl, wherein C 5-10 Aryl and 5-10 membered heteroaryl groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, carboxyl.

[0083] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0084] X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 、

[0085] -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 、

[0086] -C(=O)-W-(CR X1 R X2 ) m -G, -C(=O)-W-(CR X1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q 、

[0087] -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,

[0088] -C(=O)-O-R7, -C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-G and -C(=O)-W-(CR X1 R X2 ) m-G-NR5R5';

[0089] W is O or a bond;

[0090] m is selected from 1, 2 or 3;

[0091] p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;

[0092] Each R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, C4 cycloalkyl,

[0093] 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,

[0094] -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C5 aryl, -(CH2)2-C6 aryl, -(CH2)2-C7 aryl,

[0095] -(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 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, -(CH2)2-10-membered heteroaryl, -(CH2)3-5-membered heteroaryl, -(CH2)3-6-membered heteroaryl, -(CH2)3-7-membered heteroaryl, -(CH2)3-8-membered heteroaryl,

[0096] -(CH2)3-9 membered heteroaryl and -(CH2)3-10 membered heteroaryl, and the methyl, ethyl, propyl, isopropyl,

[0097] The methoxy group, the ethoxy group, the propoxy group, the isopropoxy group, the C5 aryl group, the C6 aryl group, the C7 aryl group, the C8 aryl group, the C9 aryl group, the 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,

[0098] 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 10 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 -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 Aryl, 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 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-3 Alkyl)2, -SC 1-3alkyl, carboxyl; and each heteroaryl group independently optionally contains 1 or 2 heteroatoms selected from N, O or S;

[0099] or R X1 and R X2 Together with the carbon atoms to which they are commonly attached, they form a 3-membered carbocyclic ring, a 4-membered carbocyclic ring, a 5-membered carbocyclic ring or a 6-membered carbocyclic ring, a 4-membered heterocyclic ring, a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, and each heterocyclic ring independently optionally contains 1 or 2 heteroatoms selected from N or O; each ring system may be optionally substituted by one or more independently selected from the group consisting of: deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, oxo, carboxyl, C 1-3 Alkoxy, C 1-3 Substitution of alkyl groups;

[0100] R X3 independently selected from the group consisting of hydrogen, deuterium, 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, -(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 Aryl, -(CH2)3-C 10Aryl, wherein the methyl, the ethyl, the propyl, the isopropyl, the methoxy, the ethoxy, the propoxy, the isopropoxy, the C3 cycloalkyl, the C4 cycloalkyl, the C5 cycloalkyl, the C6 cycloalkyl, the -C(=O)-CH3, the -C(=O)-CH2CH3, the -C(=O)-CH2CH2CH3, the -C(=O)-CH(CH3)2, the -CH2-C5 aryl, the -(CH2)2-C5 aryl, 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 -(CH2)2-C 10 Aryl and the -(CH2)3-C 10 Aryl, optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl, 4-6 membered heterocyclic group, -C 6-10 Aryl, -C(=O)-C 1-3 Alkyl, -NH-C(=O)-C 1-3 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-3 Alkyl and -C(=O)-N(C 1-3 Alkyl)2;

[0101] or R X1 and R X3 Together with the carbon atom and oxygen atom to which they are commonly attached, they form a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, an 8-membered heterocyclic group, a 9-membered heterocyclic group, or a 10-membered heterocyclic group, wherein the 4-membered heterocyclic group, the 5-membered heterocyclic group, the 6-membered heterocyclic group, the 7-membered heterocyclic group, the 8-membered heterocyclic group, the 9-membered heterocyclic group, or the 10-membered heterocyclic group 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, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 and each heterocyclic group independently optionally contains 1 or 2 heteroatoms selected from N, O or S; R5 and R5' are each independently selected from the group consisting of 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 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered heterocyclic radical, 6-membered heterocyclic radical, 7-membered heterocyclic radical, 8-membered heterocyclic radical, 9-membered heterocyclic radical, 10-membered heterocyclic radical, and the methyl, the ethyl, the propyl, the isopropyl, the methoxy, the ethoxy, the propoxy, the isopropoxy, the -C3 cycloalkyl, the -C4 cycloalkyl, the -C5 cycloalkyl, the -C6 cycloalkyl, the C5 aryl, the C6 aryl, the C7 aryl, the C8 aryl, the C9 aryl, the C 10 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, 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl;

[0102] Each 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, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, vinyl, propenyl, -C3 cycloalkenyl, -C4 cycloalkenyl, -C5 cycloalkenyl, -C6 cycloalkenyl, and the methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, , the -C5 cycloalkyl, the -C6 cycloalkyl, the 5-membered heterocyclyl, the 6-membered heterocyclyl, the 7-membered heterocyclyl, the 8-membered heterocyclyl, the 9-membered heterocyclyl, the 10-membered heterocyclyl, the vinyl, the propenyl, 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl;

[0103] or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;

[0104] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, ethenyl, propenyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 The methyl group, the ethyl group, the propyl group, the isopropyl group, the C3 cycloalkyl group, the C4 cycloalkyl group, the C5 cycloalkyl group, the C6 cycloalkyl group, the 5-10 membered heterocyclic group, the 5-membered heterocyclic group, the 6-membered heterocyclic group, the 7-membered heterocyclic group, the 8-membered heterocyclic group, the 9-membered heterocyclic group, the 10-membered heterocyclic group, the vinyl group, the propenyl group, the C3 cycloalkenyl group, the C4 cycloalkenyl group, the C5 cycloalkenyl group, the C6 cycloalkenyl group, the C5 aryl group, the C6 aryl group, the C7 aryl group, the C8 aryl group, the C9 aryl group, the C 10The 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl, the 9-membered heteroaryl, 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2, carboxyl;

[0105] R8 and R9 are each independently selected from the group consisting of: C 1-3 Alkyl, C 3-6 Cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 Aryl and 5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the monosaccharide, the acylated monosaccharide, the C 5-10 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl,

[0106] -NH2、-NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 or carboxyl; or

[0107] G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, wherein the C5 aryl, the C6 aryl, the C7 aryl, the C8 aryl, the C9 aryl, the C 10 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, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, carboxyl.

[0108] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0109] X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, -C(=O)-G, -C(=O)-W-(CR X1 R X2 ) m -OR X3 、

[0110] -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 、–

[0111] C(=O)-W-(CR X1 R X2 ) m -G、–C(=O)-W-(CR X1 R X2 ) m -NR5R5', -P(=O)(OR6) p (NHR7) q 、–

[0112] C(=O)-W-(CR X1 R X2 ) m -GOC(=O)-R8, –C(=O)-W-(CR X1 R X2 ) m -GO-R8,

[0113] 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 –

[0114] C(=O)-W-(CR X1R X2 ) m -G-NR5R5';

[0115] W is O or a bond;

[0116] m is selected from 1, 2 or 3;

[0117] p and q are each independently selected from 0, 1 or 2, provided that the sum of p and q is 2;

[0118] R X1 and R X2 Each is independently selected from the group consisting of 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) 2-10 membered heteroaryl, -(CH2)3-5 membered heteroaryl, -(CH2)3-6 membered heteroaryl, -(CH2)3-7 membered heteroaryl, -(CH2)3-8 membered heteroaryl, -(CH2)3-9 membered heteroaryl and -(CH2)3-10 membered heteroaryl, 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 -(C H2) 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 heteroaryl and the -(CH2)3-10 membered heteroaryl are 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, isopropyloxy, -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 independently optionally contains 1 or 2 heteroatoms selected from N, O or S;

[0119] or R X1 and R X2 Together with the carbon atoms to which they are commonly attached, they form a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each ring system 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, isopropoxy;

[0120] R X3independently selected from the group consisting of hydrogen, deuterium, 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, -(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 Aryl, -(CH2)3-C 10 Aryl, wherein the methyl, the ethyl, the propyl, the isopropyl, the methoxy, the ethoxy, the propoxy, the isopropoxy, the C3 cycloalkyl, the C4 cycloalkyl, the C5 cycloalkyl, the C6 cycloalkyl, the -C(=O)-CH3, the -C(=O)-CH2CH3, the -C(=O)-CH2CH2CH3, the -C(=O)-CH(CH3)2, the -CH2-C5 aryl, the -(CH2)2-C5 aryl, 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 -(CH2)2-C 10 Aryl and the -(CH2)3-C 10 Aryl, 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, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -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;

[0121] or R X1 and R X3 Together with the carbon atom and oxygen atom to which they are commonly attached, they form a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, an 8-membered heterocyclic group, a 9-membered heterocyclic group, or a 10-membered heterocyclic group, wherein the 4-membered heterocyclic group, the 5-membered heterocyclic group, the 6-membered heterocyclic group, the 7-membered heterocyclic group, the 8-membered heterocyclic group, the 9-membered heterocyclic group, or the 10-membered heterocyclic group 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; and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;

[0122] Each R5 and R5' is independently selected from the group consisting of 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 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, 10-membered heteroaryl, 5-membered heterocyclic radical, 6-membered heterocyclic radical, 7-membered heterocyclic radical, 8-membered heterocyclic radical, 9-membered heterocyclic radical, 10-membered heterocyclic radical, and the methyl, the ethyl, the propyl, the isopropyl, the methoxy, the ethoxy, the propoxy, the isopropoxy, the -C3 cycloalkyl, the -C4 cycloalkyl, the -C5 cycloalkyl, the -C6 cycloalkyl, the C5 aryl, the C6 aryl, the C7 aryl, the C8 aryl, the C9 aryl, the C 10The 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, 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, 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;

[0123] Each 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, 6-membered heterocyclyl, 7-membered heterocyclyl, 8-membered heterocyclyl, 9-membered heterocyclyl, 10-membered heterocyclyl, vinyl, propenyl, -C3 cycloalkenyl, -C4 cycloalkenyl, -C5 cycloalkenyl, -C6 cycloalkenyl, and the methyl, ethyl, propyl, isopropyl, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, the 5-membered heterocyclyl, the 6-membered heterocyclyl, the 7-membered heterocyclyl, the 8-membered heterocyclyl, the 9-membered heterocyclyl, the 10-membered heterocyclyl, the vinyl, the propenyl 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, 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;

[0124] or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;

[0125] Each R7 is independently selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, vinyl, propenyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl,

[0126] C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 The methyl group, the ethyl group, the propyl group, the isopropyl group, the C3 cycloalkyl group, the C4 cycloalkyl group, the C5 cycloalkyl group, the C6 cycloalkyl group, the 5-10 membered heterocyclic group, the 5-membered heterocyclic group, the 6-membered heterocyclic group, the 7-membered heterocyclic group, the 8-membered heterocyclic group, the 9-membered heterocyclic group, the 10-membered heterocyclic group, the vinyl group, the propenyl group, the C3 cycloalkenyl group, the C4 cycloalkenyl group, the C5 cycloalkenyl group, the C6 cycloalkenyl group, the C5 aryl group, the C6 aryl group, the C7 aryl group, the C8 aryl group, the C9 aryl group, the C 10 aryl, the 5-membered heteroaryl, the 6-membered heteroaryl, the 7-membered heteroaryl, the 8-membered heteroaryl,

[0127] The 9-membered heteroaryl and the 10-membered heteroaryl may be optionally substituted by one or more substituents independently selected from the group consisting of: deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl,

[0128] Methoxy, ethoxy, propoxy, isopropoxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2,

[0129] -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2,

[0130] -N(CH(CH3)2)2, and carboxyl;

[0131] Each of R8 and R9 is independently selected from the group consisting of: C 1-3 Alkyl, C 3-6 Cycloalkyl, monosaccharide, acylated monosaccharide, C 5-10 Aryl and 5-10 membered heteroaryl, and the C 1-3 Alkyl, the C 3-6 Cycloalkyl, the monosaccharide, the acylated monosaccharide, the C5-10 The aryl group and the 5-10 membered heteroaryl group 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,

[0132] -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; or

[0133] G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, wherein the C5 aryl, the C6 aryl, the C7 aryl,

[0134] The C8 aryl, the C9 aryl, the C 10 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

[0135] The substituents are 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,

[0136] -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2,

[0137] -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl.

[0138] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0139] X is -C(=O)-W-(CR X1 R X2 ) m -OR X3 ;

[0140] W is a key;

[0141] m is 1 or 2;

[0142] Each R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, 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,

[0143] -CH2-C8 aryl, -CH2-C9 aryl, -CH2-C 10 Aryl, -(CH2)2-C5 aryl, -(CH2)2-C6 aryl, -(CH2)2-C7 aryl,

[0144] -(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 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, -(CH2)2-10-membered heteroaryl, -(CH2)3-5-membered heteroaryl, -(CH2)3-6-membered heteroaryl, -(CH2)3-7-membered heteroaryl, -(CH2)3-8-membered heteroaryl,

[0145] -(CH2)3-9 membered heteroaryl and -(CH2)3-10 membered heteroaryl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10Aryl, 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

[0146] -(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 10 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 -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

[0147] -(CH2)3-5 membered heteroaryl, said -(CH2)3-6 membered heteroaryl, said -(CH2)3-7 membered heteroaryl, said -(CH2)3-8 membered heteroaryl, said -(CH2)3-9 membered heteroaryl and said -(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 group independently optionally contains 1 or 2 heteroatoms selected from N, O or S;

[0148] or R X1 and RX2 Together with the carbon atoms to which they are commonly attached, they form a 3-membered carbocycle, a 4-membered carbocycle, a 5-membered carbocycle, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, and each heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each ring system 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; or

[0149] R X3 independently selected from the group consisting of hydrogen, deuterium, 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, -(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 Aryl, -(CH2)3-C 10 Aryl, wherein the methyl, the ethyl, the propyl, the isopropyl, the methoxy, the ethoxy, the propoxy, the isopropoxy, the C3 cycloalkyl, the C4 cycloalkyl, the C5 cycloalkyl, the C6 cycloalkyl, the -C(=O)-CH3, the -C(=O)-CH2CH3, the -C(=O)-CH2CH2CH3, the -C(=O)-CH(CH3)2, the -CH2-C5 aryl, the -(CH2)2-C5 aryl, 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 -(CH2)2-C10 Aryl and the -(CH2)3-C 10 Aryl, 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, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, -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;

[0150] or R X1 and R X3 Together with the carbon atom and oxygen atom to which they are commonly attached, they form a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, a 7-membered heterocyclyl, an 8-membered heterocyclyl, a 9-membered heterocyclyl, or a 10-membered heterocyclyl, wherein the 4-membered heterocyclyl, the 5-membered heterocyclyl, the 6-membered heterocyclyl, the 7-membered heterocyclyl, the 8-membered heterocyclyl, the 9-membered heterocyclyl, or 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, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl, -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3,

[0151] -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH(CH3)2)2 and carboxyl; and each heterocyclic group independently optionally contains 1 or 2 heteroatoms selected from N, O or S.

[0152] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0153] X is -C(=O)-W-(CR X1 R X2 ) m -OR X3 ;

[0154] W is a key;

[0155] m is 1 or 2;

[0156] Each R X1 and R X2 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, cyclobutyl, cyclopentyl,

[0157] -C(=O)-CH 3、

[0158]

[0159] and each of said groups is independently optionally substituted with deuterium, -F, -Cl, -Br, -I,

[0160] -NH2, -CN, -OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHmethyl, -NHethyl, -NHpropyl, -NHisopropyl,

[0161] -N(CH3)2, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, or -S-methyl substitution;

[0162] or R X1 and R X2 Together with the carbon atoms to which they are attached, they form

[0163] or

[0164] R X3 are independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C(=O)-CH2-CN,

[0165] -C(=O)-C(CH3)3, -C(=O)-CH3, -C(=O)-CH2CH3, -C(=O)-NH-CH3, -C(=O)-CH2-N(CH3)2,

[0166] -CH2-C(=O)-CH3, -CH2-C(=O)-NHCH3, -CH2-C(=O)-N(CH3)2, -CH2-NH2, -CH2-NH-CH3, -CH2CH2-O H, -CH2CH2-CN, -CH2-CN, -CH2CH2-C(=O)-NH2, -CH2CH2-C(=O)-NH-CH3, -CH2CH2-NH-C(=O)-CH3,

[0167] or R X1 and R X3 Together with the carbon and oxygen atoms to which they are attached, they form

[0168] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, isomers, tautomers, and isotopic substitutions thereof, wherein:

[0169] X is -C(=O)-CR X1 R X2 -OR X3 ;

[0170] Each R X1 and R X2 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, cyclobutyl, cyclopentyl, -C(=O)-CH 3、 -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, or

[0171] R X3 independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, tert-butyl, -CD3, -C(=O)-CH2-CN, -C(=O)-C(CH3)3, -C(=O)-CH3, -C(=O)-CH2CH3,

[0172] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and carboxyl.

[0173] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0174] In some embodiments, the compounds of Formula I, IA, and IB, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0175] In some embodiments, the compounds of Formula I, IA, IB, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of: Preferably, R is 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. Preferably, R2 is selected from hydrogen or deuterium.

[0176] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R3 and R3' are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and carboxyl.

[0177] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R3 and R3' are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0178] In some embodiments, the compounds of Formula I, IA, and IB, and their pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes, wherein R3 and R3' are each 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0179] In some embodiments, the compounds of Formula I, IA, and IB, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein R3 and R3' are each 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 groups may be optionally substituted with one or more substituents, and the substituents are independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy groups. R3 and R3' are each independently selected from hydrogen or deuterium.

[0180] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0181] Y is a bond or -(CR Y1 RY2 ) n -;

[0182] n is selected from 1, 2 or 3;

[0183] Each R Y1 and R Y2 independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3

[0184] Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 alkyl),

[0185] -N(C 1-6 alkyl)2 and carboxyl.

[0186] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0187] Y is a bond or -(CR Y1 R Y2 ) n -;

[0188] n is selected from 1, 2 or 3;

[0189] R Y1 and R Y2 Each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3

[0190] Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0191] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0192] Y is a bond or -(CR Y1 R Y2 ) n -;

[0193] n is selected from 1, 2 or 3;

[0194] Each R Y1 and R Y2 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy,

[0195] -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0196] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein

[0197] Y is a bond or -(CR Y1 R Y2 ) n -;

[0198] n is selected from 1, 2 or 3;

[0199] Each R Y1 and R Y2 independently selected from the group consisting of: F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropyloxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropyloxy 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, isopropyloxy, -C3 cycloalkyl, -C4 cycloalkyl, -C5 cycloalkyl, -C6 cycloalkyl,

[0200] -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2CH3)2, and -N(CH(CH3)2)2 and carboxyl.

[0201] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein Y is -CH2-.

[0202] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and carboxyl.

[0203] In some embodiments, the compound of Formula I, IA, IB, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0204] In some embodiments, the compounds of Formula I, IA, and IB, and pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes thereof, wherein 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0205] In some embodiments, the compounds of Formula I, IA, and IB, their pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutes, wherein 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of: Preferably, R is selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, -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.

[0206] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein R 10 Selected from the group consisting of: hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, -OH, oxo, -CN, -C 1-6 Alkyl, -C1-6 Alkoxy, -C 3-8 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2 and carboxyl.

[0207] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein R 10 Selected from the group consisting of: hydrogen, deuterium, halogen, C 1-3 Alkyl and C 1-3 Alkoxy, and the C 1-3 Alkyl and the C 1-3 The alkoxy group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0208] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein R 10 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 groups may be optionally substituted with one or more substituents independently selected from the group consisting of: deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 alkyl)2 and carboxyl.

[0209] In some embodiments, the compound of Formula I, IA, IB, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, wherein R 10is selected from the group consisting of: hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropyloxy, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy and isopropyloxy groups are 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, isopropyloxy, -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 Selected from hydrogen or deuterium.

[0210] A compound represented by formula IC, and its pharmaceutically acceptable salts, stereoisomers, tautomers, and isotope substitutions:

[0211]

[0212] It is characterized in that Q is O, S, SO or SO2, Z, R X1 、R X2 、R X3 and m are defined as above in this document.

[0213] A compound represented by formula II, and its pharmaceutically acceptable salts, stereoisomers, tautomers, and isotope-substituted products:

[0214]

[0215] It is characterized by Z, R X1 、R X2 、R X3 and m are defined as above in this document.

[0216] In some embodiments of the compound described herein as Formula I, IA, IB, IC or II, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutions thereof, the compound is a compound of Formula III:

[0217]

[0218] It is characterized by R1, R X1 、R X2 、R X3 and m are defined as above in this document.

[0219] In some embodiments of the compounds described herein as Formula I, IA, IB, IC, II or III, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, the compound is a compound of Formula IV:

[0220]

[0221] It is characterized by R1, R X1 、R X2 and R X3 The definition of is as given above in this article.

[0222] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III or IV herein, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutions thereof, it is characterized in that the compound is a compound of Formula V:

[0223]

[0224] It is characterized by R1, R X1 、R X2 and R X3 The definition of is as shown above in this article.

[0225] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III or IV, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, it is characterized in that the compound is a compound of Formula VI:

[0226]

[0227] It is characterized by R1, R X1 、R X2 and R X3 The definition of is as shown above in this article.

[0228] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III or IV, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, it is characterized in that the compound is a compound of Formula VII:

[0229]

[0230] It is characterized by R1, R X1 、R X2 and R X3 The definition of is as shown above in this article.

[0231] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III or IV, or pharmaceutically acceptable salts, stereoisomers, tautomers, and isotopic substitutions thereof, the compound is characterized in that the compound is a compound of Formula VIII:

[0232]

[0233] It is characterized by R1, R X1 、R X2 and R X3 The definition of is as shown above in this article.

[0234] In some embodiments of the compounds described herein as Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic substitutes thereof, it is characterized in that one or more hydrogens are optionally replaced by deuterium.

[0235] In some embodiments of the compounds described in Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII herein, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutions thereof, it is characterized in that R1 or R X3 One or more hydrogen atoms are optionally replaced by deuterium; preferably, one or more hydrogen atoms on all CH3, CH2 or CH groups are replaced by deuterium.

[0236] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutes thereof, R1 is selected from the group consisting of hydrogen, deuterium, C 1-3 Alkyl, C 1-3 and each R1 may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 alkoxy;

[0237] R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, CN, OH, C 1-4 Alkyl, C 1-3 Alkoxy; and each group may be optionally substituted by one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-3 Alkyl)2, SC 1-3 alkyl; or

[0238] R X3 Selected from the group consisting of: hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy; and each group may be optionally substituted by one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -CN, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 3-6 Cycloalkyl, -NH2, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, carboxyl, -SC 1-3 alkyl.

[0239] In some embodiments of the compounds of Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII herein, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic substitutes thereof, characterized in that R1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each group 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;

[0240] R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy, butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl; and each group may be optionally substituted with one or more substituents independently selected from the group consisting of deuterium, F, Cl, Br, I, -OH, oxo, -NH2, CN, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropyloxy;

[0241] or

[0242] R X3 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, tert-butyl, and each group may be optionally substituted with deuterium.

[0243] In some embodiments of the compounds described in Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII herein, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic substitutes thereof, characterized in that R1 is selected from hydrogen, deuterium, isopropyl, methyl, ethyl, tert-butyl, isopentyl, -CD3, -CH2CD3, -CD2CD3, -CD(CD3)2, -CH(CD3)2,

[0244]

[0245] R X1 and R X2 independently selected from the group consisting of hydrogen, deuterium, CN, OH, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, isobutyl, tert-butyl, or

[0246] R X3 Selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, -CD3, -CH2CD3, -CD2CD3.

[0247] In some embodiments of the compounds described in Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutes thereof, R1 containing deuterium is selected from -CD3, -CD2H, -CDH2, -CH2CD3, CD2CD3, -CD(CD3)2, -CH(CD3)2, R containing heavy hydrogen X3 Selected from -CD3, -CH2CD3, -CD2CD3.

[0248] In some embodiments of the compounds described herein as Formula I, IA, IB, IC, II, III, IV, V, VI, VII or VIII, or pharmaceutically acceptable salts, stereoisomers, tautomers, or isotopic substitutes thereof, the compound is selected from:

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] Preparation method:

[0276] The compounds of the present invention can be prepared by various methods well known to those skilled in the art of organic synthesis using the methods described below or variations thereon as understood by those skilled in the art. The references cited herein are hereby incorporated by reference in their entirety.

[0277] The synthetic methods described below are intended to serve as illustrations of the present invention and are not intended to limit the scope of the subject matter of the present invention and the compounds claimed to be protected to these examples. If the preparation of the starting compound is not described, the compound can be obtained commercially or similarly prepared according to the known compounds or methods described herein. Any of the compounds of the general formula described herein can be synthesized by referring to the methods shown in the following schemes. As shown herein, the final compound is a product having the same structural formula as that described in any of the general structural formulas herein. It should be understood that any compound in the general formula can be prepared by appropriately selecting reagents with suitable substitutions. Solvents, temperature, pressure and other reaction conditions can be easily selected by those skilled in the art.

[0278] For ease of illustration, Synthetic Schemes 1 and 2 provide general synthetic methods for preparing the compounds described herein. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic pathways can be used to synthesize these compounds. In addition, many of the compounds prepared according to the present invention using the methods described below can be further modified using conventional chemical methods well known to those skilled in the art.

[0279] Synthesis Route 1

[0280]

[0281] Synthesis Route 2

[0282]

[0283] Synthetic Scheme 1 and Synthetic Scheme 2 describe the general synthetic routes of the present invention, wherein Z, R X1 、R X2 、R X3 and m and other groups or functional groups, can be converted into the desired final substituent.

[0284] As shown in Synthesis Schemes 1 and 2, acid i undergoes a condensation reaction with amine ii in the presence of an organic base and a condensation reagent to produce iii. Hydrolysis of iii using LiOH, NaOH, or the like yields iv. Condensation of iv with an alcohol or thiol in the presence of an organic base and a condensation reagent yields iii, which may be various esters or thioesters.

[0285] 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.

[0286] It will be understood that other synthetic routes may be used in the practice of the present invention.

[0287] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope thereof; and a pharmaceutically acceptable carrier, diluent, or excipient.

[0288] The present invention provides a method for treating a disease or condition, comprising administering to a subject in need thereof a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, an isotopic substitution thereof, or a pharmaceutical composition thereof, in an amount effective to treat the disease or condition. In other aspects, the present application further provides a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, an isotopic substitution thereof, or a pharmaceutical composition thereof for use in treating a disease or condition. In some embodiments, the disease or condition is selected from the group consisting of infection, cancer, autoimmune disease, inflammatory disease, and neurodegenerative disease or nervous system disease.

[0289] As used herein, "cancer" in a patient refers to the presence of cells with typical oncogenic characteristics, e.g., uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, a significant increase in anti-apoptotic activity, rapid growth and proliferation rates, and certain characteristic morphologies and cell markers. In some cases, cancer cells will be in the form of tumors; such cells may be present locally within an animal, or circulate in the bloodstream as independent cells, such as leukemia cells. As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. As used herein, "solid tumor" is an abnormal tissue mass that generally does not contain cysts or fluid areas. As non-limiting examples, solid tumors can be in the brain, colon, breast, prostate, liver, kidney, lung, esophagus, head and neck, ovary, cervix, stomach, colon, rectum, bladder, uterus, testicles, and pancreas. In some embodiments, after treatment of a solid tumor with the methods disclosed herein, the solid tumor regresses or its growth slows or arrests. In other embodiments, the solid tumor is malignant. In some embodiments, the cancer comprises a stage 0 cancer. In some embodiments, the cancer comprises a stage I cancer. In some embodiments, the cancer comprises a stage II cancer. In some embodiments, the cancer comprises a stage III cancer. In some embodiments, the cancer comprises a stage IV cancer. In some embodiments, the cancer is refractory and / or metastatic. For example, the cancer may be refractory to monotherapy with radiation therapy, chemotherapy, or immunotherapy. Cancer as used herein includes newly diagnosed or relapsed cancers, including but not limited to acute lymphoblastic leukemia, acute myeloid leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or invasive breast cancer, carcinoma, bronchogenic carcinoma, choriocarcinoma, chronic myeloid leukemia, colon cancer, colorectal cancer, Ewing's sarcoma, gastrointestinal cancer, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, colorectal cancer, leukemia, liver cancer, lung cancer, Lewis lung cancer, carcinoma), lymphoma, malignant fibrous histiocytoma, breast tumors, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, pontine tumors, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, solid tumors, gastric cancer, testicular cancer, and uterine cancer.

[0290] Also provided herein is a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer; or a pharmaceutical composition thereof. In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, leukemia, glioblastoma, or head and neck cancer.

[0291] In another aspect, provided is the use of the compound of the present invention, its stereoisomer, its pharmaceutically acceptable salt or pharmaceutically acceptable salt of its stereoisomer, or the pharmaceutical composition thereof for preparing a drug for treating cancer.

[0292] In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, leukemia, glioblastoma, or head and neck cancer.

[0293] In some embodiments, the drug acts as a glutamine antagonist.

[0294] As used herein, the term "glutamine antagonist" refers to a glutamine analog that interferes with a glutamine metabolic pathway, such as inhibiting or blocking a metabolic pathway downstream of glutamine, in which glutamine serves 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 cases, the term glutamine antagonist also includes glutamine analogs that inhibit cellular uptake of glutamine, thereby reducing its biological activity. Diseases or conditions in which excess and / or abnormal glutamine activity is implicated include, but are not limited to, infections, cancer, autoimmune diseases, and neurodegenerative or neurological diseases and other central nervous system disorders.

[0295] In another aspect, provided is the use of the above-mentioned compound of the present invention, its stereoisomers, pharmaceutically acceptable salts, stereoisomers, tautomers, isotopic substitutes thereof, or the pharmaceutical composition of the present invention for treatment.

[0296] In another aspect, provided is the use of the above-mentioned compound of the present invention, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-substituted product, or the pharmaceutical composition of the present invention as a medicine.

[0297] In another aspect, the present invention provides the above-mentioned compound of the present invention, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution, or pharmaceutical composition of the present invention for use in treating a disease or condition. In some embodiments, the disease or condition is selected from the group consisting of infection, cancer, autoimmune disease, inflammatory disease and neurodegenerative disease or nervous system disease.

[0298] In another aspect, provided is use of the above-mentioned compound of the present invention, its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope substitution product, or the pharmaceutical composition of the present invention for treating cancer.

[0299] In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, leukemia, glioblastoma, or head and neck cancer.

[0300] The compound of the present invention, as an active ingredient, has the characteristics of improved water solubility, improved stability, improved safety, improved pKa properties and high activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0301] Figure 1 The plasma stability of the compounds after 4 hours of incubation in the presence of dog, monkey, pig and human plasma is shown.

[0302] Figure 2 Shown are changes in body weight after administration of control Compound A and Compound 2 in MC38 tumor-bearing C57BL / 6 mice.

[0303] Figure 3 The antitumor efficacy of control Compound A and Compound 2 in MC38 tumor-bearing C57BL / 6 mice is shown.

[0304] Figure 4 Shown are changes in body weight after administration of control Compound A and Compound 2 in CES1- / - mice bearing MC38 tumors.

[0305] Figure 5 The antitumor efficacy of control Compound A and Compound 2 in CES1- / - mice bearing MC38 tumors is shown.

[0306] Figure 6 Shown are changes in body weight after administration of Compound 2, Compound 3, Compound 81, Compound 443, and Compound 459 in C57BL / 6 mice bearing MC38 tumors.

[0307] Figure 7 The anti-tumor efficacy of Compound 2, Compound 3, Compound 81, Compound 443, and Compound 459 in C57BL / 6 mice bearing MC38 tumors was shown.

[0308] definition

[0309] Unless otherwise specified, the term "halogen" herein refers to fluorine, chlorine, bromine or iodine. Preferably, halogen includes fluorine, chlorine and bromine. The term "halogenated C 1-6 Alkyl", "halogenated C 2-6 Alkenyl", "halogenated C 2-6 Alkynyl" and "halogenated C 1-6 "Alkoxy" refers to a group in which one or more (especially 1, 2 or 3) hydrogen atoms are replaced by halogen atoms, especially fluorine or chlorine atoms. In some embodiments, fluorinated C 1-6 Alkyl, fluorinated C 2-6 Alkenyl, fluorinated C 2-6 Alkynyl and fluorinated C 1-6 Alkoxy, especially fluorinated C 1-3 Alkyl groups, such as CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3; fluoro-C 1-3 Alkoxy, for example OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3; in particular CF3, OCF3 and OCHF2.

[0310] Unless otherwise specified, the alkyl groups in the present invention include saturated monovalent hydrocarbon groups having linear, branched or cyclic moieties. For example, the alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C 1-6 Alkyl is defined as a group having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement.

[0311] 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)-).

[0312] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds and generally having a length of 2 to 20 carbon atoms. For example, "C 2-6 The term "alkenyl" refers to a group consisting of 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0313] The term "alkynyl" encompasses straight or branched chain hydrocarbon groups containing one or more triple bonds and generally 2 to 20 carbon atoms in length. For example, "C 2-6 "Alkynyl" contains 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0314] The alkoxy group is an oxygen ether formed from the above-described linear, branched or cyclic alkyl group.

[0315] As used herein, unless otherwise indicated, the term "aryl" refers to an unsubstituted or substituted monocyclic or polycyclic aromatic hydrocarbon containing carbon ring atoms. Preferably, the aryl group is a monocyclic or bicyclic 6-10 membered aromatic ring system. Phenyl and naphthyl are preferred aryl groups. Most preferably, the aryl group is phenyl.

[0316] As used herein, unless otherwise indicated, the term "heterocycle" or "heterocyclyl" refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more heteroatoms. This includes monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles, or spiroheterocycles. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to ten members and is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included in this definition.

[0317] Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, oxadiazole, or oxazepinyl.

[0318] Unless otherwise indicated, the term "heteroaryl" as used herein, by itself or as part of another substituent, refers to an aromatic ring system containing carbon and at least one heteroatom. Heteroaryl groups can be monocyclic or polycyclic, substituted or unsubstituted. Monocyclic heteroaryl groups can have 1 to 4 heteroatoms in the ring, while polycyclic heteroaryl groups can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused spiro or bridged rings, for example, cyclic heteroaryl groups are polycyclic heteroaryl groups. Bicyclic heteroaryl rings can contain 8 to 12 member atoms. Monocyclic heteroaryl rings can contain 5 to 8 member atoms (carbon number and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl, or isoquinolinyl.

[0319] As used herein, unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsubstituted hydrocarbon radical, which optionally includes an alkylene linker through which the cycloalkyl radical can be attached. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0320] The term "substituted" herein means that one or more (preferably 1-6, more preferably 1-3) hydrogen atoms in a group are replaced by the same or different substituents. Representative substituents include, but are not limited to, X, C l-6 Alkyl, C l-6 Alkoxy, C 3-20 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 ); wherein any one of X is an independent halogen (F, Cl, Br or I), R 13and R 14 Independently selected from hydrogen, lower alkyl or lower haloalkyl. Preferred substituents are: -F, -Cl, -Br, -I, -OH, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, CHF2, methoxy, ethoxy, propoxy, isopropyloxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(OCH3), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl or acetyl. Particularly preferred substituents are -F, -Cl or -Br.

[0321] In the present invention, the term "composition" refers to a product containing a specific amount of a specific ingredient, and also includes any product formed directly or indirectly by a combination of specific amounts of specific ingredients. Therefore, pharmaceutical compositions with 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. In addition, some crystalline forms of the compounds of the present invention may exist in the form of polymorphs and are included in the present invention. In addition, some compounds can form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present invention.

[0322] The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salts 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 by an inorganic or organic acid. Representative organic or inorganic acids include, but are not limited to, 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, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid, salicylic acid, saccharin, or trifluoroacetic acid. Pharmaceutically acceptable basic / cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc. Prodrugs of the compounds of the present invention are also included within the scope of the present invention. Typically, such prodrugs are functional derivatives of the compounds of the present invention that are easily converted into the desired compound in vivo. Therefore, in the therapeutic methods of the present invention, the term "administering" will include administering the compounds of the present invention as specifically disclosed, as well as administering compounds that may not be specifically disclosed, but which, upon administration to a patient, can be converted into specific compounds in vivo for the treatment of various conditions or discomforts. Conventional methods for selecting and preparing suitable prodrugs are described in many publications, such as "Prodrug Design," edited by H. Bundgaard and Elsevier and published in 1985.

[0323] In the present invention, the definition of any substituent or variable at a particular position is independent of the definitions of that substituent or variable at other positions in the molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art as well as those proposed herein.

[0324] The compounds encompassed by the present invention may contain one or more asymmetric centers and may therefore produce diastereomers and optical isomers. The present invention includes all those possible diastereomers and their racemic mixtures, their substantially pure resolvable enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0325] The present invention includes all stereoisomers of Formula I or II and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated, well-defined stereoisomers are also included. In the synthetic methods used to prepare these compounds, or in the process of using racemization or epimerization methods known to those skilled in the art, the products of these methods may be mixtures of stereoisomers.

[0326] The term "stereoisomer" as used herein refers to isomers in which the atoms or atomic groups in a molecule are connected in the same order but arranged differently in space, including conformational isomers and configurational isomers. Configurational isomers include geometric isomers and optical isomers, with optical isomers primarily including enantiomers and diastereomers. The present invention encompasses all possible stereoisomers of the compound.

[0327] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented by 1H (hydrogen), 2H (deuterium), and 3H (tritium). They are also commonly represented by D for deuterium and T for tritium. In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterated. Isotopes of carbon include 13C and 14C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using suitable isotopically labeled reagents instead of non-isotopically labeled reagents.

[0328] Unless otherwise specified, when the compounds described herein exist as tautomers, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof.

[0329] When the compounds of the present invention and their pharmaceutically acceptable salts exist as solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, etc. can be used.

[0330] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base (including inorganic bases and organic bases). When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids and organic acids). Since the compounds of the present invention 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 (% by weight).

[0331] Pharmaceutical composition of the present invention comprises the compound represented by formula I or VII (or its pharmaceutically acceptable salt) as active component, pharmaceutically acceptable carrier and optional other treatment composition or adjuvant.Although the most suitable approach in any given case depends on the character and the severity of specific main body and its disease (this active component is applied to this disease), said composition includes the composition that is suitable for oral, rectal, local and parenteral (including subcutaneous, intramuscular and intravenous) administration.Pharmaceutical composition can exist in unit dosage form easily and can be prepared by any method known in pharmaceutical field.

[0332] In practice, according to conventional pharmaceutical mixing technology, the compound of the present invention or its prodrug or metabolite or its pharmaceutically acceptable salt as the active ingredient can be intimately mixed with a pharmaceutical carrier according to conventional pharmaceutical compounding technology (intimate admixture). Depending on the dosage form required for administration, such as oral or parenteral (including intravenous), the carrier can take a variety of forms. Therefore, the pharmaceutical composition of the present invention can be provided as an independent unit suitable for oral administration, such as a capsule, cachet (cachets) or tablet each containing a predetermined amount of active ingredient. In addition, the composition can be in the form of a powder, granules, solution, suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion. In addition to the above-mentioned common dosage forms, the compound of the present invention or its pharmaceutically acceptable salt can also be administered by a controlled release device and / or a delivery device. The composition can be prepared by any pharmaceutical method. Typically, such methods include the step of combining the active ingredient with a carrier comprising one or more essential ingredients. Typically, the composition is prepared by uniformly and intimately admixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently shaped into the desired appearance.

[0333] Therefore, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier and the compound of the present invention or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0334] The pharmaceutical carrier used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing a composition for oral dosage form, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavorings, preservatives, colorants, etc. can be used to form oral liquid preparations (e.g., suspensions, elixirs, and solutions); and carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used to form oral solid preparations (e.g., powders, capsules, and tablets). Tablets and capsules are preferred oral dosage units due to their ease of administration, and thus solid pharmaceutical carriers are used. Optionally, tablets can be coated by standard aqueous or non-aqueous techniques.

[0335] Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, mixed with a suitable and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition. Unit dosage forms will generally contain between about 1 mg and about 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

[0336] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants can include, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0337] The pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions can be in the form of sterile powders for the temporary preparation of such sterile injectable solutions or dispersions. In all cases, the final injection must be sterile and must be an effective liquid for easy injection. The pharmaceutical compositions must be stable under manufacturing and storage conditions; therefore, contamination by microorganisms such as bacteria and fungi should preferably be prevented. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a vegetable oil, and a suitable mixture thereof.

[0338] The pharmaceutical compositions of the present invention may be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, powder, or the like. Furthermore, the compositions may be in a form suitable for transdermal application. These formulations may be prepared using the compounds of the present invention or pharmaceutically acceptable salts thereof by conventional processing methods. For example, a cream or ointment may be prepared by mixing a hydrophilic material with water and from about 0.05 wt % to about 10 wt % of the compound to prepare a cream or ointment having the desired consistency.

[0339] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration and the carrier is a solid. Preferably, the mixture forms a unit dose suppository. 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 and then cooling and molding in a mold.

[0340] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may optionally include one or more other carrier components, such as diluents, buffers, flavorings, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the target receptor. Compositions containing the compounds of the present invention or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

[0341] In general, dosage levels of about 0.01 mg / kg body weight to about 150 mg / kg body weight per day, or alternatively about 0.5 mg to about 7 g per patient per day, can be used to treat the above-mentioned conditions. For example, inflammation, cancer, psoriasis, allergies / asthma, diseases and disorders of the immune system, and diseases and disorders of the central nervous system (CNS) can be effectively treated by administering about 0.01 to 50 mg of the compound per kilogram of body weight per day, or about 0.5 mg to about 3.5 g of the compound per patient per day.

[0342] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

[0343] These and other aspects will become apparent from the following written description of the invention. Example

[0344] Unless otherwise expressly stated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0345]

[0346] Intermediate A1

[0347]

[0348] Intermediate A1 was prepared by referring to compound 3 in Scheme 1 on page 82 of WO2017023774.

[0349] The following compounds were synthesized using the above steps or modified steps and the corresponding starting materials.

[0350]

[0351] Intermediate B1

[0352]

[0353] Step a: To a solution of 7-fluoroindole (308 mg, 2.279 mmol) and ytterbium(III) trifluoromethanesulfonate (219 mg, 343.119 μmol) in chloroform (3 mL) under nitrogen was added methyl (2S)-glycidyl ester (121 mg, 1.185 mmol). The reaction was incubated at 85°C for 3 h. After cooling to room temperature, the resulting solution was quenched with Na2CO3(aq) (10 mL) and the pH value was adjusted to 5-6 with 2M HCl. The aqueous layer was separated and extracted with DCM (2 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc / hexane (1:2) as the eluent to afford methyl (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propionic acid methyl ester (136 mg, 573.292 μmol). MS:m / z238(M+H) + .

[0354] Step b: To a solution of methyl (2S)-3-(7-fluoro-1H-indol3-yl)-2-hydroxy-propionic acid methyl ester (136 mg, 573.292 μmol) in water (1 mL) was added LiOH (2 M aqueous solution, 1 mL). The mixture was heated from RT to 60 ° C and stirred overnight. The resulting solution was added with citric acid (solid), diluted with water (5 mL), and extracted with EA (2×10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (2S)-3-(7-fluoro-1H-indol3-yl)-2-hydroxy-propionic acid (165 mg, 739.247 μmol). It was used directly in the next step without any further purification. MS: m / z (224) + .

[0355] Intermediate B2

[0356]

[0357] Step a: To a solution of indole (302 mg, 2.578 mmol) in DMF (3 mL) was added NaH (217 mg, 9.043 mmol) and the mixture was ice-bathed for 1 h. (2S)-glycidyl ester (685 mg, 6.710 mmol) was added to the resulting solution, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and the pH was adjusted to 3-4 with citric acid. The aqueous layer was extracted with EA. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by FLASH with H2O / MeCN (5%-95%) to give (S)-2-hydroxy-3-(1H-indol1-yl)propanoic acid (222 mg, 1.082 mmol). MS: m / z 206 (M+H) + .

[0358] The following compounds were synthesized using the above steps or modified steps and the corresponding starting materials.

[0359]

[0360]

[0361] Intermediate C1

[0362]

[0363] Step a: Under nitrogen, to a solution of (S)-(-)-methyl lactate (1099 mg, 10.5567 mmol) and iodoethane (3726 mg, 23.8900 mmol) in diethyl ether (10 mL) was added Ag2O (4772 mg, 20.5925 mmol). 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). LiOH (246 mg, 10.2721 mmol) was added to the reaction solution and 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 under reduced pressure to 5 mL, the aqueous layer was extracted with EA (3×10 mL), and the combined organic layers were washed with saturated NaCl solution (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-2-ethoxypropionic acid (772 mg, 6.5351 mmol). MS: m / z 119 (M+H) + .

[0364] Intermediate C2

[0365]

[0366] Step a: To a solution of 2-hydroxy-4-(methylthio)butanoic acid (0.68 g, 4.5274 mmol) and CHI (3.35 g, 23.6019 mmol) in diethyl ether (10 mL) was added AgO (4.41 g, 19.0303 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was monitored by LC-MS, filtered, and concentrated under reduced pressure. The residue was dissolved in MeOH (6 mL) and HO (2 mL), and NaOH (318 mg, 7.9506 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 3 h. The reaction mixture was monitored by TLC and the pH was adjusted to 3 with 1 M HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layer was extracted with EA (3 × 10 mL). The combined organic layers were washed with saturated NaCl solution (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 2-methoxy-4-(methylthio)butanoic acid (128 mg, 779.4318 μmol). MS: m / z 165 (M+H) + .

[0367] Intermediate C3

[0368]

[0369] Step a: To a solution of 2-hydroxy-3-(1H-indol-3-yl)propanoic acid (152 mg, 740.706 μmol) in THF (10 mL) was added NaH (55 mg, 2.292 mmol). The reaction was stirred at room temperature for 20 min, and CHCl (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CHCl (358 mg, 2.522 mmol) was added again, and the reaction mixture was monitored by LC-MS. The mixture was stirred at 40°C for 3 h. HO (5 mL) was added to the reaction mixture, and the mixture was extracted with EA (10 mL). The combined aqueous layers were purified by FLASH with HO / MeCN (0% to 100%, 40 min, C18). The product layer was concentrated under reduced pressure to yield 2-methoxy-3-(1-methyl-1H-indol-3-yl)propanoic acid (119 mg, 510.155 μmol). MS: m / z 234 (M+H) + .

[0370] The following compounds were synthesized using the above steps or modified steps and the corresponding starting materials.

[0371]

[0372]

[0373]

[0374]

[0375]

[0376] Intermediate D1

[0377]

[0378] Step a: To a solution of (S)-methyl 2-hydroxy-3-(1H-indol3-yl)propanoate (2 g, 9.123 mmol) in DCM (20 mL) was added imidazolyl (2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol). The reaction system was stirred at room temperature overnight. The reaction system was quenched with water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and the organic extracts were collected. The aqueous phase was extracted with DCM (2×10 mL). The residue was purified by wet column chromatography using EA / Hex (0-20%). The product solution was concentrated under reduced pressure to give (S)-methyl 2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol3-yl)propanoate (3099 mg). MS: m / z 334 (M+H) + .

[0379] Step b: To a -78°C solution of (S)-methyl 2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol-3-yl)propanoate (3.099 g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol). The reaction was stirred at -78°C for 30 min. Carboxybenzyl chloride (4623 mg, 27.100 mmol) was added dropwise at -78°C and stirred for 1 h. The mixture was quenched with saturated NH4Cl solution, and the aqueous phase was extracted with EA (2 x 10 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide benzyl (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (4345 mg). MS:m / z468(M+H) + .

[0380] Step c: To a solution of (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylic acid benzyl ester (4.345 g, 9.292 mmol) in THF (30 mL) was added tetrabutylammonium fluoride (5 mL). The reaction system was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by FLASH using EA / Hex (0-60%). The product solution was concentrated under reduced pressure to give 3-[(2S)-2-hydroxy-3-methoxy-3-oxopropyl]indole-1-carboxylic acid benzyl ester (2.21 g). MS: m / z 354 (M+H) + .

[0381] Step d: To a solution of benzyl 3-[(2S)-2-hydroxy-3-methoxy-3-oxopropyl]indole-1-carboxylate (103 mg, 291.481 μmol) and 4A molecular sieves in CH3I (1 mL) was added silver oxide (216 mg, 932.098 μmol). The reaction system was stirred at room temperature overnight, concentrated under reduced pressure, diluted with EA (5 mL), filtered, and the filtrate was concentrated to afford benzyl (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate (107.088 mg, 100.000% yield). MS: m / z 368 (M+H) + .

[0382] Step e: To a solution of (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylic acid benzyl ester (0.107 g, 291.240 μmol) in THF (5 mL) and MeOH (5 mL) was added NaOH (3 mL, 3 M / L). The reaction system was stirred at room temperature for 1 h and the pH was adjusted to 3 with 1 M HCl. The aqueous phase was extracted with EA (2 × 10 mL), and the combined organic extracts were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give (S)-3-(1H-indol-3-yl)-2-methoxypropanoic acid (71 mg). MS: m / z 220 (M+H) + .

[0383] The following compounds were synthesized using intermediate D1, the above steps or modified steps and the corresponding starting materials.

[0384]

[0385]

[0386]

[0387] Example 1

[0388] Isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropionamido)-5-oxohexanoic acid (Compound 1)

[0389]

[0390] To a solution of (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propionic acid (0.165 g, 739.247 μmol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoic acid (123 mg, 576.834 μmol) in DCM (2 mL) at 0°C were added N,N'-diisopropylcarbodiimide (95 mg, 752.779 μmol), 2,4,6-collidine (115 mg, 949.008 μmol) and ethyl 2-oximecyanoacetate (83 mg, 584.044 μmol). The reaction system was stirred at room temperature for 16 h, concentrated under reduced pressure, and the residue was purified by pre-HPLC, concentrated under reduced pressure, and freeze-dried to give isopropyl (2S)-6-diazo-2-[[(2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propionyl]amino]-5-oxo-hexanoic acid (41.6 mg, 99.422 μmol). MS: m / z 419 (M+H) + , 1H NMR (400MHz, CDCl3) δ8.47–8.39(m,1H),7.47(d,J=7.9Hz,1H),7.21–7.19(m,1H),7.16(d,J =7.8Hz,1H),7.05(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).

[0391] Example 2

[0392] Isopropyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (Compound 2)

[0393]

[0394] To a solution of (S)-2-methoxypropionic acid (267 mg, 2.565 mmol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoic acid (0.152 g, 712.835 μmol) in DMF (5 mL) was added N,N'-diisopropylcarbodiimide (327 mg, 2.591 mmol), 2,4,6-collidine (412 mg, 3.400 mmol), and ethyl 2-oximecyanoacetate (375 mg, 2.639 mmol) at 0°C. The reaction system was stirred at room temperature for 15 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (20 mL x 3). The combined organic phases 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 give isopropyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (60.2 mg, 201.1211 μmol; readily soluble in water). MS: m / z 300 (M+H) + , 1H NMR (400MHz, CDCl3) δ7.22–7.08(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).

[0395] Example 3

[0396] Methyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (Compound 3)

[0397]

[0398] To a solution of (S)-2-methoxypropionic acid (2.06 g, 19.7879 mmol) and methyl (S)-2-amino-6-diazo-5-oxohexanoic acid (2308 mg, 12.4635 μmol) in DMF (5 mL) at 0°C was added NMM (3.73 g, 36.8770 mmol) and HATU (6.26 g, 16.4637 mmol). The reaction system was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-100%, 40 min) and concentrated under reduced pressure to give methyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (2.87 g, 10.5799 mmol; freely soluble in water). MS: m / z 272 (M+H) + , 1 H NMR(400MHz,CD3OD)δ5.82(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).

[0399] Example 4

[0400] (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (Compound 4)

[0401]

[0402] To a solution of methyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (0.96 g, 3.5389 mmol) in THF (10 mL) was added a solution of NaOH (176 mg, 4.4003 mmol) in water (5 mL) at 0°C. The reaction system was stirred at room temperature for 40 min and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-80%, 30 min) and concentrated under reduced pressure to afford (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (866 mg, 3.3665 mmol; freely soluble in water). MS: m / z 258 (M+H) + , 1 H NMR (400MHz, CD3OD) δ5.82(s,1H),4.27(t,J=5.8Hz,1H),3.72(q,J=6.6Hz,1H),3.40( s,3H),2.46–2.27(m,2H),2.28–2.13(m,1H),2.06–1.91(m,1H),1.33(d,J=6.7Hz,3H).

[0403] Example 5

[0404] Isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid (Compound 5)

[0405]

[0406] To a solution of isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropionamido)-5-oxohexanoic acid (0.166 g, 396.7325 μmol) in DMF (3.5 mL) was added piperidine (189 mg, 2.3894 mmol) and acetic anhydride (104 mg, 1.0187 mmol) at room temperature. The reaction system was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 2-80%) and concentrated under reduced pressure to give isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propionamido)-6-diazo-5-oxohexanoic acid (75.2 mg, 163.3196 μmol). MS: m / z 461 (M+H). + , 1H NMR (400MHz, CD3OD) δ7.39 (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=12.4,6.3 Hz,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).

[0407] Example 6

[0408] Ethyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (Compound 6)

[0409]

[0410] To a solution of (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (104 mg, 404.2870 μmol) and EtOH (96 mg, 2.0839 mmol) in DMF (5 mL) at 0°C was added NMM (117 mg, 1.1567 mmol) and HATU (237 mg, 623.3081 μmol). The reaction system was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN / H2O = 0-100%, 30 min) and concentrated under reduced pressure to afford ethyl (S)-6-diazo-2-((S)-2-methoxypropionamido)-5-oxohexanoic acid (0.0332 g, 116.3705 μmol; freely soluble in water). MS: m / z 286 (M+H) + , 1 H NMR (400MHz, CD3OD) δ4.49–4.35(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).

[0411] The compounds in the following table were synthesized using the steps of the above examples or improved steps with the corresponding starting materials and intermediates.

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510] Synthesis of reference compound:

[0511] Compound 60 (named “control compound A”) was obtained by referring to the synthetic route and operation steps of compound 60 on page 124 of WO2017023774.

[0512] Compound 25 (named “control compound 1”) was obtained by referring to the synthetic route and operation steps of compound 25 on pages 100-101 of WO2017023774.

[0513] Compound 9 (named “control compound 2”) was obtained by referring to the synthetic route and operation steps of compound 9 on pages 87-88 of WO2017023774.

[0514] Compound 47 (named “control compound 3”) was obtained by referring to the synthetic route and operation steps of compound 47 on pages 115-116 of WO2017023774.

[0515] Example 7 Plasma stability in different species

[0516] Control compound A, control compound 1, control compound 2, compound 2, compound 3, compound 81, compound 443, and compound 459 were used to test the plasma stability of compounds in different species. The specific compounds are as follows:

[0517]

[0518] Metabolic stability was tested using dog, monkey, pig and human plasma, with prodrugs (1 μM) added to their respective solutions in a 37°C water bath. A 50 μL aliquot of the mixture was taken out in duplicate and the reaction was quenched by adding four times the volume of ice-cold acetonitrile with an internal standard (dexamethasone 100 ng / mL). The sample was vortexed for 30 seconds and centrifuged at 15,000 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. Liquid chromatography and tandem mass spectrometry (LC-MS / MS) were used to monitor the changes in prodrug over time.

[0519] For LC-MS / MS, prodrugs were analyzed using an ExionLC AD HPLC system coupled to a REF Triple Quad 5500+ mass spectrometer system, using an ESI source in positive ionization mode on a Phenomenex Kinetex 5μm C18 100A (2.1 x 50 mm) UPLC column. The autosampler was temperature-controlled and operated at 4°C. The mobile phase for chromatographic separation consisted of acetonitrile / water containing 0.1% formic acid, using a gradient elution at a flow rate of 0.6 mL / min for 3.5 min. Samples were introduced into the ionization source via a heated nebulizer probe (400°C). Changes in the prodrug were measured as the ratio of the analyte peak area to the IS.

[0520] For quantification of residual compounds, the change in prodrug was measured as the ratio of the analyte peak area to the internal standard.

[0521] Figure 1The data show the plasma stability of the compounds after 4 hours of incubation in the presence of canine, monkey, porcine, and human plasma. The data show that control compound A, compound 2, compound 3, compound 81, compound 443, and compound 459 remained relatively stable in the presence of canine, monkey, porcine, and human plasma for 4 hours, while control compound 1 and control compound 2 remained almost unchanged under these conditions.

[0522] Example 8 Stability of liver microsomes from different species

[0523] Control compound A, control compound 1, control compound 2, compound 2, compound 3, compound 81, compound 443, and compound 459 were used to detect the stability of liver microsomes of different species.

[0524] Metabolic stability assays were performed using canine, monkey, porcine, and human plasma. The prodrug (1 μM) was added to each microsomal matrix and incubated at 37°C on an orbital shaker. 50 μL aliquots were removed from the reaction solution at 0, 15, 30, 45, and 60 minutes. The reaction was terminated by adding 4 volumes of cold acetonitrile containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 2 μM ketoprofen). Samples were centrifuged at 3220 g for 40 minutes. 100 μL of the supernatant was mixed with 100 μL of ultrapure HO and then used for LC-MS / MS analysis.

[0525] For LC-MS / MS, prodrugs were analyzed on an API 4000 liquid chromatography tandem mass spectrometer using an ESI source on a Waters XSelect HSS T3 C18, 2.5 μm, 2.1 x 30 mm column. The mobile phase for chromatographic separation consisted of phase A: water (0.1% formic acid); phase B: acetonitrile (0.1% formic acid), using a gradient elution at a flow rate of 1.0 mL / min for 1.0 min. Samples were introduced into the ionization source via a heated nebulizer probe (500°C). Changes in prodrug concentration were measured as the ratio of the analyte peak area to the internal standard.

[0526] For data analysis, peak areas were determined from extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the parent drug remaining percentage versus incubation time curve. 1 / 2 ) is determined by the slope value:

[0527] in vitro 1 / 2 =-(0.693 / k)

[0528] The in vitro t 1 / 2 (min) converted to in vitro intrinsic clearance (in vitro CL int , units are μL / min / mg protein):

[0529]

[0530] Table 1 shows the in vitro clearance of the compounds after 60 min incubation in human, monkey, dog, rat, and mouse liver microsomes. The lower the clearance, the more stable the compound.

[0531] Table 1. Clearance of compounds in liver microsomes of different species (μL / min / mg protein)

[0532] Compound people monkey dog rats mice Control compound 1 95.34 167.25 63.64 123.55 114.88 Control compound 2 110.42 280.56 50.25 437.21 125.68 Control compound A 118.61 393.20 60.41 95.16 152.92 Compound 2 43.44 31.78 12.70 62.43 67.14 Compound 3 124.33 46.39 10.90 49.47 71.15 Compound 81 16.82 25.97 5.49 268.83 60.81 Compound 443 73.52 179.92 81.89 238.84 407.55 Compound 459 18.88 130.50 9.57 114.96 71.74

[0533] Example 9: Antitumor efficacy study in a C57BL / 6 mouse MC38 subcutaneous homograft model

[0534] Antitumor efficacy of control compound A and compound 2 in the MC38 subcutaneous homograft model of C57BL / 6 mice.

[0535] Animals: mice; strain: C57BL / 6; age: 6-8 weeks, sex: female

[0536] MC38 tumor cells were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. Cells in the exponential growth phase were collected and counted for tumor inoculation. MC38 cells were collected and counted at 1×10 7 The cells were resuspended in PBS containing 50% Matrigel at a density of 1×10 cells / mL. All experimental mice were subcutaneously inoculated with 0.1 mL of cell suspension (1×10 6 cells).

[0537] When the tumor volume reaches 79-118mm 3 (mean tumor volume 96 mm 3 ) were randomly divided into groups and administered. The experimental groups were divided into: Group 1: control group (10% DMSO + 90% saline), Group 2: control compound A (2 μmol / kg), and Group 3: compound 2 (2 μmol / kg). Each group consisted of 8 tumor-bearing mice. All tested drugs were administered subcutaneously once daily. The dosing schedule for each test drug is shown in Table 2 below.

[0538] During the administration period, the tumor volume and animal body weight were monitored twice a week. The efficacy was evaluated based on the absolute tumor inhibition rate (TGI) of tumor growth, and the safety was evaluated based on the changes in mouse body weight and death.

[0539] Table 2.

[0540]

[0541] weight:

[0542] The results of weight changes of tumor-bearing mice are shown in Table 3. Figure 2 .

[0543] Table 3. Body weight changes of mice in different groups (%)

[0544]

[0545] Tumor volume:

[0546] The tumor volume results of different groups at different time points after tumor inoculation are shown in Tables 4 and Figure 3 . The tumor growth inhibition is summarized in Table 5. The control group and each treatment group were compared for homogeneity of variance of tumor volume using one-way ANOVA. Subsequently, the Games-Howell test (data with unequal variance) was used to compare the significant differences in tumor volume between the control group and each treatment group, with P < 0.05 indicating a significant difference. All data were analyzed using SPSS 22.0 software. The results showed that both treatment groups showed significant anti-tumor effects compared with the blank control group.

[0547] Table 4. Average tumor volume in different treatment groups

[0548]

[0549] Table 5: Antitumor activity of the tested compounds in the MC38 model

[0550]

[0551] Example 10 Study on the anti-tumor efficacy of CES1c- / - mice MC38 subcutaneous transplanted tumors

[0552] The antitumor efficacy of reference compound A and compound 2 was tested in MC38 subcutaneous transplanted tumors in CES1c- / - mice.

[0553] Animals: Mouse; Strain: C57BL / 6- Ces1cem1Smoc Age: 6-8 weeks; Sex: female. (Shanghai Model Organisms).

[0554] MC38 tumor cells were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. Cells in the exponential growth phase were collected and counted for tumor inoculation. MC38 cells were collected and counted at 1×10 7 The cells were resuspended in PBS containing 50% Matrigel at a density of 1×10 cells / mL. All experimental mice were subcutaneously inoculated with 0.1 mL of cell suspension (1×10 6 cells).

[0555] When the tumor volume reaches 52-132 mm3 (mean tumor volume 95mm 3 ) were randomly divided into groups and administered. The experimental groups were divided into: Group 1: control group (10% DMSO + 90% saline), Group 2: control compound A (2 μmol / kg), and Group 3: compound 2 (2 μmol / kg). Each group consisted of 5 tumor-bearing mice. All tested drugs were administered subcutaneously once daily. The dosing schedule for each test drug is shown in Table 6 below.

[0556] During the administration period, the tumor volume and animal body weight were monitored twice a week. The efficacy was evaluated based on the absolute tumor inhibition rate (TGI) of tumor growth, and the safety was evaluated based on the changes in mouse body weight and death.

[0557] Table 6

[0558] Group number Compound Dosage (μmol / kg) Route of administration Dosing frequency 1 Blank control 2 SC QD×21 2 Control compound A 2 SC QD×21 3 Compound 2 2 SC QD×21

[0559] weight

[0560] The control compound A treatment group showed a slight weight loss, but the blank control group and compound 2 treatment group were well tolerated by the tumor-bearing mice. The results of the weight changes of tumor-bearing mice are shown in Table 7. Figure 4 .

[0561] Table 7. Body weight changes of mice in different groups (%)

[0562]

[0563] Tumor volume

[0564] The tumor volume results of different groups at different time points after tumor inoculation are shown in Table 8 and Figure 5 . The tumor growth inhibition is summarized in Table 9. The control group and each treatment group were compared for homogeneity of variance of tumor volume using one-way ANOVA. Subsequently, the Games-Howell test (data with unequal variance) was used to compare the significant difference in tumor volume between the control group and each treatment group, with P < 0.05 indicating a significant difference. All data were analyzed using SPSS 22.0 software. The results showed that both treatment groups showed significant anti-tumor effects compared with the blank control group.

[0565] Table 8. Average tumor volume of different treatment groups

[0566]

[0567]

[0568] Table 9. Antitumor activity of the tested compounds in the MC38 model

[0569]

[0570] Example 11 Study on antitumor efficacy in a C57BL / 6 mouse MC38 subcutaneous homograft model

[0571] Antitumor efficacy testing of Compound 2, Compound 3, Compound 81, Compound 443 and Compound 459 in the MC38 subcutaneous transplant tumor model of C57BL / 6 mice.

[0572] Animals: mice; strain: C57BL / 6; age: 6-8 weeks; sex: female.

[0573] MC38 tumor cells were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. Cells in the exponential growth phase were collected and counted for tumor inoculation. MC38 cells were collected and counted at 1×10 7 All experimental mice were subcutaneously inoculated with 0.1 mL of cell suspension (1×10 cells / mL) on the right side of the back. 6 cells).

[0574] When the tumor volume reaches 82-129mm 3 (mean tumor volume 102 mm 3 ) were randomly divided into groups for dosing. The experimental groups were divided into: Group 1 control group (10% DMSO + 90% saline), Group 2 received 2 μmol / kg of compound 2, Group 3 received 2 μmol / kg of compound 81, Group 4 received 2 μmol / kg of compound 443, Group 5 received 2 μmol / kg of compound 459, and Group 6 received 2 μmol / kg of compound 3. Each group contained 6 tumor-bearing mice. All tested drugs were administered subcutaneously once daily. The dosing schedule for each test drug is shown in Table 10 below.

[0575] During the administration period, the tumor volume and animal body weight were monitored twice a week. The efficacy was evaluated based on the absolute tumor inhibition rate (TGI) of tumor growth, and the safety was evaluated based on the changes in mouse body weight and death.

[0576] Table 10

[0577]

[0578]

[0579] weight

[0580] The results of weight changes of tumor-bearing mice are shown in Table 11. Figure 6 .

[0581] Table 11. Body weight changes of mice in different groups (%)

[0582]

[0583] Tumor volume

[0584] The tumor volume results of different groups at different time points after tumor inoculation are shown in Tables 12 and Figure 7 . The tumor growth inhibition is summarized in Table 13. The control group and each treatment group were compared for the homogeneity of variance of tumor volume using one-way ANOVA. Subsequently, the Games-Howell test (data with unequal variance) was used to compare the significant differences in tumor volume between the control group and each treatment group, with P < 0.05 indicating a significant difference. All data were analyzed using SPSS22.0 software. The results showed that both treatment groups showed significant anti-tumor effects compared with the blank control group.

[0585] Table 12. Average tumor volume of different treatment groups

[0586]

[0587]

[0588] Table 13. Antitumor activity of the tested compounds in the MC38 model

[0589]

Claims

1. A compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotope-substituted compound thereof, characterized in that: The compound is selected from:

2. A compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, selected from the group consisting of:

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

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

6. The use according to claim 5, characterized in that The cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colorectal cancer, leukemia, glioblastoma or head and neck cancer.

7. The use according to claim 5, characterized in that The drug acts as a glutamine antagonist.

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