KRAS inhibitor compound, pharmaceutical composition thereof and use thereof

Abstract

The present invention relates to the technical field of medicine. Specifically, the present invention relates to a KRAS inhibitor compound, a pharmaceutical composition thereof, and a use thereof. Specifically, the present invention relates to a compound as represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound as represented by formula (I). The compound and the pharmaceutical composition thereof provided in the present invention can be used for preparing medicaments for preventing or treating diseases related to KRAS amplification or mutations such as KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H, and can especially be used for preparing medicaments for preventing or treating cancer.

Description

KRAS inhibitor compounds, pharmaceutical compositions thereof, and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and in particular, the present application relates to a compound capable of inhibiting one or more KRAS mutants, a pharmaceutical composition thereof, and the use of the compound and the pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a disease related to KRAS. BACKGROUND

[0002] RAS gene is one of the most common mutated genes in cancer (20-25%), and the currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%. KRAS has the highest mutation rate in pancreatic ductal adenocarcinoma (PDAC), reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, accounting for 52%, 42% and 32%, respectively. The most common mutation sites of KRAS gene are codons 12, 13 and 61, and the mutant forms include KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12A, KRAS G12V, KRAS G13D and KRAS Q61H mutations. RAS gene mutation is often associated with poor prognosis of cancer, KRAS can be activated by upstream growth factors or tyrosine kinases (such as EGFR), and activated KRAS can activate downstream pathways, common ones are PI3K-AKT-mTOR signaling pathway that controls cell generation, and RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation, which also lays a biological foundation for the use of multiple targets.

[0003] In recent years, some progress has been made in drug research and development using the allosteric site of KRAS G12C mutant, for example, in 2013, a research group reported the discovery of KRAS G12C small molecule inhibitors (Nature, 2013, 503, 548-551). In addition, Mirati Company disclosed KRAS G12D inhibitor compounds in patent WO2021041671, and a broad-spectrum KRAS (including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H) inhibitor in patent WO2022132200, for treating KRAS-mediated related cancers.

[0004] The discovery that KRAS is frequently mutated in various tumor types has made KRAS an extremely attractive target for the pharmaceutical industry for cancer treatment, and compounds that inhibit KRAS activity are still very much worth researching. SUMMARY

[0005] The present application provides a compound capable of inhibiting one or more KRAS mutants, including KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D and KRAS Q61H. In addition, a pharmaceutical composition comprising such a compound is involved, and the use of such a compound and its pharmaceutical composition in the preparation of a medicament for preventing or treating a related disease mediated by KRAS. The medicament treats diseases and / or conditions, especially cancer, by inhibiting KRAS activity.

[0006] In one aspect, the present application provides a compound represented by Formula (I), or a stereoisomer, tautomer, isotopologue, nitroxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound represented by Formula (I),

[0007] wherein,

[0008] R 1 -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 , -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 , -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1-6 alkyl NR 6 C(=O)R 7 , -C 1-6 alkyl NR 6 R 7 , -C 1-6alkyl-C(=O)OR 6 , -C 1-6 alkyl-C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxyC 1-6 alkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, (3-12 membered heterocyclyl)-C 1-6 alkyl, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (C 3-12 cycloalkyl)-O-C 1-6 alkyl, (3-12 membered heterocyclyl)-O-C 1-6 alkyl, C 1-6 mercaptoalkyl, C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl; wherein said C 1-6 alkoxyC 1-6 alkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, (3-12 membered heterocyclyl)-C 1-6 alkyl, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (C 3-12 cycloalkyl)-O-C 1-6 alkyl, (3-12 membered heterocyclyl)-O-C 1-6 alkyl, C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or C 1-6 alkyl;

[0009] T is

[0010] represents a single or double bond;

[0011] Z and Z 3 each independently N or CH;

[0012] Z 1 and Z 2 each independently -O-, -S- or -NH-;

[0013] each X 1 and X 2 independently a bond, -O-, -S-, -NH-, -CH2-, -CH=CH-, -CH2-NH-, -CH2-NH-CH2-, -(CH2)3-, -(CH2)2-, -NH-CH2-, -O-CH2-, -CH2-O-, -CH2-S- or -S-CH2-;

[0014] each R 5 independently H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b , -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1-4 Alkylene-S(=O)2N(R 7b )2, C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Haloalkynyl, C1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced;

[0015] Or, two R atoms attached to the same carbon atom 5 Together

[0016] Or, two R atoms attached to the same carbon atom 5 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced;

[0017] Or, two R atoms connected to two adjacent atoms 5 Together with the two adjacent atoms connected to it, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced;

[0018] Each R 8 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 6-10 heteroaryl, -C(=O)OC 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2;

[0019] Ring B is C 6-12Aryl or 5-12 heteroaryl groups;

[0020] R 2 For -OR 10 -SR 10 -OC(=O)R 11 -OC(=O)NR 12 R 13 -OC(=O)OR 11 -OC 1-6 Alkyl-OC(=O)NR 12a R 13a -OC 1-6 Alkyl-OC(=O)OR 11a -OC 1-6 Alkyl-OP(=O)(OR) 11 (OR) 11c -OP(=O)(OR) 11 (OR) 11c -OC 1-6 Alkyl-OC(=O)R 11b -NR 14 C(=O)OR 11 -NR 14 S(=O)2OR 11 -OS(=O)R 11 -OS(=O)2R 11 -OS(=O)2OR 11 or -OP(=O)(OR) 11 )2;

[0021] Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, C 6-12 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, C 6-12 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C

[0022] R 3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, i-propyl, n-butyl or C 1-4 haloalkyl;

[0023] Y is a bond, O or S;

[0024] R 4 is 3-10 membered heterocyclyl, -L-(3-12 membered heterocyclyl), -L-(C 3-12 cycloalkyl), -L-(5-12 membered heteroaryl) or -L-(C 6-10 aryl), wherein said 3-10 membered heterocyclyl, -L-(C 3-12 cycloalkyl), -L-(5-12 membered heteroaryl) and -L-(C 6-10 aryl) are each independently optionally substituted with 1, 2, 3 or 4 R 9a substituents, said -L-(3-12 membered heterocyclyl) is optionally substituted with 1, 2, 3 or 4 R 9b substituents;

[0025] R 9a and R 9b each independently is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, (C 3-6 cycloalkyl)-C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, each independently is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 1-6 R 1-6 alkyl and C 1-6 alkoxy, C 1-6 haloalkyl, C 6-10 haloalkoxy, (C 1-6 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 3-6 alkyl, (C 1-6 cycloalkyl)-C 6-10 alkyl, C 3-6 aryl, 5-12 membered heteroaryl, C 6e cycloalkyl and 3-6 membered heterocyclyl, each independently is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 7e , -C(=O)C 1-6 alkyl and C 1-6 alkyl;

[0026] or, two R 9b together with the ring carbon atom to which they are attached form

[0027] or, two R 9b and the ring carbon atom to which they are attached form C 3-6cycloalkyl and 3- to 6-membered heterocyclyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-6 alkyl and C 1-6 alkyl;

[0028] L is C 1-6 alkylene;

[0029] R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl;

[0030] or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e , respectively, together with the N atom to which they are attached form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl;

[0031] R 6a , R 6cR 6g R 7g R 6h R 7h R 7k R 6j R 7j each independently -H, -D, -F, -CI, -Br, -I, or C 1-6 alkyl;

[0032] R 10 is C 7-10 alkyl, C 11-20 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl, or 3-12 membered heterocyclyl, wherein R 10 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -OC(=O)R 6a , -C(=O)R 6a , C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 cyanoalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy, and C 1-6 haloalkyl;

[0033] R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a , and R 13a are each independently H, D, C 7-10 alkyl, C 11-20 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl, or 3-12 membered heterocyclyl; wherein said C7-10 alkyl, C 11-20 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -C(=O)R 6a , -C(=O)OR 6a , C 1-6 alkyl, C 7-10 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl, said substituents on C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl, said substituents on C

[0034] or R 12 and R 13 , or R 12a and R 13a each optionally form, together with the N atom to which they are attached, a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl substituted by one or more substituents selected from the group consisting of:

[0035] n is 0, 1, 2, 3, 4, 5 or 6;

[0036] q1 is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0037] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 , -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 , -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1-4 alkylNR 6 C(=O)R 7 , -C 1-4 alkylNR 6 R 7 , -C 1-4 alkyl-C(=O)OR 6 , -C 1-4 alkyl-C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 alkoxy C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, (C 7-12 cycloalkyl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C1-4 alkyl, (7-12 membered heterocyclyl)-C 1-4 alkyl, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-O-C 1-4 alkyl, (C 7-12 cycloalkyl)-O-C 1-4 alkyl, (3-6 membered heterocyclyl)-O-C 1-6 alkyl, (3-7 membered heterocyclyl)-O-C 1-6 alkyl, (7-12 membered heterocyclyl)-O-C 1-4 alkyl, C 1-4 thioalkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; wherein said C 1-4 alkoxy C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, (C 7-12 cycloalkyl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (7-12 membered heterocyclyl)-C 1-4 alkyl, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-O-C 1-4 alkyl, (C 7-12 cycloalkyl)-O-C 1-4 alkyl, (3-6 membered heterocyclyl)-O-C 1-6 alkyl, (3-7 membered heterocyclyl)-O-C 1-6 alkyl, (7-12 membered heterocyclyl)-O-C 1-4 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; wherein said C 6 , -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 7 , -C(=O)NR 6 , -NR 7 C(=O)R 6 and C 7 alkyl; wherein, R 1-4 , R 6 and R 7 6a ​each has the definition as described in the present application.

[0038] In some embodiments, R 1 -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a -C(=O)OR 6a -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 -NR 6a S(=O)2NR 6 R 7 -NR 6 R 7 -CH2NR 6 C(=O)R 7 -CH2NR 6 R 7 -(CH2)2NR 6 R 7 -CH2C(=O)OR 6 -(CH2)2C(=O)OR 6 -(CH2)3C(=O)OR 6 -CH2C(=O)NR 6 R 7 -(CH2)2C(=O)NR 6 R 7 -(CH2)3C(=O)NR 6 R 7-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptanyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, or pyrrolidinyl; wherein said -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptanyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, or pyrrolidinyl is optionally substituted with 1 to 3 groups that are the same or different;3] heptyl, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, and pyrrolidinyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 6 7 6 7 6 7 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl; wherein R 6 , R 7 , and R 6a each have the definition as described in the application.

[0039] In some embodiments, T is

[0040] each R 5 is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b , -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1-4 alkyleneS(=O)2N(R 7b )2, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, -NH(C 1-4 ​​​​​​alkyl), -N(C 1-4 alkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 ;

[0041] or, two R 5 on the same carbon atom, together with the carbon atom to which they are attached form a C

[0042] or, two R 5 on the same carbon atom, together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 ;

[0043] or, two R 5 on two adjacent atoms, together with the two adjacent atoms to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 ;

[0044] each R 8 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 6-10 aryl, 6-10 membered heteroaryl, -C(=O)OC 1-4 alkyl, -C(=O)NHC 1-4 alkyl, -C(=O)N(C 1-4alkyl)2;

[0045] R 6h , R 7h , and R 7k each independently is -H, -D, or C 1-4 alkyl;

[0046] wherein R 6b , R 6c , and R 7b each has the definition as described herein.

[0047] In some embodiments, T is

[0048] each R 5 independently is -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b , -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -CH2S(=O)2N(R 7b )2, -(CH2)2S(=O)2N(R 7b)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl,-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 substituents;

[0049] or, two R 5 on the same carbon atom together form

[0050] or, two R 5and the carbon atom to which it is attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 substituents;

[0051] or, two R 5 and the two adjacent atoms to which they are attached to form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 substituents;

[0052] each R 8 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2, or -C(=O)N(CH3)CH2CH3;

[0053] R 6h , R 7h , and R 7k are each independently -H, -D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl;

[0054] wherein R 6b , R 6c , and R 7b each have the definitions as described herein.

[0055] In some embodiments, T is

[0056] In some embodiments, R 2 is -OR 10 , -SR 10 , -OC(=O)R 11 , -OC(=O)NR 12 R 13 , -OC(=O)OR 11 , -O-C 1-6 alkyl-O-C(=O)NR 12a R 13a , -O-C 1-4 alkyl-O-C(=O)NR 12a R 13a , -O-C 1-4 alkyl-O-C(=O)OR 11a , -O-C 1-4 alkyl-OP(=O)(OR 11 )(OR 11c ), -OP(=O)(OR 11 )(OR 11c ), -O-C 1-4 alkyl-O-C(=O)R 11b , -NR 14 C(=O)OR 11 , -NR 14 S(=O)2OR 11 , -OS(=O)R 11 , -OS(=O)2R 11 , -OS(=O)2OR 11 , or -OP(=O)(OR 11 )2, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R12a and R 13a each have the meaning as described in the present application; or R 2 is -OR 10 , -SR 10 , -OC(=O)R 11 , -OC(=O)NR 12 R 13 , -OC(=O)OR 11 , -O-CH2-O-C(=O)NR 12a R 13a , -O-CH(CH3)-O-C(=O)NR 12a R 13a , -O-CH2-O-C(=O)OR 11a , -O-CH(CH3)-O-C(=O)OR 11a , -O-CH2-OP(=O)(OR 11 )(OR 11c ), -O-CH(CH3)-OP(=O)(OR 11 )(OR 11c ), -OP(=O)(OR 11 )(OR 11c ), -O-CH2-O-C(=O)R 11b , -O-CH(CH3)-O-C(=O)R 11b , -NR 14 C(=O)OR 11 , -NR 14 S(=O)2OR 11 , -OS(=O)R 11 , -OS(=O)2R 11 , -OS(=O)2OR 11 or -OP(=O)(OR 11 )2, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a each have the meaning as described in the present application.

[0057] In some embodiments, R 10 is C 7-10 1-6alkyl, C 11-20 1-6alkyl, C 1-4 1-6alkyl, C 2-4 2-6alkenyl, C 2-4alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein R 10 is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NO2, -NR 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -OC(=O)R 6a , -C(=O)R 6a , C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein R 6 , R 7 and R 6a each have the definition as described in the present application;

[0058] R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a are each independently H, D, C 7-10 alkyl, C 11-20 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; wherein said C 7-10 alkyl, C 11-20 alkyl, C 1-4 alkyl, C 7-10 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NO2, -NR 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR6a -C(=O)R 6a -C(=O)OR 6a -C(=O)N(R 1-4 alkyl, C 4-6 alkyl, C 7-10 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein the substituents of the phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NO2, -NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein R 6 , R 7 and R 6a each have the definition as described in the present application;

[0059] or R 12 and R 13 , or R 12a and R 13a form together with the N atom to which they are attached a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.

[0060] In some embodiments, R 10 is -C9H 19 , -C 10 H 21 , -C 15 H 31-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6 R 7 , -OC(=0)NR 6 R 7 , -OC(=0)OR 6a , -OC(=0)R 6a , -C(=0)R 6a , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, oxazolidinyl, imidazolidinyl, phenyl, pyridyl, pyrimidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl, wherein R 6 , R 7 and R 6a each have the definition as described in the present application;

[0061] R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a each independently is H, D, -C9H 19 , -C 10 H 21 , -C 15 H 31-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazole, isoxa Azolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxacyclobutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl; wherein the -C9H 19 -C 10 H 21 -C 15 H 31 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazole, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl Pyrimidinyl, pyridazinyl, pyrazinyl, thiopheneyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazolyl, pyrazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl are optionally represented by 1, 2, 3, or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, and -NR. 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -C(=O)R 6a -C(=O)OR 6asubstituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl and 1,2-dichloroethyl, R 6 7 6a each having the definition as described in the present application;

[0062] or R 12 and R 13 , or R 12a and R 13a each optionally form, together with the N atom to which they are attached, an azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein said azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl or 1,2-dichloroethyl.

[0063] In some embodiments, each R 0 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b ​​R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 6-10 -C(=O)R 3-6 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 2-4 -C(=O)R 2-4 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 6-10 -C(=O)R 3-6 -C(=O)R 1-4 -C(=O)R 1-4 -C(=O)R 3-6 -C(=O)R 6b -C(=O)R 6c -C(=O)R 7b -C(=O)R

[0064] -C(=O)R 0independently -D, -OH, -F, -CI, -Br, -I, -CN, -SH, -CH2C(=0)NR 6b R 7b , -C(=0)R 6c , -C(=0)OR 6c , -C(=0)NR 6b R 7b , -NR 6b C(=0)R 7b , -NR 6b R 7b-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -CºCF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, or piperazinyl,-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl, wherein R, 6b 6c 7b each have the definitions as described herein.

[0065] In some embodiments, ring B is one of the following substructures,

[0066] each R 0 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1-4 ​​alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-12 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein the C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=0)H, -C(=0)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=0)H, -C(=0)OH, C 6b , R 6c and R 7b each have the definition as described in the present application.

[0067] In some embodiments, each R 0 is independently -D, -OH, -F, -CI, -Br, -I, -CN, -SH, -CH2C(=0)NR 6b R 7b , -C(=0)R 6c , -C(=0)OR 6c , -C(=0)NR 6b R 7b , -NR 6b C(=0)R7b , -NR 6b R 7b-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -CºCF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, or piperazinyl,each of -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl; 6b 6c 7b each of R

[0068] In some embodiments, R 4 is 3-6 membered heterocyclyl, -L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizidinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-lH-indenyl, -L-decahydronaphthalenyl, -L-pyridyl, -L-pyrazolyl, or -L-phenyl, wherein each of said 3-6 membered heterocyclyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-lH-indenyl, -L-decahydronaphthalenyl, -L-pyridyl, -L-pyrazolyl, and -L-phenyl is independently optionally substituted with 1, 2, 3, or 4 R 9a ​​​ -L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, and -L-octahydroindolizinyl, are each optionally substituted with 1, 2, 3, or 4 R 9b substituted;

[0069] R 9a and R 9b each independently is -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NR 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-4 alkyl, and C 1-4 alkyl;

[0070] or, two R 9b attached to the same ring carbon atom, together form

[0071] or, two R groups attached to the same ring carbon atom 9b and together with the ring carbon atom to which they are attached form C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-4 alkyl and C 1-4 alkyl;

[0072] L is C 1-4 alkylene;

[0073] R 6j and R 7j are each independently -H, -D, -F, -Cl, -Br, -I, or C 1-4 alkyl;

[0074] wherein, R 6d , R 7d , R 6d , R 7e and R 7e each have the definitions as described herein.

[0075] In some embodiments,

[0076] R 4 is piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindolizidinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, -CH2-octahydrocyclopenta-dienyl, -CH2-octahydro-lH-indenyl, -CH2-decahydronaphthalenyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, or -CH2-phenyl, wherein said piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, -CH2-octahydrocyclopenta-dienyl, -CH2-octahydro-lH-indenyl, -CH2-decahydronaphthalenyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, and -CH2-phenyl are each independently optionally substituted with 1, 2, 3, or 4 R 9a substituents, said -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, and -CH2-octahydroindolizinyl are each optionally substituted with 1, 2, 3, or 4 R 9b substituted;

[0077] R 9a and R 9b each independently is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, i-propoxy, -CHF2, -CF3, -OCF3, phenylmethyl, pyridinylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, tetrahydropyranyl methyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or azetidinyl, wherein each of the methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, i-propoxy, -CHF2, phenylmethyl, pyridinylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, tetrahydropyranyl methyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and azetidinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and i-propyl;

[0078] or, two R 9b on the same ring carbon atom, taken together, form

[0079] or, two R 9band together with the ring carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or azetidinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and azetidinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and i-propyl;

[0080] R 6j and R 7j each independently is -H, -D, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl;

[0081] wherein R 6d , R 7d , R 6d , R 7e and R 7e each has the definition as described herein.

[0082] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e each independently is -H, -D, or C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0083] or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7e, and the other with the same N atom to which they are attached together form a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkyl, C 3-6 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C

[0084] R 6a , R 6c , R 6g , and R 7g are each independently -H, -D, or C 1-4 alkyl.

[0085] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e , and R 7e are each independently -H, -D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, wherein said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl are each optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, i-propoxy, i-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl, and pyrrolidinyl;

[0086] or R 6 and R 7 , or R 6b and R 7b , or R 6d and R 7d , or R 6e and R 7eEach of these compounds, together with the same N atom attached thereto, forms a pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, or imidazoline, wherein each of the pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, and imidazoline is independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolylalkyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl.

[0087] R 6a R 6c R 6g and R 7g Each can be independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0088] In some implementation schemes, R 4 for

[0089] In some embodiments, the compound of the present invention is a compound of formula (I-1), or a stereoisomer, tautomer, isotopic compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (I-1).

[0090] Among them, R 1 R 2 R 3 R 4 Y and T each have the definitions described in this invention;

[0091] R 01 and R 02 Each has the characteristics of the present invention R 0 The same definition.

[0092] On the other hand, the present invention provides a pharmaceutical composition comprising the compounds described herein.

[0093] In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

[0094] In some embodiments, the excipients described in this invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof. In some embodiments, the pharmaceutical composition may be a liquid, solid, semi-solid, gel, or spray formulation.

[0095] In another aspect, the present application provides use of the pharmaceutical composition of the present application in the preparation of a medicament for preventing, treating or alleviating a KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation related disease.

[0096] In some embodiments, the KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation related disease of the present application is a cancer.

[0097] In some embodiments, the cancer of the present application is a cancer of the heart: sarcoma, myxoma, rhabdomyoma, fibroma, lipoma or teratoma; a cancer of the lung: bronchus, non-small cell lung, small cell lung, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; a cancer of the gastrointestinal tract: esophagus, stomach, pancreas, small intestine, large intestine; a cancer of the genitourinary tract: kidney, bladder and urethra, prostate, testis; a cancer of the liver: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; a cancer of the biliary tract: gall bladder, ampulla of Vater, bile duct; a cancer of the bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, giant cell tumor chordoma, benign chondroma, chondroblastioma, chondromyxofibroma, osteoid osteoma and giant cell tumor; a cancer of the nervous system: skull, brain; a gynecological cancer: uterus, vulva, vagina, fallopian tubes, ovary, breast; a hematological cancer: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma; a cancer of the skin: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; a cancer of the adrenal gland: neuroblastoma.

[0098] In another aspect, the present application also provides a method of preventing or treating a KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation related disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof.

[0099] In another aspect, the present application also provides the use of the compound or the pharmaceutical composition thereof for treating a disease associated with KRAS wild type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation.

[0100] In another aspect, the present application relates to a method for preparing, isolating and purifying the compound of formula (I) or (I-1).

[0101] Unless otherwise stated, all stereoisomers, tautomers, nitroso isomers, hydrates, solvates, metabolites, salts, and prodrugs of the compounds of the present application are within the scope of the application.

[0102] In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemical and toxicological, in relation to other components of the formulation and the mammal for treatment.

[0103] The salts of the compounds of the present application also include salts of intermediates used in preparing or purifying the compound of formula (I) or (I-1), or the isolated enantiomers of the compound of formula (I) or (I-1), but are not necessarily pharmaceutically acceptable salts.

[0104] The foregoing outlines some aspects of the present application, but is not limited to such aspects. Additional aspects will be set forth in more detail in the description that follows.

[0105] Detailed description of the application

[0106] Definitions and general terms

[0107] Certain embodiments of the application now will be described in detail with reference to the accompanying drawings and chemical formulas. The application is intended to encompass all alternatives, modifications and equivalents that can be included within the scope of the application as defined by the claims. One skilled in the art will recognize many methods and materials as being suitable for the practice of the application. No method or material is intended to be disclaimed apart from or in addition to the application as described herein. In the event that one or more publications, patents, or patent applications are cited in this application, the citation of such a document is not intended as an admission that it is commonly owned, is incorporated by reference, or is part of the common general knowledge as it is expressly recited that, to the extent that such a document can be at variance with the contents of this application, including definitions, terms of use and techniques described, it is to be taken as being superseded by the disclosure of this application.

[0108] It is to be further understood that, for brevity, certain aspects of the application are described in terms of several interconnected embodiments or figures. It is to be understood that such descriptions are used only for purposes of clarity, and that each of the individual embodiments or figures can be implemented independently of one another in some embodiments. Conversely, various features of the application can also be provided in combination in a single embodiment.

[0109] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications referred to in this application are incorporated herein by reference in their entirety.

[0110] The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0111] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0112] The term "comprising" is used in the inclusive sense of "including" and not the exclusive sense (i.e., "consisting only of").

[0113] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise specified, all stereoisomers and mixtures thereof of the compounds described herein are within the scope of the application. In addition, unless otherwise specified, the chemical structures depicted herein encompass one or more isotopic enrichments of one or more atoms.

[0114] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0115] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0116] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0117] The term "isotopic compound" refers to a product obtained by substituting one or more atoms of a compound with their isotopes. Different atoms of the same element with the same number of protons but different numbers of neutrons are called isotopes. For example, hydrogen has three isotopes: protium (H), deuterium (D, heavy hydrogen), and tritium (T, superheavy hydrogen). As described in this invention, the compounds of this invention can be independently and optionally substituted by one or more substituents, such as the general formula compounds above, or as in the specific examples, subclasses, and classes of compounds included in this invention. It should be understood that the terms "independently and optionally substituted" or "optionally substituted" are used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0118] Further, it should be noted that the descriptive manner "each independently" and "each is independently" and "independently" used in the present application can be interchangeable unless explicitly indicated otherwise, and should be interpreted broadly, which means that the specific options expressed by the same symbols among different groups can not affect each other, or the specific options expressed by the same symbols among the same groups can not affect each other.

[0119] In various portions of the specification, substituents of the compounds disclosed herein are disclosed in terms of chemical groups or ranges. It is specifically intended that the present application include each and every independent combination of the members of such groups and ranges. For example, the term "C 1-6 "alkyl" specifically refers to the individually disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0120] In various portions of the specification, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be interpreted as the connecting group. For example, if the structure requires a connecting group and the Markush group definition recites "alkyl" or "aryl" for that variable, then it should be understood that the "alkyl" or "aryl" represents the connecting alkylene or arylene group, respectively.

[0121] The term "alkyl" denotes a saturated straight or branched chain monovalent hydrocarbon radical of from 1 to 20 carbon atoms, wherein the alkyl group can optionally be substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1-6 carbon atoms, denoted as C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C 1-4 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, denoted as C 1-3Alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), i-propyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), i-butyl (i-Bu, -CH2CH(CH3)2), s-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0122] The term "alkylene" denotes a saturated divalent hydrocarbyl radical resulting from the removal of two hydrogen atoms from a saturated straight chain or branched chain hydrocarbon. In some embodiments, the alkylene group contains 1 to 6 carbon atoms, denoted as C 1-6 alkylene; in other embodiments, the alkylene group contains 1 to 4 carbon atoms, denoted as C 1-4 alkylene; in other embodiments, the alkylene group contains 1 to 3 carbon atoms, denoted as C 1-3 alkylene; in other embodiments, the alkylene group contains 1 to 2 carbon atoms, denoted as C 1-2 alkylene. Examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like.

[0123] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, with at least one unsaturated site, i.e., one carbon-carbon sp. 2 The double bond, wherein the alkenyl group may optionally be substituted by one or more substituents described in this invention, including the orientation of "cis" and "trans", or the orientation of "E" and "Z". In one embodiment, the alkenyl group comprises 2-6 carbon atoms, denoted as C 2-6 Alkenyl group; in another embodiment, the alkenyl group comprises 2-4 carbon atoms, denoted as C1 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 1-propenyl (i.e., propenyl, -CH=CH-CH3), etc.

[0124] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more substituents described in this invention. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, denoted as C1. 2-6 Alkynyl group; in yet another embodiment, the alkynyl group comprises 2-4 carbon atoms, denoted as C0. 2-4 Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.

[0125] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups, wherein the cyano and alkyl groups have the definitions described herein. In some embodiments, "cyanoalkyl" refers to an alkyl group substituted with one cyano group. In some embodiments, "cyanoalkyl" is C10. 1-6 Cyanoalkyl, i.e., C4 groups substituted with one or more cyano groups. 1-6 Alkyl group. In some preferred embodiments, C 1-6 Cyanoalkyl is a C group substituted with one cyano group. 1-6 Alkyl. In other embodiments, "cyanoalkyl" is C1 1-4 Cyanoalkyl, i.e., C4 groups substituted with one or more cyano groups. 1-4 Alkyl groups. Examples of cyanoalkyl groups include, but are not limited to, -CH2CN, -CH2CH2CH2CH2CN, -CH2CH2CN, -CH2CH(CN)CH2CH2CN, -CH2CH(CN)CH2CH(CH3)CN, etc.

[0126] The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups, wherein alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl denotes an alkyl group substituted with 1, 2, 3, or 4 hydroxyl groups. In some embodiments, hydroxyalkyl denotes an alkyl group substituted with one or two hydroxyl groups. In some embodiments, hydroxyalkyl denotes a C 1-6 hydroxyalkyl, i.e. a C 1-6 alkyl group substituted with one or more hydroxyl groups, preferably a C 1-6 hydroxyalkyl denotes a C 1-6 alkyl group substituted with one hydroxyl group. In some embodiments, hydroxyalkyl denotes a C 1-4 hydroxyalkyl. In some embodiments, hydroxyalkyl denotes a C 1-3 hydroxyalkyl. Examples of hydroxyalkyl include, but are not limited to, -CH2OH, -CH2CH2CH2CH2OH, -CH2CH2OH, -CH2CH(OH)CH2CH2OH, -CH2CH(OH)CH2CH(CH3)OH, and the like.

[0127] The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein. In some embodiments, haloalkyl is a C 1-6 haloalkyl, denotes a C 1-6 alkyl group substituted with one or more halogen atoms; in other embodiments, haloalkyl is a C 1-4 haloalkyl, denotes a C 1-4 alkyl group substituted with one or more halogen atoms; in other embodiments, haloalkyl is a C 1-3 haloalkyl, denotes a C 1-3 alkyl group substituted with one or more halogen atoms. Examples include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.

[0128] The term "haloalkenyl" denotes an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein. In some embodiments, haloalkenyl is a C 2-6 haloalkenyl, denotes a C 2-6 alkenyl group substituted with one or more halogen atoms; in other embodiments, haloalkenyl is a C 2-4 haloalkenyl, denotes a C 2-4Alkynyl groups are substituted with one or more halogen atoms. Examples of such include, but are not limited to, 2-chloroethynyl (-CºCCl), 1-chloropropynyl (-CHCºCH), 3-chloropropynyl (-CºC-CH2Cl), and the like.

[0129] The term "haloalkynyl" denotes an alkynyl group substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein. In some embodiments, haloalkynyl is C 2-6 haloalkynyl, denotes C 2-6 alkynyl group is substituted with one or more halogen atoms; in other embodiments, haloalkynyl is C 2-4 haloalkynyl, denotes C 2-4 alkynyl group is substituted with one or more halogen atoms. Examples of such include, but are not limited to, 2-chloroethynyl (-CºCCl), 1-chloropropynyl (-CHCºCH), 3-chloropropynyl (-CºC-CH2Cl), and the like.

[0130] The term "alkoxyalkyl" denotes an alkyl group substituted with one alkoxy group, wherein alkoxy and alkyl have the definition as described herein. In some embodiments, alkoxyalkyl denotes C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl denotes C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl denotes C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl denotes C 1-3 alkoxy C 1-3 alkyl. Examples of alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propyloxymethyl, isopropyloxymethyl, methoxyethyl, methoxy-n-propyl, methoxyisopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxyisopropyl, n-propoxyethyl, isopropoxyethyl, n-propyloxy-n-propyl, n-propyloxyisopropyl, isopropyloxy-n-propyl, isopropyloxyisopropyl, and the like.

[0131] The term "carboxyalkyl" denotes an alkyl group substituted with one or more carboxy groups, wherein carboxy and alkyl groups have the definition as specifically described herein. In some embodiments, carboxyalkyl is C 1-6 carboxyalkyl, denotes C 1-6 alkyl; in other embodiments, carboxyalkyl is C 1-4 carboxyalkyl, denotes C 1-4Alkyl; in other embodiments, the carboxyl alkyl group is C10. 1-3 Carboxyalkyl, indicating a C group substituted with one or more carboxyl groups. 1-3 Alkyl groups. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH2COOH), 2-carboxyethyl (-(CH2)2COOH), 3-carboxypropyl (-(CH2)3COOH), etc.

[0132] The term "alkylamino" or "alkylamino" refers to an amino group substituted with one or two alkyl groups, including "N-alkylamino" and "N,N-dialkylamino," wherein the alkyl and amino groups have the meanings as described in this invention. In some embodiments, alkylamino represents C 1-6 Alkylamino refers to an alkylamino group containing 1-6 carbon atoms; in other embodiments, alkylamino represents C... 1-4 Alkylamino refers to an alkylamino group containing 1-4 carbon atoms; alkylamino represents C... 1-3 Alkylamino refers to an alkylamino group containing 1 to 3 carbon atoms. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and examples include, but are not limited to, N-methylamino (methylamino, -NHCH3), N-ethylamino (ethylamino, -NHCH2CH3), N,N-dimethylamino (dimethylamino, -N(CH3)2), N,N-diethylamino (diethylamino, -N(CH2CH3)2), etc.

[0133] The term "thiol alkyl" refers to an alkyl group substituted with one or more mercapto groups, wherein the alkyl group has the meaning as described in this invention. In some embodiments, thiol alkyl represents C 1-6 Mercaptoalkyl, which is a C group substituted with one or more mercapto groups. 1-6 Alkyl; preferably, C 1-6 The mercaptoalkyl group is a C group substituted with a mercapto group. 1-6 Alkyl group. In other embodiments, mercaptoalkyl group represents C10. 1-4 Mercaptoalkyl. In other embodiments, mercaptoalkyl represents C... 1-3 Mercaptoalkyl. Examples of mercaptoalkyl include, but are not limited to, mercaptomethyl (-CH2SH), 2-mercaptoethyl (-(CH2)2SH), 3-mercaptopropyl (-(CH2)3SH), 2,3-dimercaptopropyl (-CH2CH(SH)CH2(SH)), etc.

[0134] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule by an oxygen atom, wherein the alkyl group has the meaning as described in this invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing C0. 1-6Alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing C 1-4 Alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing C 1-3 Alkoxy group. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2- Propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentoxy (n-pentoxy, -OCH2CH2CH2CH2CH3), 2-pentoxy (-OCH(CH3)CH2CH2CH3), 3-pentoxy (-OCH(CH2CH3)2), 2-methyl-2-butoxy (-OC(CH3)2CH2CH3), 3-methyl-2-butoxy (-OCH(CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (-OCH2CH(CH3)CH2CH3), etc.

[0135] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group and the halogen have the definitions as defined in this invention. In some embodiments, a haloalkoxy group refers to a haloalkoxy group containing 1-6 carbon atoms, i.e., C6. 1-6 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-4 carbon atoms, i.e., C646-C ... 1-4 Haloalkoxy group; in other embodiments, haloalkoxy group refers to a haloalkoxy group containing 1-3 carbon atoms, i.e., C646-C ... 1-3 Halogenated alkoxy groups. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy (-OCF3), monofluoromethoxy (-OCH2F), 2-fluoroethoxy (-OCH2CH2F), etc.

[0136] The term "carbocyclo" or "carbocyclyl" denotes a saturated or partially unsaturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-12 ring atoms, wherein a -CH2- group in the carbocyclo ring can optionally be replaced with -C(=O)- (or -(CO)-). In one embodiment, the carbocyclyl group contains 3-6 ring carbon atoms, denoted as C 3-6 carbocyclo; in other embodiments, the carbocyclo group is a saturated ring containing 3-6 ring carbon atoms, denoted as C 3-6 cycloalkyl; in other embodiments, the C 3-6 cycloalkyl is a saturated monocyclic ring. In one embodiment, the carbocyclyl group contains 7-12 ring carbon atoms, denoted as C 7-12 carbocyclo; in other embodiments, the carbocyclo group is a saturated ring containing 7-12 ring carbon atoms, denoted as C 7-12 cycloalkyl. Examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-lH-indenyl, octahydrocyclopenta-2-benzene, and the like. Examples of carbocyclo rings wherein a -CH2- group is replaced with -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0137] The term "cycloalkyl" denotes a monovalent saturated monocyclic or bicyclic carbocyclic ring system of 3-12 carbon atoms, wherein a -CH2- group in the carbocyclo ring can optionally be replaced with -C(=O)- (or -(CO)-). In some embodiments, the cycloalkyl group contains 3-12 ring carbon atoms, i.e., C 3-12 cycloalkyl. In other embodiments, the cycloalkyl group contains 3-10 ring carbon atoms, i.e., C 3-10 cycloalkyl. In other embodiments, the cycloalkyl group contains 7-12 ring carbon atoms, i.e., C 7-12 cycloalkyl. In other embodiments, the C 7-12 cycloalkyl is a bicyclic ring system. In other embodiments, the cycloalkyl group contains 7-10 ring carbon atoms, i.e., C 7-10 cycloalkyl. In other embodiments, the C 7-10 cycloalkyl is a bicyclic ring system. In other embodiments, the cycloalkyl group contains 3-6 ring carbon atoms, i.e., C 3-6 cycloalkyl. In other embodiments, the C 3-6 cycloalkyl is a monocyclic ring system. In other embodiments, the cycloalkyl group contains 3-5 ring carbon atoms, i.e., C 3-5 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-lH-indenyl, octahydrocyclopenta-2-benzene, and the like. Examples of cycloalkyl rings wherein a -CH2- group is replaced with -C(=O)- include, but are not limited to, cyclopentanone, cyclobutanone, and the like.

[0138] The term "heterocycle" or "heterocyclyl" means a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing between 3 and 12 ring atoms, wherein at least one ring atom is a nitrogen, sulfur, and oxygen atom; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings. When a heterocycle is attached to the remainder of the molecule through a single bond, the heterocycle is represented as a monovalent heterocyclyl radical. Unless otherwise specified, a heterocyclyl group can be carbon-based or nitrogen-based, and a -CH2- group can optionally be replaced with -C(=O)-. A sulfur atom of a ring can optionally be oxidized to the S-oxide or S-oxide. A nitrogen atom of a ring can optionally be oxidized to an N-oxide. In some embodiments, the heterocycle or heterocyclyl consists of 3-12 atoms, denoted as a 3-12 membered heterocycle or 3-12 membered heterocyclyl. In some embodiments, the heterocycle or heterocyclyl consists of 3-10 atoms, denoted as a 3-10 membered heterocycle or 3-10 membered heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, denoted as a 3-9 membered heterocycle or 3-9 membered heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, denoted as a 5-9 membered heterocycle or 5-9 membered heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 3-7 atoms, denoted as a 3-7 membered heterocycle or 3-7 membered heterocyclyl. In other embodiments, the 3-7 membered heterocycle or 3-7 membered heterocyclyl is a 3-7 membered monocyclic heterocycle or 3-7 membered monocyclic heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, denoted as a 3-6 membered heterocycle or 3-6 membered heterocyclyl. In other embodiments, the 3-6 membered heterocycle or 3-6 membered heterocyclyl is a 3-6 membered monocyclic heterocycle or 3-6 membered monocyclic heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 7-12 atoms, denoted as a 7-12 membered heterocycle or 7-12 membered heterocyclyl. In other embodiments, the 7-12 membered heterocycle or 7-12 membered heterocyclyl is a 7-12 membered bicyclic heterocycle or 7-12 membered bicyclic heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 7-10 atoms, denoted as a 7-10 membered heterocycle or 7-10 membered heterocyclyl. In other embodiments, the 7-10 membered heterocycle or 7-10 membered heterocyclyl is a 7-10 membered bicyclic heterocycle or 7-10 membered bicyclic heterocyclyl. In other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, denoted as a 5-6 membered heterocycle or 5-6 membered heterocyclyl. Examples of heterocycles include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane.The heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, and the like.

[0139] The term "aryl" denotes a monovalent monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms in the ring. In some embodiments, aryl contains 6-12 ring atoms, denoted as C 6-12 aryl or 6-12 membered aryl. In some embodiments, aryl contains 6-10 ring atoms, denoted as C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracene.

[0140] The term "heteroaryl" or "heteroaromatic" denotes a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, sulfur. The heteroaryl group is typically, but not necessarily, attached to the remainder of the molecule through an aromatic ring of the heteroaryl group. When a -CH2- group is present in the heteroaryl group, said -CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the remainder of the molecule (e.g., the main structure in a general formula) through any reasonable site (which can be C or N). The term "heteroaryl" can be used interchangeably with the term "heteroaromatic" or "heteroaromatic compound". In some embodiments, the heteroaryl is a heteroaryl containing 5-12 ring atoms, denoted as 5-12 membered heteroaryl; in other embodiments, the heteroaryl is a heteroaryl containing 5-10 ring atoms, denoted as 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a heteroaryl containing 5-6 ring atoms, denoted as 5-6 membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolyl, and the like.

[0141] The term "alkylthio" denotes an alkyl group, as defined herein, attached to the remainder of the molecule through a sulfur atom. In some embodiments, alkylthio is C 1-6alkylthio, represents an alkylthio group containing 1 to 6 carbon atoms; in other embodiments, the alkylthio group is C 1-4 alkylthio, represents an alkylthio group containing 1 to 4 carbon atoms; in other embodiments, the alkylthio group is C 1-3 alkylthio, represents an alkylthio group containing 1 to 3 carbon atoms. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH3), ethylthio (-SCH2CH3), and the like.

[0142] The term "haloalkylthio" represents an alkylthio group substituted with one or more halogen atoms, wherein the alkylthio group has the definition as described herein. In some embodiments, the haloalkylthio group is C 1-6 haloalkylthio, represents a C 1-6 alkylthio; in other embodiments, the haloalkylthio group is C 1-4 haloalkylthio, represents a C 1-4 alkylthio; in other embodiments, the haloalkylthio group is C 1-3 haloalkylthio, represents a C 1-3 alkylthio. The definition of haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF3), 2,2,2-trifluoroethylthio (-SCH2CF3), monofluoromethylthio (-SCH2F), and the like.

[0143] The term "arylalkyl" represents an alkyl group substituted with one aryl group, wherein the aryl and alkyl groups have the definition as described herein. In some embodiments, the arylalkyl group is (C 6-10 aryl)-C 1-6 alkyl or (6-10 membered aryl)-C 1-6 alkyl; in other embodiments, the arylalkyl group is (C 6-10 aryl)-C 1-4 alkyl or (6-10 membered aryl)-C 1-4 alkyl; in other embodiments, the arylalkyl group is (C 6-10 aryl)-C 1-3 alkyl or (6-10 membered aryl)-C 1-3 alkyl; in other embodiments, the arylalkyl group is phenyl C 1-6 alkyl; in other embodiments, the arylalkyl group is phenyl C 1-4 alkyl; in other embodiments, the arylalkyl group is phenyl C 1-3 alkyl. Examples of arylalkyl groups include, but are not limited to, phenylmethyl, phenylethyl, naphthylmethyl, and the like.

[0144] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the heteroaryl group and the alkyl group have the definitions described herein. In some embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-6 Alkyl; in other embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-4 Alkyl; in other embodiments, the heteroarylalkyl group is (5-12-membered heteroaryl)-C 1-3 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-6 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-4 Alkyl; in other embodiments, the heteroarylalkyl group is (5-6 membered heteroaryl)-C 1-3 Alkyl groups. Examples of heteroarylalkyl groups include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinylethyl, pyrazolylmethyl, etc.

[0145] The term "heterocyclic alkyl" refers to an alkyl group substituted with a heterocyclic group, wherein the heterocyclic group and alkyl group are specifically defined as described herein. In some embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-6 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-4 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-4 Alkyl; in other embodiments, the heterocyclic alkyl group is (3-6 membered heterocyclic)-C 1-3 Alkyl groups. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, etc.

[0146] The term "cycloalkylalkyl" refers to an alkyl group substituted with one cycloalkyl group. In some embodiments, the cycloalkylalkyl group is (C 3-6 cycloalkyl)-C 1-6 Alkyl; in other embodiments, the cycloalkyl group is (C 3-6 cycloalkyl)-C 1-4 Alkyl; in other embodiments, the cycloalkyl group is (C 3-6 cycloalkyl)-C 1-3 Alkyl. Examples of cycloalkyl groups include, but are not limited to: cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc.

[0147] The term "cycloalkyl-O-alkyl" refers to an alkyl group substituted with a cycloalkyloxy group (cycloalkyl-O-). In some embodiments, the cycloalkyl-O-alkyl group is (C 3-12 cycloalkyl)-OC 1-6alkyl; in other embodiments, cycloalkyl-O-alkyl is (C 3-6 cycloalkyl)-O-C 1-6 alkyl; in other embodiments, cycloalkyl-O-alkyl is (C 3-6 cycloalkyl)-O-C 1-4 alkyl; in other embodiments, cycloalkyl-O-alkyl is (C 3-6 cycloalkyl)-O-C 1-3 alkyl. Examples of cycloalkyl-O-alkyl include, but are not limited to: -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, and the like.

[0148] The term "heterocyclyl-O-alkyl" means alkyl substituted with one heterocyclyloxy (heterocyclyl-O-). In some embodiments, heterocyclyl-O-alkyl is (3-12 membered heterocyclyl)-O-C 1-6 alkyl; in other embodiments, heterocyclyl-O-alkyl is (3-6 membered heterocyclyl)-O-C 1-4 alkyl; in other embodiments, heterocyclyl-O-alkyl is (7-12 membered heterocyclyl)-O-C 1-4 alkyl; in other embodiments, heterocyclyl-O-alkyl is (3-6 membered heterocyclyl)-O-C 1-3 alkyl. Examples of heterocyclyl-O-alkyl include, but are not limited to: -CH2O-azetidinyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptanyl, and the like.

[0149] The term "halogen" or "halo" means F (fluorine), Cl (chlorine), Br (bromine), or I (iodine).

[0150] The term "oxo" means =O.

[0151] The term "cyano" means -CN or -C≡N.

[0152] The term "mercapto" means -SH.

[0153] The term "hydroxyl" means -OH.

[0154] The term "carboxyl" means -C(=O)OH.

[0155] The term "amino" means -NH2.

[0156] The term "consisting of" or "consisting" means that a composition, method or process can only include the specified elements, and excludes the presence of other elements. The term "consisting of" or "consisting" is intended to be synonymous with "consisting only of". The term "j-k atoms" or "j-k membered" means that the cyclic group consists of j-k ring atoms, including carbon atoms and / or O, N, S, P, and the like heteroatoms; j and k are each independently any non-zero natural number, and k > j; "j-k" includes j, k, and any natural number in between. For example, "3-8 atoms" or "3-8 membered", "3-6 atoms" or "3-6 membered", "5-10 atoms" or "5-10 membered", or "5-6 atoms" or "5-6 membered" means that the cyclic group consists of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, including carbon atoms and / or O, N, S, P, and the like heteroatoms.

[0157] As described herein, substituents (R 0 ) n A ring system formed by one bond to the center ring represents n substituents R 0 Substitution can occur at any substitutable position or any reasonable position on the ring. For example, a naphthalene ring represented by formula a can be substituted with n R 0 and 1 R 2 , R 0 and R 2 are substituents at any substitutable position or any reasonable position on the ring, respectively, and when n is greater than 1, each R 0 may be independently selected from the same or different substituents.

[0158] The term "prodrug" as used herein refers to a compound that is converted into a compound of Formula (I) or (I-1) in vivo. Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion of the prodrug to the parent structure in the blood or tissues. Prodrugs of the present application can be esters, and in the present application esters can be benzoic acid esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present application containing a hydroxyl group can be acylated to provide a compound in the form of a prodrug. Other prodrug forms include phosphates, such as those compounds which are phosphorylated on a hydroxyl group of the parent.

[0159] "Metabolite" refers to a product produced through metabolism of a specified compound or salt thereof in the body. Metabolites of a compound can be identified using techniques known in the art, and have activities that are substantially similar to those of the compound. Such products can be oxidation, reduction, hydrolysis, am idation, deam idation, esterification, deesterification, enzymatic cleavage, and the like of a given compound. Accordingly, the present application includes metabolites of a compound of the present application, including those produced in vivo, upon administration of the compound to a mammal.

[0160] "Pharmaceutically acceptable salt" as used herein refers to organic and inorganic salts of the compounds of the present application. Pharmaceutically acceptable salts are well known in the art, for examples, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable, non-toxic acid addition salts include, but are not limited to, salts of inorganic acids such as hydrochloride, hydrobromide, phosphate, sulphate, perchlorate, and organic acids such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, salicylate, or by other methods well known in the art such as ion exchange. The present application also contemplates the quaternary ammonium salts of any of the compounds containing N. Water or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a free amine group of the present application. Such salts include, but are not limited to, those of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, and organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, salicylic acid, and the like.

[0161] "Solvate" as used herein refers to an association or complex of one or more solvent molecules with a compound of the present application. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" refers to the complex that contains water as the solvent.

[0162] When the solvent is water, the term "hydrate" can be used. In one embodiment, one molecule of a compound of the application can be associated with one molecule of water, such as a monohydrate; in another embodiment, one molecule of a compound of the application can be associated with more than one molecule of water, such as a dihydrate; in yet another embodiment, one molecule of a compound of the application can be associated with less than one molecule of water, such as a hemihydrate. It is noted that the hydrates of the compounds described herein retain the bioavailability of the non-hydrated form of the compounds.

[0163] The term "treat" or "treatment" of any disease or disorder, as used herein, means, in some embodiments, to ameliorate the disease or disorder (i.e., to slow or arrest or reduce the development of the disease or at least one of the clinical symptoms thereof). In other embodiments, "treatment" means to alleviate or ameliorate at least one physical parameter including those not discernible by the patient. In other embodiments, "treatment" means to mediate a disease or disorder either physically, e.g., stabilize discernible symptoms, or physiologically, e.g., stabilize a physical parameter. In other embodiments, "treatment" means to prevent or delay the onset, occurrence or worsening of a disease or disorder.

[0164] The terms "prevent" or "prevention" mean a reduction in risk of acquiring a disease or disorder (i.e., causing the at least one clinical symptom of the disease not to develop in a subject that can be, or predisposed to be, exposed to the disease but does not yet experience or exhibit symptoms of the disease).

[0165] The term "therapeutically effective amount" means an amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the condition, age, sex, body weight of the subject to be treated.

[0166] Unless otherwise stated, all isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the application are intended to be covered herein by the scope of the present application.

[0167] In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are intended to be covered herein and are included within the scope of the present application. When the stereochemistry is indicated by a solid or dashed wedge, then the stereoisomer is specifically intended and defined by the disclosure.

[0168] N-oxides of the compounds of the present application are also within the scope of the present application. N-oxides of the compounds of the present application can be prepared by oxidation of the corresponding nitrogen-containing base using conventional oxidizing agents (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

[0169] The compound represented by formula (I) or (I-1) can exist in the form of a salt.

[0170] Any formula given herein is also intended to represent hydrates, solvates, polymorphs, tautomers, and isomers of the compounds described herein including those resulting from isotope exchange or priming. 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.

[0171] Description of the compounds of the present application

[0172] The present application provides a compound, or a pharmaceutical composition thereof, which can act as a KRAS inhibitor, especially as a KRAS12D inhibitor. The present application further relates to the use of the compound, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a disease and / or a disorder by the compound inhibiting KRAS activity.

[0173] The superior properties of the compounds of the present application, such as half-life, clearance, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility, etc., can lead to a reduction in side effects, an enlargement of the therapeutic index, or an improvement in tolerability, etc.

[0174] In one aspect, the present application provides a compound represented by formula (I), or a stereoisomer, a tautomer, an isotopologue, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound represented by formula (I),

[0175] wherein, R is0 R 1 R 2 R 3 R 4 Y, T, ring B, n each have the definitions as described in the present application.

[0176] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 , -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 , -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1-6 alkylNR 6 C(=O)R 7 , -C 1-6 alkylNR 6 R 7 , -C 1-6 alkyl-C(=O)OR 6 , -C 1-6 alkyl-C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxyC 1-6 alkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, (3-12 membered heterocyclyl)-C 1-6 alkyl, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (C 3-12 cycloalkyl)-O-C 1-6alkyl, (3- to 12-membered heterocyclyl)-O-C 1-6 alkyl, C 1-6 mercaptoalkyl, C 6-12 aryl, 5- to 12-membered heteroaryl, C 3-12 cycloalkyl or 3- to 12-membered heterocyclyl; wherein said C 1-6 alkoxyC 1-6 alkyl, (C 3-12 cycloalkyl)-C 1-6 alkyl, (3- to 12-membered heterocyclyl)-C 1-6 alkyl, (C 6-10 aryl)-C 1-6 alkyl, (5- to 12-membered heteroaryl)-C 1-6 alkyl, (C 3-12 cycloalkyl)-O-C 1-6 alkyl, (3- to 12-membered heterocyclyl)-O-C 1-6 alkyl, C 6-12 aryl, 5- to 12-membered heteroaryl, C 3-12 cycloalkyl and 3- to 12-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -OH, -F, -CI, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , and C 1-6 alkyl; wherein R 6 , R 7 and R 6a each have a definition as described in the application.

[0177] In some embodiments, T is

[0178] represents a single or double bond;

[0179] Z and Z 3 are each independently N or CH;

[0180] Z 1 and Z 2 are each independently -O-, -S-, or -NH-;

[0181] each X 1 and X 2Independently, it can be a bond, -O-, -S-, -NH-, -CH2-, -CH=CH-, -CH2-NH-, -CH2-NH-CH2-, -(CH2)3-, -(CH2)2-, -NH-CH2-, -O-CH2-, -CH2-O-, -CH2-S-, or -S-CH2-;

[0182] q1 is 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0183] Among them, R 5 It has the definition as described in this invention.

[0184] In some implementation schemes, each R 5 Independently, it can be H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b S(=O)2R 7b -S(=O)2N(R) 7b )2、-NR 6b C(=O)N(R 7b )2、-NR 6b S(=O)2N(R 7b )2、-OS(=O)2N(R 7b )2、-S(=O)2R 6c -C 1-4 Alkylene-S(=O)2N(R) 7b 2. C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced, of which R 6b R 7c R 6c and R 8 Each has the definition as described in this invention.

[0185] In some implementations, two R atoms attached to the same carbon atom 5 Together Among them, R 6h R 7h and R 7k Each has the definition as described in this invention.

[0186] In some implementations, two R atoms attached to the same carbon atom 5 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced, of which R 8 It has the definition as described in this invention;

[0187] In some implementations, two R atoms are connected to two adjacent atoms. 5 Together with the two adjacent atoms connected to it, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced, of which R 8 It has the definition as described in this invention.

[0188] In some implementation schemes, each R 8 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10aryl, 6-10 membered heteroaryl, -C(=O)OC 1-6 alkyl, -C(=O)NHC 1-6 alkyl, -C(=O)N(C 1-6 alkyl)2.

[0189] In some embodiments, ring B is C 6-12 aryl or 5-12 membered heteroaryl.

[0190] In some embodiments, R 2 is -OR 10 , -SR 10 , -OC(=O)R 11 , -OC(=O)NR 12 R 13 , -OC(=O)OR 11 , -O-C 1-6 alkyl-O-C(=O)NR 12a R 13a , -O-C 1-6 alkyl-O-C(=O)OR 11a , -O-C 1-6 alkyl-OP(=O)(OR 11 )(OR 11c ), -OP(=O)(OR 11 )(OR 11c ), -O-C 1-6 alkyl-O-C(=O)R 11b , -NR 14 C(=O)OR 11 , -NR 14 S(=O)2OR 11 , -OS(=O)R 11 , -OS(=O)2R 11 , -OS(=O)2OR 11 , or -OP(=O)(OR 11 )2, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a each have the definition as described herein.

[0191] In some embodiments, each R 0 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR6b R 7b , -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b R 7b , C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, C 6-12 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 haloalkylthio, C 6-12 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 6b , R 7b and R 6c each have the definition as given in the present application.

[0192] In some embodiments, R3 -H, -D, -OH, -SH, -F, -CI, -Br, -I, -CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, or C 1-4 haloalkyl.

[0193] In some embodiments, Y is a bond, O, or S.

[0194] In some embodiments, R 4 is 3-10 membered heterocyclyl, -L-(3-12 membered heterocyclyl), -L-(C 3-12 cycloalkyl), -L-(5-12 membered heteroaryl), or -L-(C 6-10 aryl), wherein said 3-10 membered heterocyclyl, -L-(C 3-12 cycloalkyl), -L-(5-12 membered heteroaryl), and -L-(C 6-10 aryl) are each independently optionally substituted with 1, 2, 3, or 4 R 9a groups, and said -L-(3-12 membered heterocyclyl) is optionally substituted with 1, 2, 3, or 4 R 9b groups, wherein L, R 9a , and R 9b each have the definitions as described herein.

[0195] In some embodiments, L is C 1-6 alkylene.

[0196] In some embodiments, wherein R 9a is -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, (C 3-6 cycloalkyl)-C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein said C 1-6alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, (C 3-6 cycloalkyl)-C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-6 alkyl and C 1-6 alkyl, wherein R 6d and R 7d each have the definition as described in the application.

[0197] In some embodiments, wherein R 9b is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 6-10 aryl)-C 1-6 alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, (C 3-6 cycloalkyl)-C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, (C 6-10 aryl)-C 1-6alkyl, (5-12 membered heteroaryl)-C 1-6 alkyl, (3-6 membered heterocyclyl)-C 1-6 alkyl, (C 3-6 cycloalkyl)-C 1-6 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-6 alkyl and C 1-6 alkyl, wherein R 6d and R 7d each have the definition as described in the application.

[0198] In some embodiments, two R 9b attached to the same ring carbon atom are taken together to form wherein R 6j and R 7j each have the definition as described in the application.

[0199] In some embodiments, two R 9b attached to the same ring carbon atom are taken together with the ring carbon atom to which they are attached to form C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-6 alkyl and C 1-6 alkyl.

[0200] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e each independently is -H, -D, or C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-6alkyl, C 6-12 aryl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl, wherein R 6g and R 7g each have the definitions as described in the application.

[0201] In some embodiments, R 6 and R 7 , and together with the same N atom to which they are attached form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy or C 1-6 haloalkyl.

[0202] In some embodiments, R 6b and R 7b , and together with the same N atom to which they are attached form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy or C 1-6 haloalkyl.

[0203] In some embodiments, R 6d and R 7d , and together with the same N atom to which they are attached form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy or C1-6 The alkyl halogroup is substituted by a substituent.

[0204] In some implementation schemes, R 6e and R 7e Together with the same N atom attached thereto, they form a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally composed of 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The alkyl halogroup is substituted by a substituent.

[0205] In some implementation schemes, R 6a R 6c R 6g R 7g R 6h R 7h R 7k R 6j and R 7j Each can be independently -H, -D, -F, -Cl, -Br, -I, or -C. 1-6 alkyl.

[0206] In some implementation schemes, R 10 C 7-10 Alkyl, C 11-20 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, wherein R 10 Optionally, it is selected by 1, 2, 3 or 4 elements chosen from -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -OC(=O)R 6a -C(=O)R 6a C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkoxy, C1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 haloalkyl, wherein R 6 , R 7 and R 6a each have the definition as described in the application.

[0207] In some embodiments, R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a are each independently H, D, C 7-10 alkyl, C 11-20 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl; wherein said C 7-10 alkyl, C 11-20 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclyl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NR 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -C(=O)R 6a , -C(=O)OR 6a alkyl, C 1-6 alkyl, C 7-10 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 6 , R 7 and R 6a each have the meaning as described in the present invention.

[0208] In some embodiments, R 12 and R 13 , and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C

[0209] In some embodiments, R 12a and R 13a , and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 alkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkoxy and C 1-6 substituted by 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C

[0210] In some embodiments, n is 0, 1, 2, 3, 4, 5 or 6.

[0211] In some embodiments, R1 -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R 7 , -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 , -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -C 1-4 alkylNR 6 C(=O)R 7 , -C 1-4 alkylNR 6 R 7 , -C 1-4 alkyl-C(=O)OR 6 , -C 1-4 alkyl-C(=O)NR 6 R 7 , C 1-6 alkyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 alkoxy C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, (C 7-12 cycloalkyl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (7-12 membered heterocyclyl)-C 1-4 alkyl, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-O-C 1-4 alkyl, (C 7-12 cycloalkyl)-O-C 1-4 alkyl, (3-6 membered heterocyclyl)-O-C 1-6 alkyl, (3-7 membered heterocyclyl)-O-C 1-6alkyl, (7-12 membered heterocyclyl)-O-C 1-4 alkyl, C 1-4 mercaptoalkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl; wherein said C 1-4 alkoxy C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, (C 7-12 cycloalkyl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (7-12 membered heterocyclyl)-C 1-4 alkyl, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-O-C 1-4 alkyl, (C 7-12 cycloalkyl)-O-C 1-4 alkyl, (3-6 membered heterocyclyl)-O-C 1-6 alkyl, (3-7 membered heterocyclyl)-O-C 1-6 alkyl, (7-12 membered heterocyclyl)-O-C 1-4 alkyl, C 6-10 aryl, 5-12 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR 6 , -NR 6 R 7 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , and C 1-4 alkyl; wherein R 6 , R 7 and R 6a each have the definition as described herein.

[0212] In some embodiments, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -NR 6a C(=O)NR 6 R7 , -C(=O)R 6a , -C(=O)OR 6a , -NR 6 S(=O)2R 7 , -S(=O)2NR 6 R 7 , -NR 6a S(=O)2NR 6 R 7 , -NR 6 R 7 , -CH2NR 6 C(=O)R 7 , -CH2NR 6 R 7 , -(CH2)2NR 6 R 7 , -CH2C(=O)OR 6 , -(CH2)2C(=O)OR 6 , -(CH2)3C(=O)OR 6 , -CH2C(=O)NR 6 R 7 , -(CH2)2C(=O)NR 6 R 7 , -(CH2)3C(=O)NR 6 R 7-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptanyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, or pyrrolidinyl; wherein said -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azetidinyl, -CH2O-oxetanyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexanyl, -CH2O-spiro[3.3]heptanyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, or pyrrolidinyl is optionally substituted with 1 to 3 groups that are the same or different;3] heptyl, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, oxetanyl, tetrahydropyranyl, azetidinyl, and pyrrolidinyl, each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 6 R 7 6 R 7 6 C(=O)R 7 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl; wherein R 6 , R 7 , and R 6a each have the definition as described in the present application.

[0213] In some embodiments, T is wherein R 5 and each q1 have the definition as described in the present application.

[0214] In some embodiments, each R 5 is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c , -C(=O)OR 6c , -C(=O)NR 6b R 7b , -NR 6b C(=O)R 7b , -NR 6b S(=O)2R 7b , -S(=O)2N(R 7b )2, -NR 6b C(=O)N(R 7b )2, -NR 6b S(=O)2N(R 7b )2, -OS(=O)2N(R 7b )2, -S(=O)2R 6c , -C 1-4 alkyleneS(=O)2N(R 7b )2, C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 cyanoalkyl, C​​​1-4 hydroxyalkyl, C 1-4 haloalkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 1-4 alkylthio, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, 6-10 membered aryl, 5-10 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 , wherein R 6b , R 7c , R 6c and R 8 each have the definition as described herein.

[0215] In some embodiments, two R 5 attached to the same carbon atom together form wherein R 6h , R 7h and R 7k each have the definition as described herein.

[0216] In some embodiments, two R 5 attached to the same carbon atom together with the carbon atom to which they are attached form C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 , wherein R 8 has the definition as described herein.

[0217] In some embodiments, two R 5 attached to two adjacent atoms together with the two adjacent atoms to which they are attached form C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 , wherein R8 has the definition as described in the present application.

[0218] In some embodiments, each R 8 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=0)OH, -C(=0)NH2, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 6-10 aryl, 6-10 membered heteroaryl, -C(=0)OC 1-4 alkyl, -C(=0)NHC 1-4 alkyl, -C(=0)N(C 1-4 alkyl)2;

[0219] In some embodiments, R 6h , R 7h and R 7k are each independently -H, -D, or C 1-4 alkyl.

[0220] In some embodiments, each R 5 is independently -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=0)H, -C(=0)R 6c , -C(=0)OR 6c , -C(=0)NR 6b R 7b , -NR 6b C(=0)R 7b , -NR 6b S(=0)2R 7b , -S(=0)2N(R 7b )2, -NR 6b C(=0)N(R 7b )2, -NR 6b S(=0)2N(R 7b )2, -OS(=0)2N(R 7b )2, -S(=0)2R 6c , -CH2S(=0)2N(R 7b )2, -(CH2)2S(=0)2N(R 7b)2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl,-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are each independently optionally substituted with 1, 2, 3, or 4 R 8 , R 6b , R 7c , R 6c , and R 8 each have the definitions as described herein.

[0221] In some embodiments, two R 5and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 has the meaning as described herein.

[0222] In some embodiments, each R 5 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 and the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, wherein each of said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl is independently optionally substituted with 1, 2, 3, or 4 R 8 has the meaning as described herein.

[0223] In some embodiments, each R 8Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, phenyl, furanyl, imidyl Azolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazoleyl, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2 or -C(=O)N(CH3)CH2CH3.

[0224] In some implementation schemes, R 6h R 7h and R 7k Each can be independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0225] In some implementations, T is

[0226] In some implementation schemes, R 2 For -OR 10 -SR 10 -OC(=O)R 11 -OC(=O)NR 12 R 13 -OC(=O)OR 11 -OC 1-6 Alkyl-OC(=O)NR 12a R 13a -OC 1-4 Alkyl-OC(=O)NR 12a R 13a -OC 1-4 Alkyl-OC(=O)OR 11a -OC 1-4 Alkyl-OP(=O)(OR) 11 (OR) 11c -OP(=O)(OR) 11 (OR) 11c-O-C(=O)R 1-4 alkyl-O-C(=O)R 11b , -NR 14 C(=O)OR 11 , -NR 14 S(=O)2OR 11 , -OS(=O)R 11 , -OS(=O)2R 11 , -OS(=O)2OR 11 or -OP(=O)(OR 11 )2, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a each have the definition as described in the application.

[0227] In some embodiments, R 2 is -OR 10 , -SR 10 , -OC(=O)R 11 , -OC(=O)NR 12 R 13 , -OC(=O)OR 11 , -O-CH2-O-C(=O)NR 12a R 13a , -O-CH(CH3)-O-C(=O)NR 12a R 13a , -O-CH2-O-C(=O)OR 11a , -O-CH(CH3)-O-C(=O)OR 11a , -O-CH2-OP(=O)(OR 11 )(OR 11c ), -O-CH(CH3)-OP(=O)(OR 11 )(OR 11c ), -OP(=O)(OR 11 )(OR 11c ), -O-CH2-O-C(=O)R 11b , -O-CH(CH3)-O-C(=O)R 11b , -NR 14 C(=O)OR 11 , -NR 14 S(=O)2OR 11 , -OS(=O)R 11, -OS(=0)2R 11 , -OS(=0)2OR 11 or -OP(=0)(OR 11 )2, wherein R 10 , R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a each have a definition as indicated in the present application.

[0228] In some embodiments, R 10 is C 7-10 alkyl, C 11-20 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein R 10 is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6 R 7 , -OC(=0)NR 6 R 7 , -OC(=0)OR 6a , -OC(=0)R 6a , -C(=0)R 6a , C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein R 6 , R 7 and R 6a each have a definition as indicated in the present application.

[0229] In some embodiments, R 10 is -C9H 19 , -C 10 H 21 , -C 15 H 31-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl, R 10 optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -OC(=O)R 6a -C(=O)R 6a -methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, oxazolidinyl, imidazolidinyl, phenyl, pyridinyl, pyrimidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl, wherein R 6 R 7 and R 6a each have the definition as described in the application.

[0230] In some embodiments, R 11 R 12 R 13 R 14 R 11a R 11b R 11c R 12a and R 13a are each independently H, D, C 7-10 alkyl, C 11-20 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl; wherein said C7-10 alkyl, C 11-20 alkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -C(=O)R 6a , -C(=O)OR 6a , C 1-4 alkyl, C 4-6 alkyl, C 7-10 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein the phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl, wherein R 6 , R 7 and R 6a each have the definition as described in the present application.

[0231] In some embodiments, R 11 , R 12 , R 13 , R 14 , R 11a , R 11b , R 11c , R 12a and R 13a are each independently H, D, -C9H 19 , -C 10 H21 , -C 15 H 31 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein said -C9H 19 , -C 10 H 21 , -C 15 H 31 , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl are optionally substituted with 1, 2, 3, or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NR 6 R 7 , -OC(=O)NR 6 R 7 , -OC(=O)OR 6a , -C(=O)R 6a , -C(=O)OR 6a , -C(=O)ORThe substituents are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, pyrrolyl, aziridine, pyrrolyl, piperazine, piperidinyl, morpholinyl, oxazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl, wherein the substituents are phenyl, naphthyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, or aziridine. The aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl groups are optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl. 6 R 7 and R 6a Each has the definition as described in this invention.

[0232] In some implementation schemes, R 12 and R 13 Together with the N atom attached thereto, it forms a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally composed of 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 The alkyl halogroup is substituted by a substituent.

[0233] In some implementation schemes, R 12 and R 13, and together with the N atom to which they are attached form an azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazolidine, wherein said azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazolidine is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl.

[0234] In some embodiments, R 12a and R 13a , and together with the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, and C 1-4 haloalkyl.

[0235] In some embodiments, R 12a and R 13a , and together with the N atom to which they are attached form an azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazolidine, wherein said azetidine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazolidine is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl.

[0236] In some embodiments, ring B is one of the following substructures,

[0237] In some embodiments, each R 0 is independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b , -C(=O)R6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein said C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 haloalkylthio, C 6-10 aryl, 5- to 12-membered heteroaryl, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl; wherein R 6b , R 6c and R 7b each have the definition as described in the present application.

[0238] In some embodiments, each R 0independently -D, -OH, -F, -CI, -Br, -I, -CN, -SH, -CH2C(=0)NR 6b R 7b , -C(=0)R 6c , -C(=0)OR 6c , -C(=0)NR 6b R 7b , -NR 6b C(=0)R 7b , -NR 6b R 7b-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -CºCF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, or piperazinyl,-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºCCH2OH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl; wherein R, 6b 6c 7b each have the definitions as described herein.

[0239] In some embodiments, wherein R 2 each have the definitions as described herein.

[0240] In some embodiments, R 4 is a 3-6 membered heterocyclyl, ​​​-L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-lH-indenyl, -L-decahydronaphthalenyl, -L-pyridinyl, -L-pyrazolyl, or -L-phenyl, wherein each of said 3-6 membered heterocyclyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-lH-indenyl, -L-decahydronaphthalenyl, -L-pyridinyl, -L-pyrazolyl, and -L-phenyl is independently optionally substituted with 1, 2, 3, or 4 R 9a said -L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, and -L-octahydroindolizinyl are each optionally substituted with 1, 2, 3, or 4 R 9b , R 9a , and R 9b each have the definitions as described herein.

[0241] In some embodiments, L is C 1-4 alkylene.

[0242] In some embodiments, R 9a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e , -C(=O)C 1-4 alkyl and C 1-4 alkyl, wherein R 6d , R 7d , R 6e , R 7e each have the definitions as described in the application.

[0243] In some embodiments, R 9b is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, (3-6 membered heterocyclyl)-C 1-4 alkyl, (C 3-6 cycloalkyl)-C 1-4 alkyl, phenyl, 5-6 membered heteroaryl, C 3-6each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-4 alkyl and C 1-4 alkyl, wherein R 6d and R 7d each have the definition as described herein.

[0244] In some embodiments, two R 9b together form wherein R 6j and R 7j each have the definition as described herein.

[0245] In some embodiments, R 6j and R 7j each independently is -H, -D, -F, -CI, -Br, -I, or C 1-4 alkyl.

[0246] In some embodiments, two R 9b together with the ring carbon atom to which they are attached form a C 3-6 cycloalkyl and 3-6 membered heterocyclyl, wherein said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-4 alkyl and C 1-4 alkyl.

[0247] In some embodiments, two R 9b together with the ring carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or azetidinyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and azetidinyl is each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and i-propyl.

[0248] In some embodiments,

[0249] R 4 is piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindolizinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, -CH2-octahydropentalenyl, -CH2-octahydro-lH-indenyl, -CH2-decahydronaphthalenyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, or -CH2-phenyl, each of which is independently optionally substituted with 1, 2, 3, or 4 R 9a , and -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, and -CH2-octahydroindolizinyl, each of which is optionally substituted with 1, 2, 3, or 4 R 9b , and R 9a each have the definitions as described herein. 9b

[0250] In some embodiments, R 9a is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d , -C(=O)NR 6d R 7d , -CH2NR 6d R 7d , -CH2OC(=O)NR 6d R 7d ​, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CHF2, -CF3, -OCF3, phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolylmethyl, piperazineylmethyl, azacyclobutylmethyl, piperidinylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazineyl or azacyclobutyl, wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CHF2, phenylmethyl, Pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolylmethyl, piperazinylmethyl, aziridinemethyl, piperidylmethyl, tetrahydropyranylmethyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazinyl, and aziridine are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and isopropyl;

[0251] In some implementation schemes, R 9b is -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d, -H, -D, -F, -CI, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, isopropoxy, -CHF2, -CF3, -OCF3, phenylmethyl, pyridinylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, tetrahydropyranyl methyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, or azetidinyl, wherein each of said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, methoxy, ethoxy, isopropoxy, -CHF2, phenylmethyl, pyridinylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperazinylmethyl, azetidinylmethyl, piperidinylmethyl, tetrahydropyranyl methyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridinyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, and azetidinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -F, -CI, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and isopropyl, wherein R 6d and R 7d each have the definition as described herein.

[0252] In some embodiments, two R 9b , taken together with the carbon atom to which they are attached, form

[0253] In some embodiments, R 6j and R 7j each independently is -H, -D, -F, -CI, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or t-butyl.

[0254] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e each independently is -H, -D, or C 1-4 alkyl, wherein said C 1-4alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , C 1-4 alkyl, C 6-10 aryl, C 3-6 cycloalkyl, and 3- to 6-membered heterocyclyl.

[0255] In some embodiments, R 6 and R 7 , together with the same N atom to which they are attached, form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, or C 1-4 haloalkyl.

[0256] In some embodiments, R 6b and R 7b , together with the same N atom to which they are attached, form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, or C 1-4 haloalkyl.

[0257] In some embodiments, R 6d and R 7d , respectively, together with the same N atom to which they are attached, form a 4- to 6-membered heterocyclic ring, wherein said 4- to 6-membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 1-4 alkoxy, C1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy or C 1-4 haloalkyl.

[0258] In some embodiments, R 6e and R 7e , and together with the same N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein said 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy or C 1-4 haloalkyl.

[0259] In some embodiments, R 6a , R 6c , R 6g and R 7g are each independently -H, -D, or C 1-4 alkyl.

[0260] In some embodiments, R 4 is

[0261] In some embodiments, R 4 is

[0262] In some embodiments, R 4 is

[0263] In some embodiments, R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7eeach independently -H, -D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, wherein each of said methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g , methoxy, ethoxy, n-propoxy, i-propoxy, i-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, oxiranyl, oxetanyl, azetidinyl, and pyrrolidinyl.

[0264] In some embodiments, R 6 and R 7 , and together with the same N atom to which they are attached form a pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, or imidazolidine, wherein each of said pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, and imidazolidine is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl.

[0265] In some embodiments, R 6b and R 7b , and together with the same N atom to which they are attached form a pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, or imidazolidine, wherein each of said pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, and imidazolidine is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl.

[0266] In some embodiments, R 6d and R 7d, and together with the same N atom to which they are attached form a pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, or imidazolidine, wherein each of said pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, and imidazolidine is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl.

[0267] In some embodiments, R 6e and R 7e , and together with the same N atom to which they are attached form a pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, or imidazolidine, wherein each of said pyrrolidine, piperazine, piperidine, morpholino, oxazolidine, and imidazolidine is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, i-propoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl.

[0268] In some embodiments, R 6a , R 6c , R 6g and R 7g each independently is -H, -D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

[0269] In some embodiments, the compound of the present application is a compound of Formula (I-1), or a stereoisomer, a tautomer, an isotopologue, a nitroso, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of Formula (I-1),

[0270] wherein R 1 , R 2 , R 3 , R 4 , Y, and T each have the definitions as described herein;

[0271] R 01 and R 02 each have the same definitions as R 0 described herein.

[0272] In some implementation schemes, R 01 and R 02 Each of the following can be independently represented as -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, or -CH2C(=O)NR. 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups;

[0273] R 6b R 7b and R 6c Each has the definition as described in this invention.

[0274] In some implementation schemes, R 01 and R 02 Each of the following can be independently represented as -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, or -CH2C(=O)NR. 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=0)H, -C(=0)OH, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -CI, -Br, -I, -CN, -NH2, -C(=0)H, -C(=0)OH, C

[0275] R 6b , R 7b , and R 6c each have the definition as described herein.

[0276] In some embodiments, R 01 and R 02 are each independently -D, -OH, -F, -CI, -Br, -I, -CN, -SH, -CH2C(=0)NR 6b R 7b , -C(=0)R 6c , -C(=0)OR 6c , -C(=0)NR 6b R 7b , -NR 6b C(=0)R 7b , -NR 6b R 7b-CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -CºCF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, or piperazinyl,each -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CºCH, -CºCCH3, -CH2CºCH, -CºC(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -CºCCH2F, -CºC(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl is independently optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy, n-propyloxy, i-propyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolidinyl, tetrahydrofuranyl, piperidinyl, and piperazinyl.

[0277] In some embodiments, the compound of the present application is a compound of Formula (I-2), or a stereoisomer, a tautomer, an isotopologue, a nitroxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of a compound of Formula (I-2),

[0278] wherein R 2 has the meaning as described in the present application.

[0279] In some embodiments, the compound of the present application is a compound of the following structure, or a stereoisomer, a tautomer, a nitroxide, an isotopologue, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

[0280] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application.

[0281] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable adjuvant.

[0282] In some embodiments, the adjuvant of the present application includes, but is not limited to, a carrier, an excipient, a diluent, a vehicle, or a combination thereof. In some embodiments, the pharmaceutical composition can be in a liquid, solid, semi-solid, gel or spray form.

[0283] In another aspect, the present application provides use of the pharmaceutical composition of the present application in the manufacture of a medicament for preventing, treating or alleviating a KRAS wild type, or a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation related disease.

[0284] In some embodiments, the KRAS wild type, or a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutation related disease of the present application is a cancer.

[0285] In some embodiments, the cancer according to the present application is a cancer of the heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, etc.), myxoma, rhabdomyoma, fibroma, lipoma and teratoma, etc.; lung cancer: bronchus (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, etc.; gastrointestinal cancer: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (lymphoma, leiomyosarcoma) cancer, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) cancer, large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) cancer, etc.; urogenital tract cancer: kidney (adenocarcinoma, nephroblastoma, lymphoma) cancer, bladder and urethra cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testis (seminoma, teratoma, embryonal carcinoma, dysgerminoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma) cancer, etc.; liver cancer: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, etc.; biliary tract cancer: gallbladder cancer, ampullary cancer, cholangiocarcinoma, etc.; bone cancer: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor, etc.; nervous system cancer: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) tumor, brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma), etc.; gynecological cancer: uterine cancer (endometrial carcinoma, granulosa cell tumor, interstitial cell tumor, arrhenoblastoma, malignant teratoma), vulva cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina cancer (clear cell carcinoma, squamous cell carcinoma, grape-like sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, ovarian cancer, breast cancer, etc.; hematological cancer: acute or chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc.; skin cancer: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, etc.; and adrenal gland cancer: neuroblastoma, etc.

[0286] In another aspect, the present application also provides a method of preventing or treating a KRAS related disease, the method comprising administering to a patient a therapeutically effective amount of a compound of the present application or a pharmaceutical composition thereof.

[0287] In another aspect, the present application also provides a use of a compound of the present application or a pharmaceutical composition thereof for treating a KRAS wild-type, or a KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutation related disease.

[0288] In another aspect, the present application relates to a method of preparing, isolating and purifying a compound of formula (I) or (I-1).

[0289] Unless otherwise indicated, all stereoisomers, tautomers, nitroso isomers, hydrates, solvates, metabolites, salts, and pharmaceutically acceptable prodrugs of the compounds of the present application are within the scope of the application.

[0290] In particular, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemical or toxicological, in relation to other components of the formulation and the mammal for treatment.

[0291] The salts of the compounds of the present application also include salts of intermediates used in making or purifying a compound of formula (I) or (I-1), or salts of isolated enantiomers of a compound of formula (I) or (I-1), but are not necessarily pharmaceutically acceptable salts.

[0292] Formulation, administration and use of pharmaceutical compositions of the compounds of the present application

[0293] The pharmaceutical compositions of the present application feature a compound of formula (I), (I-1), or (I-2), a compound listed in the present application, or a compound of the Examples, and a pharmaceutically acceptable carrier. The amount of the compound in the pharmaceutical compositions of the present application is effective to treat or alleviate a KRAS-mediated disease in a patient.

[0294] The compounds of the present application exist in free form or in a suitable, pharmaceutically acceptable derivative. According to the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative which upon administration to a patient is capable of providing (directly or indirectly) a compound described in other aspects of the present application, a metabolite or residue thereof.

[0295] As described herein, the pharmaceutically acceptable compositions of the present application further comprise a pharmaceutically acceptable carrier, which as used herein includes any and all solvents, diluents, or other liquid vehicles, suspending agents, or dispersing agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, and the like, as suited to the particular dosage form desired. General considerations relating to various pharmaceutically acceptable carriers can also be found in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the application, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this application.

[0296] Suitable excipients for the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0297] In making the pharmaceutical compositions of the application, the active ingredients will be mixed with a pharmaceutically acceptable carrier, diluted by a carrier or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. If the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The compositions can therefore be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid forms or in liquid media), ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In one embodiment, the composition is formulated for oral administration. In one embodiment, the composition is formulated as a tablet or capsule.

[0298] The compounds or pharmaceutical compositions of this application can be administered in a form of an oral dosage, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered in intravenous (bolus injection or infusion), intraperitoneal, subcutaneous or intramuscular form, all using dosage forms well known in the pharmaceutical art. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0299] The compounds or pharmaceutical compositions of this application can be administered in a form of an oral dosage, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered in intravenous (bolus injection or infusion), intraperitoneal, subcutaneous or intramuscular form, all using dosage forms well known in the pharmaceutical art. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0300] The compounds or pharmaceutical compositions of this application can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0301] The compounds or pharmaceutical compositions of the present application can also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyethylene glycol, pyran co-polymers, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present application can be coupled to a class of biodegradable polymers useful in accomplishing controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymer of poly-lactic and poly-glycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyortho esters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block co-polymers of hydrogels.

[0302] The dosage regimen for compounds or pharmaceutical compositions of the present application will vary according to various factors, such as the pharmacokinetic characteristics of the particular agent and its mode of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment(s); the frequency with which treatment is to be effected; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian will determine and prescribe the effective amount of the drug that is appropriate for a particular patient.

[0303] The compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents. The compounds or compositions of the present application can be administered concurrently with or sequentially to other therapeutic agents by the same or different route of administration. The compounds of the present application can be included in a single formulation with other therapeutic agents or in separate formulations.

[0304] When the compounds of the present application are administered with other therapeutic agents, generally, the amount of each component in the typical daily dosage and in the typical dosage form can be reduced relative to the usual dosage when administered alone, taking into account the additive or synergistic effects of the combined administration.

[0305] The compounds of the present application, or pharmaceutically acceptable salts thereof, or hydrates thereof, or pharmaceutical compositions thereof, are effective for preventing, treating, or lessening a disease in a patient mediated by KRAS wild-type, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations, particularly cancer.

[0306] In some embodiments, the compounds of the application or pharmaceutical compositions thereof are effective for preventing, treating, or ameliorating the symptoms of cancer in a patient including, but not limited to: cardiac cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxosarcoma, rhabdomyoma, fibroma, lipoma, and teratocarcinoma, etc.; lung cancers: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, adenomas of the bronchus, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, etc.; gastrointestinal cancers: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma) cancer, stomach (lymphoma, leiomyosarcoma) cancer, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, VIPomas), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma) cancer, large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma) cancer, etc.; genito-urinary tract cancers: kidney (adenocarcinoma, nephroblastoma, lymphoma) cancer, bladder and urethra cancer (squamous cell cancer, transitional cell cancer, adenocarcinoma), prostate (adenocarcinoma, sarcoma) cancer, testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma) cancer, etc.; cancers of the liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, etc.; biliary tract cancers: gall bladder cancer, ampullary cancer, cholangiocarcinoma, etc.; cancers of the bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, benign chondroma, chondroblastioma, chondromyxofibroma, osteoid osteoma and giant cell tumors, etc.; nervous system cancers: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans) tumors, cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma), etc.; gynecological cancers: uterine cancer (endometrial carcinoma, granulosa cell tumor, interstitial cell tumor, arrhenoblastoma, malignant teratoma), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube cancer, ovarian cancer, breast cancer, etc.; hematologic cancers: acute or chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), etc.; skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic naevus, lipoma, hemangioma, dermatofibroma, keloids, psoriasis, etc.;and adrenal gland cancers: neuroblastoma, etc.

[0307] General synthetic procedures

[0308] For the purpose of describing the present application, the present application will be further illustrated by the following examples. The following examples are only used to illustrate the specific implementation methods of the present application, so that those skilled in the art can understand the present application, but not used to limit the protection scope of the present application. In the specific implementation methods of the present application, the technical means or methods not specifically described are the conventional technical means or methods in the art.

[0309] Unless otherwise indicated, the definitions of substituents are as described in the present application. The following reaction schemes and examples are used to further illustrate the content of the present application.

[0310] Those skilled in the art will recognize that the chemical reactions described in the present application can be used to appropriately prepare other compounds of the present application, and other methods for preparing compounds of the present application are considered to be within the scope of the present application. For example, the synthesis of those non-exemplified compounds according to the present application can be successfully performed by those skilled in the art by using methods analogous to the above examples, and making routine modifications to the reaction conditions, for example, appropriately selecting and / or modifying the reagents which are used, or using other known reagents, or making routine modifications to the reaction conditions described in the present application. In addition, the reaction conditions disclosed in the present application are also recognized to be applicable to the preparation of other compounds of the present application.

[0311] Unless otherwise indicated, all temperatures described in the examples described below are in degrees Celsius (°C). Room temperature in the examples means 15 °C to 30 °C; in some examples, room temperature is 20 °C to 30 °C. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co., Ltd., Tianjin Fumian Chemical Reagent Factory, Wuhan Xinhua Yuan Science and Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haoyang Chemical Factory.

[0312] Anhydrous tetrahydrofuran, dioxane, toluene, diethyl ether were dried over sodium metal by reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride by reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were used after drying with anhydrous sodium sulfate.

[0313] The following reactions are generally run under a positive pressure of nitrogen or argon or under anhydrous conditions in a drybox (unless otherwise noted), reaction vessels are fitted with a Teflon-coated septum cap and substrates are syringed into the vessel. Glassware is oven- or flame-dried.

[0314] The chromatography column is a silica gel column. Silica gel (300-400 mesh) is purchased from Qingdao Ocean Chemical Factory.

[0315] 1 H NMR spectra are recorded on a Bruker 400MHz or 600MHz NMR spectrometer. 1 H NMR spectra are recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvent (in ppm) with TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), br s (broadened singlet), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, J, are reported in Hertz (Hz).

[0316] Low resolution mass spectrometry (MS) data are measured on an Agilent 6120 quadrupole HPLC-MS (column type: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, 0.6 mL / min flow rate. Mobile phase: 5% to 95% (CH3CN with 0.1% formic acid) in (H2O with 0.1% formic acid), electrospray ionization (ESI), UV detection at 210 nm / 254 nm.

[0317] Pure compounds are measured on an Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column type: NOVASEP 50 / 80 mm DAC), UV detection at 210 nm / 254 nm.

[0318] The following abbreviations are used throughout the application:

[0319] The compounds, pharmaceutical compositions and uses thereof provided by the present application are further illustrated by the following examples.

[0320] Synthesis Scheme 1

[0321] Compound (IA-1) can be prepared by the route of synthetic scheme one, wherein R 1 , R 3 , R 4 , R 01 , R 02 , R 11 , T, Y and R 4 each have the definition as described in the present application, wherein X is halogen, preferably CI and Br. Compound (IA-1-1) and compound (IA-1-2) are reacted under basic conditions (such as triethylamine) to give compound (IA-1).

[0322] Synthetic scheme 2

[0323] Compound (IA-2) can be prepared by the route of synthetic scheme two, wherein R 1 , R 3 , R 4 , R 01 , R 02 , R 12 , R 13 , T, Y and R 4 each have the definition as described in the present application, wherein X is halogen, preferably CI and Br. Compound (IA-1-1) and compound (IA-2-2) are reacted under basic conditions (such as triethylamine) to give compound (IA-1).

[0324] Synthetic scheme 3

[0325] Compound (IA-3) can be prepared by the route of synthetic scheme two, wherein R 1 , R 3 , R 4 , R 01 , R 02 , R 11 , T, Y and R 4 each have the definition as described in the present application, wherein X is halogen, preferably CI and Br. Compound (IA-1-1) and compound (IA-3-2) are reacted under basic conditions (such as triethylamine) to give compound (IA-3). Examples

[0326] Synthesis of intermediate compound M1

[0327] Step 1: Synthesis of compound M1-2

[0328] In a 1000 mL single-neck flask, compound M1-1 (10 g, 45.74 mmol), DMAP (1.12 g, 9.15 mmol) and DCM (200 mL) were added and stirred at room temperature 30 °C, di-tert-butyl dicarbonate (21.96 g, 100.63 mmol) was added dropwise to the reaction solution, and after the addition was completed, it was stirred at 30 °C for 18 h. The reaction was stopped, and imidazole (3.11 g, 45.74 mmol) was added to the reaction solution, and after stirring for half an hour, it was washed with saturated ammonium chloride solution (100 mL x 3), and the organic phase was washed with saturated sodium chloride solution (100 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated to give 17.4 g of yellow solid product M1-2 with a yield of 90.82%, which was directly used in the next step. 1 H NMR (599 MHz, CDCl3): δ 8.79 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.41 (s, 18H), 1.38 (t, J = 7.1 Hz, 3H).

[0329] Step 2: Synthesis of compound M1-3

[0330] In a 500 mL three-neck flask, compound M1-2 (10 g, 23.88 mmol) and anhydrous THF (100 mL) were added, stirred and cooled to -40 °C, and TMPMgCl-LiCl (35.82 mL, 35.82 mmol, 1M THF solution) was added dropwise at -40 °C. Stirring was continued at -40 °C for 4 h, and a solution of dibromotetrachloroethane (9.33 g, 28.66 mmol) in THF (30 mL) was added dropwise. Stirring was continued at -40 °C for 4 h. The reaction was stopped, saturated ammonium chloride solution (100 mL) was added to quench, and then extracted with EA (100 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / DCM (v / v = 100 / 1-1 / 1) eluent to give 8.5 g of yellow solid M1-3 with a yield of 71.5%. 1 H NMR (599 MHz, CDCl3): δ 4.40 (q, J = 7.2 Hz, 2H), 1.42 (s, 18H), 1.37 (t, J = 7.2 Hz, 3H).

[0331] Step 3: Synthesis of compound M1

[0332] In a 250 mL three-necked flask, compound M1-3 (5 g, 10.05 mmol), DCM (50 mL) and TFA (14.97 mL, 200.1 mmol) were added, and stirred at 30 °C for 5 h. The reaction was stopped, and the pH was adjusted to neutral by adding saturated aqueous sodium carbonate solution, and then extracted with DCM (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give 2.9 g of light brown solid M1 with a yield of 97%. 1 H NMR (599 MHz, CDCl3): δ 6.07 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); LC-MS (ESI, pos.ion) m / z: 297.1 [M+H] + . Synthesis of intermediate compound M2

[0333] Step 1: Synthesis of compound M2-1

[0334] In a 50 mL two-necked flask, compound M1 (1.0 g, 3.36 mmol), Pd(PPh3)2Cl2 (0.472 g, 0.67 mmol) and Cul (0.128 g, 0.67 mmol) were added, and replaced with nitrogen for three times. Then 1-(trimethylsilyl)propyne (0.566 g, 5.04 mmol), TEA (2.33 mL, 16.8 mmol) and anhydrous THF (10 mL) were added, and replaced with nitrogen for three times. TBAF (5.04 mL, 5.04 mmol, 1.0 M THF solution) was added dropwise while stirring. After the dropwise addition was completed, the reaction was stirred at room temperature (25 °C) for 6 h. The reaction was stopped, and the mixture was filtered through diatomite. The filtrate was rotary evaporated to dryness, and then purified by column chromatography with PE / DCM (v / v = 100 / 1-2 / 1) as the eluent to give 0.523 g of yellow solid M2-1 with a yield of 60.6%. LC-MS (ESI, pos.ion) m / z: 257.3 [M+H] + .

[0335] Step 2: Synthesis of compound M2-2

[0336] In a 50 mL single-necked flask, compound M2-1 (0.52 g, 2.03 mmol) and anhydrous THF (6 mL) were added, and stirred to dissolve under nitrogen protection. Then 2,2,2-trichloroacetyl isocyanate (0.497 g, 2.64 mmol) was added, and stirred at room temperature (25 °C) for 1 h. The reaction was stopped, and the mixture was directly used in the next step. The yield was calculated as 100%. LC-MS (ESI, pos.ion) m / z: 445.9 [M+H] + .

[0337] Step 3: Synthesis of compound M2

[0338] To the compound M2-2 (0.885 g, 1.99 mmol) obtained in the previous step, methanol (6 mL) was added, stirred and dissolved, then ammonia methanol solution (2.84 mL, 19.99 mmol, 7M) was added, stirred at room temperature for 2 h, the reaction was stopped, the crude obtained after concentration was slurried with MTBE (10 mL) for 0.5 h, filtered to obtain 0.48 g of white solid M2, the two-step yield of step 2 and step 3 was 95%. LC-MS (ESI, pos.ion) m / z: 254.1 [M+H] + .

[0339] Synthesis of intermediate compound M3

[0340] Step 1: Synthesis of compound M3-1

[0341] In a 100 mL single-neck flask, compound M2 (1.00 g, 3.94 mmol) and anhydrous toluene (10 mL) were added, then phosphorus oxychloride (1.08 mL, 11.82 mmol) and DIPEA (3.26 mL, 19.7 mmol) were added, heated to 70°C and stirred for 1 h, the reaction was stopped, cooled and concentrated for direct use in the next step, the yield was calculated as 100%.

[0342] Step 2: Synthesis of compound M3-2

[0343] In the compound M3-1 obtained in the previous step, anhydrous dichloromethane (15 mL) was added, replaced with nitrogen for three times, stirred and dissolved, cooled to -40°C and stirred for 5 min, then DIPEA (3.27 mL, 19.8 mmol) was added, followed by addition of homomorpholine hydrochloride (0.49 g, 3.56 mmol). After stirring at -40°C for 0.5 h, the reaction was stopped, saturated ammonium chloride solution (30 mL) was added to quench, returned to room temperature, extracted with DCM (30 mL x 2), the organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography with PE / EA (v / v = 3 / 2) as the eluent to obtain 360 mg of yellow solid compound M3-2, the two-step yield of step 1 and step 2 was 25.6%. LC-MS (ESI, pos.ion) m / z: 355.1 [M+H] + .

[0344] Step 3: Synthesis of compound M3-3

[0345] In a 50 mL single neck flask, compound M3-2 (355 mg, 1.0 mmol), ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (240 mg, 1.5 mmol), DIPEA (0.33 mL, 2 mmol) and anhydrous 1,4-dioxane (8 mL) were added, replaced with nitrogen for three times, heated to 95 °C and stirred for 22 h, the reaction was stopped, cooled to room temperature, the reaction solution was concentrated, diluted with EA (30 mL), washed with saturated ammonium chloride solution (30 mL), separated, extracted with EA (20 mL x 2), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, purified by column chromatography with DCM / MeOH (v / v = 97 / 3) as eluent to give 281 mg of yellow solid compound M3-3 with a yield of 58.83%. LC-MS (ESI, pos.ion) m / z: 478.2 [M+H] + .

[0346] Step 4: Synthesis of compound M3-4

[0347] In a 25 mL single neck flask, compound M3-3 (200 mg, 0.42 mmol, 1 equiv.), M4 (0.17 g, 0.34 mmol), Xphos Pd G3 (36 mg, 0.042 mmol), K3PO4·7H2O (140 mg, 0.42 mmol) and THF / H2O (v / v = 5 mL / 0.8 mL) were added, replaced with nitrogen for three times, stirred at room temperature for 2.5 h, TLC detection showed that there was still a large amount of starting material M3-3 left, M4 (0.8 equiv.), Xphos Pd G3 (0.1 equiv.) and K3PO4·7H2O (1.5 equiv.) were added, and stirring was continued for 1.5 h, the reaction was still not complete, the above material was repeated until the starting material 1-3 was substantially completely reacted, saturated ammonium chloride solution (50 mL) was added, extracted with DCM (30 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, purified by column chromatography with DCM / MeOH (v / v = 50 / 1) as eluent to give 244 mg of red solid compound M3-4 with a yield of 70.4%. LC-MS (ESI, pos.ion) m / z: 829.0 [M+H] + .

[0348] Step 5: Synthesis of compound M3-5

[0349] In a 25 mL single neck flask, compound M3-4 (235 mg, 0.28 mmol) and acetonitrile (5 mL) were added, cooled to 0 °C and stirred for 5 min, concentrated sulfuric acid (0.04 mL, 0.74 mmol, 98% purity) was added dropwise, stirred for 45 min, the reaction was stopped, quenched with saturated aqueous sodium bicarbonate solution (20 mL), extracted with DCM (20 mL x 3), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, purified by column chromatography with DCM / MeOH (v / v = 50 / 1) as eluent to give 184 mg of red solid compound M3-5, yield 82.7%, LC-MS (ESI, pos.ion) m / z: 784.4 [M+H] + .

[0350] Step 6: Synthesis of compound M3

[0351] In a 25 mL single neck flask, compound M3-5 (184 mg, 0.23 mmol), cesium fluoride (520 mg, 3.45 mmol) and DMF (1 mL) were added, replaced with nitrogen for three times, stirred at room temperature for 15 h, the reaction was stopped, water (20 mL) was added, the solid was precipitated, filtered to give the solid crude product, the crude product was purified by column chromatography with DCM / MeOH (v / v = 30 / 1) as eluent to give 100 mg of red solid compound M3, yield 67.9%. LC-MS (ESI, pos.ion) m / z: 628.3 [M+H] + ; HRMS (ESI): 628.2530 [M+H] + ; 1 H NMR (400 MHz, CD3OD): d 7.84 (dd, J = 9.0, 5.7 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.23 (s, 1H), 5.30 (d, J = 54.0 Hz, 1H), 4.35 - 4.17 (m, 4H), 4.16 - 4.01 (m, 2H), 3.99 - 3.84 (m, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.41 - 3.36 (m, 1H), 3.29 - 3.18 (m, 2H), 3.09 - 2.94 (m, 1H), 2.39 - 2.19 (m, 2H), 2.16 (s, 3H), 2.15 - 2.08 (m, 2H), 2.08 - 1.81 (m, 5H). 19 F NMR (376 MHz, CD3OD): d -111.52 (1F), -140.76 (1F), -173.59 (1F).

[0352] Example 1: Synthesis of compound 1

[0353] In a 25 mL single neck flask, compound M3-4 (100 mg, 0.12 mmol), cesium fluoride (91 mg, 0.60 mmol) and DMF (0.6 mL) were added, nitrogen was replaced for three times, stirred at room temperature for 4 h, the reaction was stopped, water (7 mL) was added, the solid was precipitated, the crude product was obtained by filtration, the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 25 / 1) eluent, 58 mg of yellow solid compound 1 was obtained, the yield was 71.5%. LC-MS (ESI, pos.ion) m / z: 672.3 [M+H] + ; HRMS (ESI): 672.2790 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 7.97 (dd, J = 9.1, 5.7 Hz, 1H), 7.70 - 7.63 (m, 1H), 7.44 - 7.33 (m, 2H), 5.43 - 5.24 (m, 3H), 4.66 - 4.45 (m, 2H), 4.41 - 4.04 (m, 6H), 3.99 - 3.85 (m, 2H), 3.85 - 3.75 (m, 2H), 3.52 (s, 3H), 3.44 - 3.39 (m, 1H), 3.28 - 3.23 (m, 1H), 3.15 - 2.98 (m, 1H), 2.43 - 2.22 (m, 2H), 2.17 (s, 3H), 2.14 - 1.86 (m, 6H). 19 F NMR (376 MHz, CD3OD): δ -110.02 (1F), -140.76 (1F), -173.68 (1F).

[0354] Example 2: Synthesis of compound 2

[0355] In a 50 mL single neck flask, compound M3 (100 mg, 0.16 mmol), DCM (3 mL) were added, stirred at 0 °C for 5 min, TEA (0.067 mL, 0.48 mmol) and acetyl chloride (0.017 mL, 0.24 mmol) were added dropwise, stirred for 1 h. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), the liquid was separated, the aqueous phase was extracted with DCM (20 mL), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated, the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 25 / 1) eluent, 64 mg of yellow solid compound 2 was obtained, the yield was 60%. LC-MS (ESI, pos.ion) m / z: 670.5 [M+H] + ; HRMS (ESI): 692.2453 [M+Na] + ;1 H NMR (400 MHz, CD3OD) δ 8.07 (dd, J = 9.0, 5.7 Hz, 1H), 7.87 (s, 1H), 7.53 - 7.42 (m, 2H), 5.36 (d, J = 53.5 Hz, 1H), 4.43 - 4.29 (m, 2H), 4.29 - 4.05 (m, 4H), 3.95 - 3.88 (m, 2H), 3.83 - 3.77 (m, 2H), 3.54 - 3.34 (m, 4H), 3.21 - 3.00 (m, 1H), 2.47 - 2.22 (m, 6H), 2.19 - 2.03 (m, 8H); 19 F NMR (376 MHz, CD3OD): δ -107.13 (1F), -140.69 (1F), -173.70 (1F).

[0356] Example 3: Synthesis of compound 3

[0357] In a 50 mL single neck flask, compound M3 (80 mg, 0.13 mmol), DCM (3 mL) was added and stirred at 0 °C for 5 min, TEA (0.054 mL, 0.39 mmol) and pivaloyl chloride (0.024 mL, 0.20 mmol) were added dropwise, and the reaction was stirred for 3 h. The reaction was quenched by adding saturated ammonium chloride solution (15 mL), and the aqueous phase was extracted with DCM (15 mL x 2), the organic phase was combined and dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 25 / 1) as eluent to give 67 mg of yellow solid compound 3 with a yield of 74%. LC-MS (ESI, pos.ion) m / z: 712.5 [M+H] + ; HRMS (ESI): 734.2900 [M+Na] + ; 1 H NMR (400 MHz, CD3OD) δ 8.07 (dd, J = 9.0, 5.7 Hz, 1H), 7.88 - 7.80 (m, 1H), 7.51 - 7.41 (m, 2H), 5.36 (d, J = 53.4 Hz, 1H), 4.45 - 4.31 (m, 2H), 4.30 - 4.03 (m, 4H), 3.97 - 3.85 (m, 2H), 3.84 - 3.72 (m, 2H), 3.57 - 3.33 (m, 4H), 3.18 - 3.04 (m, 1H), 2.47 - 2.23 (m, 2H), 2.22 - 1.92 (m, 9H), 1.39 (s, 9H); 19F NMR (376 MHz, CD3OD): δ -107.10 (1F), -140.57 (1F), -173.65 (1F).

[0358] Example 4: Synthesis of compound 4

[0359] In a 50 mL single neck flask, compound M3 (70 mg, 0.11 mmol), DCM (3 mL) was added and stirred at 0 °C for 5 min, TEA (0.046 mL, 0.33 mmol) and methylamine carbamoyl chloride (0.014 mL, 0.17 mmol, 90% mass fraction) were added dropwise, and the reaction was stirred for 4 h. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with DCM (15 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 25 / 1) eluent to obtain 60 mg of yellow solid compound 4 with a yield of 78%. LC-MS (ESI, pos.ion) m / z: 685.5 [M+H] + ; HRMS (ESI): 685.2616 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.05 (dd, J = 8.8, 5.8 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.51 - 7.37 (m, 2H), 5.33 (d, J = 53.7 Hz, 1H), 4.40 - 4.17 (m, 4H), 4.16 - 4.02 (m, 2H), 3.98 - 3.85 (m, 2H), 3.84 - 3.71 (m, 2H), 3.53 - 3.44 (m, 1H), 3.43 - 3.33 (m, 1H), 3.30 - 3.21 (m, 2H), 3.14 - 2.99 (m, 1H), 2.81 (s, 3H), 2.44 - 2.22 (m, 2H), 2.18 - 1.90 (m, 9H); 19 F NMR (376 MHz, CD3OD): δ -107.59 (1F), -140.60 (1F), -173.64 (1F).

[0360] Example 5: Synthesis of compound 5

[0361] In a 50 mL single neck flask, compound M3 (70 mg, 0.11 mmol) and DCM (3 mL) were added and stirred at 0 °C for 5 min, TEA (0.046 mL, 0.33 mmol) and ethyl chloroformate (0.016 mL, 0.17 mmol) were added dropwise, and the reaction was stirred for 2.5 h. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), and the aqueous phase was extracted with DCM (15 mL x 2), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 25 / 1) as eluent to give 53 mg of compound 5 as a yellow solid with a yield of 68%. LC-MS (ESI, pos.ion) m / z: 700.3 [M+H] + ; HRMS (ESI): 700.2767 [M+H] + ; 1 HNMR (400 MHz, CD3OD) δ 8.08 (dd, J = 9.1, 5.7 Hz, 1H), 7.98 - 7.92 (m, 1H), 7.62 - 7.53 (m, 1H), 7.52 - 7.42 (m, 1H), 5.33 (d, J = 53.6 Hz, 1H), 4.41 - 4.17 (m, 6H), 4.16 - 4.01 (m, 2H), 3.98 - 3.85 (m, 2H), 3.84 - 3.73 (m, 2H), 3.53 - 3.46 (m, 1H), 3.42 - 3.31 (m, 2H), 3.29 - 3.20 (m, 1H), 3.12 - 2.99 (m, 1H), 2.42 - 2.21 (m, 2H), 2.21 - 2.10 (m, 5H), 2.09 - 1.86 (m, 4H), 1.37 (t, J = 7.1 Hz, 3H); 19 F NMR (376 MHz, CD3OD): δ -106.87 (1F), -140.61 (1F), -173.64 (1F).

[0362] Example 6: Synthesis of compound 6

[0363] In a 50 mL single necked flask, compound M3 (65 mg, 0.10 mmol), DCM (2 mL) were added and stirred at 0 °C for 5 min, TEA (0.042 mL, 0.30 mmol) and dimethylaminocarbonyl chloride (0.014 mL, 0.15 mmol) were added dropwise and the reaction was stirred for 1.5 h, DMAP (2.4 mg, 0.020 mmol) was added and stirring was continued for 14.5 h. DCM (20 mL) was added to dilute the reaction and it was washed with saturated sodium chloride solution (20 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated, the crude product was purified by thin layer chromatography using DCM / MeOH (v / v = 20 / 1) as eluent to obtain 58 mg of compound 6 as a yellow solid with 80% yield. LC-MS (ESI, pos.ion) m / z: 699.6 [M+H] + ; HRMS (ESI): 699.2913 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.06 (dd, J = 9.1, 5.7 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.51 (s, 1H), 7.49 - 7.41 (m, 1H), 5.33 (d, J = 53.9 Hz, 1H), 4.38 - 4.17 (m, 4H), 4.17 - 4.03 (m, 2H), 3.99 - 3.84 (m, 2H), 3.83 - 3.74 (m, 2H), 3.53 - 3.44 (m, 1H), 3.42 - 3.31 (m, 2H), 3.28 - 3.20 (m, 1H), 3.17 (s, 3H), 3.10 - 3.03 (m, 1H), 3.02 (s, 3H), 2.42 - 2.21 (m, 2H), 2.20 - 2.09 (m, 5H), 2.09 - 1.87 (m, 4H); 19 F NMR (376 MHz, CD3OD): δ -107.46 (1F), -140.57 (1F), -173.64 (1F).

[0364] Example 7: Synthesis of compound 7

[0365] In a 50 mL single neck flask, compound M3 (60 mg, 0.096 mmol) and DCM (2.5 mL) were added, stirred at 0 °C for 5 min, TEA (0.040 mL, 0.29 mmol) and o-fluorobenzoyl chloride (0.017 mL, 0.14 mmol) were added dropwise, and the reaction was stirred for 2 h. The reaction was quenched by adding saturated ammonium chloride solution (15 mL), and the aqueous phase was extracted with DCM (15 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 20 / 1) as the eluent to obtain 50 mg of compound 7 as a yellow solid with a yield of 70%, LC-MS (ESI, pos.ion) m / z: 750.6 [M+H] + ; HRMS (ESI): 750.2727 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.20 - 8.07 (m, 2H), 8.06 - 7.99 (m, 1H), 7.76 - 7.66 (m, 1H), 7.66 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.41 - 7.34 (m, 1H), 7.33 - 7.26 (m, 1H), 5.37 (d, J = 53.5 Hz, 1H), 4.46 - 4.31 (m, 2H), 4.30 - 4.17 (m, 2H), 4.16 - 4.02 (m, 2H), 3.98 - 3.84 (m, 2H), 3.84 - 3.71 (m, 2H), 3.54 - 3.35 (m, 4H), 3.18 - 3.06 (m, 1H), 2.50 - 2.27 (m, 2H), 2.27 - 2.12 (m, 5H), 2.11 - 1.92 (m, 4H). 19 F NMR (376 MHz, CD3OD): δ -106.80 (1F), -110.35 (1F), -140.60 (1F), -173.74 (1F).

[0366] Example 8: Synthesis of compound 8

[0367] In a 100 mL single neck flask, compound M3 (170 mg, 0.27 mmol) and DCM (5 mL) were added, stirred at 0 °C for 5 min, TEA (0.11 mL, 0.81 mmol) and benzoyl chloride (0.038 mL, 0.32 mmol) were added dropwise, and the reaction was stirred for 0.5 h. The reaction was quenched by adding saturated ammonium chloride solution (15 mL), and the aqueous phase was extracted with DCM (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography with DCM / MeOH (v / v = 99 / 1) as the eluent to obtain 163 mg of yellow solid compound 8 with a yield of 82%. LC-MS (ESI, pos.ion) m / z: 732.0 [M+H] + ; HRMS (ESI): 732.2869 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.18 - 8.08 (m, 1H), 8.07 - 8.02 (m, 1H), 7.98 - 7.92 (m, 1H), 7.75 - 7.68 (m, 1H), 7.64 - 7.62 (m, 1H), 7.61 - 7.55 (m, 2H), 7.53 - 7.47 (m, 1H), 7.42 - 7.35 (m, 1H), 5.40 (d, J = 54.5 Hz, 1H), 4.48 - 4.33 (m, 2H), 4.31 - 4.18 (m, 2H), 4.18 - 4.03 (m, 2H), 3.99 - 3.86 (m, 2H), 3.84 - 3.75 (m, 2H), 3.57 - 3.37 (m, 4H), 3.24 - 3.08 (m, 1H), 2.52 - 2.28 (m, 2H), 2.27 - 2.14 (m, 5H), 2.13 - 1.98 (m, 4H). 19 F NMR (376 MHz, CD3OD): δ -106.99 (1F), -140.73 (1F), -173.80 (1F).

[0368] Example 9: Synthesis of compound 9

[0369] In a 100 mL single neck flask, compound M3 (230 mg, 0.37 mmol) and DCM (15 mL) were added, stirred at 0 °C for 5 min, DIPEA (0.18 mL, 1.11 mmol) and decanoyl chloride (0.14 mL, 0.74 mmol) were added dropwise, and the reaction was stirred for 0.5 h. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), and the aqueous phase was extracted with DCM (20 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography with DCM / MeOH (v / v = 100 / 1-20 / 1) as eluent to obtain 145 mg of compound 9 as a light brown solid, with a yield of 51%, LC-MS (ESI, pos.ion) m / z: 782.3 [M+H] + ; HRMS (ESI): 782.4040 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.03 (dd, J = 9.2, 5.7 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.48 - 7.38 (m, 2H), 5.31 (d, J = 53.5 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.23 - 4.13 (m, 2H), 4.12 - 4.01 (m, 2H), 3.95 - 3.82 (m, 2H), 3.80 - 3.68 (m, 2H), 3.50 - 3.28 (m, 3H), 3.27 - 3.16 (m, 1H), 3.11 - 3.00 (m, 1H), 2.61 (t, J = 7.4 Hz, 2H), 2.44 - 2.21 (m, 2H), 2.20 - 2.09 (m, 5H), 2.06 - 1.87 (m, 4H), 1.77 - 1.66 (m, 2H), 1.29 - 1.19 (m, 12H), 0.86 - 0.81 (m, 3H). 19 F NMR (376 MHz, CD3OD): δ -107.14 (1F), -140.62 (1F), -173.68 (1F).

[0370] Example 10: Synthesis of compound 10

[0371] In a 100 mL single necked flask, compound M3 (250 mg, 0.40 mmol) and DCM (14 mL) were added, stirred at 0 °C for 5 min, DIPEA (0.20 mL, 1.20 mmol) and palmitoyl chloride (0.18 mL, 0.60 mmol) were added dropwise, the reaction was stirred for 0.5 h. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), the solution was divided, the aqueous phase was extracted with DCM (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, the crude product was purified by column chromatography with DCM / MeOH (v / v = 100 / 1-20 / 1) as eluent, 150 mg of compound 10 was obtained as a light brown oil, yield 43%, LC-MS (ESI, pos.ion) m / z: 866.5 [M+H] + ; HRMS (ESI): 866.4827 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.06 - 7.99 (m, 1H), 7.85 - 7.79 (m, 1H), 7.46 - 7.39 (m, 2H), 5.33 (d, J = 53.3 Hz, 1H), 4.40 - 4.28 (m, 2H), 4.26 - 4.14 (m, 2H), 4.13 - 4.01 (m, 2H), 3.96 - 3.82 (m, 2H), 3.80 - 3.71 (m, 2H), 3.51 - 3.40 (m, 1H), 3.33 (dd, J = 12.3, 7.6 Hz, 3H), 3.13 - 3.02 (m, 1H), 2.61 (t, J = 7.4 Hz, 2H), 2.45 - 2.22 (m, 2H), 2.22 - 2.11 (m, 5H), 2.08 - 1.91 (m, 4H), 1.77 - 1.67 (m, 2H), 1.25 - 1.22 (m, 24H), 0.87 - 0.84 (m, 3H); 19 F NMR (376 MHz, CD3OD): δ -107.10 (1F), -140.60 (1F), -173.69 (1F).

[0372] Example 11: Synthesis of compound 11

[0373] Compound M3 (250 mg, 0.40 mmol), N-benzyl carbamoyl chloride (678.44 mg, 4 mmol) and DIPEA (0.66 mL, 4 mmol) were dissolved in DCM (5 mL), the reaction was stirred at 0 °C for 2.5 h. The reaction was quenched with saturated ammonium chloride solution (10 mL), the aqueous phase was extracted with DCM (20 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 15 / 1) to give 120 mg of compound 11 as a light yellow solid with a yield of 39.6%. LC-MS (ESI, pos.ion) m / z: 761.3 [M+H] + ; HRMS (ESI): 761.3098 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.05 (dd, J = 9.0, 5.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.44 (t, J = 8.9 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.29 - 7.20 (m, 2H), 5.30 (d, J = 53.9 Hz, 1H), 4.39 (s, 2H), 4.35 - 4.17 (m, 5H), 4.15 - 4.03 (m, 2H), 3.95 - 3.84 (m, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.27 - 3.18 (m, 2H), 3.08 - 2.97 (m, 1H), 2.42 - 2.29 (m, 1H), 2.28 - 2.18 (m, 2H), 2.16 (s, 3H), 2.14 - 2.05 (m, 3H), 2.04 - 1.95 (m, 2H), 1.93 - 1.82 (m, 1H); 19 F NMR (376 MHz, CD3OD) δ -107.62 (1F), -140.52 (1F), -173.62 (1F).

[0374] Example 12: Synthesis of compound 12

[0375] Compound M3 (250 mg, 0.40 mmol) was dissolved in DCM (10 mL) at room temperature, TEA (0.28 mL, 2 mmol), DMAP (4.89 mg, 0.040 mmol) and [1,4']bipiperidine-1'-formyl chloride (138.44 mg, 0.60 mmol) were added, and the mixture was stirred at 40 °C for 3 h. The reaction was concentrated, and the crude product was purified by thin layer chromatography with DCM / MeOH (v / v = 12 / 1) as eluent to give 200 mg of compound 12 as a light brown solid in 61.09% yield. LC-MS (ESI, pos.ion) m / z: 822.3 [M+H] + ; HRMS (ESI): 822.3955 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.07 (dd, J = 9.1, 5.7 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.50 (dt, J = 17.8, 5.8 Hz, 2H), 5.31 (d, J = 54.3 Hz, 1H), 4.45 (d, J = 12.6 Hz, 1H), 4.36 - 4.18 (m, 5H), 4.17 - 4.05 (m, 2H), 3.98 - 3.86 (m, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.30 - 3.14 (m, 3H), 3.13 - 2.98 (m, 2H), 2.96 - 2.85 (m, 1H), 2.72 - 2.56 (m, 5H), 2.40 - 2.20 (m, 2H), 2.18 (s, 3H), 2.16 - 2.04 (m, 3H), 2.03 - 1.93 (m, 4H), 1.91 - 1.84 (m, 1H), 1.72 - 1.44 (m, 9H); 19 F NMR (376 MHz, CD3OD) δ -107.39 (1F), -140.47 (1F), -173.59 (1F).

[0376] Example 13: Synthesis of compound 13

[0377] Compound M3 (250 mg, 0.40 mmol), ethyl isocyanate (170.58 mg, 2.4 mmol), TEA (0.28 mL, 2 mmol) and DMAP (24.43 mg, 0.20 mmol) were dissolved in THF (10 mL) and the reaction was refluxed at 70 °C for 5 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and DCM (30 mL) was added. The organic phase was combined, dried over anhydrous sodium sulfate and the crude product was purified by column chromatography using DCM / MeOH (v / v = 100 / 1-95 / 5) as eluent and by thin layer chromatography using DCM / MeOH (v / v = 15 / 1) as eluent to give 105.3 mg of compound 13 as a yellow foamy solid. LC-MS (ESI, pos.ion) m / z: 699.3 [M+H] + ; 1 H NMR (599 MHz, CD3OD) δ 8.06 (dd, J = 9.1, 5.7 Hz, 1H), 7.86 (t, J = 4.4 Hz, 1H), 7.46 (dt, J = 17.8, 5.9 Hz, 2H), 5.36 (d, J = 53.2 Hz, 1H), 4.37 (dd, J = 36.3, 10.9 Hz, 2H), 4.29 - 4.18 (m, 2H), 4.17 - 4.05 (m, 2H), 3.97 - 3.87 (m, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.50 - 3.41 (m, 1H), 3.40 - 3.32 (m, 2H), 3.24 (q, J = 7.2 Hz, 2H), 3.13 (q, J = 7.2 Hz, 3H), 2.44 - 2.25 (m, 2H), 2.22 - 2.17 (m, 1H), 2.17 (s, 3H), 2.15 - 2.11 (m, 1H), 2.10 - 2.03 (m, 3H), 1.99 - 1.90 (m, 1H), 1.09 (t, J = 7.2 Hz, 3H); 19 F NMR (564 MHz, CD3OD) δ -107.66 (1F), -140.67 (1F), -173.72 (1F).

[0378] Example 14: Synthesis of compound 14

[0379] Compound M3 (350 mg, 0.56 mmol), tert-butyl isocyanate (333.08 mg, 3.36 mmol), DMAP (34.21 mg, 0.28 mmol) and TEA (0.47 mL, 3.36 mmol) were dissolved in THF (10 mL) and the reaction was refluxed at 70 °C for 4.5 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and DCM (30 mL) was added. The organic phase was dried over anhydrous sodium sulfate, concentrated and the crude product was purified by thin layer chromatography using DCM / MeOH (v / v = 15 / 1) as eluent to give 166 mg of compound 14 as a light yellow solid. LC-MS (ESI, pos.ion) m / z: 727.3 [M+H] + ; 1 H NMR (599 MHz, CD3OD) δ 8.05 (dd, J = 9.1, 5.7 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.45 (dt, J = 17.9, 5.9 Hz, 2H), 5.36 (d, J = 53.4 Hz, 1H), 4.36 (dd, J = 35.3, 10.9 Hz, 2H), 4.29 - 4.18 (m, 2H), 4.17 - 4.04 (m, 2H), 3.97 - 3.87 (m, 2H), 3.83 - 3.75 (m, 2H), 3.51 - 3.48 (m, 1H), 3.47 - 3.38 (m, 2H), 3.37 - 3.32 (m, 1H), 3.11 (tt, J = 17.5, 8.6 Hz, 1H), 2.44 - 2.24 (m, 2H), 2.123 - 2.18 (m, 1H), 2.17 (s, 3H), 2.16 - 2.10 (m, 1H), 2.09 - 2.01 (m, 3H), 1.99 - 1.90 (m, 1H), 1.37 (s, 9H); 19 F NMR (564 MHz, CD3OD) δ -107.78 (1F), -140.62 (1F), -173.70 (1F).

[0380] Example 15: Synthesis of compound 15

[0381] In a 50 mL two-necked flask, compound M3 (140 mg, 0.22 mmol) and THF (5 mL) were added, stirred for 5 min, isocyanoacetic acid ethyl ester (0.030 mL, 0.26 mmol) and TEA (0.092 mL, 0.66 mmol) were added, the reaction was stirred at room temperature for 1 h. Diluted with EA (30 mL), quenched with saturated ammonium chloride solution (30 mL), separated, dried over anhydrous sodium sulfate, concentrated, the crude product was purified by column chromatography with DCM / MeOH (v / v = 9 / 1) eluent to give 140 mg of yellow solid compound 15, with a yield of 82.94%. LC-MS (ESI, pos.ion) m / z: 757.2 [M+H] + ; 1 H NMR (599 MHz, CD3OD) δ 8.08 (dd, J = 9.1, 5.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.46 (t, J = 8.9 Hz, 1H), 5.37 (d, J = 52.4 Hz, 1H), 4.58 (br s, 1H), 4.37 (dd, J = 40.0, 10.9 Hz, 2H), 4.29 - 4.04 (m, 7H), 4.01 - 3.72 (m, 7H), 3.51 - 3.44 (m, 1H), 3.44 - 3.34 (m, 2H), 3.17 - 3.09 (m, 1H), 2.49 - 2.25 (m, 2H), 2.23 - 1.89 (m, 10H); 19 F NMR (564 MHz, CD3OD) δ -107.47 (1F), -140.71 (1F), -173.76 (1F).

[0382] Example 16: Synthesis of compound 16

[0383] Step 1: Synthesis of compound 16-1

[0384] A reaction vial was charged with compound M3 (200 mg, 0.32 mmol), DCM (5 mL), 2-((tert-butoxycarbonyl)amino)-6-methylbenzoic acid (0.12 g, 0.48 mmol), DMAP (0.059 g, 0.48 mmol) and N,N'-dicyclohexylcarbodiimide (0.13 g, 0.64 mmol), stirred at room temperature for 2.5 h, then warmed to 40 °C for 18 h. The stirring was stopped, the reaction was added to 30 mL of saturated ammonium chloride solution, the aqueous phase was extracted with DCM (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM / MeOH (v / v = 30 / 1)) to give 206 mg of compound 16-1 as a yellow solid in 75.09% yield. LC-MS (ESI, pos.ion) m / z: 861.4 [M+H] + .

[0385] Step 2: Synthesis of compound 16

[0386] A reaction vial was charged with compound 16-1 (196 mg, 0.23 mmol) and DCM (5 mL), stirred at 0 °C for 5 min, trifluoroacetic acid (0.17 mL, 2.30 mmol) was added dropwise, and the reaction was stirred at room temperature for 2 h. The stirring was stopped, 50 mL of saturated NaHCO3solution was added to quench the reaction, the aqueous phase was separated, the aqueous phase was extracted with DCM (30 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin layer chromatography (DCM / MeOH (v / v = 20 / 1)) to give 135 mg of compound 16 as a yellow solid in 77.94% yield. LC-MS (ESI, pos.ion) m / z: 761.3 [M+H] + ; HRMS (ESI): 761.3065 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.15 (dd, J = 9.1, 5.7 Hz, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.61 (s, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 7.3 Hz, 1H), 5.63 - 5.41 (m, 1H), 4.67 - 4.53 (m, 4H), 4.36 - 4.05 (m, 4H), 4.00 - 3.86 (m, 3H), 3.86 - 3.69 (m, 5H), 3.56 - 3.44 (m, 1H), 2.62 (s, 3H), 2.59 - 2.46 (m, 2H), 2.40 - 2.24 (m, 3H), 2.18 (s, 3H), 2.15 - 2.03 (m, 3H).

[0387] Example 17: Synthesis of compound 17

[0388] In a 50 mL single neck flask, triethyl phosphite (0.085 mL, 0.50 mmol), DCM (15 mL), triflic anhydride (0.13 mL, 0.75 mmol) and pyridine (0.091 mL, 1.13 mmol) were added, stirred at room temperature for 10 min, compound M3 (160 mg, 0.25 mmol) was added, stirred at room temperature for 4 h. The stirring was stopped, diluted with 30 mL of DCM, washed with 30 mL of water and 30 mL of saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, concentrated, purified by TLC preparative plate with DCM / MeOH (v / v = 20 / 1) to give 143 mg of compound 17 as a yellow solid with a yield of 73.45%. LC-MS (ESI, pos.ion) m / z: 764.5 [M+H] + ; HRMS (ESI): 764.2824 [M+H] + ; 1 H NMR (400 MHz, CD3OD) d 8.10 (dd, J = 9.1, 5.7 Hz, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 7.50 (t, J = 8.9 Hz, 1H), 5.39 (d, J = 53.5 Hz, 1H), 4.60 (br s, 1H), 4.46 - 4.19 (m, 8H), 4.18 - 4.03 (m, 2H), 3.99 - 3.87 (m, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.51 (d, J = 4.8 Hz, 1H), 3.47 - 3.39 (m, 2H), 3.22 - 3.08 (m, 1H), 2.38 - 1.95 (m, 11H), 1.39 - 1.35 (m, 6H).

[0389] Example 18: Synthesis of compound 18

[0390] In a 50 mL single neck flask, compound M3 (140 mg, 0.22 mmol), THF (5 mL), isopropyl isocyanate (0.026 mL, 0.26 mmol) and TEA (0.092 mL, 0.66 mmol) were added, stirred at room temperature for 2 h. Then the temperature was raised to 40 °C and stirred for 24 h. The reaction was stopped, diluted with 30 mL of dichloromethane, quenched with 30 mL of saturated ammonium chloride solution, separated, the aqueous phase was extracted with 30 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparative plate with DCM / MeOH (v / v = 93 / 7) to give 124 mg of yellow solid compound 18 with a yield of 78.00%. LC-MS (ESI, pos.ion) m / z: 713.4 [M+H] + ; HRMS (ESI): 713.3071 [M+H] + ; 1 H NMR (400 MHz, CD3OD) δ 8.07 (dd, J = 9.0, 5.7 Hz, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.53 - 7.39 (m, 2H), 5.42 (d, J = 54.0 Hz, 1H), 4.59 (br s, 1H), 4.53 - 4.35 (m, 2H), 4.32 - 4.04 (m, 4H), 4.00 - 3.73 (m, 5H), 3.68 - 3.42 (m, 4H), 3.26 - 3.14 (m, 1H), 2.58 - 1.93 (m, 11H), 1.23 (d, J = 6.5 Hz, 6H).

[0391] Example 19: Synthesis of compound 19

[0392] In a 50 mL single neck flask, compound M3 (140 mg, 0.22 mmol), THF (5 mL), 4-cyano phenyl isocyanate (0.041 g, 0.29 mmol) and TEA (0.092 mL, 0.66 mmol) were added, stirred at room temperature for 5 h. The reaction was stopped, quenched with 20 mL of saturated ammonium chloride solution, separated, the aqueous phase was extracted with DCM (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by TLC preparative plate with DCM / MeOH (v / v = 93 / 7) to give 120 mg of yellow solid compound 19 with a yield of 69.71%. LC-MS (ESI, pos.ion) m / z: 772.0 [M+H] + ; 1HNMR (400 MHz, CD3OD) δ 7.90 - 7.43 (m, 8H), 5.38 (d, J = 53.0 Hz, 1H), 4.48 - 4.03 (m, 6H), 4.02 - 3.72 (m, 4H), 3.58 - 3.34 (m, 4H), 3.23 - 3.08 (m, 1H), 2.53 - 1.90 (m, 11H).

[0393] Example 20: Synthesis of compound 20

[0394] Compound M3 (200 mg, 0.32 mmol), N, N'-dicyclohexylcarbodiimide (0.13 g, 0.64 mmol) and DMAP (0.059 g, 0.48 mmol) were dissolved in DCM (5 mL) and stirred at 30 °C for 16 h. The reaction was stopped, the reaction solution was poured into 50 mL of saturated ammonium chloride solution to quench, and then extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography preparation plate DCM / MeOH (v / v = 20 / 1) to obtain 110 mg of yellow solid compound 20, with a yield of 44.16%. LC-MS (ESI, pos.ion) m / z: 781.9 [M+H] + ; HRMS (ESI): 782.2962 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 8.7 Hz, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 7.94 - 7.89 (m, 2H), 7.69 - 7.62 (m, 2H), 7.58 (dd, J = 12.4, 7.3 Hz, 2H), 7.47 - 7.39 (m, 1H), 7.36 (t, J = 8.8 Hz, 1H), 4.64 (d, J = 10.3 Hz, 1H), 4.50 (d, J = 11.0 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.08-4.01 (m, 2H), 3.85-3.70 (m, 3H), 3.73 - 3.66 (m, 3H), 3.48 (s, 3H), 3.38 (dd, J = 21.1, 11.6 Hz, 1H), 3.21 - 3.07 (m, 1H), 2.95 (d, J = 5.3 Hz, 1H), 2.47 (dd, J = 29.9, 13.5 Hz, 3H), 2.02 (d, J = 12.9 Hz, 3H), 1.41 - 1.12 (m, 2H); 19F NMR (376 MHz, CDCb) δ -105.46 (d, J = 2.3 Hz), -137.97 (d, J = 17.4 Hz), -172.34 (s).

[0395] Example 21: Synthesis of compound 21

[0396] Compound M3 (200 mg, 0.32 mmol), N,N'-dicyclohexylcarbodiimide (0.13 g, 0.64 mmol) and DMAP (0.059 g, 0.48 mmol) were dissolved in DCM (5 mL) and stirred at 30 °C for 16 hours. The reaction was stopped, the reaction solution was poured into 50 mL of saturated ammonium chloride solution to quench, and then extracted with DCM (20 mL x 3). The combined organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography preparation plate DCM / MeOH (v / v = 20 / 1) to obtain 90 mg of yellow solid compound 21, with a yield of 34.79%. LC-MS (ESI, pos.ion) m / z: 776.9 [M+H] + ; HRMS (ESI): 777.2648 [M+H] + ; 1 H NMR (400 MHz, CDCb) δ 8.43 - 8.34 (m, 4H), 7.93 - 7.90 (m, 2H), 7.58 (s, 1H), 7.37 (t, J = 8.7 Hz, 1H), 5.30 (s, 1H), 4.55 (s, 1H), 4.60 - 4.52 (m, 1H), 4.26 - 4.04 (m, 5H), 3.87 (d, J = 3.2 Hz, 2H), 3.80 (d, J = 4.6 Hz, 2H), 3.67 (d, J = 23.5 Hz, 1H), 3.48 (s, 2H), 3.42 - 3.29 (m, 1H), 3.11 (s, 1H), 3.00 (d, J = 7.4 Hz, 1H), 2.54 - 2.25 (m, 4H), 2.12 (s, 3H), 1.26 (dd, J = 13.1, 5.9 Hz, 2H); 19 F NMR (376 MHz, CDCb) δ -104.81 (d, J = 2.6 Hz), -138.10 (d, J = 16.3 Hz), -171.96 - -172.80 (s).

[0397] Example 22: Synthesis of compound 22

[0398] Compound M3 (200 mg, 0.32 mmol), N,N'-dicyclohexylcarbodiimide (0.13 g, 0.64 mmol) and DMAP (0.059 g, 0.48 mmol) were dissolved in DCM (5 mL) and stirred at 30 °C for 16 h. The reaction was stopped and the reaction solution was poured into 50 mL of saturated ammonium chloride solution to quench, and then extracted with DCM (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography preparation plate DCM / MeOH (v / v = 20 / 1) to give 200 mg of yellow solid compound 22 with a yield of 81.75%. LC-MS (ESI, pos.ion) m / z: 767.9 [M+H] + ; HRMS (ESI): 768.2619 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 10.3 Hz, 1H), 8.01 (d, J = 6.4 Hz, 1H), 7.90 (dd, J = 9.1, 5.7 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.55 (s, 1H), 7.39 - 7.27 (m, 2H), 5.36 (d, J = 51.1 Hz, 1H), 4.50 - 4.36 (m, 2H), 4.25 - 4.02 (m, 5H), 3.85 (d, J = 6.7 Hz, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.62 (d, J = 17.6 Hz, 2H), 3.49 (d, J = 14.3 Hz, 1H), 3.37 - 3.24 (m, 1H), 3.07 (dd, J = 14.7, 8.8 Hz, 1H), 2.93 (d, J = 3.6 Hz, 1H), 2.57 - 2.22 (m, 4H), 2.11 (s, 3H), 1.26 (dd, J = 15.3, 8.1 Hz, 2H); 19 FNMR (376 MHz, CDCl3) δ -105.11 (1F), -128.38 (1F), -135.67 (1F), -138.11 (1F), -172.61 (1F).

[0399] Example 23: Synthesis of compound 23

[0400] Compound M3 (150 mg, 0.24 mmol), 3-ethoxy-isovanillic acid (56.51 mg, 0.29 mmol), N,N'-dicyclohexylcarbodiimide (74.28 mg, 0.36 mmol) and DMAP (87.96 mg, 0.72 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 3.5 h. The reaction was stopped, the solid was filtered off, 30 mL dichloromethane was added to dilute, the filtrate was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography preparation plate with DCM / MeOH (v / v = 13 / 1) to obtain 135 mg of yellow foam solid compound 23 with a yield of 70.10%. LC-MS (ESI, pos.ion) m / z: 806.0 [M+H] + ; HRMS (ESI): 806.3175 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.02 (dd, J = 9.1, 5.7 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 11.9 Hz, 1H), 7.61 (s, 1H), 7.44 (t, J = 8.9 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 5.37 (d, J = 53.1 Hz, 1H), 4.39 (dd, J = 23.0, 11.1 Hz, 2H), 4.30 - 4.16 (m, 2H), 4.14 - 4.02 (m, 4H), 3.98 - 3.83 (m, 5H), 3.78 (t, J = 5.3 Hz, 2H), 3.58 - 3.35 (m, 3H), 3.20 - 3.08 (m, 1H), 2.50 - 2.25 (m, 2H), 2.24 - 2.17 (m, 1H), 2.16 (s, 3H), 2.13 - 2.03 (m, 4H), 2.02 - 1.88 (m, 2H), 1.40 (t, J = 6.9 Hz, 3H); 19 F NMR (376 MHz, MeOD) δ -107.01 (1F), -140.54 (1F), -173.73 (1F).

[0401] Example 24: Synthesis of compound 24

[0402] Compound M3 (250 mg, 0.40 mmol), 5-fluoro-2-(methylthio)benzoic acid (81.93 mg, 0.44 mmol), N,N'-dicyclohexylcarbodiimide (123.80 mg, 0.60 mmol) and DMAP (146.60 mg, 1.20 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 4.5 h. The reaction was stopped, the solid was filtered off, 30 mL DCM was added, the filtrate was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification was performed by thin layer chromatography preparative plate (DCM / MeOH = 13 / 1) to give 160 mg of compound 24 as a yellow foam, with a yield of 50.48%. LC-MS (ESI, pos.ion) m / z: 795.9 [M+H] + ; HRMS (ESI): 796.2588 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.08 (dd, J = 9.1, 5.7 Hz, 1H), 7.99 (m, 2H), 7.65 (t, J = 2.5 Hz, 1H), 7.51 - 7.36 (m, 3H), 5.30 (d, J = 53.5 Hz, 1H), 4.35 - 4.17 (m, 4H), 4.15 - 4.03 (m, 2H), 3.96 - 3.87 (m, 2H), 3.79 (t, J = 5.3 Hz, 2H), 3.52 (d, J = 4.3 Hz, 1H), 3.30 - 3.13 (m, 3H), 3.05 - 2.96 (m, 1H), 2.48 (s, 3H), 2.42 - 2.18 (m, 2H), 2.16 (s, 3H), 2.13 - 2.02 (m, 3H), 2.01 - 1.92 (m, 2H), 1.90 - 1.80 (m, 1H); 19 F NMR (376 MHz, MeOD) δ -106.86 (1F), -121.19 (1F), -140.36 (1F), -173.59 (1F).

[0403] Example 25: Synthesis of compound 25

[0404] Compound M3 (300 mg, 0.48 mmol), 2-chloro-3-fluorobenzoic acid (0.13 g, 0.72 mmol), N,N'-dicyclohexylcarbodiimide (0.20 g, 0.96 mmol) and DMAP (0.088 g, 0.72 mmol) were dissolved in DCM (7.5 mL) and stirred at room temperature for 16 hours. The reaction was stopped, the reaction liquid was poured into saturated ammonium chloride solution (20 mL) to quench, then extracted with DCM (20 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography preparation plate DCM / MeOH (v / v = 20 / 1) to obtain 220 mg of yellow solid compound 25 with a yield of 56.47%. LC-MS (ESI, pos.ion) m / z: 783.9 [M+H] + ; HRMS (ESI): 784.2315 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 7.97-7.84 (m, 3H), 7.59 (s, 1H), 7.44-7.33 (m, 3H), 5.34 (d, J = 50.9 Hz, 1H), 4.39 (s, 2H), 4.27-4.01 (m, 5H), 3.87 (d, J = 2.9 Hz, 2H), 3.80 (t, J = 5.1 Hz, 2H), 3.48 (s, 2H), 3.36-3.21 (m, 2H), 3.10-3.07 (m, 1H), 2.97-2.93 (m, 1H), 2.36 (d, J = 30.4 Hz, 2H), 2.23 (dd, J = 16.4, 8.9 Hz, 2H), 2.12 (s, 3H), 1.27 (d, J = 14.2 Hz, 2H); 19 F NMR (376 MHz, CDCl3) δ -105.07, -111.45, -138.07, -138.10, -172.70.

[0405] Example 26: Synthesis of compound 26

[0406] Compound M3 (250 mg, 0.40 mmol), o-fluorocinnamic acid (0.10 g, 0.60 mmol), N,N'-dicyclohexylcarbodiimide (0.17 g, 0.80 mmol) and DMAP (.073 g, 0.60 mmol) were dissolved in DCM (7.5 mL) and stirred at room temperature for 12 h. The reaction was stopped, quenched by adding 15 mL of ammonium chloride solution, diluted with 5 mL of DCM, partitioned, the aqueous phase was extracted with DCM (10 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM / MeOH (v / v = 20 / 1) to give 219.4 mg of yellow powder compound 26 with a yield of 68.93%. LC-MS (ESI, pos.ion) m / z: 776.3 [M+H] + ; HRMS (ESI): 776.2868 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.11 (dd, J = 9.1, 5.8 Hz, 1H), 8.05 (d, J = 16.2 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.81 (t, J = 7.1 Hz, 1H), 7.58 (s, 1H), 7.49 (t, J = 8.9 Hz, 2H), 7.31 - 7.18 (m, 2H), 6.90 (d, J = 16.2 Hz, 1H), 4.58 (s, 1H), 4.34 - 4.03 (m, 6H), 3.92 (d, J = 3.2 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.51 (d, J = 4.8 Hz, 1H), 3.23 (d, J = 20.2 Hz, 2H), 3.08 - 2.98 (m, 1H), 2.17 (s, 3H), 2.01 (s, 2H), 1.88 (s, 2H), 1.71 (d, J = 13.1 Hz, 1H), 1.24 (ddd, J = 30.4, 27.9, 11.3 Hz, 4H).

[0407] Example 27: Synthesis of compound 27

[0408] Compound M3 (180 mg, 0.29 mmol), nicotinic acid (0.071 g, 0.58 mmol), N,N'- dicyclohexylcarbodiimide (0.12 g, 0.58 mmol) and DMAP (0.053 g, 0.43 mmol) were dissolved in DCM (7.5 mL) and stirred at room temperature for 12 h. The reaction was stopped, quenched by adding 15 mL of ammonium chloride solution, 5 mL of DCM was added, the solution was separated, the aqueous phase was extracted with DCM (10 mL x 2), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the silica gel was mixed. Purification was performed by silica gel column chromatography using DCM / MeOH (v / v = 20 / 1) to obtain 80.5 mg of yellow powder compound 27. Yield 19.77%. LC-MS (ESI, pos.ion) m / z: 733.4 [M+H] + ; HRMS (ESI): 733.2767 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 9.25 (d, J = 90.3 Hz, 1H), 8.81 (dd, J = 40.3, 3.5 Hz, 1H), 8.53 (dd, J = 85.9, 8.1 Hz, 1H), 8.23 - 8.06 (m, 1H), 8.05 - 7.82 (m, 1H), 7.75 - 7.44 (m, 3H), 7.39 - 7.22 (m, 1H), 5.51 (s, 2H), 5.36 (s, 1H), 4.61 (s, 3H), 4.38 (dd, J = 27.2, 10.9 Hz, 2H), 4.25 (d, J = 15.8 Hz, 2H), 4.12 (dd, J = 14.2, 7.0 Hz, 2H), 4.00 - 3.90 (m, 2H), 3.84 (dd, J = 11.8, 6.4 Hz, 2H), 3.51 (dd, J = 22.6, 8.3 Hz, 1H), 3.14 (s, 1H), 2.40 - 2.28 (m, 1H), 2.09 (s, 2H), 1.97 (s, 1H), 1.41 (dd, J = 21.5, 10.5 Hz, 2H), 0.91 (d, J = 7.4 Hz, 2H).

[0409] Example 28: Synthesis of compound 28

[0410] Compound M3 (213 mg, 0.34 mmol), p-n-octylbenzoic acid (95.61 mg, 0.41 mmol), N,N'-dicyclohexylcarbodiimide (105.23 mg, 0.51 mmol) and DMAP (124.61 mg, 1.02 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 4 h. The reaction was stopped, the solid was filtered off, 50 mL of DCM was added, the filtrate was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography preparative plate with DCM / MeOH (v / v = 13 / 1) to give 135 mg of yellow foam solid with a yield of 47.14%. LC-MS (ESI, pos.ion) m / z: 844.3 [M+H] + ; HRMS (ESI): 844.4054 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.09 (dd, J = 11.4, 7.0 Hz, 3H), 7.99 (d, J = 2.2 Hz, 1H), 7.60 (t, J = 2.4 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 5.34 (d, J = 53.5 Hz, 1H), 4.42 - 4.28 (m, 2H), 4.26 - 4.16 (m, 2H), 4.15 - 4.03 (m, 2H), 3.96 - 3.84 (m, 2H), 3.79 (t, J = 5.4 Hz, 2H), 3.50 (d, J = 3.5 Hz, 1H), 3.48 - 3.32 (m, 2H), 3.15 - 3.04 (m, 1H), 2.70 (t, J = 7.6 Hz, 2H), 2.46 - 2.17 (m, 2H), 2.16 (s, 3H), 2.14 - 1.98 (m, 4H), 1.96 - 1.84 (m, 1H), 1.70 - 1.58 (m, 2H), 1.32 (m, 12H), 0.89 (t, J = 6.7 Hz, 3H); 19 FNMR (376 MHz, MeOD) δ -107.01 (1F), -140.54 (1F), -173.76 (1F).

[0411] Example 29: Synthesis of compound 29

[0412] Compound M3 (200 mg, 0.32 mmol), 4-butylbenzoic acid (68.44 mg, 0.38 mmol), N,N'-dicyclohexylcarbodiimide (99.04 mg, 0.48 mmol) and DMAP (117.28 mg, 0.96 mmol, dissolved in DCM (5 mL) were stirred at room temperature for 3 h. The reaction was stopped, the solid was filtered off, 50 mL DCM was added to dilute, the filtrate was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by TLC preparative plate with DCM / MeOH (v / v = 13 / 1) to give 142 mg of yellow foamy solid compound 29. Yield 56.56%. LC-MS (ESI, pos.ion) m / z: 788.2 [M+H] + ; HRMS (ESI): 788.3431 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.08 (dd, J = 12.6, 6.9 Hz, 3H), 7.99 (d, J = 2.2 Hz, 1H), 7.60 (t, J = 2.4 Hz, 1H), 7.46 (t, J = 8.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 5.33 (d, J = 53.7 Hz, 1H), 4.39 - 4.26 (m, 2H), 4.23 - 4.16 (m, 2H), 4.15 - 4.02 (m, 2H), 3.96 - 3.86 (m, 2H), 3.78 (t, J = 5.4 Hz, 2H), 3.50 (d, J = 3.4 Hz, 1H), 3.44 - 3.32 (m, 2H), 3.29 - 3.22 (m, 1H), 3.12 - 3.03 (m, 1H), 2.71 (t, J = 7.7 Hz, 2H), 2.44 - 2.34 (m, 1H), 2.33 - 2.17 (m, 2H), 2.16 (s, 3H), 2.14 - 1.98 (m, 4H), 1.96 - 1.83 (m, 1H), 1.69 - 1.57 (m, 2H), 1.43 - 1.31 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 19 F NMR (376 MHz, MeOD) δ -107.00 (1F), -140.50 (1F), -173.67 (1F).

[0413] Example 30: Synthesis of compound 30

[0414] Compound M3 (800 mg, 1.27 mmol) and di-tert-butyl chloromethyl phosphate (361.38 mg, 1.40 mmol) were dissolved in DMF (2 mL), followed by the addition of sodium iodide (571.08 mg, 3.81 mmol) and cesium carbonate (1241.37 mg, 3.81 mmol), and the reaction was stirred at 60 °C for 4 h under nitrogen. The reaction was stopped, 100 mL of water was added to the reaction, and a large amount of solid was precipitated, which was filtered and dried to obtain a crude product. The crude product was mixed with silica gel and purified by column chromatography on silica gel using DCM / MeOH (v / v = 20 / 1) to obtain 623 mg of a brown solid, with a yield of 57.51%. LC-MS (ESI, pos.ion) m / z: 849.5 [M+H] + ; HRMS (ESI): 850.3643 [M+H] + ; 1 H NMR (400 MHz, MeOD) δ 8.03 (dd, J = 9.1, 5.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 18.5, 9.5 Hz, 2H), 5.87 - 5.77 (m, 2H), 5.31 (d, J = 54.0 Hz, 1H), 4.37 - 4.18 (m, 4H), 4.17 - 4.01 (m, 2H), 3.97 - 3.86 (m, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.46 (d, J = 4.6 Hz, 1H), 3.29 - 3.16 (m, 3H), 3.07 - 2.98 (m, 1H), 2.40 - 2.20 (m, 2H), 2.17 (s, 3H), 2.15 - 2.05 (m, 3H), 2.04 - 1.95 (m, 2H), 1.93 - 1.81 (m, 1H), 1.46 (s, 18H); 19 FNMR (376 MHz, MeOD) δ -109.17 (1F), -140.68 (1F), -173.63 (1F).

[0415] Example 31: Synthesis of compound 31

[0416] Compound 30 (62 mg, 0.073 mmol) was dissolved in glacial acetic acid (1 mL) and water (0.5 mL), and the reaction was stirred at 40 °C for 24 h under nitrogen. The reaction was stopped, and the reaction liquid was directly concentrated to obtain a black crude product. The crude product was dissolved in 0.5 mL of water and 0.5 mL of acetonitrile, and was then wet-loaded and purified by column chromatography on C18 using H2O / MeCN (v / v = 0%-30%) to obtain 31 mg of yellow powder of compound 31. LC-MS (ESI, pos.ion) m / z: 738.2 [M+H] +HRMS (ESI): 738.2313 [M+H] + .

[0417] Example 32: Synthesis of compound 32

[0418] Compound M3 (110 mg, 0.18 mmol), sodium tert-butoxide (0.026 g, 0.23 mmol) were dissolved in THF (10 mL), stirred at room temperature for 5 min, then tetra-benzyl pyrophosphate (0.13 g, 0.23 mmol,) was added, and the temperature was raised to 60 °C and stirred for 6 h. The reaction was stopped, 15 ml of saturated ammonium chloride solution was added to quench, 10 mL of EA was added to dilute, the liquid was separated, the aqueous phase was extracted with EA (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the sample was mixed with silica gel and purified by silica gel column chromatography with DCM / MeOH (v / v = 97 / 3) to obtain 70 mg of yellow powder compound 32 with a yield of 43.78%. LC-MS (ESI, pos.ion) m / z: 887.9 [M+H] + ; HRMS (ESI): 888.3161 [M+H] + ; 1 H NMR (599 MHz, MeOD) δ 7.94-7.89 (m, 1H), 7.71 (s, 1H), 7.43 (t, J = 8.9 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.35-7.31 (m, 4H), 7.30-7.27 (m, 4H), 7.26-7.24 (m, 2H), 5.43 (d, J = 50.8 Hz, 1H), 5.22-5.14 (m, 4H), 4.56-4.47 (m, 2H), 4.30-4.17 (m, 2H), 4.15-4.05 (m, 2H), 3.96-3.85 (m, 2H), 3.78 (dd, J = 11.2, 5.8 Hz, 2H), 3.70-3.62 (m, 2H), 3.59-3.52 (m, 1H), 3.28-3.20 (m, 1H), 2.50-2.35 (m, 2H), 2.32-2.23 (m, 1H), 2.20-2.18 (m, 2H), 2.16 (s, 3H), 2.14-2.09 (m, 2H), 2.07-2.01 (m, 2H).

[0419] Example 33: Synthesis of compound 33

[0420] Compound M3 (150 mg, 0.24 mmol) and TEA (0.024 g, 0.24 mmol) were dissolved in ACN (6 mL), stirred at room temperature for 10 min, then diphenyl chlorophosphate (0.10 g, 0.38 mmol) was added dropwise slowly, stirred at room temperature for 6 h. The reaction was stopped, 15 mL saturated ammonium chloride solution was added to quench, 10 mL EA was added to dilute, the liquid was separated, the aqueous phase was extracted with EA (10 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and then silica gel was added for mixing, purified by silica gel column chromatography with DCM / MeOH (v / v = 97 / 3) to obtain 112 mg of yellow powder compound 33, with a yield of 79.10%. LC-MS (ESI, pos.ion) m / z: 859.9 [M+H] + ; HRMS (ESI): 860.2838 [M+H] + ; 1 H NMR (400 MHz, MeOD) d 8.10 (dd, J = 9.0, 5.7 Hz, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.51 (t, J = 8.9 Hz, 1H), 7.42 (t, J = 7.0 Hz, 4H), 7.27 (t, J = 14.5 Hz, 6H), 5.70 - 5.40 (m, 1H), 4.67 (s, 2H), 4.35 - 4.21 (m, 2H), 4.13 (d, J = 14.6 Hz, 2H), 3.95 (s, 3H), 3.82 (s, 4H), 3.57 (dd, J = 21.8, 12.7 Hz, 2H), 3.42 (s, 1H), 3.36 (d, J = 7.4 Hz, 1H), 2.63 - 2.50 (m, 1H), 2.40 (d, J = 7.7 Hz, 1H), 2.31 (s, 2H), 2.19 (s, 3H), 1.91 (d, J = 13.4 Hz, 1H), 1.31 (dd, J = 19.8, 10.7 Hz, 1H).

[0421] Example 34: Synthesis of compound 34

[0422] Compound M3 (350 mg, 0.56 mmol) and TEA (0.28 g, 2.80 mmol) in 10 mL DCM solution was added, and the reaction was continued at -20 °C for 2 h. Transferred to room temperature, 20 mL saturated sodium bicarbonate solution was added and stirred for 3 h. Stop stirring, extract the aqueous phase with 30 mL DCM, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography with DCM / MeOH (v / v = 10 / 1) to obtain 350 mg of brown solid compound 34, with a yield of 85.32%. LC-MS (ESI, pos.ion) m / z: 736.2 [M+H] + ; HRMS (ESI): 736.2 514 [M+H] + ; 1 H NMR (599 MHz, MeOD) δ 8.00 (dd, J = 9.1, 5.7 Hz, 1H), 7.92 (d, J = 11.7 Hz, 1H), 7.58 (dd, J = 8.9, 2.1 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 5.41 (dd, J = 52.9, 3.1 Hz, 1H), 4.50 - 4.37 (m, 2H), 4.28 - 4.17 (m, 2H), 4.16 - 4.08 (m, 2H), 4.06 - 3.98 (m, 2H), 3.95 - 3.86 (m, 2H), 3.82 - 3.75 m, 2H), 3.65 - 3.45 (m, 3H), 3.41 (d, J = 3.2 Hz, 1H), 3.24 - 3.12 (m, 3H), 2.55 - 2.32 (m, 2H), 2.24 (d, J = 8.9 Hz, 1H), 2.15 (s, 3H), 2.14 - 2.10 (m, 2H), 2.08 - 1.93 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0423] Example 35: Synthesis of compound 35

[0424] Compound 30 (420 mg, 0.57 mmol) and glacial acetic acid (2 mL, 34.97 mmol) were dissolved in water (0.5 mL) and stirred at 30 °C for 24 h. Stop the reaction and directly concentrate the reaction liquid to obtain a black solid crude product, which was purified by reverse C18 column chromatography with H2O / ACN (v / v = 100 / 0-30 / 1) to obtain 200 mg of brown solid with a yield of 61.18%. LC-MS (ESI, pos.ion) m / z: 794.2 [M+H] + ; HRMS (ESI): 794.2938 [M+H]+ ; 1 H NMR (599 MHz, MeOD) δ 7.98 (dd, J = 8.9, 5.7 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.45 - 7.25 (m, 2H), 5.72 - 5.62 (m, 2H), 5.59 - 5.43 (m, 1H), 4.67 - 4.56 (m, 2H), 4.30 - 4.20 (m, 2H), 4.18 - 4.00 (m, 3H), 3.93 - 3.84 (m, 3H), 3.81 - 3.62 (m, 3H), 3.43 - 3.34 (m, 2H), 2.72 - 2.48 (m, 2H), 2.37 (dd, J = 15.8, 7.5 Hz, 1H), 2.28 (dt, J = 11.0, 6.0 Hz, 2H), 2.17 (s, 3H), 2.14 - 2.08 (m, 2H), 2.05 - 1.96 (m, 2H), 1.37 (d, J = 2.5 Hz, 9H).

[0425] Example 36: Synthesis of compound 36

[0426] Phosphorous oxychloride (0.31 mL, 3.36 mmol) was dissolved in ACN (10 mL), cooled to -20 °C and stirred for 5 min, then slowly added a solution of compound M3 (700 mg, 1.12 mmol) and DIPEA (0.93 mL, 5.60 mmol) in DCM (10 mL) and continued to stir at -20 °C for 2 h. Transferred to room temperature, added 50 mL of saturated sodium bicarbonate solution and continued to stir for 3 h. Stopped stirring, added 100 mL of ethyl acetate and 50 mL of water, shaken to separate the phases and took the aqueous phase. The aqueous phase was concentrated under reduced pressure to obtain a white solid residue, added 50 mL of mixed solvent DCM / MeOH (v / v = 20 / 1), ultrasonic for 5 min, filtered to remove the insoluble, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 580 mg of yellow solid, yield 73.49%. LC-MS (ESI, pos.ion) m / z: 708.2 [M+H] + ; HRMS (ESI): 708.2198 [M+H] + ; 1H NMR (599 MHz, MeOD) δ 8.02 - 7.95 (m, 2H), 7.54 (d, J = 45.6 Hz, 1H), 7.37 (t, J = 8.9 Hz, 1H), 5.47 - 5.32 (m, 1H), 4.51 - 4.42 (m, 2H), 4.26 - 4.17 (m, 2H), 4.16 - 4.04 (m, 2H), 3.94 - 3.68 (m, 4H), 3.66 - 3.53 (m, 2H), 3.48 (dd, J = 31.8, 15.3 Hz, 1H), 3.39 (d, J = 6.9 Hz, 1H), 3.24 - 3.15 (m, 1H), 2.56 - 2.32 (m, 2H), 2.30 - 2.21 (m, 1H), 2.16 (s, 3H), 2.15 - 2.07 (m, 3H), 2.06 - 1.95 (m, 2H).

[0427] Example 37-116: Synthesis of compound 37-116

[0428] Compound 37-116 was prepared according to the procedures of Reference Example 1, or other examples, or the methods of Synthetic Scheme 2 or 3, mutatis mutandis, as necessary.

[0429] Example 37-116: Synthesis of compound 37-116

[0430] Table A

[0431] Biological activity examples

[0432] I. KRAS G12D / SOS1 binding experiment

[0433] (1) Compound was prepared with DMSO, and compound was diluted with DMSO in 4-fold gradient.

[0434] (2) 0.1 μL of the gradient diluted compound was added to the 384-well plate.

[0435] (3) 5 μL of Tag2-KRAS G12D & GTP at a specific concentration was added to the 384-well plate, and centrifuged at 1000 rpm for 1 minute.

[0436] (4) Continue to add 5 μL of Tag1-SOS1 of a specific concentration to the 384-well plate, centrifuge at 1000 rpm for 1 minute.

[0437] (5) Incubate at 25℃ for 15 minutes.

[0438] (6) Continue to add 10 μL of anti-Tag1-Tb 3+ and anti-Tag2-XL665 mixture to the 384-well plate.

[0439] (7) Centrifuge at 1000 rpm for 1 minute, incubate at 4℃ for 3 hours.

[0440] (8) Read the ratio of 665 / 615 nm by the microplate reader.

[0441] (9) Data analysis: take the log value of the compound concentration as the abscissa, take the ratio of 665 / 615 nm as the ordinate, and use GraphPad Prism 8.0 software to analyze the data and calculate the IC 50 value.

[0442] The analysis results show that the compound of the present application can effectively bind to KRAS G12D-GTP, and hinder the binding of KRAS and SOS1 protein.

[0443] II. In-cell Western method for detecting the inhibitory effect of the compound on intracellular pERK

[0444] Reagents used

[0445] Experimental steps:

[0446] (1) On the first day, resuscitate the following cells with the corresponding medium, and incubate in a 37℃ 5%CO2 incubator until they are fully grown:

[0447] (2) On the third day, remove the culture medium, and rinse once with DPBS, add 2mL TrypLETM trypsin for digestion, and place it at room temperature until the cells fall off.

[0448] (3) Add 5mL of new culture medium to resuspend the cells to stop digestion, and gently blow the cells with a pipette, centrifuge at 1000 rpm for 5 minutes at room temperature.

[0449] (4) Remove the supernatant, add 5mL of new culture medium to resuspend the cells, and count them.

[0450] (5) Adjust the cell concentration to the appropriate cell concentration with complete culture solution, and plate the cells in a 384-well plate, and incubate in a 37℃ 5%CO2 incubator overnight.

[0451] (6) Add 200 nL of prepared gradient dilution compounds (DMSO final concentration 0.5%) and incubate in a 37°C 5% CO2 incubator for 3h (HPAC cell line only needs to be incubated in the incubator for 1h).

[0452] (7) Fix cells.

[0453] (8) Wash with PBS twice.

[0454] (9) Add blocking solution and incubate at room temperature for 1 hour.

[0455] (10) Remove blocking solution and add primary antibody (phospho-ERK Rabbit mAb + GAPDH (D4C6R) Mouse mAb) and incubate at 4°C overnight.

[0456] (11) Wash with PBST (PBS + 0.05% Tween 20) twice for 2 minutes each.

[0457] (12) Remove PBST and add secondary antibody (IRDye 800CW Goat anti-Rabbit IgG (H+L) + IRDye 680RD Goat anti Mouse IgG (H+L)) at room temperature, protected from light.

[0458] (14) Discard secondary antibody and wash with PBST twice for 2 minutes each.

[0459] (15) Invert 384-well and centrifuge at 1000 rpm for 1 minute at room temperature and scan 384-well plate using Odyssey CLx.

[0460] (16) Data analysis:

[0461] a) Use DMSO and reference quality control data to perform test stability check: Relative signal value = pERK (signal value of 800 channel) / GAPDH (signal value of 700 channel) Inhibition rate % = 100 - (sample signal value - quality control relative signal value) / (DMSO well signal value - quality control relative signal value) x 100

[0462] b) Compound IC 50 Non-linear fit: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 - ) x HillSlope)).

[0463] The experimental test results are shown in Table 1.

[0464] Table 1 Inhibition of pERK of KRAS mutant cell line AGS by compounds of the present application

[0465] As shown in Table 1, the compound of the present application can effectively inhibit the phosphorylation of ERK protein of KRAS G12D mutant type cell strain.

[0466] III. 3D-CTG method for detecting the effect of the compound on the proliferation inhibition of GP2D, HPAC, AGS, MKN1, NCI-H727 and NCI-H358 cells:

[0467] Experimental steps:

[0468] (1) Resuscitate AGS cells with F12K medium containing 10% fetal bovine serum, resuscitate GP2D and HPAC cells with DMEM medium containing 10% fetal bovine serum, resuscitate MKN1, NCI-H727 and NCI-H358 cells with RPMI 1640 medium containing 10% fetal bovine serum, subculture twice, and then prepare for use after the cells recover.

[0469] (2) On the first day, rinse the cells with PBS once, add preheated trypsin, and place in a 37°C 5% CO2 incubator for 3-5 minutes; add an appropriate amount of complete culture medium (containing 10% fetal bovine serum) to terminate digestion, and transfer it to a centrifuge tube, centrifuge at 1000 rpm for 5 minutes.

[0470] (3) Resuspend the cells with complete culture medium, count, and adjust to the appropriate cell concentration with complete culture medium.

[0471] (4) Use ECHO 655 acoustic liquid treatment system to take 0.2 μl of prepared 200x gradient diluted compound (DMSO final concentration is 0.5%) and add it to the 384-well plate, then add 40 μl of cell suspension counted in step (3) to each well, and place in a 37°C 5% CO2 incubator for incubation.

[0472] (6) After AGS is incubated for 4 days, and GP2D, HPAC, MKN1, NCI-H727 and NCI-H358 are incubated for 8 days, add 3D CTG detection reagent to each well.

[0473] (7) Read the signal value with Envision.

[0474] (8) Data analysis:

[0475] a) Test the stability of the experimental method using DMSO and culture solution: H = DMSO well L = culture solution well H, CV% (DMSO well) = 100 x (DMSO well SD value / DMSO well average value) L, CV% (corresponding culture solution well) = 100 x (culture solution well SD value / corresponding culture solution well average value) Z' = 1-3 x (DMSO well SD value + culture solution well SD value) / (DMSO well average value - corresponding culture solution well average value) Inhibition rate, % = (DMSO well average value - sample well average value) / (DMSO well average value - corresponding culture solution well average value) x 100

[0476] b) IC50 fitting of the compound using the nonlinear regression equation of XLfit 5.5.0 software. Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0477] X: log value of compound concentration

[0478] Y: inhibition rate (%inh)

[0479] Conclusion: The IC50 of the compound of the present application on the inhibition of the proliferation of GP2D, HPAC, AGS, MKN1, NCI-H727, NCI-H358 cells, respectively 50 <1 μM, most of the compounds have an IC50 of the inhibition of the proliferation of the aforementioned cells 50 <100 nM; wherein most of the compounds have an IC50 of the inhibition of the proliferation of the aforementioned cells <10 nM. Therefore, the compound of the present application has good inhibition effect on the proliferation of GP2D, HPAC, AGS, MKN1, NCI-H727, NCI-H358 cells. The partial inhibition activity of some compounds of the present application is shown in Table 2.

[0480] Table 2 Inhibition of the proliferation of KRAS mutant cell strain GP2D by the compound of the present application

[0481] Four, pharmacokinetic evaluation of the compound of the present application by intravenous injection or gavage of mice, rats and dogs

[0482] The inventors have carried out pharmacokinetic evaluation of the compound of the present application in mice, rats and dogs. The animal information is shown in Table 3.

[0483] Table 3: Information table of test animals of the present application

[0484] Experimental method

[0485] The compound of the present application is administered to the test animals in the form of a 5% DMSO + 30% PEG400 + 65% saline solution, a 10% DMSO + 10% Kolliphor HS15 + 80% saline solution, a 10% DMSO + 89% (25% SBE-B-CD) + (2% HCl) solution, a 20% PEG400 + 80% sterilized water for injection solution, or a 10% DMA + 10% HS15 + 30% PEG400 + 50% sterilized water for injection solution. The animals are fasted for 12 hours before administration, and are allowed to drink water freely. For the intravenous injection administration group, the administration dose is 1 mg / kg, and intravenous blood is taken at the following time points (blood volume is about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h (for dogs), 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 h (for mice and rats), or 0.083, 0.25, 0.5, 1.0, 2.0, 6.0, 8.0, and 24 h (for monkeys) after administration. The blood is collected in a blood collection tube pre-added with EDTA-K2 as an anticoagulant. The blood sample is centrifuged at 12,000 rpm for 2 minutes, the plasma is collected, and is stored at -20°C or -70°C. For the oral administration group, the administration dose is 1 mg / kg (for mice, dogs, and monkeys) or 5 mg / kg (for rats), and intravenous blood is taken at the following time points (blood volume is about 0.15 mL): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 h (for dogs), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 h (for mice and rats), or 0.25, 0.5, 1.0, 2.0, 6.0, 8.0, and 24 h (for monkeys) after administration. The blood is collected in a blood collection tube pre-added with EDTA-K2 as an anticoagulant. The blood sample is centrifuged at 12,000 rpm for 2 minutes, the plasma is collected, and is stored at -20°C or -70°C.

[0486] The collected plasma samples are processed (after the frozen plasma is thawed at room temperature, stirred for 15 s, 10-20 μL of the plasma is taken, 120-150 μL of an acetonitrile solution containing an internal standard is added, stirred for 5 min, centrifuged at 4,000 rpm for 5 min, 100 μL of the supernatant is taken, and 120-150 μL of methanol / water (v / v = 1 / 1) is added and stirred) and then analyzed by LC-MS / MS to determine the concentration of the compound in the plasma.

[0487] The analysis results show that the compound of the present application has better oral absorption exposure (AUC) and more optimal pharmacokinetic properties in the animal body. This indicates that the compound of the present application has better drug properties and has better clinical application prospects. The pharmacokinetic parameters of the compound of the present application in mice are shown in Table 4.

[0488] Table 4: Pharmacokinetic parameters of the compound of the present application in mice

[0489] qd: once daily.

[0490] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "some embodiments", "example", "specific example" or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Also, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. Furthermore, the person skilled in the art can combine and combine the different embodiments, embodiments or examples described in the present specification and the features of the different embodiments, embodiments or examples without contradiction.

[0491] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and the person skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application without departing from the principles and spirit of the present application, and the scope of the present application is defined by the claims and their equivalents.

Claims

1. A compound, which is a compound of formula (I), or a stereoisomer, tautomer, isotopic compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (I), in, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a -C(=O)OR 6a -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 -NR 6a S(=O)2NR 6 R 7 -NR 6 R 7 -C 1-6 Alkyl-NR 6 C(=O)R 7 -C 1-6 Alkyl-NR 6 R 7 -C 1-6 Alkyl-C(=O)OR 6 -C 1-6 Alkyl-C(=O)NR 6 R 7 C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 (aryl)-C 1-6 Alkyl, (5-12-membered heteroaryl)-C 1-6 Alkyl, (C 3-12 cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 1-6 mercaptoalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 1-6 Alkoxy C 1-6 Alkyl, (C 3-12 cycloalkyl)-C 1-6 Alkyl, (3-12 membered heterocyclic)-C 1-6 Alkyl, (C 6-10 (aryl)-C 1-6 Alkyl, (5-12-membered heteroaryl)-C 1-6 Alkyl, (C 3-12 cycloalkyl)-OC 1-6 Alkyl, (3-12 membered heterocyclic)-OC 1-6 Alkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 -NR 6 R 7 -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 and C 1-6 Substituents of alkyl groups; T is Indicates a single bond or a double bond; Z and Z 3 Each can be either N or CH independently; Z 1 and Z 2 Each can be independently -O-, -S-, or -NH-; Each X 1 and X 2 Independently, it can be a bond, -O-, -S-, -NH-, -CH2-, -CH=CH-, -CH2-NH-, -CH2-NH-CH2-, -(CH2)3-, -(CH2)2-, -NH-CH2-, -O-CH2-, -CH2-O-, -CH2-S-, or -S-CH2-; Each R 5 Independently, it can be H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b S(=O)2R 7b -S(=O)2N(R) 7b )2、-NR 6b C(=O)N(R 7b )2、-NR 6b S(=O)2N(R 7b )2、-OS(=O)2N(R 7b )2、-S(=O)2R 6c -C 1-4 Alkylene-S(=O)2N(R) 7b 2. C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 6-10 Aryl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Or, two R atoms attached to the same carbon atom 5 Together Or, two R atoms attached to the same carbon atom 5 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Or, two R atoms connected to two adjacent atoms 5 Together with the two adjacent atoms connected to it, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Each R 8 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 6-10 Aryl, 6-10 heteroaryl, -C(=O)OC 1-6 Alkyl group, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C) 1-6 Alkyl)2; Ring B is C 6-12 Aryl or 5-12 heteroaryl groups; R 2 For -OR 10 -SR 10 -OC(=O)R 11 -OC(=O)NR 12 R 13 -OC(=O)OR 11 -OC 1-6 Alkyl-OC(=O)NR 12a R 13a -OC 1-6 Alkyl-OC(=O)OR 11a -OC 1-6 Alkyl-OP(=O)(OR) 11 (OR) 11c -OP(=O)(OR) 11 (OR) 11c -OC 1-6 Alkyl-OC(=O)R 11b -NR 14 C(=O)OR 11 -NR 14 S(=O)2OR 11 -OS(=O)R 11 -OS(=O)2R 11 -OS(=O)2OR 11 or -OP(=O)(OR) 11 )2; Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Hydroxyalkynyl group, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 2-6 Haloalkenyl, C 2-6 Halogenated alkynyl group, C 1-6 Halogenated alkoxy groups, C 1-6 Haloalkylthio group, C 6-12 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups; R 3 -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, or C 1-4 Halogenated alkyl groups; Y represents a bond, O, or S; R 4 It is a 3-10 membered heterocyclic group, -L-(3-12 membered heterocyclic group), -L-(C 3-12 cycloalkyl), -L-(5-12-membered heteroaryl), or -L-(C 6-10 Aryl), wherein the 3-10 member heterocyclic group, -L-(C 3-12 cycloalkyl), -L-(5-12-membered heteroaryl) and -L-(C 6-10 Aryl groups are each independently and optionally bounded by 1, 2, 3 or 4 R groups. 9a Instead, the -L-(3-12-membered heterocyclic group) is optionally replaced by 1, 2, 3 or 4 R groups. 9b Replaced; R 9a and R 9b Each of the following can be independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, (C 6-10 (aryl)-C 1-6 Alkyl, (5-12-membered heteroaryl)-C 1-6 Alkyl, (3-6 membered heterocyclic)-C 1-6 Alkyl, (C 3-6 cycloalkyl)-C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, (C 6-10 (aryl)-C 1-6 Alkyl, (5-12-membered heteroaryl)-C 1-6 Alkyl, (3-6 membered heterocyclic)-C 1-6 Alkyl, (C 3-6 cycloalkyl)-C 1-6 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-6 Alkyl and C 1-6 Substituents of alkyl groups; Or, two R atoms attached to the same ring carbon atom 9b Together Or, two R atoms attached to the same ring carbon atom 9b Together with the attached ring carbon atom, they form C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-6 Alkyl and C 1-6 Substituents of alkyl groups; L is C 1-6 Alkylene; R 6 R 7 R 6b R 7b R 6d R 7d R 6e and R 7e Each can be independently -H, -D, or -C. 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g C 1-6 Alkoxy, C 6-12 Aryl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups; or R 6 and R 7 、or R 6b and R 7b 、or R 6d and R 7d 、or R 6e and R 7e Each of the four elements can optionally form a 4-6 membered heterocycle with the N atom it is attached to, wherein the 4-6 membered heterocycle is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R 6a R 6c R 6g R 7g R 6h R 7h R 7k R 6j and R 7j Each can be independently -H, -D, -F, -Cl, -Br, -I, or -C. 1-6 alkyl; R 10 C 7-10 Alkyl, C 11-20 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, wherein R 10 Optionally, it is selected by 1, 2, 3 or 4 elements chosen from -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -OC(=O)R 6a -C(=O)R 6a C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; R 11 R 12 R 13 R 14 R 11a R 11b R 11c R 12a and R 13a Each is independently H, D, C 7-10 Alkyl, C 11-20 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group; wherein the C 7-10 Alkyl, C 11-20 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Aryl, 5-10 heteroaryl, C 3-12 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -C(=O)R 6a -C(=O)OR 6a C 1-6 Alkyl, C 7-10 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 The substituent of the haloalkyl group is replaced by a C10 substituent. 3-6 cycloalkyl, 3-6 membered heterocyclic, C 6-10 The aryl group and the 5-10 heteroaryl group are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; or R 12 and R 13 、or R 12a and R 13a Each of the four or six members can be optionally combined with the N atom it is attached to to form a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Substituents of haloalkyl groups; n is 0, 1, 2, 3, 4, 5, or 6; q1 can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound according to claim 1, wherein, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 -NR 6a C(=O)NR 6 R 7 -C(=O)R 6a -C(=O)OR 6a -NR 6 S(=O)2R 7 -S(=O)2NR 6 R 7 -NR 6a S(=O)2NR 6 R 7 -NR 6 R 7 -C 1-4 Alkyl-NR 6 C(=O)R 7 -C 1-4 Alkyl-NR 6 R 7 -C 1-4 Alkyl-C(=O)OR 6 -C 1-4 Alkyl-C(=O)NR 6 R 7 C 1-6 Alkyl, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 cycloalkyl)-C 1-4 Alkyl, (C 7-12 cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclic)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6-membered heteroaryl)-C 1-4 Alkyl, (C 3-6 cycloalkyl)-OC 1-4 Alkyl, (C 7-12 cycloalkyl)-OC 1-4 Alkyl, (3-6 membered heterocyclic)-OC 1-6 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 1-4 mercaptoalkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 1-4 Alkoxy C 1-4 Alkyl, (C 3-6 cycloalkyl)-C 1-4 Alkyl, (C 7-12 cycloalkyl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (7-12 membered heterocyclic)-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (5-6-membered heteroaryl)-C 1-4 Alkyl, (C 3-6 cycloalkyl)-OC 1-4 Alkyl, (C 7-12 cycloalkyl)-OC 1-4 Alkyl, (3-6 membered heterocyclic)-OC 1-6 Alkyl, (3-7 membered heterocyclic)-OC 1-6 Alkyl, (7-12 membered heterocyclic)-OC 1-4 Alkyl, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 -NR 6 R 7 -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 and C 1-4 Alkyl groups are substituted.

3. The compound according to any one of claims 1-2, wherein, R 1 is -H, -D, -CN, -NH2, -C(=O)H, -C(=O)OH, -C(=O)OR 6a 、-C(=O)NR 6 R 7 、-NR 6 C(=O)R 7 、-NR 6a C(=O)NR 6 R 7 、-C(=O)R 6a 、-C(=O)OR 6a 、-NR 6 S(=O)2R 7 、-S(=O)2NR 6 R 7 、-NR 6a S(=O)2NR 6 R 7 、-NR<000049i>R 7 、-CH2NR 6 C(=O)R 7 、-CH2NR 6 R 7 、-(CH2)2NR 6 R 7 、-CH2C(=O)OR 6 、-(CH2)2C(=O)OR 6 、-(CH2)3C(=O)OR 6 、-CH2C(=O)NR 6 R 7 、-(CH2)2C(=O)NR 6 R 7 、-(CH2)3C(=O)NR 6 R 7 It should be noted that there may be a typo in "ID=37" where it says "<000049i>" which should probably be " 6 ". If this is a real error in the original text, it may affect the accuracy of the translation in terms of the overall context understanding related to that specific tag., -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CN, -(CH2)2CN, -(CH2)3CN, -C H(CH3)CN, -C(CH3)2CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2CHF2, -(CH2)2CF(CF3)2, -CF3, -CHF2, -CH2F, -(CH2)2F, - (CH2)2Cl, -CH2CF3, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O -cyclopentyl, -CH2O-azacyclobutyl, -CH2O-oxacyclobutyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexyl, -CH2O-spiro[3.3]heptyl, -CH2SH, -(CH2)2SH, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxacyclobutyl, tetrahydropyranyl, azacyclobutyl or pyrrolidinyl; wherein -CH2OCH3, -(CH2)2OCH3, -(CH2)2OCH2CH3, -CH2OCH2CH3, -CH2OC(CH3)3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -(CH2)2-cyclopentyl, -(CH2)3-cyclopentyl, -(CH2)2-cyclohexyl, -CH2-phenyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2O-cyclopropyl, -CH2O-cyclobutyl, -(CH2)2O-cyclobutyl, -CH2O-cyclopentyl, -(CH2)2O-cyclopentyl, -CH2O-azacyclobutyl, -CH2O-oxacyclobutyl, -CH2O-tetrahydrofuranyl, -CH2O-pyrrolidinyl, -CH2O-spiro[2.3]hexyl, -CH2O-spiro[3.[3] Heptyl, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, oxacyclobutyl, tetrahydropyranyl, aziridine, and pyrrolidinyl are each independently and optionally separated by 1, 2, 3, or 4 of the groups selected from D, -OH, -F, -Cl, -Br, -I, CN, -C(=O)OR. 6 -NR 6 R 7 -C(=O)NR 6 R 7 -NR 6 C(=O)R 7 It is substituted by substituents such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

4. The compound according to any one of claims 1-3, wherein, T is Each R 5 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NHC(=O)H, -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b S(=O)2R 7b -S(=O)2N(R) 7b )2、-NR 6b C(=O)N(R 7b )2、-NR 6b S(=O)2N(R 7b )2、-OS(=O)2N(R 7b )2、-S(=O)2R 6c -C 1-4 Alkylene S(=O)2N(R) 7b 2. C 1-4 Alkyl, C 1-4 Alkylthio, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio, 6-10 aryl, 5-10 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 Alkyne group, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl) 2, 6-10 aryl, 5-10 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Or, two R atoms attached to the same carbon atom 5 Together Or, two R atoms attached to the same carbon atom 5 Together with the carbon atom attached to it, they form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Or, two R atoms connected to two adjacent atoms 5 Together with the two adjacent atoms connected to it, it forms C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 R groups. 8 Replaced; Each R 8 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 6-10 Aryl, 6-10 heteroaryl, -C(=O)OC 1-4 Alkyl group, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C) 1-4 Alkyl)2; R 6h R 7h and R 7k Each can be independently -H, -D, or -C. 1-4 alkyl.

5. The compound according to any one of claims 1-4, wherein, T is Each R 5 Independently, -H, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -COOH, oxo, -NH(C=O)H, -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b S(=O)2R 7b -S(=O)2N(R) 7b )2、-NR 6b C(=O)N(R 7b )2、-NR 6b S(=O)2N(R 7b )2、-OS(=O)2N(R 7b )2、-S(=O)2R 6c -CH2S(=O)2N(R) 7b )2、-(CH2)2S(=O)2N(R 7b )2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2CH (CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -CH 2CH=CH2、-C≡CH、-C≡CCH3、-CH2C≡CH、-CH2CN、-(CH2)2CN、-(CH2)3CN、-CH2OH、-(CH2)2OH、-(CH2)3OH、-CH(OH )CH3, -CF3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2) 3CH3), -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHC H2F, -C≡CCH2F, -OCF3, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCF3, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, Phenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxaziridinebutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl, wherein,The -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -S(CH2)2CH3, -SCH2C H(CH3)2, -SCH(CH3)2, -OCH3, -OCH2CH3, -O(CH2)2CH3, -OCH2CH(CH3)2, -OCH(CH3)2, -CH=CH2, -CH=CHCH3, -C H2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(O H)CH3, -CHF2, -CH2F, -(CH2)2F, -(CH2)2Cl, -CH2CF3, -NHCH3, -NH(CH2CH3), -NH((CH2)2CH3), -NH((CH2)3CH 3) -NH(CH(CH3)2), -N(CH3)2, -N(CH2CH3)2, -N((CH2)2CH3)2, -CHFCH=CH2, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -OCH2F, -OCHF2, -OCH2CF3, -OCH2CHF2, -SCH2F, -SCHF2, -SCH2CF3, -SCH2CHF2, phenyl, furanyl, imidazolyl, isoxazolyl Oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxaziridinebutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolylalkyl, piperidinyl, piperazinyl, and morpholinyl are each independently and optionally marked with 1, 2, 3, or 4 Rs. 8 Replaced; Or, two R atoms attached to the same carbon atom 5 Together Or, two R atoms attached to the same carbon atom 5 Together with the carbon atom attached thereto, they form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, aziridine, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, aziridine, oxacyclobutyl, thiazolyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl groups are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 8 Replaced; Or, two R atoms connected to two adjacent atoms 5 Together with two adjacent atoms, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl group, wherein each of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridine, aziridine, oxacyclobutyl, pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl groups is independently and optionally surrounded by 1, 2, 3, or 4 R groups. 8 Replaced; Each R 8 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)OH, -C(=O)NH2, oxo, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, phenyl, furanyl, imidyl Azolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazole, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)O(CH2)2CH3, -C(=O)OCH(CH3)2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -C(=O)N(CH3)2 or -C(=O)N(CH3)CH2CH3; R 6h R 7h and R 7k Each can be independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

6. The compound according to any one of claims 1-5, wherein, T is 7. The compound according to any one of claims 1-6, wherein, R 2 is -OR 10 、-SR 10 、-OC(=O)R 11 、-OC(=O)NR 12 R 13 、-OC(=O)OR 11 、-O-C 1-6 alkyl -O-C(=O)NR 12a R 13a 、-O-C 1-4 alkyl -O-C(=O)NR 12a R 13a 、-O-C 1-4 alkyl -O-C(=O)OR 11a 、-O-C 1-4 alkyl -OP(=O)(OR 11 )(OR 11c )、-OP(=O)(OR 11 )(OR 11c 、-O-C 1-4 alkyl -O-C(=O)R 11b 、-NR 14 C(=O)OR 11 、-NR 14 S(=O)2OR 11 、-OS(=O)R 11 、-OS(=O)2R 11 、-OS(=O)2OR 11 or -OP(=O)(OR 11 )2; or R 2 is -OR 10 、-SR 10 、-OC(=O)R 11 、-OC(=O)NR 12 R 13 、-OC(=O)OR 11 、-O-CH2-O-C(=O)NR 12a R 13a 、-O-CH(CH3)-O-C(=O)NR 12a R 13a 、-O-CH2-O-C(=O)OR 11a 、-O-CH(CH3)-O-C(=O)OR 11a 、-O-CH2-OP(=O)(OR 11 )(OR 11c )、-O-CH(CH3)-OP(=O)(OR 11 )(OR 11c )、 -OP(=O)(OR 11 )(OR 11c )、 -O-CH2-O-C(=O)R 11b 、 -O-CH(CH3)-O-C(=O)R 11b 、 -NR 14 C(=O)OR 11 、 -NR 14 S(=O)2OR 11 、 -OS(=O)R 11 、 -OS(=O)2R 11 、 -OS(=O)2OR 11 or -OP(=O)(OR 11 )2。 8. The compound according to any one of claims 1-7, wherein, R 10 C 7-10 Alkyl, C 11-20 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5-6 quinone heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein R 10 Optionally, it is selected by 1, 2, 3 or 4 elements chosen from -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -OC(=O)R 6a -C(=O)R 6a C 1-4 Alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Substituents of haloalkyl groups; R 11 R 12 R 13 R 14 R 11a R 11b R 11c R 12a and R 13a Each is independently H, D, C 7-10 Alkyl, C 11-20 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group; wherein the C 7-10 Alkyl, C 11-20 Alkyl, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne, phenyl, naphthyl, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -C(=O)R 6a -C(=O)OR 6a C 1-4 Alkyl, C 4-6 Alkyl, C 7-10 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 The alkyl group is substituted by a substituent, wherein the substituent is phenyl, naphthyl, 5-6 membered heteroaryl, or C. 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Substituents of haloalkyl groups; or R 12 and R 13 、or R 12a and R 13a Each of the four or six members can be optionally combined with the N atom it is attached to to form a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 The alkyl halogroup is substituted by a substituent.

9. The compound according to any one of claims 1-8, wherein, R 10 -C9H 19 -C 10 H 21 -C 15 H 31 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, furanyl, imidazole Isoxazolyl, oxazolyl, pyrrolyl, pyrazoleyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxaziridine, pyrrolylyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolylyl, pyrazolylyl, pyrazolinyl, oxazolylyl, imidazolyl, piperidinyl, piperazinyl or morpholinyl, R 10 Optionally, it is selected by 1, 2, 3 or 4 elements chosen from -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -OC(=O)R 6a -C(=O)R 6a Substituents of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, pyrrolyl, azacyclobutyl, pyrrolyl, piperazine, piperidinyl, morpholinyl, oxazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl; R 11 R 12 R 13 R 14 R 11a R 11b R 11c R 12a and R 13a Each is independently H, D, -C9H 19 -C 10 H 21 -C 15 H 31 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazole, isoxa Azolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxacyclobutyl, pyrrolylalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolylalkyl, pyrazolylalkyl, pyrazolinyl, oxazolylalkyl, imidazolyl, piperidinyl, piperazinyl, or morpholinyl; wherein the -C9H 19 -C 10 H 21 -C 15 H 31 -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, phenyl, naphthyl, furanyl, imidazole, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl Pyrimidinyl, pyridazinyl, pyrazinyl, thiopheneyl, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, aziridinepropyl, aziridinebutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, thiazolyl, pyrazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl are optionally represented by 1, 2, 3, or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, and -NR. 6 R 7 -OC(=O)NR 6 R 7 -OC(=O)OR 6a -C(=O)R 6a -C(=O)OR 6a The substituents of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, pyrrolyl, aziridine, pyrrolyl, piperazine, piperidinyl, morpholinyl, oxazolyl, imidazolyl, phenyl, pyridinyl, pyrimidinyl, methoxy, ethoxy, isopropoxy, methylthio, ethylthio, isopropylthio, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl, wherein the substituents are phenyl, naphthyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, triazolyl, tetrazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, or aziridine The α-heterobutyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, imidazolyl, piperidinyl, piperazinyl, and morpholinyl groups are optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NO2, -NH2, -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)2CH(CH3)2, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -CH2CH(CH3)2, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, and 1,2-dichloroethyl. or R 12 and R 13 、or R 12a and R 13a Optionally, together with the N atom attached thereto, they form aziridine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazoline, wherein the aziridine, pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazoline is optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, pyrrolylalkyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl.

10. The compound according to any one of claims 1-9, wherein, Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups and 3-6 membered heterocyclic groups; or, Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡ CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -( CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, tetrahydrofuranyl, piperidinyl or piperazineyl,The terms -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, - OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolylalkyl, oxazolylalkyl, tetrahydrofuranyl The piperidinyl and piperazinyl groups are each optionally and independently substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, oxazolyl, tetrahydrofuranyl, piperidinyl, and piperazinyl.

11. The compound according to any one of claims 1-10, wherein, Ring B is one of the following substructures: Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkylthio, C 2-4 alkenyl, C 2-4 alkynyl group, C 2-4 Hydroxyalkynyl group, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Haloalkenyl, C 2-4 Halogenated alkynyl group, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 6-10 Aryl, 5-12 heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Substituents of cycloalkyl groups and 3-6 membered heterocyclic groups; or, Each R 0 Independently, -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH2C(=O)NR 6b R 7b -C(=O)R 6c -C(=O)OR 6c -C(=O)NR 6b R 7b -NR 6b C(=O)R 7b -NR 6b R 7b , -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡ CH, -C≡CCH2OH, -C≡C(CH2)2OH, -OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -( CH2)2F, -CH2CHF2, -CF3, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -C≡CF, -OCF3, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCF3, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, oxazolyl, tetrahydrofuranyl, piperidinyl or piperazineyl,The terms -CH3, -CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -C(CH3)3, -CH(CH3)2, -SCH3, -SCH2CH3, -CH=CH2, -CH=CHCH3, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, -C≡CCH2OH, -C≡C(CH2)2OH, - OCH3, -OCH2CH3, -O(CH2)2CH3, -CH2CN, -(CH2)2CN, -(CH2)3CN, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH(OH)CH3, -(CH2)2F, -CH2CHF2, -CH2CF3, -CHF2, -CH2F, -(CH2)2Cl, -CH=CHF, -CH=CHCl, -CH=CHCH2F, -C≡CCH2F, -C≡C(CH2)2F, -OCHF2, -OCH2CHF2, -OCH2CF3, -OCHClCHCl2, -OCH2CH2F, -SCH2CF3, -SCH2CHF2, phenyl, naphthyl, pyridyl, pyrimidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolylalkyl, oxazolylalkyl, tetrahydrofuranyl The piperidinyl and piperazinyl groups are each optionally and independently substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, -C(=O)H, -C(=O)OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, oxazolyl, tetrahydrofuranyl, piperidinyl, and piperazinyl.

12. The compound according to any one of claims 1-11, wherein, R 4 3-6 membered heterocyclic groups, -L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxetanebutyl, -L-oxetanepropyl, -L-tetrahydrofuranyl, -L-octahydroindoleazinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-1H-indenyl, -L-dehydronaphthyl, -L-pyridyl, -L-pyrazolyl, or -L-phenyl, wherein the 3-6 membered heterocyclic group, -L-cyclopropyl, -L-cyclopentyl, -L-octahydrocyclopentadienyl, -L-octahydro-1H-indenyl, -L-dehydronaphthyl, -L-pyridyl, -L-pyrazolyl, and -L-phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R... 9a Replaced, the aforementioned -L-pyrrolidinyl, -L-piperidinyl, -L-morpholinyl, -L-oxecyclobutyl, -L-oxecyclopropyl, -L-tetrahydrofuranyl, and -L-octahydroindolazinyl are each optionally surrounded by 1, 2, 3, or 4 R's. 9b Replaced; R 9a and R 9b Each of the following can be independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl-C 1-4 Alkyl, (5-6-membered heteroaryl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 cycloalkyl)-C 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 cycloalkyl or 3-6 membered heterocyclic group, wherein the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, phenyl-C 1-4 Alkyl, (5-6-membered heteroaryl)-C 1-4 Alkyl, (3-6 membered heterocyclic)-C 1-4 Alkyl, (C 3-6 cycloalkyl)-C 1-4 Alkyl, phenyl, 5-6 membered heteroaryl, C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-4 Alkyl and C 1-4 Substituents of alkyl groups; Or, two R atoms attached to the same ring carbon atom 9b Together Or, two R atoms attached to the same ring carbon atom 9b Together with the attached ring carbon atom, they form C 3-6 cycloalkyl and 3-6 membered heterocyclic groups, wherein the C 3-6 The cycloalkyl group and the 3-6 membered heterocyclic group are each independently and optionally surrounded by 1, 2, 3 or 4 groups selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NR 6e R 7e -C(=O)C 1-4 Alkyl and C 1-4 Substituents of alkyl groups; L is C 1-4 Alkylene; R 6j and R 7j Each can be independently -H, -D, -F, -Cl, -Br, -I, or -C. 1-4 alkyl.

13. The compound according to any one of claims 1-12, wherein, R 4 Piperidinyl, piperazineyl, pyrrolidinyl, imidazolidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxacyclobutyl, -CH2-oxacyclopropyl, -CH2-tetrahydrofuranyl, -CH2-octahydroindoleazinyl, -CH2-cyclopropyl, -CH2-cyclopentyl, -CH2-octahydrocyclopentadienyl, -CH2-octahydro-1H-indenyl, -CH2-decahydronaphthyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, -CH2-pyridine The radical is azole, -(CH2)2-pyrazolyl, or -CH2-phenyl, wherein the piperidinyl, piperazinyl, pyrrolyl, imidazoalkyl, -CH2-cyclopropyl, -CH2-cyclopentyl, -CH2-octahydrocyclopentadienyl, -CH2-octahydro-1H-indenyl, -CH2-decahydronaphthyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, and -CH2-phenyl are each independently and optionally surrounded by 1, 2, 3, or 4 R groups. 9a Replaced, the aforementioned -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-morpholinyl, -(CH2)2-morpholinyl, -CH2-oxetanebutyl, -CH2-oxetanepropyl, -CH2-tetrahydrofuranyl, and -CH2-octahydroindolazinyl are each optionally surrounded by 1, 2, 3, or 4 R's. 9b Replaced; R 9a and R 9b Each of the following can be independently -D, -OH, -F, -Cl, -Br, -I, -CN, -NR 6d R 7d -C(=O)NR 6d R 7d -CH2NR 6d R 7d -CH2OC(=O)NR 6d R 7d , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CHF2, -CF3, -OCF3, phenylmethyl, pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolylmethyl, piperazineylmethyl, azacyclobutylmethyl, piperidinylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazineyl or azacyclobutyl, wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, isopropoxy, -CHF2, phenylmethyl, Pyridylmethyl, pyrazolylmethyl, morpholinylmethyl, pyrrolylmethyl, piperazineylmethyl, aziridinemethyl, piperidylmethyl, tetrahydropyranylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazine, and aziridine are each independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and isopropyl. Or, two R atoms attached to the same ring carbon atom 9b They can form together Or, two R atoms attached to the same ring carbon atom 9b Together with the cyclic carbon atom attached thereto, it forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazine, or azircyclic butyl, wherein each of the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, piperidinyl, pyrrolyl, piperazine, and azircyclic butyl groups is independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -F, -Cl, -Br, -I, -OH, -CN, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, methyl, ethyl, n-propyl, and isopropyl. R 6j and R 7j Each can be independently -H, -D, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

14. The compound according to any one of claims 1-13, wherein, R 6 R 7 R 6b R 7b R 6d R 7d R 6e and R 7e Each can be independently -H, -D, or -C. 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, -NR 6g R 7g C 1-4 Alkoxy, C 6-10 Aryl, C 3-6 Substituents of cycloalkyl and 3-6 membered heterocyclic groups; or R 6 and R 7 、or R 6b and R 7b 、or R 6d and R 7d 、or R 6e and R 7e Each of these atoms, together with the same N atom attached to it, forms a 4-6 membered heterocycle, wherein the 4-6 membered heterocycle is optionally surrounded by 1, 2, 3 or 4 atoms selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 1-4 Alkoxy, C 1-4 Cyanoalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups and C 1-4 Substituents of haloalkyl groups; R 6a R 6c R 6g and R 7g Each can be independently -H, -D, or -C. 1-4 alkyl.

15. The compound according to any one of claims 1-14, wherein, R 6 R 7 R 6b R 7b R 6d R 7d R 6e and R 7e Each of the following is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl groups are each optionally replaced by 1, 2, 3, or 4 groups selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C(=O)H, -C(=O)OH, and -NR. 6g R 7g Substituents of methoxy, ethoxy, n-propoxy, isopropoxy, isobutoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, ethylene oxide, oxetyl, aziridine, and pyrrolidinyl; or R 6 and R 7 、or R 6b and R 7b 、or R 6d and R 7d 、or R 6e and R 7e Each of these compounds, together with the same N atom attached thereto, forms a pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, or imidazoline, wherein each of the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine, and imidazoline is independently and optionally substituted by 1, 2, 3, or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolylalkyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, or 1,2-dichloroethyl. R 6a R 6c R 6g and R 7g Each can be independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

16. The compound according to any one of claims 1-15, wherein, R 4 for 17. The compound according to any one of claims 1-16, wherein it is a compound of formula (I-1), or a stereoisomer, tautomer, isotopic compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of the compound of formula (I-1). in, R 1 R 2 R 3 R 4 Y and T each have the definition as described in any one of claims 1-16; R 01 and R 02 Each has R as described in claims 1-16 0 The same definition.

18. The compound according to any one of claims 1-17, wherein it is a compound with the following structure, or a stereoisomer, tautomer, isotopic compound, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug, 19. A pharmaceutical composition comprising a compound according to any one of claims 1-18; optionally, the pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

20. Use of the compound of any one of claims 1-18 or the pharmaceutical composition of claim 19 in the preparation of a medicament for the prevention, treatment or relief of diseases associated with KRAS amplification, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D or KRAS Q61H mutations.

21. The use according to claim 20, wherein, Diseases associated with KRAS amplifications, or KRAS G12A, KRAS G12C, KRAS G12D, KRAS G12R, KRAS G12S, KRAS G12V, KRAS G13D, or KRAS Q61H mutations, are cancers.

22. The use according to claim 21, wherein, The cancers mentioned include: heart cancers: sarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, or teratoma; lung cancers: bronchial cancer, non-small cell lung cancer, small cell lung cancer, alveolar cancer, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, or mesothelioma; gastrointestinal cancers: esophageal cancer, gastric cancer, pancreatic cancer, small bowel cancer, or colorectal cancer; genitourinary cancers: kidney cancer, bladder and urethral cancer, prostate cancer, or testicular cancer; liver cancers: hepatocellular carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, or hemangioma; biliary tract cancers: gallbladder cancer, ampullary cancer, or bile duct cancer; bone cancers: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Tumors, malignant lymphomas, multiple myelomas, malignant giant cell tumors, chordomas, benign chondromas, chondroblastomas, chondromycinomas, osteoid osteomas, or giant cell tumors; Nervous system cancers: skull tumors or brain cancers; Gynecological cancers: uterine cancer, vulvar cancer, vaginal cancer, fallopian tube cancer, ovarian cancer, or breast cancer; Hematologic cancers: acute or chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, or non-Hodgkin's lymphoma; Skin cancers: melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus of dysplasia, lipomas, hemangiomas, dermatofibromas, keloids, or psoriasis; or adrenal cancers: neuroblastoma.

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