Benzo[5]-Hypercyclic Derivatives and Their Applications

Abstract

This invention relates to benzo[a]-5-membered heterocyclic derivatives and their applications. Specifically, this invention discloses compounds with the structures shown in formula (I) or formula (II), wherein the definitions of each group and substituent are as described in the specification. This invention also discloses the use of said compounds in the treatment or prevention of PARG activity-related diseases, particularly proliferative diseases (such as cancer).

Description

Benzo-five-membered heterocyclic derivatives and their applications Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a method for preparing aromatic heterocyclic compounds that regulate PARG [Poly (ADP-ribose) glycohydrolase] activity, as well as pharmaceutical compositions containing these compounds and their use in anti-tumor treatment. Background Art

[0002] Cancer, one of the leading causes of death worldwide, is caused by uncontrolled and abnormal cell proliferation. This rapid proliferation is often accompanied by DNA damage within tumor cells and a significant increase in mutation rates. Therefore, tumor cell proliferation is critically dependent on DNA damage repair mechanisms. Single-strand breaks (SSBs) are the most common type of lesion in cells. PARG, along with PARP (poly ADP-ribose polymerase), and other proteins, collaborate in single-strand break repair (SSBR) and base excision repair (BER). The single-strand DNA repair process begins with PARP binding to the break, where it rapidly synthesizes poly (ADP-ribose) (PAR). This molecular structure acts as a signal to recruit other DNA repair proteins to repair the break. The signal initiated by these PAR chains is short-lived, as they are rapidly degraded by PARG. When PARP binds to PAR, its catalytic activity is reduced, so PARG intervention activates PARP to restore its catalytically active form. DNA damage-dependent PARylation / dePARylation is a rapid and dynamic process that requires careful regulation, as an imbalance between these two processes can lead to DNA damage. Full-length PARG is primarily localized in the nucleus; smaller isoforms are primarily present in the cytoplasm. Although primarily known for its direct role in DNA repair, PARG influences PAR signaling in splicing, transcription, and epigenetic pathways. Genomic aberrations in tumor suppressor genes or oncogenes can render cancer cells dependent on specific DNA repair pathways.

[0003] Studies have shown that PARP inhibitors are particularly effective against tumors carrying BRCA1 and BRCA2 gene mutations. Targeting synthetic lethal interactions like those between PARP and BRCA is an attractive new approach to treating cancer. Currently, PARP inhibitors have achieved good results in a large number of clinical trials, but clinical resistance to PARP inhibitors has also been revealed, necessitating the discovery of alternative inhibitors targeting the DNA damage repair mechanism. Studies have shown that the depletion of PARG inhibits SSBR and reduces the survival rate of BRCA2-deficient cells. Other tumor mutations may also cause defects in the double-stranded DNA repair mechanism, rendering tumor cells sensitive to PARG inhibition.

[0004] In summary, there is an urgent need to develop a new PARG inhibitor in this field. Summary of the Invention

[0005] An object of the present invention is to provide a compound having excellent PARG inhibitory activity.

[0006] The first aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, wherein the compound has a structure shown in Formula I or Formula II:

[0007] Among them, X 1 Each independently selected from the group consisting of: C, N;

[0008] X 2 Each independently selected from the group consisting of: C, N;

[0009] X 6 Each independently selected from the group consisting of: CR 6 , N;

[0010] Ring A is independently a partially saturated 5-membered heterocyclyl or 5-membered heteroaryl;

[0011] Ring C is independently a substituted or unsubstituted saturated or partially unsaturated 5-6 membered heterocyclic group or a substituted or unsubstituted 5-6 membered heteroaryl group; wherein the substitution on ring C means that one or more hydrogen atoms on the heterocyclic group or heteroaryl ring are replaced by a group selected from the group consisting of H, halogen, cyano, hydroxyl, amino, oxo (=O), C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl (such as cyclopropyl), C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6(like ),-COC 3-6 Cycloalkyl, C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1- 6 alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -N(C 1-6 Alkyl)2;

[0012] R 1 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 alkyl halide;

[0013] R 2 and R 3 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-10 Alkyl and C 1-10 Haloalkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl, 3-6 membered saturated heterocyclic group;

[0014] R 4 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, -NR 4a R 4b 、-C(O)R 4c、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c 、C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3 an alkyl-substituted or unsubstituted 5- to 8-membered heteroaryl group;

[0015] p is 0, 1, or 2;

[0016] R 4a and R 4b each the same or different;

[0017] R 4a 、R 4b and R 4c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic group and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are each independently optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C(=O)R 4c 、-C(=O)OR 4c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, -N(C1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0018] Or, R 4a and R 4b Each together with the nitrogen atom to which it is commonly attached forms a 5-8 membered heterocyclic group, and the heterocyclic group formed is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0019] R 6 For hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 alkyl halide;

[0020] Ar is independently selected from a substituted or unsubstituted 5-10 membered heteroaromatic ring, or a substituted or unsubstituted 5-10 membered heterocyclic ring, wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring or heterocyclic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-6 Ester group, C 1-6 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy and C 1-6 Halogenated alkoxy.

[0021] In another preferred embodiment, the substitution on ring C refers to the substitution of one or more hydrogen atoms on the heterocyclic group or heteroaromatic ring by a group selected from the group consisting of H, halogen, cyano, hydroxy, amino, oxo (=O), C1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl (such as cyclopropyl), C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6 (like ),-COC 3-6 Cycloalkyl, C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, preferably selected from halogen, cyano, hydroxyl, amino, C 1-6 Alkyl and C 1-6 The haloalkyl group is more preferably selected from methyl, ethyl and isopropyl.

[0022] In another preferred embodiment, ring A has one or two N atoms.

[0023] The present invention further provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, wherein the compound has a structure shown in Formula Ia or Formula II-a:

[0024] in,

[0025] X 1 Each independently selected from the group consisting of: C, N;

[0026] X 2 Each independently selected from the group consisting of: C, N;

[0027] X 3 Each independently selected from the group consisting of: CR 5a R 5b NR 5c , O, S, SO, SO2;

[0028] X 4 Each independently selected from the group consisting of: CR 5a R 5b NR 5c , O, S, SO, SO2;

[0029] X 5 Each independently selected from the group consisting of: CR 5a R 5b NR 5c , O, S, SO, SO2;

[0030] X 6 Each independently selected from the group consisting of: CR 6 , N; R 1 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 alkyl halide;

[0031] R 2 and R 3 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-10 Alkyl and C 1-10 Haloalkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl, 3-6 membered saturated heterocyclic group;

[0032] R 4 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c 、C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3 an alkyl-substituted or unsubstituted 5- to 8-membered heteroaryl group;

[0033] p is 0, 1, or 2;

[0034] R 4a and R 4b each the same or different;

[0035] R 4a 、R 4b and R 4c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic group and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are each independently optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C(=O)R 4c 、-C(=O)OR 4c 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0036] Or, R 4a and R 4b Each together with the nitrogen atom to which it is commonly attached forms a 5-8 membered heterocyclic group, and the heterocyclic group formed is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c 、C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0037] R 5a and R 5b Each independently selected from the group consisting of: H, halogen, cyano, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 3-6 Cycloalkyl (such as cyclopropyl), hydroxyl, amino, C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6 (like ), C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 5-8 membered heterocyclic group, 5-8 membered heteroaryl, or R 5a and R 5b Together form = O;

[0038] R 5c Each independently selected from the following group: H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, -COC 1-6 Alkoxy (such as ),-COC 1-6 Alkyl or haloalkyl (such as ),-COC 3-6 Cycloalkyl, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3- 6-cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, -C(=O)C1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -N(C 1-6 Alkyl)2;

[0039] R 6 Each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 alkyl halide;

[0040] Ar is independently selected from a substituted or unsubstituted 5-10 membered heteroaromatic ring, or a substituted or unsubstituted 5-10 membered heterocyclic ring, wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring or heterocyclic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-6 Ester group, C 1-6 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy and C 1-6 Halogenated alkoxy.

[0041] In another preferred embodiment, X 2 is N, and X 3 、X 4 and X 5 There is only one selected from the following group: NR 5c , O, S, SO, SO2.

[0042] In another preferred embodiment, the above X 1 is N, and X 4 NR 5c .

[0043] In another preferred embodiment, R 1 Each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 Halogenated alkyl.

[0044] In another preferred embodiment, R 2 and R3 Each independently selected from the following group: C 1-10 Alkyl and C 1-10 Haloalkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl, C 3-6 Saturated heterocyclic group.

[0045] In another preferred embodiment, R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c 、C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3 Alkyl-substituted or unsubstituted 5- to 8-membered heteroaryl.

[0046] In another preferred embodiment, R 6 are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6Halogenated alkyl, preferably hydrogen.

[0047] In another preferred embodiment, R 1 Each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl.

[0048] In another preferred embodiment, R 2 and R 3 Each independently selected from the following group: C 1-6 Alkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-8 Cycloalkyl or 3-6 membered saturated heterocyclic group.

[0049] In another preferred embodiment, R 1 Each independently selected from the group consisting of: cyano, C 1-6 Alkyl, C 1-6 haloalkyl; and R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-6 Cycloalkyl, 3-6 membered saturated heterocyclic group.

[0050] In another preferred embodiment, R 4 Each independently selected from the following group: C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b -C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3Alkyl-substituted or unsubstituted 5- to 8-membered heteroaryl.

[0051] In another preferred embodiment, X 3 、X 4 、X 5 Each independently selected from the group consisting of: CR 5a R 5b NR 5c ;

[0052] R 5a 、R 5b Each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C 1-3 Alkyl or C 1-3 alkyl halide;

[0053] R 5c Each independently selected from the following group: H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, -COC 1-6 Alkoxy (such as ),-COC 1-6 Alkyl or haloalkyl (such as ), C 1-6 Haloalkyl, -COC 3-6 Cycloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkyl hydroxyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, -C(=O)C 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, -N(C 1-3 Alkyl)2.

[0054] In another preferred embodiment, Ar is independently selected from a substituted or unsubstituted 5-7 membered heteroaromatic ring, or a substituted or unsubstituted 5-7 membered heterocyclic ring, wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring or heterocyclic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-6 Ester group, C 1-6 Aldehyde, -NH2, amide, C 1-6 Alkyl, C 1-6 Haloalkyl (such as difluoromethyl or trifluoromethyl), C 1-6 Hydroxyalkyl and C 1-6Alkoxy.

[0055] In another preferred embodiment, ring A is selected from the following group:

[0056] In another preferred embodiment, in Formula I or Formula Ia, Ring C is selected from the following group:

[0057] In another preferred embodiment, in Formula II or Formula IIa, Ring C is selected from the following group:

[0058] R 5a and R 5b Each independently selected from the group consisting of: H, halogen, cyano, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 3-6 Cycloalkyl (such as cyclopropyl), hydroxyl, amino, C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6 (like ), C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 5-8 membered heterocyclic group, 5-8 membered heteroaryl, or R 5a and R 5b Together form = O;

[0059] R 5c Each independently selected from the following group: H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, -COC 1-6 Alkoxy (such as ),-COC 1-6 Alkyl or haloalkyl (such as ),-COC 3-6 Cycloalkyl, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3- 6-cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, -C(=O)C1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -N(C 1-6 Alkyl)2.

[0060] In another preferred embodiment, R 5a 、R 5b Each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0061] In another preferred embodiment, R 5c Each independently selected from the following group: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 5-10 Aryl and 5-10 membered heteroaryl, -CONH2, -CH2CN, -CONH-C 1-3 Alkyl, -COC 3-6 Cycloalkyl, -CH2OH, -CH2CH2O-C 1-6 Alkyl, -CH2CH2NH-C 1-3 Alkyl, -CH2CH2N(C 1-3 Alkyl)2.

[0062] In another preferred embodiment, Ar is selected from a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein said substitution means that one or more hydrogen atoms on the heteroaromatic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-4 Ester group, C 1-4 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0063] In another preferred embodiment, Ar is selected from the following group:

[0064] In another preferred embodiment, R 4 are independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C3-8 Cycloalkyl, 5-9 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each independently substituted by a substituent selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, phenyl group and C 1-3 an alkyl-substituted or unsubstituted 5- to 8-membered heteroaryl group;

[0065] Among them, R 4a 、R 4b are the same or different and are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl and 5-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl and heterocyclic group are each independently optionally substituted by a substituent selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy and -N(C 1-3 Alkyl)2;

[0066] Or, R 4a and R 4b Each of them together with the nitrogen atom to which they are commonly attached forms a 5-8 membered heterocyclic group, and the heterocyclic group formed is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, oxo (=O), C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, nitro, hydroxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0067] R 4c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, phenyl, 5-8 membered heterocyclic group and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl and heterocyclic group are each independently optionally substituted by one or more substituents each independently selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Halogenated alkoxy.

[0068] In another preferred embodiment, R 4 Select from the following groups:

[0069] In another preferred embodiment, ring C is optionally substituted independently by one or more groups selected from the following groups:

[0070] In another preferred embodiment, R 5a 、R 5b 、R 5c One or more of are independently selected from the following group:

[0071] In another preferred embodiment, the compound is selected from the following group:

[0072] In another preferred embodiment, in Formula I, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 , Ar, ring A and ring C are independently selected from the corresponding groups in the above-mentioned specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

[0073] In another preferred embodiment, in Formula II, R 1 、R 2 、R 3 、X1 、X 6 , Ar, ring A and ring C are independently selected from the corresponding groups in the above-mentioned specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

[0074] In another preferred embodiment, in Formula Ia, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、X 5 , Ar, ring A and ring C are independently selected from the corresponding groups in the above-mentioned specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

[0075] In another preferred embodiment, in Formula II-a, R 1 、R 2 、R 3 、X 1 、X 3 、X 4 、X 5 、X 6 , Ar, ring A and ring C are independently selected from the corresponding groups in the above-mentioned specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

[0076] In a second aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof.

[0077] In a third aspect, the present invention provides a use of the compound according to the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, or the pharmaceutical composition according to the second aspect of the present invention, for preparing a medicament or preparation, wherein the medicament or preparation is used for a use selected from the group consisting of:

[0078] 1) Used to regulate PARG enzyme activity;

[0079] 2) a mutation type associated with regulating PARG activity in DNA repair, wherein the mutation type is selected from the group consisting of MUTYH, BRCA2, CHEK2, BRCA1, ATM, and RAD51C;

[0080] 3) for preventing and / or treating diseases related to PARG activity, such as cancer;

[0081] 4) For the prevention and / or treatment of proliferative diseases, such as cancer.

[0082] In another preferred embodiment, the PARG activity-related disease is selected from the following group: ovarian cancer, breast cancer, pancreatic cancer, lung cancer, and prostate cancer.

[0083] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0084] After extensive and in-depth research, the inventors have developed a novel PARG inhibitor for the first time, specifically targeting cells resistant to PARP inhibitors. The compound exhibits excellent PARG inhibitory activity and is capable of effectively inhibiting the proliferation of Kuramochi cells harboring BRAC2 mutations. This led to the present invention.

[0085] the term

[0086] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0087] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0088] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- includes -OCH2-.

[0089] As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" means substituted with an atom selected from F, Cl, Br, and I.

[0090] In the present invention, "C1-6 alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0091] In the present invention, the term "C2-6 alkenyl" refers to a straight chain or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0092] In the present invention, the term "C2-6 alkynyl" refers to a straight chain or branched alkynyl group having 2 to 6 carbon atoms and containing one triple bond, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0093] In the present invention, the term "C3-8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, such as C3-6 alkyl) including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0094] In the present invention, the term "C1-6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc. Preferably, it is a C1-4 alkoxy group.

[0095] In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, such as a 3-10 membered heterocyclic group, a 4-9 membered heterocyclic group, or a 5-6 membered heterocyclic group. The heterocyclic group may have 1 or 2 double bonds. The S atoms in the ring may be optionally oxoed to form SO or SO2. The heterocycloalkyl group may be a monocyclic, bicyclic, or polycyclic ring system. Heterocyclyl groups include, but are not limited to, the following groups:

[0096] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C6-C10 aryl group". The term "C6-C10 aryl group" refers to an aromatic ring group having 6 to 10 carbon atoms and no heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0097] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms (such as selected from oxygen, sulfur and nitrogen). For example, "5-10 membered heteroaryl" refers to an aromatic heterocycle containing 1 to 4 (such as 2 or 3) heteroatoms selected from oxygen, sulfur and nitrogen and 5-10 ring atoms. Heteroaryl preferably includes 5-9 membered heteroaryl or 5-6 membered heteroaryl. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted.

[0098] In the present invention, the term "halo" means substituted with halogen.

[0099] In the present invention, the term "deuterated" means substituted with deuterium.

[0100] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. Unless otherwise specified, the substitution refers to the substitution that one or more H atoms on the group are independently and optionally substituted by a group selected from the following group (but not limited to):

[0101] Preferably selected from the group consisting of halogen, cyano, hydroxy, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, C(=O)C 1-6 Alkyl, -N(C 1-6 alkyl)2, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0102] In the present invention, the term 1 to 6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.

[0103] The term "ester group" has a -C(O)-O-R' or R'-C(O)-O- structure, wherein R' independently represents hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, heteroaryl, heterocyclyl, as defined above.

[0104] In the present invention, It can be a single bond or a double bond.

[0105] The term "amido" refers to a group having the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety.

[0106] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0107] It should be understood that when a group is present at multiple different positions in a compound, the definition at each position is independent of each other and may be the same or different. That is, the term "selected from the group:" and the term "each independently selected from the group:" have the same meaning.

[0108] Active ingredient

[0109] The present invention provides compounds for inhibiting PARG, primarily for the treatment or prevention of proliferative diseases such as cancer, and particularly for the modulation and treatment of cancers associated with PARG activity. Because PARG depletion results in a decrease in SSBR to the same extent as PARP1 depletion, PARG inhibition may provide therapeutic advantages for cells resistant to PARP inhibitors. The present invention provides cell-permeable inhibitors of PARG.

[0110] Specifically, the present invention provides a compound represented by Formula I or II or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,

[0111] wherein each group is as defined above.

[0112] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with the compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0113] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0114] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0115] The present invention is also intended to include the crystal forms, hydrates, and solvates of the above compounds.

[0116] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0117] In addition, the compounds of the present invention also include prodrugs of the compounds of Formula I and Formula II. The term "prodrug" includes a compound that may be biologically active or inactive, and when administered by appropriate methods, undergoes metabolism or chemical reactions in the human body to convert into a compound of Formula I or Formula II, or a salt or solution composed of a compound of Formula I or Formula II. Such prodrugs include (but are not limited to) carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compounds.

[0118] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates.3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0119] The examples of the present invention specifically describe the preparation methods of the compounds of Formula I or II of the present invention, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily made by those skilled in the art.

[0120] Typically, the raw materials and reagents used in the process for preparing the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0121] Pharmaceutical compositions and methods of administration

[0122] The present invention also provides a pharmaceutical composition comprising the compound of formula I, a pharmaceutically acceptable salt thereof, or a stereoisomer, solvate or prodrug thereof; and a pharmaceutically acceptable carrier.

[0123] The compounds of the present invention have poly (adenosine diphosphate ribose) hydrolase (PARP inhibition) activity and are therefore useful for preventing or treating diseases mediated by PARP, particularly cancer. The cancers include, but are not limited to, fibrosarcoma, bladder cancer, ovarian cancer, adenocarcinoma, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, and the like.

[0124] In particular, the compounds of the present invention have an inhibitory effect on tumor cells that are resistant to PARP inhibitors. In particular, the compounds of the present invention can specifically inhibit the DNA damage repair mechanism of tumor cells, thereby inhibiting their proliferation and achieving the effect of preventing or treating tumors.

[0125] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 1-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0126] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0127] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0128] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0129] The prodrug compounds of the present invention can be conveniently formulated into pharmaceutical compositions comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier. See Remington: The Science and Practice of Pharmacy, 19th ed. (Easton, PA, Mack Publishing Co., 1995), which discloses typical carriers and general methods for preparing pharmaceutical compositions, which can be used as described or modified to produce pharmaceutical formulations containing the compounds of the present invention. As previously mentioned, the compounds of the present invention can also be administered in the form of pharmaceutically acceptable salts, etc.

[0130] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0131] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0132] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0133] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0134] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0135] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0136] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0137] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0138] When administered in combination, the pharmaceutical composition may also include one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents, such as chemotherapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents may be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat tumor-related diseases.

[0139] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 1 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0140] Compared with the prior art, the main advantages of the present invention include:

[0141] (1) The compounds of the present invention have excellent PARG inhibitory activity;

[0142] (2) The compounds of the present invention are able to effectively inhibit the proliferation of cancer cells such as Kuramochi cells with BRAC2 mutations (especially PARP inhibitor-resistant cells), thereby providing a new solution for cancer treatment.

[0143] (3) The compounds of the present invention have good pharmacokinetic and pharmacodynamic properties, as well as excellent drugability, and are very suitable for preparing drugs for preventing or / treating diseases or conditions related to PARG activity.

[0144] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0145] Example 1: Synthesis of T-001

[0146] The synthetic route is as follows:

[0147] The experimental process is as follows:

[0148] (1) Synthesis of compound T1-02

[0149] Compound T1-01 (5.00 g, 24.20 mmol) was added to a 250 mL round-bottom reaction flask, followed by the addition of 20 mL of concentrated hydrochloric acid and the reaction was cooled to 0°C. An aqueous solution of NaNO2 (2.50 g, 36.30 mmol, dissolved in 15 mL) was then slowly added dropwise, and the reaction was continued at 0°C for 1 h. SnCl2 (13.50 g, 71.20 mmol dissolved in a small amount of concentrated hydrochloric acid) solution was then slowly added, and the reaction was continued at room temperature for 3 h. After the reaction was completed, the mixture was allowed to stand, filtered, washed with water, washed with EA, and dried in vacuo to obtain the target compound T1-02 (4.60 g, 17.90 mmol).

[0150] (2) Synthesis of compound T1-03

[0151] Compound T1-02 (4.60 g, 17.90 mmol) was added to a 100 mL reaction bottle, followed by 50 mL of EtOH, a catalytic amount of AcOH (0.1 mL), and ethyl pyruvate (2.07 g, 17.90 mmol). The mixture was refluxed at 90°C overnight, and then cooled to precipitate a solid, which was filtered and washed with cold ethanol to obtain the target compound T1-03 (4.01 g, 12.60 mmol).

[0152] (3) Synthesis of Compound T1-04

[0153] In a 100 mL reaction flask, compound T1-03 (4.01 g, 12.60 mmol) was added, and 80 mL of AcOH was added to dissolve it. Then, ZnCl2 (10.30 g, 75.60 mmol) was added. The mixture was refluxed at 130 ° C overnight, and then cooled. Most of the solvent was evaporated under vacuum, water was added, and the mixture was extracted with EA. The mixture was dried over anhydrous sodium sulfate, concentrated, and then recrystallized with EtOH. The target compound T1-04 (2.17 g, 7.23 mmol) was obtained by filtration.

[0154] (4) Synthesis of Compound T1-05

[0155] Compound T1-024 (2.17 g, 7.23 mmol) was added to a 100 mL reaction flask, dissolved in 100 mL of THF, cooled to 0°C, and LiAlH4 (0.64 g, 15.90 mmol) was added in batches under nitrogen protection. The reaction was continued at 0°C for 1 h. After the reaction, 0.5 M NaOH was added to quench the reaction. A small amount of water was added and extracted three times with EA. The aqueous phase was filtered through celite and washed with 10:1 DCM / MeOH. The extracted phase was extracted three times with DCM and combined with the previous EA. The mixture was dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain the target compound T1-05 (1.81 g, 7.01 mmol).

[0156] (5) Synthesis of Compound T1-06

[0157] Compound T1-05 (1.06 g, 4.10 mmol) was added to a 100 mL reaction flask, dissolved in 100 mL DCM, and cooled to 0°C. Under nitrogen protection, KOH (0.57 g, 10.30 mmol) was added in batches. The mixture was reacted at room temperature overnight. After the reaction, it was directly concentrated and purified by silica gel column chromatography to obtain T1-06 (0.80 g, 3.10 mmol).

[0158] (6) Synthesis of Compound T1-07

[0159] To a 100 mL reaction flask, compound T1-06 (0.8 g, 3.10 mmol), Xantphos (0.15 g, 0.30 mmol), Pd2(dba)3·CHCl3 (0.13 g, 0.15 mmol) were added, and the atmosphere was replaced with nitrogen three times. Then, 20 MlDioxane was added to dissolve the mixture, and DIPEA (1.09 g, 9.30 mmol) and benzyl mercaptan (0.69 g, 6.20 mmol) were added. The mixture was bubbled with nitrogen for 0.5 min, and then refluxed at 120 ° C overnight. After the reaction, the mixture was directly concentrated and purified by silica gel column chromatography to obtain the target compound T1-07 (0.92 g, 2.80 mmol).

[0160] (7) Synthesis of Compound T1-08

[0161] Compound T1-07 (0.92 g, 2.80 mmol) was added to a 50 mL reaction bottle, and 20 mL of DMF was added to dissolve it. The mixture was cooled to 0°C, and then NIS (0.95 g, 4.20 mmol) was added. The temperature was naturally raised to room temperature and the reaction was carried out for 2 h. After the reaction, water was added to quench the reaction. The mixture was then extracted with EA, washed with saturated brine three times, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography to obtain the target compound T1-08 (1.09 g, 2.40 mmol).

[0162] (8) Synthesis of Compound T1-09

[0163] In a 100 mL autoclave, T1-08 (1.09 g, 2.40 mmol), Pd(dppf)Cl2 (0.09 g, 0.12 mmol), Cs2CO3 (2.31 g, 7.20 mmol), and DMSO / MeOH (4.30 mL / 26.00 mL) were added, and then the gas was replaced with CO three times, and the CO pressure was maintained at 0.6 MPa. The reaction was carried out at 80°C overnight. After the reaction, it was directly concentrated and purified by silica gel column chromatography to obtain 09 (0.69 g, 7.01 mmol). The aqueous phase was filtered through celite and washed with 10:1 DCM / MeOH. It was extracted with DCM three times and combined with the previous EA, dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography to obtain the target compound T1-09 (0.77 g, 1.97 mmol).

[0164] (9) Synthesis of Compound T1-10

[0165] In a 35 mL sealed reaction tube, T1-09 (0.77 g, 1.97 mmol) was added, followed by 8 mL of anhydrous EtOH and 6 mL of 50% hydrazine hydrate. The mixture was reacted at 120°C for 24 h. After the reaction, the temperature was cooled to room temperature and concentrated under reduced pressure. Water was then added and the mixture was extracted with DCM four times. The mixture was then dried over anhydrous sodium sulfate and concentrated. The target product T1-10 (0.41 g, 1.06 mmol) was obtained by separation and purification by silica gel column chromatography. T1-09 (0.28 g, 0.72 mmol) was recovered.

[0166] (10) Synthesis of Compound T1-11

[0167] In a 50 mL sealed reaction tube, T1-10 (0.41 g, 1.06 mmol) was added, and then 15 mL of DCM was added to dissolve it. Then, TEA (1.01 g, 10.00 mmol) was added. The reaction system was cooled to 0°C, and then difluoroacetic anhydride (0.37 g, 2.12 mmol) was slowly added dropwise. The temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. After the reaction was completed, it was directly concentrated and separated and purified by silica gel column chromatography to obtain T1-11 (0.18 g, 0.41 mmol).

[0168] (11) Synthesis of Compound T1-12

[0169] T1-11 (0.100 g, 0.22 mmol), piperazine (0.056 g, 0.33 mmol), Pd-PEPPSI-IHeptCl (0.019 g, 0.02 mmol), and Cs2CO3 (0.215 g, 0.66 mmol) were added to a microwave reaction tube, and then replaced with nitrogen three times. The mixture was microwaved at 100°C for 15 min under nitrogen protection. After the reaction, the mixture was directly concentrated and purified by silica gel column chromatography to obtain the target product T1-12 (0.089 g, 0.15 mmol).

[0170] (12) Synthesis of compound T-001

[0171] In a 25 mL reaction flask, T1-12 (0.089 g, 0.15 mmol) and 3 mL of acetonitrile were added, followed by 8 μL of AcOH and 16 μL of H2O. The mixture was cooled to 0°C, and then DCDMH (0.046 g, 0.23 mmol) was added and the reaction was maintained at 0°C for 1 h. After the reaction was completed, the mixture was directly concentrated and dried in vacuo to obtain the intermediate xanthoxylated chloride.

[0172] In a 25 mL reaction flask, ammonium salt (0.036 g, 0.30 mmol) was added, and 3 mL of pyridine was added to dissolve it, and the mixture was cooled to 0°C. Then, the yellow acyl chloride obtained above was dissolved in a small amount of DCM and slowly added dropwise to the pyridine reaction solution. The reaction was allowed to proceed at room temperature overnight. After the reaction, water was added to quench the reaction, and most of the pyridine was evaporated. The mixture was then extracted with DCM three times, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the target compound T-001 (0.066 g, 0.11 mmol) as a light grayish yellow powder. 1HNMR (400MHz, CDCl3) δ8.61 (s, 1H), 7.66 (s, 1H), 6.95 (t, J = 51.8Hz, 1H), 4.81 (s, 2H), 4 .18(t,J=4.5Hz,2H),4.11–4.01(m,1H),3.50–3.39(m,1H),3.29–3.17(m,2H),3.06–2.9 2(m,2H),2.68(dd,J=13.5,6.8Hz,1H),2.06–1.97(m,1H),1.79–1.71(m,1H),1.69–1.6 4(m,2H),1.52–1.34(m,4H),1.23–1.11(m,4H),1.00–0.84(m,4H).LC-MS[M+1]: 604.60.

[0173] Referring to the synthesis method of Example T-001, the following compounds were synthesized:

[0174] Example 2: Synthesis of T-002

[0175] The synthetic route is as follows:

[0176] The experimental process is as follows:

[0177] (1) Synthesis of compound T2-02

[0178] Compound T2-01 (5.00 g, 19.68 mmol) was added to a 500 mL round-bottom reaction flask, followed by addition of 250 ml of NaNO2 (13.57 g, 196.80 mmol) aqueous solution. The mixture was then cooled to 0°C and 6 M concentrated hydrochloric acid was slowly added dropwise. After the addition was complete, the mixture was reacted at room temperature for 24 h. After the reaction, the mixture was extracted four times with EA containing 10% THF, dried over anhydrous sodium sulfate, and then recrystallized with EA. The target compound T2-02 (3.01 g, 10.6 mmol) was obtained by filtration.

[0179] (2) Synthesis of Compound T2-03

[0180] Compound T2-02 (0.80 g, 2.83 mmol) was added to a 25 mL round-bottom reaction flask, 10 mL of Dioxane was added to dissolve, and then 0.10 mL of AcOH and amine (0.46 g, 4.23 mmol) were added. The mixture was reacted at 60 ° C for 2 h, then cooled to room temperature, NaBH (OAc) 3 (1.80 g, 8.49 mmol) was added, and the reaction was carried out at room temperature for 4 h. After the reaction, the mixture was concentrated and separated and purified by silica gel column chromatography to obtain the target compound T2-03 (0.55 g, 1.47 mmol).

[0181] (3) Synthesis of Compound T2-04

[0182] Compound T2-03 (0.55 g, 1.47 mmol) was added to a 25 mL round-bottom reaction flask, replaced with nitrogen three times, and 10 ml of methanol was added to dissolve it. The flask was cooled to 0°C, and then MeONa (0.24 g, 4.41 mmol) was added. The temperature was then raised to room temperature and the reaction was allowed to react overnight. After the reaction, a few drops of water were added to quench the reaction. After concentration, the target compound T2-04 (0.29 g, 0.85 mmol) was obtained by separation and purification by silica gel column chromatography.

[0183] (4) Synthesis of Compound T2-05

[0184] Compound T2-04 (0.290 g, 0.85 mmol), Pd(dba)Cl2·CHCl3 (0.037 g, 0.04 mmol), and Xantphos (0.046 g, 0.08 mmol) were added to a 25 mL round-bottom reaction flask, and the atmosphere was replaced with nitrogen three times. 8 ml of dioxane was added to dissolve the mixture, followed by the addition of DIPEA (0.328 g, 2.55 mmol) and BnSH (0.211 g, 1.70 mmol). The mixture was reacted at 100°C under nitrogen for 3 h. After the reaction, the mixture was cooled to room temperature, concentrated in vacuo, and separated and purified by silica gel column chromatography to obtain the target compound T2-05 (0.280 g, 0.72 mmol).

[0185] (5) Synthesis of Compound T2-06

[0186] Compound T2-05 (0.280 g, 0.72 mmol) was added to a 25 mL round-bottom reaction flask, replaced with nitrogen three times, and dissolved in 8 ml of THF. The mixture was cooled to 0°C under nitrogen protection, and then LiAlH4 (0.060 g, 1.58 mmol) was added to react for 2 h. After the reaction, the mixture was cooled to room temperature and quenched with a small amount of water. The reaction was concentrated in vacuo and separated and purified by silica gel column chromatography to obtain the target compound T2-06 (0.260 g, 0.70 mmol).

[0187] (6) Synthesis of Compound T2-07

[0188] Compound T2-06 (0.260 g, 0.70 mmol) and Cs2CO3 (0.684 g, 2.10 mmol) were added to a 25 mL round-bottom reaction flask, replaced with nitrogen three times, and 6 ml of DMF was added to dissolve. The mixture was cooled to 60 ° C under nitrogen protection and reacted for 1 h. After the reaction, it was cooled to room temperature and water was added to quench the reaction. Then, EA was extracted 3-4 times, and the organic phases were combined, washed with Brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by silica gel column chromatography to obtain the target compound T2-07 (0.087 g, 0.17 mmol).

[0189] (7) Synthesis of compound T-002

[0190] Compound T2-07 (0.056 g, 0.11 mmol) was added to a 25 mL reaction flask, 3 mL of acetonitrile was added to dissolve, and then AcOH / H2O (8 μL / 16 μL) was added. The mixture was cooled to 0°C, and then DCDMH (0.034 g, 0.17 mmol) was added and the reaction was maintained at 0°C for 1 h. After the reaction, it was directly concentrated and dried in vacuo to obtain the intermediate xanthoxylated chloride.

[0191] In a 25 mL reaction flask, ammonium salt (0.027 g, 0.22 mmol) was added, and 3 mL of pyridine was added to dissolve it, and the mixture was cooled to 0°C. Then, the yellow acyl chloride obtained above was dissolved in a small amount of DCM and slowly added dropwise to the pyridine reaction solution. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water was added to quench the reaction, and most of the pyridine was evaporated. The mixture was then extracted with DCM three times, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the target compound T-002 (0.050 g, 0.09 mmol) as an off-white powder. 1 HNMR(400MHz, CDCl3)δ8.86(s,1H),8.57(d,J=5.7Hz,2H),7.79(d,J=7.8Hz,1H),7.70(s,1H),7.43–7.33(m, 2H), 7.00 (t, J = 53.56Hz, 1H), 4.24 (s, 2H), 4.03 (s, 2H), 3.79 (s, 2H), 1.46–1.41 (m, 4H). LC-MS [M+1]: 529.20.

[0192] Test Example 3 Enzyme activity test

[0193] The following biological activity tests were conducted on some of the compounds in the above examples and comparative examples.

[0194] The experimental process of biological activity test is as follows:

[0195] 1. Kinase activity test:

[0196] PARG kinase IC 50 Value detection.

[0197] (1) Reagent information

[0198] (2) Equipment information

[0199] (3) Research design

[0200] (1) Compound preparation:

[0201] ①All synthesized compounds were stored at -20℃.

[0202] ② Prepare the test compound into 0.5 mM DMSO solution.

[0203] (2) Enzyme assay:

[0204] ① Dilute the test compound according to the reference concentration, and use this dilution as the initial compound solution to perform three-fold dilution to obtain 10 compound solutions of different concentrations.

[0205] ② Transfer 100 μL of test compound or DMSO to the appropriate wells of a 384-well microtiter plate, with each column containing two replicates. Centrifuge the plate at 1000 rpm for 1 minute.

[0206] ③ Add 2.5 μL of PARG enzyme solution to each well and incubate at room temperature for 10 minutes.

[0207] ④ Add 2.5 μL of PARP1 enzyme solution to each well.

[0208] ⑤ Add 5 μL of His-Tb and SA-XL665 solution to each well to start the reaction, and centrifuge the plate at 1000 rpm for 1 minute.

[0209] ⑥ Incubate the sample at room temperature for 50 minutes.

[0210] ⑦ Use BMG to read the HTRF signal 665 / 615 ratio and analyze the data of each test well.

[0211] (3) Data analysis:

[0212] Fitting compound IC according to nonlinear regression equation 50 :

[0213] %inh=100%-(cmpds-Low control) / (High control-Low control)*100%

[0214] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-)*Hillslope))

[0215] X:Log of cpds concentration

[0216] Y:Ratio 665 / 615nm

[0217] Top and Bottom:Plateaus in samne units as Y

[0218] LogIC50:same log units as X

[0219] Hillslop:Slop factor or Hill slope

[0220] Experiments have shown that the compounds of the present invention have excellent PARG kinase inhibitory activity.

[0221] The results of PARG biological activity (enzyme inhibition experiment) are shown in Table 1, where A≤0.2μM; 0.2μM <B<2μM;2μM<C<20μM。

[0222] Table 1

[0223] Example 4: Cell anti-proliferation experiment

[0224] The PARG inhibitor compounds of the present invention were tested for their inhibitory effects on the proliferation of human ovarian cancer cells KURAMOCHI.

[0225] Experimental materials and equipment: KURAMOCHI was purchased from Nanjing Kebai Biotechnology Co., Ltd. RPMI-1640 medium (Bio-Channel), DMSO (dimethyl sulfoxide), CCK8 (WST-8) cell analysis kit (Biyuntian), 0.25% EDTA-Tripsin (trypsin digestion solution), 1x PBS (phosphate buffered saline, pH 7.2), 96-well plates (Corning), fetal bovine serum (FBS), 10,000 U / mL penicillin-G / streptomycin, a high-speed refrigerated centrifuge (EPPENDORF 5810R), and an enzyme-linked immunosorbent assay (Tecan Spark).

[0226] Experimental preparation:

[0227] 1. Cell plating

[0228] A) Tumor cells were cultured in RPMI-1640 (containing 10% FBS and 100 U / mL penicillin-G / streptomycin) at 37°C, 5% CO2 and saturated humidity to 80-90% confluence.

[0229] B) Remove the culture medium from the 10 cm culture dish;

[0230] C) Rinse the cells once with 10 ml of 1x PBS;

[0231] D) Add 4 ml of 0.25% EDTA-Tripsin and place in a 37°C, 5% CO2 incubator for trypsinization for 5 minutes. Transfer to a 15 ml centrifuge tube and centrifuge at 200 g for 5 minutes. Discard the supernatant to obtain the cell pellet.

[0232] E) Resuspend in 4 ml of DMEM medium, count and adjust to 10,000 cells / ml.

[0233] F) The cell suspension was added to a 96-well plate at a volume of 100 μL per well and cultured overnight in a 37° C., 5% CO 2 incubator.

[0234] 2. Compound treatment

[0235] Compound dilution

[0236] A) Prepare test compound serial dilutions: Prepare a 1 mM stock solution of the test compound. Dissolve 1.5 μl of the stock solution in 1.5 ml of DMSO-free culture medium. Perform a 3-fold serial dilution in 0.1% DMSO culture medium for a total of 9 concentrations. The compound concentrations after dilution are as follows:

[0237] 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM.

[0238] B) After thorough mixing, 100 μL of the culture compound solution was taken to replace the culture medium in the cell culture plate, with 4 replicates per concentration;

[0239] C) The cells were transferred to an incubator and incubated for 3 days.

[0240] 3. CCK8 (WST-8) cell analysis

[0241] A) Remove the cell culture plate and add 10 μl of CCK-8 (WST-8) solution to each well in a biosafety cabinet.

[0242] B) Return the cell culture plate to the incubator and continue incubating for 3 hours;

[0243] C) The absorbance value was measured on a TECAN enzyme-linked immunosorbent assay (ELISA) at a wavelength of 450 nm.

[0244] 4. Data Analysis

[0245] The cell viability (% Cell Viability) was calculated using the following formula:

[0246] Cell viability (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)] × 100

[0247] A(drug added): absorbance of the wells containing cells, CCK8 solution, and drug solution

[0248] A (blank): absorbance of the well with culture medium and CCK8 solution but no cells

[0249] A(0 drug addition): absorbance of the well containing cells, CCK8 solution but no drug solution

[0250] Cell viability: Cell proliferation activity or cytotoxicity activity was obtained by curve fitting using GraphPad Prism 8 software. 50 The values ​​are shown in Table 2, where A≤0.2μM; 0.2μM <B<2μM;2μM<C<20μM

[0251] Table 2

[0252] It can be seen from the results in Table 1 that the compound of the present invention has a very good inhibitory effect on human ovarian cancer cells.

[0253] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, wherein: The compound has a structure shown in Formula I or Formula II: Among them, X 1 Each independently selected from the following group: C, N; X 2 Each independently selected from the following group: C, N; X 6 Each independently selected from the following group: CR 6 , N; Ring A is independently a partially saturated 5-membered heterocyclyl or 5-membered heteroaryl; Ring C is independently a substituted or unsubstituted saturated or partially unsaturated 5-6 membered heterocyclic group or a substituted or unsubstituted 5-6 membered heteroaryl group; wherein the substitution on ring C means that one or more hydrogen atoms on the heterocyclic group or the heteroaryl ring are replaced by a group selected from the group consisting of H, halogen, cyano, hydroxyl, amino, oxo (=O), C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl (such as cyclopropyl), C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6 (like ),-COC 3-6 Cycloalkyl, C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the following group: halogen, cyano, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1- 6 alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(C 1-6 Alkyl)2; R 1 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 Haloalkyl; R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-10 Alkyl and C 1-10 A haloalkyl group, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl, 3-6 membered saturated heterocyclic group; R 4 are independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3 Alkyl-substituted or unsubstituted 5-8-membered heteroaryl; p is 0, 1, or 2; R 4a and R 4b each the same or different; R 4a , R 4b and R 4c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic group and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; Or, R 4a and R 4b Each of them together with the nitrogen atom to which they are commonly attached forms a 5-8 membered heterocyclic group, and the formed heterocyclic group is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; R 6 Hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 Haloalkyl; Ar is independently selected from a substituted or unsubstituted 5-10 membered heteroaromatic ring, or a substituted or unsubstituted 5-10 membered heterocyclic ring, wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring or heterocyclic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-6 Ester group, C 1-6 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy and C 1-6 Halogenated alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: Ring A is selected from the following group:

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: In Formula I, Ring C is selected from the following group: In formula II, ring C is selected from the following group:

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: R 4 Select from the following group:

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: R 1 Each independently selected from the group consisting of cyano, C 1-6 Alkyl, C 1-6 haloalkyl; and R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-6 Cycloalkyl, 3-6 membered saturated heterocyclic group.

6. A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, wherein: The compound has a structure shown in Formula Ia or Formula II-a: in, X 1 Each independently selected from the following group: C, N; X 2 Each independently selected from the following group: C, N; X 3 Each independently selected from the following group: CR 5a R 5b NR 5c , O, S, SO, SO2; X 4 Each independently selected from the following group: CR 5a R 5b NR 5c , O, S, SO, SO2; X 5 Each independently selected from the following group: CR 5a R 5b NR 5c , O, S, SO, SO2; X 6 Each independently selected from the following group: CR 6 , N; R 1 Each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 Haloalkyl; R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, C 1-10 Alkyl and C 1-10 A haloalkyl group, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl, 3-6 membered saturated heterocyclic group; R 4 are independently selected from the following groups: hydrogen atom, deuterium, halogen, cyano, hydroxyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , C 3-10 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -NH2, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group, C 6-10 Aryl and C 1-3 Alkyl-substituted or unsubstituted 5-8-membered heteroaryl; p is 0, 1, or 2; R 4a and R 4b each the same or different; R 4a , R 4b and R 4c are independently selected from the group consisting of hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 3-8 membered heterocyclic group and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclic group and heteroaryl are each independently substituted by a substituent selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; Or, R 4a and R 4b Each of them together with the nitrogen atom to which they are commonly attached forms a 5-8 membered heterocyclic group, and the formed heterocyclic group is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, oxo (=O), -C (=O) R 4c 、-C(=O)OR 4c , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; R 5a and R 5b Each independently selected from the group consisting of H, halogen, cyano, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 3-6 Cycloalkyl (such as cyclopropyl), hydroxyl, amino, C 1-6 Alkoxy (such as methoxy), -COC 1-6 Alkoxy (such as ),-COC 1-6 (like ), C 1-6 Haloalkyl (such as CF3), C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, 5-8 membered heterocyclic group, 5-8 membered heteroaryl, or R 5a and R 5b co-form = O; R 5c Each independently selected from the following group: H, C 1-6 Alkyl (such as methyl, ethyl, isopropyl), C 2-6 Alkenyl, C 2-6 Alkynyl, -COC 1-6 Alkoxy (such as ),-COC 1-6 Alkyl or haloalkyl (such as ),-COC 3-6 Cycloalkyl, C 1- 6 haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -CONH-C 1-6 Alkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3- 6-cycloalkyl, 5-10-membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl are each independently substituted by a substituent selected from the following group: halogen, cyano, -C(=O)C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, -N(C 1-6 Alkyl)2; R 6 Each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH2, -CH2OH, -CH2O-C 1-6 Alkyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Halogenated alkoxy, C 1-10 Haloalkyl; Ar is independently selected from a substituted or unsubstituted 5-10 membered heteroaromatic ring, or a substituted or unsubstituted 5-10 membered heterocyclic ring, wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring or heterocyclic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-6 Ester group, C 1-6 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1- 6 alkoxy and C 1-6 Halogenated alkoxy.

7. The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: Ring A is selected from the following group:

8. The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: In Formula Ia, Ring C is selected from the following group: In formula II-a, ring C is selected from the following group:

9. The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: Ar is selected from substituted or unsubstituted 5-6 membered heteroaromatic rings; wherein the substitution means that one or more hydrogen atoms on the heteroaromatic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C 1-4 Ester group, C 1-4 Aldehyde, -NH2, -CO-N(C 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy and C 1-4 Preferably, Ar is selected from the group consisting of:

10. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: R 4 Select from the following group:

11. The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: R 5a , R 5b , R 5c One or more of are independently selected from the following group:

12. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, characterized in that: The compound is selected from the following group:

13. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof.

14. Use of the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, or the pharmaceutical composition according to claim 13, characterized in that: For use in preparing a medicament or preparation for use selected from the group consisting of: 1) Used to regulate PARG enzyme activity; 2) a mutation type related to the regulation of PARG activity in DNA repair, wherein the mutation type is selected from the group consisting of MUTYH, BRCA2, CHEK2, BRCA1, ATM, and RAD51C; 3) for preventing and / or treating diseases related to PARG activity, such as cancer; 4) For the prevention and / or treatment of proliferative diseases, such as cancer.

15. The use according to claim 14, characterized in that The PARG activity-related disease is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung cancer, and prostate cancer.

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