WO2025108384A1 - Benzo five-membered heterocyclic derivative and use thereof - Google Patents

Abstract

The present invention relates to a benzo five-membered heterocyclic derivative and a use thereof. Specifically, disclosed is a compound having a structure as shown in formula (I) or formula (II), the definitions of the groups and substituents being as set forth in the description. Also disclosed is a use of the compound in treating or preventing diseases related to PARG activity, in particular proliferative diseases (such as cancer).

Description

Benzo five-membered heterocyclic derivatives and their applications Technical Field

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

Background Art

Cancer, one of the leading causes of death in the world today, is caused by uncontrolled and abnormal cell proliferation. This rapid proliferation is often accompanied by DNA damage in tumor cells and a greatly increased mutation rate. Therefore, tumor cell proliferation is heavily dependent on DNA damage repair mechanisms. Single-strand breaks (SSBs) are the most common type of lesions in cells. PARG works together with PARP (poly ADP-ribose polymerase) and some other proteins to repair single-strand breaks (SSBR) and base excision repair (BER). The first step in the single-strand DNA repair process is for PARP to bind to the break, and PARP itself quickly synthesizes poly ADP ribose (PAR). This molecular structure acts as a signal to recruit other DNA repair proteins to repair the break. The signals initiated by these PAR chains are short-lived because they are rapidly degraded by PARG. When PARP binds to PAR, its catalytic activity is reduced, so the intervention of PARG will prompt PARP to return to the catalytically active form. DNA damage-dependent PARylation/dePARylation is a fast and dynamic process that needs to be well regulated because an imbalance between these two processes can lead to DNA damage. Full-length PARG is primarily nuclear; smaller isoforms are primarily found in the cytoplasm. Although PARG is primarily known for its direct role in DNA repair, it affects 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.

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, so it is necessary to find alternative inhibitors targeting DNA damage repair mechanisms. 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, making tumor cells sensitive to PARG inhibition.

In summary, there is an urgent need in this field to develop a new type of PARG inhibitor.

Summary of the invention

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

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:

Wherein, X ¹ is independently selected from the following group: C, N;

^X2 is independently selected from the following group: C, N;

X ⁶ is 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 refers to 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, hydroxy, 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 (such as ), -COC _3-6 cycloalkyl, C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, 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 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-6 haloalkoxy, -N(C _1-6 alkyl) ₂ ;

R ¹ is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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 haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached together form a C _3-10 cycloalkyl, a 3-6 membered saturated heterocyclic group;

^R4 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, _C1-10 alkyl, _C1-10 alkoxy, _C1-10 haloalkyl, _C1-10 haloalkoxy, _C1-10 hydroxyalkyl, ^-NR4aR4b , -C(O) ^R4c , -C(O) ^OR4c , -C(O) ^NR4aR4b , _-S(O)pR4c ^, _C3-10 ^cycloalkyl , 5-10 membered ^heterocyclyl , _C6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, C1-6 _1-6 haloalkoxy, -NH ₂ , -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , hydroxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclyl, 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 are each the same or different;

R ^4a , R ^4b and R ^4c are each 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 heterocyclyl and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl 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 haloalkyl, C _1-6 haloalkoxy, NH ₂ , -N(C _1-3 alkyl) ₂ , C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-8 membered heterocyclyl, C _6-10 membered aryl and 5-7 membered heteroaryl;

Alternatively, R ^4a and R ^4b each together with the nitrogen atom to which they are commonly attached form 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, hydroxy, 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, NH ₂ , —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 is hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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, C _1-6 aldehyde, -NH ₂ , -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 haloalkoxy.

In another preferred embodiment, the substitution on ring C refers to that one or more hydrogens on the heterocyclic group or the heteroaromatic ring are replaced by a group selected from the group consisting of H, halogen, cyano, hydroxy, 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 (such as ), -COC _3-6 cycloalkyl, C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, 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 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, preferably selected from halogen, cyano, hydroxyl, amino, C _1-6 alkyl and C _1-6 haloalkyl, more preferably selected from methyl, ethyl, isopropyl.

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

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:

in,

^X1 is independently selected from the following group: C, N;

^X2 is independently selected from the following group: C, N;

X ³ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ;

X ⁴ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ;

X ⁵ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ;

X ⁶ is independently selected from the following group: CR ⁶ , N; R ¹ is independently selected from the following group: hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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 haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached together form a C _3-10 cycloalkyl, a 3-6 membered saturated heterocyclic group;

^R4 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, _C1-10 alkyl, _C1-10 alkoxy, _C1-10 haloalkyl, _C1-10 haloalkoxy, _C1-10 hydroxyalkyl, ^-NR4aR4b , -C(O) ^R4c , -C(O) ^OR4c , -C(O) ^NR4aR4b , _-S(O)pR4c ^, _C3-10 ^cycloalkyl , 5-10 membered ^heterocyclyl , _C6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, C1-6 _1-6 haloalkoxy, -NH ₂ , -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , hydroxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclyl, 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 are each the same or different;

R ^4a , R ^4b and R ^4c are each 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 heterocyclyl and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl 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 haloalkyl, C _1-6 haloalkoxy, NH ₂ , -N(C _1-3 alkyl) ₂ , C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-8 membered heterocyclyl, C _6-10 membered aryl and 5-7 membered heteroaryl;

Alternatively, R ^4a and R ^4b each together with the nitrogen atom to which they are commonly attached form 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, hydroxy, 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, NH ₂ , —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 are each independently selected from the group consisting of H, halogen, cyano, C _1-6 alkyl (e.g., methyl, ethyl, isopropyl), C _3-6 cycloalkyl (e.g., cyclopropyl), hydroxy, amino, C _1-6 alkoxy (e.g., methoxy), -COC _1-6 alkoxy (e.g., ), -COC _1-6 (such as ), C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl, or R ^5a and R ^5b together form ＝O;

R ^5c is 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 haloalkoxy, 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 heterocyclyl, C 6-10 aryl ,} 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-6 haloalkoxy, -N(C _1-6 alkyl) ₂ ;

R ⁶ is each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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, C _1-6 aldehyde, -NH ₂ , -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 haloalkoxy.

In another preferred embodiment, X ² is N, and one and only one of X ³ , X ⁴ and X ⁵ is selected from the following group: NR ^5c , O, S, SO, SO ₂ .

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

In another preferred embodiment, R ¹ is independently selected from the following group: hydrogen, cyano, nitro, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _{1-10 haloalkoxy, C 1-10 haloalkyl} .

In another preferred embodiment, R ² and R ³ are 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 atom to which they are connected form a C _3-10 cycloalkyl, a C _3-6 saturated heterocyclic group.

In another preferred embodiment, R ⁴ is each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C _1-10 alkyl group, a C _1-10 alkoxy group, a C _1-10 haloalkyl group, a C _1-10 haloalkoxy group, a C _1-10 hydroxyalkyl group, -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , a C _3-10 cycloalkyl group, a 5-10 membered heterocyclic group, a C _6-10 aryl group and a 5-10 membered heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl group are each independently optionally substituted by one or more substituents selected from the group consisting of a halogen, an oxo group (＝O), a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a C _-1-6 haloalkoxy, _-NH2 , -NR4aR4b, -C(O) ^R4c , -C(O) ^OR4c , -C(O) ^NR4aR4b , -S(O ^{) pR4c} , ^hydroxy , _C1-6 hydroxyalkyl, _{C3-6 cycloalkyl} , 5-6 membered _heterocyclyl , ^C6-10 aryl and _C1-3 alkyl substituted or unsubstituted 5-8 membered heteroaryl.

In another preferred embodiment, R ⁶ is independently selected from the group consisting of hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-6 haloalkyl, preferably hydrogen.

In another preferred embodiment, R ¹ is independently selected from the following group: hydrogen, cyano, nitro, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkoxy, C _{1-6 haloalkoxy, C 1-6 haloalkyl} .

In another preferred embodiment, R ² and R ³ are each independently selected from the following group: C _1-6 alkyl, or R ² and R ³ together with the carbon atom to which they are commonly connected form a C _3-8 cycloalkyl or a 3-6 membered saturated heterocyclic group.

In another preferred embodiment, R ¹ is independently selected from the following group: cyano, C _1-6 alkyl, C _1-6 haloalkyl; and R ² and R ³ together with the carbon atom to which they are connected form a C _3-6 cycloalkyl, a 3-6 membered saturated heterocyclic group.

In another preferred embodiment, R ⁴ is each independently selected from the following group: C _3-6 cycloalkyl, 5-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the following group: halogen, oxo (＝O), C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, -NH ₂ , -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 heterocyclyl, C _6-10 aryl and C _1-3 alkyl substituted or unsubstituted 5-8 membered heteroaryl.

In another preferred embodiment, X ³ , X ⁴ , and X ⁵ are each independently selected from the following group: CR ^5a R ^5b , NR ^5c ;

R ^5a and R ^5b are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C _1-3 alkyl or C _1-3 haloalkyl;

R ^5c is 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 haloalkoxy, C _1-6 alkylhydroxy, C _3-6 cycloalkyl, 5-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-3 alkoxy, C _1-3 haloalkoxy, -N(C _1-3 alkyl) ₂ .

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, C _1-6 aldehyde, -NH ₂ , amide, C _1-6 alkyl, C _1-6 haloalkyl (such as difluoromethyl or trifluoromethyl), C _1-6 hydroxyalkyl and C _1-6 alkoxy.

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

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

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

R ^5a and R ^5b are each independently selected from the group consisting of H, halogen, cyano, C _1-6 alkyl (e.g., methyl, ethyl, isopropyl), C _3-6 cycloalkyl (e.g., cyclopropyl), hydroxy, amino, C _1-6 alkoxy (e.g., methoxy), -COC _1-6 alkoxy (e.g., ), -COC _1-6 (such as ), C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl, or R ^5a and R ^5b together form ＝O;

R ^5c is 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 haloalkoxy, 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 heterocyclyl, C 6-10 aryl ,} 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-6 haloalkoxy, -N(C _1-6 alkyl) ₂ .

In another preferred embodiment, R ^5a and R ^5b are each independently selected from the following group: hydrogen, halogen, cyano, hydroxyl, C _1-3 alkyl or C _1-3 haloalkyl.

In another preferred embodiment, R ^5c is each independently selected from the following group: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, 3-9 membered heterocyclyl, C _5-10 aryl and 5-10 membered heteroaryl, -CONH ₂ , -CH ₂ CN, -CONH-C _1-3 alkyl, -COC _3-6 cycloalkyl, -CH ₂ OH, -CH ₂ CH ₂ OC _1-6 alkyl, -CH ₂ CH ₂ NH-C _1-3 alkyl, -CH ₂ CH ₂ N(C _1-3 alkyl) ₂ .

In another preferred embodiment, Ar is selected from a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means that one or more hydrogens on the heteroaromatic ring are replaced by a group selected from the following group: halogen, hydroxyl, C _1-4 ester group, C _1-4 aldehyde group, -NH ₂ , -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 haloalkoxy.

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

In another preferred embodiment, R ⁴ is independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a C _1-6 hydroxyalkyl group, a C _3-8 cycloalkyl group, and a 5-9 membered heterocyclic group, wherein the alkyl group, the alkoxy group, the cycloalkyl group and the heterocyclic group are independently substituted by a substituent selected from the group consisting of a halogen, an oxo group (＝O), a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkyl group, a C _1-6 haloalkoxy group, -NH ₂ , -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , a hydroxyl group, a C _1-6 hydroxyalkyl group, a C _3-6 cycloalkyl group, a 5-6 membered heterocyclic group, a phenyl group and a C _1-3 alkyl-substituted or unsubstituted 5-8 membered heteroaryl;

wherein R ^4a and 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 haloalkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, phenyl and 5-8 membered heterocyclic group, wherein the alkyl, cycloalkyl, phenyl and heterocyclic group are independently substituted by a substituent selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy and -N(C _1-3 alkyl) ₂ ;

Alternatively, R ^4a and R ^4b each together with the nitrogen atom to which they are commonly attached form 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, oxo (=O), C _1-6 alkyl, C _1-6 alkoxy, C _{1-6 haloalkyl} , C _1-6 haloalkoxy, NH ₂ , -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;

R ^4c is each independently selected from the following group: hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, phenyl, 5-8 membered heterocyclyl and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl and heterocyclyl are each independently optionally substituted by one or more substituents each independently selected from the following group: halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy.

In another preferred embodiment, ^R4 is selected from the following group:

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

In another preferred embodiment, one or more of R ^5a , R ^5b , and R ^5c are independently selected from the following group:

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

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 specific compounds, preferably independently selected from the corresponding groups in the embodiments of the present invention.

In another preferred embodiment, in Formula II, R ¹ , R ² , R ³ , X ¹ , X ⁶ , Ar, Ring A and Ring C are independently selected from the corresponding groups in the above specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

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 specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

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 specific compounds, preferably independently selected from the corresponding groups in the examples of the present invention.

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.

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 drug or preparation, wherein the drug or preparation is used for a 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.

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.

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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

DETAILED DESCRIPTION

After extensive and in-depth research, the inventors have provided for the first time a PARG inhibitor that has an inhibitory effect on cells that are resistant to PARP inhibitors. The compounds of the present invention have excellent PARG inhibitory activity and can well inhibit the proliferation of Kuramochi cells with BRAC2 mutations. Based on this, the inventors have completed the present invention.

the term

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

As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- includes _-OCH2- .

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.

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

In the present invention, the term "C2-6 alkenyl" refers to a straight 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.

In the present invention, the term "C2-6 alkynyl" refers to a straight 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.

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

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.

In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O, S, such as a 3-10 membered heterocyclyl, a 4-9 membered heterocyclyl or a 5-6 membered heterocyclyl. The heterocyclyl may have 1 or 2 double bonds. The S atoms on the ring may be optionally oxoed to form SO or SO ₂ . The heterocycloalkyl may be a monocyclic, bicyclic or polycyclic system. The heterocyclyl includes (but is not limited to) the following groups:

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 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

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: furanyl, 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.

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

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

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 a substituent described above, or a 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 combination of substituents contemplated by the present invention is a combination that is stable or chemically feasible. If not otherwise specified, the substitution refers to one or more H on the substitution group being independently and optionally substituted by a group selected from the following group (but not limited to):

Preferably, it is selected from the group consisting of halogen, cyano, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, _C3-6 cycloalkyl, 5-10 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, C(=O) _C1-6 alkyl, -N( _C1-6 alkyl) ₂ , amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

In the present invention, the term 1-6 means 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.

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, heterocyclic group, as defined above.

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

The term "amido" refers to a group with 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 fragment.

The compounds of the present application can be prepared by a variety of synthesis 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

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

Active ingredients

The present invention provides a compound for inhibiting PARG, which is mainly used for the treatment or prevention of proliferative diseases (such as cancer), and in particular for regulating and treating cancers associated with PARG activity. Since depletion of PARG leads to a decrease in SSBR to the same extent as depletion of PARP1, inhibition of PARG can provide therapeutic advantages for cells resistant to PARP inhibitors. The purpose of the present invention is to provide a cell-permeable inhibitor of PARG.

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

wherein each group is as defined above.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by a 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.

Another preferred salt is a salt of the compound of the present invention and 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.

Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (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 conformational isomers) are all within the scope of the present invention.

The present invention is also intended to include the crystalline forms, hydrates, and solvates of the above compounds.

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

In addition, the compounds of the present invention also include prodrugs of compounds shown in Formula I and Formula II. The term "prodrug" includes a compound that can be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds of Formula I or Formula II, or a salt or solution composed of a compound of Formula I or Formula II. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like of the compound.

The present invention also includes isotopically labeled compounds, which 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 from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, 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 radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. ^14C , are relatively easy to prepare and detect. is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e., ² H, may be preferred in some cases due to their good metabolic stability, which has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

The embodiments of the present invention specifically describe the preparation methods of the compounds of formula I or II, 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, and such combination can be easily carried out by those skilled in the art to which the present invention belongs.

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.

Pharmaceutical compositions and methods of administration

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

The compounds of the present invention have poly (adenosine diphosphate ribose) hydrolase (PARP inhibition) activity and can therefore be used to prevent or treat mediated diseases, especially 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 body 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, etc.

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.

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

"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 compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. 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, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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

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

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 Edition (Easton, Pennsylvania, Mack Publishing Co., 1995), which discloses typical carriers and common methods for preparing pharmaceutical compositions, which can be used as described or modified to prepare medicaments containing the compounds of the present invention. As mentioned above, the compounds of the present invention can also be administered in the form of pharmaceutically acceptable salts, etc.

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 starch 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.

Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

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

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

Compositions for parenteral injection may include 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.

Dosage forms for topical administration of the compounds of the 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.

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

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 compounds of the present invention to prevent and/or treat tumor-related diseases.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 1 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

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

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

(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.

(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.

The present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are generally carried out according to 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.

Example 1: Synthesis of T-001

The synthetic route is as follows:

The experimental process is as follows:

(1) Synthesis of Compound T1-02

Compound T1-01 (5.00 g, 24.20 mmol) was added to a 250 mL round-bottom reaction bottle, and then 20 mL of concentrated hydrochloric acid was added and cooled to 0°C, and then NaNO ₂ (2.50 g, 36.30 mmol, dissolved in 15 mL) aqueous solution was slowly added dropwise, and then the reaction was continued at 0°C for 1 h, and then SnCl ₂ (13.50 g, 71.20 mmol dissolved in a small amount of concentrated hydrochloric acid) solution was slowly added, and the reaction was continued at room temperature for 3 h. After the reaction was completed, it 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).

(2) Synthesis of Compound T1-03

Add compound T1-02 (4.60 g, 17.90 mmol) to a 100 mL reaction bottle, then add 50 mL EtOH, add a catalytic amount of AcOH (0.1 mL), ethyl pyruvate (2.07 g, 17.90 mmol), reflux at 90 ° C overnight, then cool, precipitate solid, filter and wash with cold ethanol to obtain the target compound T1-03 (4.01 g, 12.60 mmol).

(3) Synthesis of Compound T1-04

Compound T1-03 (4.01 g, 12.60 mmol) was added to a 100 mL reaction bottle, and 80 mL of AcOH was added to dissolve it. Then ZnCl ₂ (10.30 g, 75.60 mmol) was added. The mixture was refluxed at 130°C overnight, cooled, and most of the solvent was evaporated in vacuo. Water was added, extracted with EA, 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.

(4) Synthesis of Compound T1-05

Compound T1-024 (2.17 g, 7.23 mmol) was added to a 100 mL reaction bottle, dissolved in 100 mL 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 diatomaceous earth and washed with 10:1 DCM/MeOH. The DCM was extracted three times 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).

(5) Synthesis of Compound T1-06

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

(6) Synthesis of Compound T1-07

In a 100 mL reaction bottle, 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, replaced with nitrogen three times, then 20 MlDioxane was added to dissolve, DIPEA (1.09 g, 9.30 mmol), benzyl mercaptan (0.69 g, 6.20 mmol) were added, nitrogen was blown for 0.5 min, and then refluxed at 120 ° C overnight. After the reaction, it was directly concentrated and purified by silica gel column chromatography to obtain the target compound T1-07 (0.92 g, 2.80 mmol).

(7) Synthesis of Compound T1-08

In a 50mL reaction bottle, add compound T1-07 (0.92 g, 2.80 mmol), add 20 mL DMF to dissolve, cool to 0°C, then add NIS (0.95 g, 4.20 mmol), naturally warm to room temperature and react for 2 hours. After the reaction, add water to quench the reaction, then extract with EA, wash with saturated brine 3 times, dry with anhydrous sodium sulfate, concentrate in vacuo, and separate and purify by silica gel column chromatography to obtain the target compound T1-08 (1.09 g, 2.40 mmol).

(8) Synthesis of Compound T1-09

In a 100 mL autoclave, T1-08 (1.09 g, 2.40 mmol), Pd(dppf)Cl ₂ (0.09 g, 0.12 mmol), Cs ₂ CO ₃ (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, and the reaction was directly concentrated after the reaction. The product was separated and purified by silica gel column chromatography to obtain 09 (0.69 g, 7.01 mmol). The aqueous phase was filtered through diatomaceous earth and washed with 10:1 DCM/MeOH. The product 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).

(9) Synthesis of Compound T1-10

In a 35 mL sealed reaction tube, add T1-09 (0.77 g, 1.97 mmol), then add 8 mL of anhydrous EtOH and 6 mL of 50% hydrazine hydrate, and then react at 120 ° C for 24 hours. After the reaction, cool to room temperature, concentrate under reduced pressure, then add water, extract with DCM 4 times, then dry with anhydrous sodium sulfate, concentrate, and separate and purify by silica gel column chromatography to obtain the target product T1-10 (0.41 g, 1.06 mmol), and recover T1-09 (0.28 g, 0.72 mmol).

(10) Synthesis of Compound T1-11

In a 50 mL sealed reaction tube, add T1-10 (0.41 g, 1.06 mmol), then add 15 mL DCM to dissolve, then add TEA (1.01 g, 10.00 mmol), cool the reaction system to 0 °C, then slowly add difluoroacetic anhydride (0.37 g, 2.12 mmol) dropwise, slowly warm to room temperature and react overnight. After the reaction, directly concentrate and separate and purify by silica gel column chromatography to obtain T1-11 (0.18 g, 0.41 mmol).

(11) Synthesis of Compound T1-12

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 reacted in a microwave at 100 °C for 15 min under nitrogen protection. After the reaction, it was directly concentrated and purified by silica gel column chromatography to obtain the target product T1-12 (0.089 g, 0.15 mmol).

(12) Synthesis of Compound T-001

In a 25 mL reaction bottle, add T1-12 (0.089 g, 0.15 mmol), add 3 mL acetonitrile, then add 8 μL AcOH and 16 μL H ₂ O, cool to 0°C, then add DCDMH (0.046 g, 0.23 mmol) and keep at 0°C for 1 h. After the reaction, directly concentrate and dry in vacuo to obtain the intermediate yellow acyl chloride.

In a 25 mL reaction bottle, ammonium salt (0.036 g, 0.30 mmol) was added, and 3 mL of pyridine was added to dissolve, and the mixture was cooled to 0°C. Then, the yellow acyl chloride obtained above was dissolved in a small amount of DCM, and the mixture was slowly added dropwise to the pyridine reaction solution. The mixture was reacted 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 for 3 times, dried over anhydrous sodium sulfate, concentrated, and separated 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. ¹ HNMR (400 MHz, CDCl ₃ )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),3.06–2.92(m,2H), 2.68(dd,J＝13.5,6.8Hz,1H),2.06–1.97(m,1H),1.79–1.71(m,1H),1.69–1.64(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.

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

Example 2: Synthesis of T-002

The synthetic route is as follows:

The experimental process is as follows:

(1) Synthesis of Compound T2-02

Compound T2-01 (5.00 g, 19.68 mmol) was added to a 500 mL round-bottom reaction bottle, and then 250 ml of NaNO ₂ (13.57 g, 196.80 mmol) aqueous solution was added, and then cooled to 0°C, and 6 M concentrated hydrochloric acid was slowly added dropwise. After the addition was completed, the reaction was carried out at room temperature for 24 h. After the reaction, it was extracted 4 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.

(2) Synthesis of Compound T2-03

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

(3) Synthesis of Compound T2-04

Compound T2-03 (0.55 g, 1.47 mmol) was added to a 25 mL round-bottom reaction bottle, replaced with nitrogen three times, 10 ml of methanol was added to dissolve, cooled to 0°C, and then MeONa (0.24 g, 4.41 mmol) was added, and then the temperature was raised to room temperature 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.

(4) Synthesis of Compound T2-05

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 bottle, replaced with nitrogen three times, 8 ml of dioxane was added to dissolve, and then DIPEA (0.328 g, 2.55 mmol) and BnSH (0.211 g, 1.70 mmol) were added. The reaction was carried out at 100 °C for 3 h under nitrogen protection. After the reaction, it 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).

(5) Synthesis of Compound T2-06

Compound T2-05 (0.280 g, 0.72 mmol) was added to a 25 mL round-bottom reaction bottle, replaced with nitrogen three times, 8 ml of THF was added to dissolve, 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, it was cooled to room temperature, a small amount of water was added to quench the reaction, and the reaction was concentrated in vacuo. The target compound T2-06 (0.260 g, 0.70 mmol) was obtained by separation and purification by silica gel column chromatography.

(6) Synthesis of Compound T2-07

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 bottle, replaced with nitrogen three times, 6 ml of DMF was added to dissolve, cooled to 60 ° C under nitrogen protection, reacted for 1 h, cooled to room temperature after the reaction, water was added to quench the reaction, and then EA was extracted 3-4 times, 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).

(7) Synthesis of Compound T-002

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

In a 25 mL reaction bottle, add ammonium salt (0.027 g, 0.22 mmol), add 3 mL of pyridine to dissolve, and cool to 0 ° C, then dissolve the above yellow acyl chloride in a small amount of DCM, slowly add it dropwise to the pyridine reaction solution, react at room temperature overnight, add water to quench the reaction after the reaction, evaporate most of the pyridine, and then extract with DCM for 3 times, dry over anhydrous sodium sulfate, concentrate, and separate and purify by silica gel column chromatography to obtain the target compound T-002 (0.050 g, 0.09 mmol) as 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.

Test Example 3 Enzyme activity test

The following is a biological activity test experiment on some compounds in the above examples and comparative examples.

The biological activity test experimental process is as follows:

1. Kinase activity test:

The IC ₅₀ values of the tested compounds were determined for PARG kinase.

(I) Reagent information

(II) Equipment information

3. Research design

(1) Compound preparation:

①All synthesized compounds were stored at -20℃.

② Prepare the test compound into 0.5 mM DMSO solution.

(2) Enzyme assay:

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

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

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

④ Add 2.5 μL of PARP1 enzyme solution into each well.

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.

⑥ Incubate the sample at room temperature for 50 minutes.

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

(3) Data analysis:

The IC ₅₀ of the compound was fitted according to the nonlinear regression equation:

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

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

X:Log of cpds concentration

Y:Ratio 665/615nm

Top and Bottom:Plateaus in samne units as Y

LogIC50:same log units as X

Hillslop:Slop factor or Hill slope

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

The results of the PARG biological activity (enzyme inhibition experiment) are shown in Table 1, wherein A≤0.2 μM; 0.2 μM<B<2 μM; 2 μM<C<20 μM.

Table 1

Example 4: Cell anti-proliferation experiment

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

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), 1xPBS (phosphate buffer, pH 7.2), 96-well plate (Corning), fetal bovine serum (FBS), 10,000U/mL penicillin-G/streptomycin, high-speed refrigerated centrifuge (EPPENDORF 5810R), enzyme-linked immunosorbent assay (Tecan Spark).

Experimental preparation:

1. Cell plating

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.

B) Remove the culture medium from the 10 cm culture dish;

C) Rinse the cells once with 10 ml 1xPBS;

D) Add 4 ml 0.25% EDTA-Tripsin and place in a 37°C, 5% CO2 incubator for trypsin digestion for 5 minutes, transfer to a 15 ml centrifuge tube, centrifuge at 200 g for 5 minutes, and discard the supernatant to obtain the cell pellet;

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

F) Add the cell suspension to each well of a 96-well plate at a volume of 100 μL and culture overnight in a 37°C, 5% CO2 incubator.

2. Compound treatment

Compound dilution

A) Prepare gradient dilution solutions of the test compound: Prepare the test compound into a 1mM stock solution. Then dissolve 1.5μl of the stock solution in 1.5ml of DMSO-free culture medium, and then perform 3-fold continuous gradient dilutions with 0.1% DMSO culture medium, for a total of 9 concentrations. The compound concentrations after dilution are as follows:

333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM.

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 replicate wells for each concentration;

C) Transfer the cells to an incubator and incubate for 3 days.

3. CCK8 (WST-8) cell analysis

A) Take out the cell culture plate and add 10 μl of CCK-8 (WST-8) solution to each well in a biosafety cabinet;

B) Place the cell culture plate back into the incubator and continue incubating for 3 hours;

C) Select 450 nm wavelength to measure the absorbance value on TECAN enzyme-linked immunosorbent assay instrument.

4. Data Analysis

Cell viability (%Cell Viability) was calculated using the following formula:

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

A (drug added): absorbance of wells with cells, CCK8 solution, and drug solution

A (blank): absorbance of wells with culture medium and CCK8 solution but no cells

A(0 drug addition): absorbance of the well with cells, CCK8 solution and no drug solution

Cell viability: The cell proliferation activity or cytotoxic activity was curve fitted by GraphPad Prism 8 software to obtain IC ₅₀ values, as shown in Table 2, where A ≤ 0.2 μM; 0.2 μM < B < 2 μM; 2 μM < C < 20 μM

Table 2

It can be seen from the results in Table 1 that the compounds of the present invention have a very good inhibitory effect on human ovarian cancer cells.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (15)

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:
Wherein, X ¹ is independently selected from the following group: C, N; ^X2 is independently selected from the following group: C, N; X ⁶ is 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 refers to 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, hydroxy, 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 (such as ), -COC _3-6 cycloalkyl, C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, 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 heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-6 haloalkoxy, -N(C _1-6 alkyl) ₂ ; R ¹ is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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 haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached together form a C _3-10 cycloalkyl, a 3-6 membered saturated heterocyclic group; ^R4 is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, _C1-10 alkyl, _C1-10 alkoxy, _C1-10 haloalkyl, _C1-10 haloalkoxy, _C1-10 hydroxyalkyl, ^-NR4aR4b , -C(O) ^R4c , -C(O) ^OR4c , -C(O) ^NR4aR4b , _-S(O)pR4c ^, _C3-10 ^cycloalkyl , 5-10 membered ^heterocyclyl , _C6-10 aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from the group consisting of halogen, oxo (=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, C1-6 _1-6 haloalkoxy, -NH ₂ , -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , hydroxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclyl, 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 are each the same or different; R ^4a , R ^4b and R ^4c are each 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 heterocyclyl and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl 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 haloalkyl, C _1-6 haloalkoxy, NH ₂ , -N(C _1-3 alkyl) ₂ , C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-8 membered heterocyclyl, C _6-10 membered aryl and 5-7 membered heteroaryl; Alternatively, R ^4a and R ^4b each together with the nitrogen atom to which they are commonly attached form 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, hydroxy, 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, NH ₂ , —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 is hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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, C _1-6 aldehyde, -NH ₂ , -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 haloalkoxy. 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:
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:
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 is selected from the group consisting of:

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 is independently selected from the following group: cyano, C _1-6 alkyl, C _1-6 haloalkyl; and R ² and R ³ together with the carbon atom to which they are connected form a C _3-6 cycloalkyl, a 3-6 membered saturated heterocyclic group. 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, ^X1 is independently selected from the following group: C, N; ^X2 is independently selected from the following group: C, N; X ³ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ; X ⁴ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ; X ⁵ is each independently selected from the group consisting of CR ^5a R ^5b , NR ^5c , O, S, SO, SO ₂ ; X ⁶ is each independently selected from the following group: CR ⁶ , N; R ¹ is each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, amino, nitro, hydroxyl, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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 haloalkyl, or R ² and R ³ together with the carbon atom to which they are attached together form a C _3-10 cycloalkyl, a 3-6 membered saturated heterocyclic group; ^R4 is each independently selected from the group consisting of a hydrogen atom, a deuterium, a halogen, a cyano group, a _hydroxyl group, a _C1-10 alkyl group, a _C1-10 alkoxy group, a _C1-10 haloalkyl group, a _C1-10 haloalkoxy group, a C1-10 hydroxyalkyl group, ^-NR4aR4b , -C(O) ^R4c , -C(O ^{)OR4c ,} -C(O) ^NR4aR4b , _-S(O)pR4c ^{, a} _C3-10 cycloalkyl group, a 5-10 membered heterocyclic group, a _C6-10 aryl group and a 5-10 membered heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl group are each independently optionally substituted by one or more substituents selected from the group consisting of a halogen, an oxo group (=O), a _C1-6 alkyl group, a _C1-6 alkoxy group, a C1-6 haloalkyl group, a _C1-6 haloalkoxy group, _1-6 haloalkoxy, -NH ₂ , -NR ^4a R ^4b , -C(O)R ^4c , -C(O)OR ^4c , -C(O)NR ^4a R ^4b , -S(O) _p R ^4c , hydroxy, C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-6 membered heterocyclyl, 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 are each the same or different; R ^4a , R ^4b and R ^4c are each 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 heterocyclyl and 5-8 membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl, heterocyclyl 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 haloalkyl, C _1-6 haloalkoxy, NH ₂ , -N(C _1-3 alkyl) ₂ , C _1-6 hydroxyalkyl, C _3-6 cycloalkyl, 5-8 membered heterocyclyl, C _6-10 membered aryl and 5-7 membered heteroaryl; Alternatively, R ^4a and R ^4b each together with the nitrogen atom to which they are commonly attached form 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, hydroxy, 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, NH ₂ , —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 are each independently selected from the group consisting of H, halogen, cyano, C _1-6 alkyl (e.g., methyl, ethyl, isopropyl), C _3-6 cycloalkyl (e.g., cyclopropyl), hydroxy, amino, C _1-6 alkoxy (e.g., methoxy), -COC _1-6 alkoxy (e.g., ), -COC _1-6 (such as ), C _1-6 haloalkyl (such as CF ₃ ), C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl, or R ^5a and R ^5b together form ＝O; R ^5c is 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 haloalkoxy, 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 heterocyclyl, C 6-10 aryl ,} 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl, 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 haloalkyl, C _1-6 haloalkoxy, -N(C _1-6 alkyl) ₂ ; R ⁶ is each independently selected from the group consisting of hydrogen, cyano, nitro, formyl, -CONH ₂ , -CH ₂ OH, -CH ₂ OC _1-6 alkyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, 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, C _1-6 aldehyde, -NH ₂ , -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 haloalkoxy. 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:
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:
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 a substituted or unsubstituted 5-6 membered heteroaromatic ring; wherein the substitution means that one or more hydrogens on the heteroaromatic ring are replaced by a group selected from the group consisting of halogen, hydroxyl, C _1-4 ester, C _1-4 aldehyde, -NH ₂ , -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 haloalkoxy; preferably, Ar is selected from the group consisting of: 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 is selected from the group consisting of:

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









A pharmaceutical composition, characterized in that it 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. A 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 it is used for preparing a drug or preparation, wherein the drug or preparation is used for a 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. The use according to claim 14, characterized in that the disease related to PARG activity is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung cancer, and prostate cancer.