Benzo five-membered heterocyclic derivative and application thereof

Abstract

The invention relates to a benzo five-membered heterocyclic derivative as well as a preparation method and application thereof. Specifically, the invention discloses a compound with a structure as shown in a formula I or a formula II, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses application of the compound in treatment or prevention of proliferative diseases (such as cancer). # imgabs0 #

Description

Technical Field

[0001] 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, poly (adenosine diphosphate ribose) hydrolase] 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 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.

[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, 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.

[0004] In summary, there is an urgent need in the art to develop a new PARG inhibitor that has an inhibitory effect on cells that are resistant to current clinical PARP inhibitors. Summary of the invention

[0005] An object of the present invention is to provide a PARG inhibitor having an inhibitory effect on cells resistant to PARP inhibitors.

[0006] Another object of the present invention is to provide a PARG inhibitor targeting the DNA damage repair mechanism.

[0007] In the first aspect of the present invention, there is provided a compound of formula I or formula II, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0008]

[0009] in,

[0010] X 1 Each independently selected from the group consisting of N, S, O;

[0011] X 2 Each independently selected from the following group: CY 1 , N;

[0012] Y 1 Each is independently selected from the following group: hydrogen, halogen, cyano or CR, wherein R is selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, -CONH2, -CONH-C 1-10 Alkyl, -CH2OH, -CH2CH2O-C 1-10 Alkyl, -CH2CH2NH-C 1-10 Alkyl, -OC 1-10 Alkyl, -NHC 1-2 Alkyl, or Y 1 With R 5 and the atoms to which they are connected together form a five-membered, six-membered, or seven-membered heterocyclic ring or a heteroaromatic ring;

[0013] 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 Haloalkoxy, C 1-10 Haloalkyl;

[0014] R 2 and R 3 Each independently selected from the following group: C 1-10 Alkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl;

[0015] R 4 are independently selected from the following groups: hydrogen atom, halogen, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Halogenated alkoxy, C 1-10 Hydroxyalkyl, C 3-10 Cycloalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , 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;

[0016] p is 0, 1, or 2;

[0017] R 4a and R 4b each the same or different;

[0018] R 4a , R 4band R 4c are independently selected from the following groups: a hydrogen atom, a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-8 membered heterocyclic group and 5-8 membered heteroaryl, or, R 4a and R 4b Each of them together with the nitrogen atom to which they are commonly connected forms a 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, 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;

[0019] R 5 Each independently selected from the following group: H, Among them, L 1 , L 2 and L 3 are the same or different and are independently selected from the following groups: hydrogen atom, cyano group, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, -C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , or R 5 With R 4and the atoms connected thereto together form a five-membered, six-membered, seven-membered heterocyclic ring or heteroaromatic ring, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents independently selected from the following groups: halogen, cyano, 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 NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0020] n is 0, 1, 2, 3 or 4;

[0021] 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, trifluoromethyl, amide, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy.

[0022] In another preferred embodiment,

[0023] Y 1 Each is independently selected from the following group: hydrogen, halogen, cyano or CR, wherein R is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CONH2, -CONH-C 1-6 Alkyl, -CH2OH, -CH2CH2O-C 1-6 Alkyl, -CH2CH2NH-C 1-6 Alkyl, -OC 1-6 Alkyl, -NHC 1-2 Alkyl, or Y 1 With R 5 and the atoms to which they are connected together form a five-membered, six-membered, or seven-membered heterocyclic ring or a heteroaromatic ring;

[0024] 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 Haloalkoxy, C 1-6 Haloalkyl;

[0025] 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;

[0026] R 4 are independently selected from the following groups: hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , 5-9 membered heterocyclic group, C 6-8 Aryl and 5-9 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 C1-3 Alkyl-substituted or unsubstituted 5-8-membered heteroaryl;

[0027] 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, trifluoromethyl, amide, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy;

[0028] X 1 , X 2 ,n,p,R 4a , R 4b , R 4c , R 5 As described in the first aspect of the present invention respectively.

[0029] In another preferred embodiment, ring A is selected from the following group:

[0030]

[0031]

[0032] In another preferred embodiment, X 1 N, R 5 Each independently selected from the following group:

[0033] Among them, L 1 , L 2 , L 3 are the same or different and are independently selected from the following groups: H, cyano, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, phenyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are each independently substituted by one or more substituents each independently selected from the following group: halogen, cyano, 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 、-NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0034] R 4a , R 4b and R 4c Each independently selected from the following group: C 1-6 alkyl;

[0035] n is 0, 1, 2, 3 or 4.

[0036] In another preferred embodiment, X 1 N, R 5 Each independently selected from the following group:

[0037] Among them, L 1 Each independently selected from the group consisting of: H, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 1-4 Alkoxy, phenyl, 5-6 membered heteroaryl;

[0038] L 2 Each independently selected from the following group: C 1-4 Alkyl, 5-6 membered heteroaryl;

[0039] wherein the alkyl, alkoxy, phenyl and heteroaryl groups are each independently optionally substituted by one or more substituents independently selected from the following groups: halogen, cyano, 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 、-NH(C 1-3Alkyl), -N(C 1-3 Alkyl)2, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0040] R 4a , R 4b and R 4c Each independently selected from the following group: C 1-6 alkyl;

[0041] n is 0, 1, 2, 3 or 4.

[0042] In another preferred embodiment, R 5 Each is independently selected from the following group: benzyl, -CH2-CN, propyne, methyl, ethyl, isopropyl, -CH2CH2N(CH3)2, -CH2CH2OMe,

[0043] 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 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, trifluoromethyl, amide, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 1-4 Alkoxy.

[0044] In another preferred embodiment, Ar is selected from the following group:

[0045] In another preferred embodiment, R 4 are independently selected from the following groups: hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 5-9 membered heterocyclic group, wherein one or more hydrogen atoms on the alkyl, alkoxy, cycloalkyl and heterocyclic group are substituted by a substituent 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)OR4c 、-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 and C 1-3 Alkyl-substituted or unsubstituted 5-8-membered heteroaryl;

[0046] Among them, R 4a , R 4b are the same or different and are independently selected from the following groups: hydrogen atoms, 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 each 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;

[0047] 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 following group: halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, nitro, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl;

[0048] R 4c are independently selected from the following group: hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 following groups: halogen, C1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Halogenated alkoxy.

[0049] In another preferred embodiment, the heterocyclic group is One or more hydrogen atoms on the heterocyclic group are substituted by a substituent 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, phenyl and C 1-3 Alkyl-substituted or unsubstituted 5-8 membered heteroaryl; wherein R 4a , R 4b and R 4c As described in the first aspect of the present invention.

[0050] In another preferred embodiment, R 4 Each independently selected from the following group: H,

[0051]

[0052] In another preferred embodiment, R 1 Each independently selected from the group consisting of cyano, C 1-6 Alkyl, C 1-6 Haloalkyl;

[0053] 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 3-6 Cycloalkyl.

[0054] In another preferred embodiment, R 1 Each independently selected from the group consisting of cyano, C 1-4 Alkyl, C 1-4 Haloalkyl;

[0055] R 2 and R 3 Each independently selected from the following group: C 1-3 Alkyl, or R 2 and R 3 The carbon atoms to which it is attached together form cyclopropane.

[0056] In another preferred embodiment, the compound is selected from the following group:

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

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

[0064]

[0065]

[0066]

[0067] In another preferred embodiment, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;

[0068] The inorganic acid salt is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate;

[0069] The organic acid salt is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, picrate, glutamate, ascorbate, camphorate, and camphorsulfonate.

[0070] In the second aspect of the present invention, a pharmaceutical composition is provided, comprising a pharmaceutically acceptable carrier and a safe and effective amount of one or more compounds described in the first aspect of the present invention.

[0071] In another preferred embodiment, in the composition, the compound accounts for 0.001-99.999wt% of the total weight of the composition; preferably 0.01-99.99wt%; more preferably 0.1-90wt%.

[0072] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0073] In the third aspect of the present invention, there is provided a use of the compound of the first aspect of the present invention or the pharmaceutical composition of the second aspect of the present invention for preparing a drug or a preparation, wherein the drug or preparation is used for a use selected from the group consisting of:

[0074] 1) Used to regulate PARG enzyme activity;

[0075] 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;

[0076] 3) for preventing and / or treating diseases related to PARG activity;

[0077] 4) For preventing and / or treating proliferative diseases.

[0078] In another preferred embodiment, the PARG-related disease is selected from the following group: ovarian cancer, breast cancer, pancreatic cancer, lung cancer and prostate cancer.

[0079] 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

[0080] 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.

[0081] the term

[0082] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0083] 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-C6 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.

[0084] In the present invention, the term "C2-C6 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.

[0085] In the present invention, the term "C2-C6 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.

[0086] In the present invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0087] In the present invention, the term "C1-C6 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-C4 alkoxy group.

[0088] In the present invention, the term "heterocyclic group" refers to a 4-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, including (but not limited to) the following groups:

[0089] 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.

[0090] 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. For example, "C3-C10 heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 carbon atoms. 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.

[0091] In the present invention, the term "halo" means substituted with halogen.

[0092] In the present invention, the term "deuterated" means substituted with deuterium.

[0093] 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 each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. It should be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those stable or chemically feasible combinations. The substituents include, for example (but not limited to): halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic radical, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, etc.

[0094] In the present invention, the term 1-6 refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] PARG inhibitor compounds

[0101] 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.

[0102] Specifically, the present invention provides a compound represented by Formula I or II or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0103]

[0104] wherein each group is as defined above.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] In addition, the compounds of the present invention also include prodrugs of the compounds shown in Formula I. 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 a salt or solution composed of a compound of Formula I. 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 forms of the compound.

[0109] The examples of the present invention specifically describe the preparation methods of the compounds of formula I 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, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.

[0110] 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.

[0111] Pharmaceutical compositions and methods of administration

[0112] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention or a pharmaceutically acceptable salt, solvate or prodrug thereof.

[0113] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) a variety of autoimmune and inflammatory-related diseases including cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases.

[0114] 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.

[0115] "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.

[0116] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0117] 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.

[0118] 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 previously mentioned, the compounds of the present invention can also be administered in the form of pharmaceutically acceptable salts, etc.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0127] When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable therapeutic agents. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable therapeutic agents can be used simultaneously, separately or sequentially with the compound of the present invention to prevent and / or treat tumor-related diseases.

[0128] 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.

[0129] Compared with the prior art, the main advantages of the present invention include:

[0130] (1) The compound has excellent PARG inhibitory activity;

[0131] (2) The compound can effectively inhibit the proliferation of Kuramochi cells carrying BRAC2 mutation.

[0132] 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 intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out according to conventional conditions such as Sambrook et al., Molecular Cloning: 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.

[0133] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0134] Example 1: Synthesis of Intermediate M-01

[0135]

[0136] The synthetic route is as follows:

[0137]

[0138] The experimental process is as follows:

[0139] (1) Synthesis of Compound 02

[0140] Compound 01 (10.0 g, 39.2 mmol) and T S OH (2.0 g, 11.7 mmol)) was added into a 250 mL round-bottom flask, and a mixed solution of ACN / H2O (10 mL / 10 mL) was added to dissolve it. The mixture was cooled to 0°C in an ice bath, and then DHP (9.9 g, 117.6 mmol) was slowly added dropwise. The mixture was naturally heated to room temperature and reacted for 24 hr. After the reaction was completed, it was directly concentrated and purified by silica gel column chromatography to obtain the target compound 02 (13.2 g, 38.9 mmol).

[0141] (2) Synthesis of Compound 03

[0142] Compound 02 (13.2 g, 38.9 mmol) was added to a 50 mL microwave reaction tube, 20 ml of ethanol was added to dissolve, and then hydrazine hydrate (2.0 g, 38.9 mmol) was added, microwave reaction was carried out at 90°C for 20 min, cooled to room temperature, and then another 1 equivalent of hydrazine hydrate (2.0 g, 38.9 mmol) was added, and microwave reaction was continued at 90°C for 20 min. After the reaction was completed, it was cooled to room temperature, concentrated, and ethanol was added for recrystallization, and the solid was filtered to obtain the solid, and then vacuum dried to obtain the target compound 03 (11.5 g, 33.9 mmol).

[0143] (3) Synthesis of Compound 04

[0144] Compound 03 (11.5 g, 33.9 mmol) was added to a 100 mL reaction bottle, dissolved in 50 mL DCM, then cooled to 0 ° C, triethylamine (6.9 g, 67.8 mmol) was added, and then difluoroacetic anhydride (11.8 g, 67.8 mmol) was slowly added dropwise, and the reaction was maintained at 0 ° C for 1 hr. After the reaction was completed, water was added to quench the reaction, and then H2O and DCM were added. The organic layer was separated, extracted with DCM three times, the organic phases were combined, washed with saturated brine, dried over sodium sulfate, directly concentrated to remove the solvent, and dried in vacuo to obtain the target product 04 (13.5 g, 32.3 mmol).

[0145] (4) Synthesis of Compound 05

[0146] Compound 04 (13.5 g, 32.3 mmol) and Lawesson's reagent (19.6 g, 48.5 mmol) were added to a 50 mL microwave reaction tube, and 20 ml of THF was added to dissolve. The mixture was subjected to microwave reaction at 80 °C for 10 min. After the reaction was completed, the mixture was cooled to room temperature and concentrated directly. The target product 05 (6.7 g, 16.1 mmol) was separated and purified by silica gel column chromatography.

[0147] (5) Synthesis of Compound M-1

[0148] Compound 05 (6.7 g, 16.1 mmol) was added to a 100 mL round-bottom flask, cooled to 0°C in an ice bath, and a mixed solution of DCM and TFA (TFA / DCM=10 mL / 30 mL) was slowly added dropwise, and then the temperature was slowly raised to room temperature. The reaction was allowed to proceed for 6 hours. After the reaction was completed, the mixture was directly concentrated, 20 mL of water was added, saturated sodium bicarbonate was slowly added dropwise, and the pH was adjusted to 8-10. The mixture was then extracted with DCM, the organic phases were combined, dried over sodium sulfate, and concentrated in vacuo. The target product M-01 (4.6 g, 13.9 mmol) was then separated and purified by silica gel column chromatography, LC-MS [M+1]: 331.00.

[0149] Example 2: Synthesis of T-001

[0150]

[0151] (1) Synthesis of Compound M-02

[0152] In a 25 mL reaction bottle, compound M-01 (100.0 mg, 0.30 mmol) was dissolved in 5 mL DMF, cooled to 0 °C in an ice bath, Cs2CO3 (153.9 mg, 0.90 mmol) was added, stirred evenly, and then BnBr (76.9 mg, 0.45 mmol) was slowly added dropwise, and then the temperature was slowly raised to room temperature. The reaction was allowed to react overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted 3 times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by silica gel column chromatography to obtain the target compound M-02 (105.1 mg, 0.22 mmol).

[0153] (2) Synthesis of Compound M-03

[0154] Compound M-01 (100.0 mg, 0.22 mmol), Xantphos (11.57 mg, 0.02 mmol), Pd2(dba)3·CHCl3 (10.2 mg, 0.01 mmol) were added to a 25 mL reaction bottle, replaced with nitrogen three times, 5 mL of dioxane was added to dissolve, and then BnSH (81.9 mg, 0.66 mmol) and DIPEA (85.1 mg, 0.66 mmol) were added. Under nitrogen protection, the reaction was carried out at 100 ° C for three hours. After the reaction was completed, it was cooled to room temperature and concentrated directly. The target product M-03 (65.0 mg, 0.14 mmol) was separated and purified by silica gel column chromatography.

[0155] (3) Synthesis of compound T-001

[0156] In a 10 mL reaction bottle, compound M-03 (65.0 mg, 0.14 mmol) was dissolved in 3 mL acetonitrile, a mixture of AcOH / H2O (10 μL / 20 μL) was added and cooled to 0°C, then DCDMH (41.4 mg, 0.21 mmol) was added, and the reaction was continued at 0°C for 2 hours. After the reaction, the solvent was directly concentrated and dried to obtain a crude product. 1-Amino-1-cyclopropylcyanide hydrochloride (24.9 mg, 0.21 mmol) was dissolved in 2 mL pyridine, cooled to 0°C, and then the crude product obtained above was dissolved in a small amount of DCM and slowly added dropwise to the reaction system, and reacted at room temperature overnight. After the reaction was completed, water was added to quench the reaction, and most of the solvent was removed by vacuum concentration. Then a small amount of water and DCM were added, the organic phase was separated, and then extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and separated and purified by silica gel column chromatography to obtain the target product T-001 (40.2 mg, 0.08 mmol).

[0157] Referring to the synthesis method of Example T-001, the following compounds were synthesized:

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164] Example 19: Synthesis of T-018

[0165]

[0166] In a 25 mL reaction bottle, compound M-01 (1.00 g, 3.01 mmol) was dissolved in 60 mL DMF, cooled to 0 °C in an ice bath, Cs2CO3 (1.54 g, 9.00 mmol) was added, stirred evenly, and then 2-cyano-5-bromomethylpyridine (0.72 g, 3.61 mmol) was slowly added dropwise, and then the temperature was slowly raised to room temperature. The reaction was allowed to react overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted 3 times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by silica gel column chromatography to obtain the target compound M-04 (0.53 g, 1.20 mmol).

[0167] Take a 25mL reaction bottle, dissolve compound M-04 (100.0 mg, 0.23 mmol) in 5mL MeOH, then add K2CO3 (62.5 mg, 0.46 mmol), stir evenly, and then slowly add 0.50mL 30% H2O2, react at room temperature overnight, add sodium sulfite to quench the reaction, extract with EA 3 times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate in vacuo, and separate and purify by silica gel column chromatography to obtain the target compound M-05 (90.0 mg, 0.19 mmol).

[0168] Using M-05 as raw material, T-018 (40.0 mg, 0.075 mmol) was synthesized according to the synthetic route of T-001. 1HNMR(400MHz,DMSO-d6)δ10.57(s,2H),9.30(s,1H),8.94(s,1H),8.69(d,J =1.5Hz,1H),8.29(d,J=9.0Hz,1H),8.11(s,1H),8.04–7.95(m,4H),7.86–7. 80(m,1H),7.71(t,J=53.1Hz,1H),7.67(s,1H),6.08(s,2H),1.43(dd,J=8. 2,5.4Hz,2H),1.29(dd,J=8.2,5.4Hz,2H).LC-MS: MS(ESI)m / z:531.30[M+H] + .

[0169]

[0170] Example 20: Synthesis of T-019

[0171]

[0172] Compound S-4-hydroxyethylpyridine (81.4 mg, 0.66 mmol), DIAD (267 mg, 1.32 mmol), and PPh3 (430.2 mg, 1.64 mmol) were added to the reaction mixture in a 25 mL reaction bottle, dissolved in 8 mL THF and stirred evenly, protected with nitrogen, and then added M-01 (200 mg, 0.60 mmol). The mixture was reacted at room temperature overnight. After the reaction was completed, water was added to quench the reaction. The mixture was extracted three times with EA, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated and purified by silica gel column chromatography to obtain M-06 (182.3 mg, 0.42 mmol).

[0173] The subsequent synthesis of compound T-019 used M-06 as the raw material, referring to the synthetic routes of M-01 and T-001, and the following compounds were synthesized by this method:

[0174]

[0175]

[0176] Example 24: T-023 Synthesis

[0177]

[0178] (1) Synthesis of Compound M-08

[0179] Compound M-07 (3.00 g, 15.26 mmol) was added to a 100 mL reaction bottle, and 38 mL of anhydrous EtOH was added to dissolve it. Then 15 drops of concentrated sulfuric acid were slowly added, and then refluxed for 5 hours. After the reaction was completed, it was cooled to room temperature and a small amount of water was added to quench the reaction. Most of the ethanol was removed by concentration, and the mixture was cooled to 0°C and neutralized with saturated sodium bicarbonate. Then, EA was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and separated and purified by silica gel column chromatography to obtain the target product M-08 (2.15 g, 9.60 mmol).

[0180] (2) Synthesis of Compound M-09

[0181] Compound M-08 (2.15 g, 9.60 mmol) was added to a 100 mL reaction bottle, and 40 mL of glacial acetic acid was added. Then Br2 (1.23 g, 76.73 mmol) was slowly added dropwise at room temperature. After the addition, the mixture was refluxed at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, and the solvent was directly distilled off under reduced pressure to obtain the crude product M-09 (2.63 g, 9.60 mmol).

[0182] (3) Synthesis of Compound M-10

[0183] Compound M-09 (2.63 g, 9.60 mmol) was added to a 100 mL reaction bottle, and 80 mL of anhydrous EtOH was added to dissolve it. Then 18 drops of concentrated sulfuric acid were slowly added, and then refluxed for 5 hours. After the reaction was completed, it was cooled to room temperature and a small amount of water was added to quench the reaction. Most of the ethanol was removed by concentration, and the mixture was cooled to 0°C and neutralized with saturated sodium bicarbonate. Then, EA was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and separated and purified by silica gel column chromatography to obtain the target product M-10 (2.55 g, 8.47 mmol).

[0184] (4) Synthesis of Compound M-12

[0185] Compound M-10 (2.55 g, 8.47 mmol) and K2CO3 (2.92 g, 21.18 mmol) were added to a 100 mL reaction bottle, 60 mL of anhydrous acetonitrile was added to dissolve, cooled to 0°C, and then MeI (2.41 g, 16.94 mmol) was slowly added dropwise, and then the temperature was naturally raised to room temperature for reaction overnight. After the reaction was completed, it was cooled to room temperature and a small amount of water was added to quench the reaction. Most of the solvent was concentrated, and then EA was extracted 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated by distillation under reduced pressure, and separated and purified by silica gel column chromatography to obtain by-product M-11 (0.70 g, 2.22 mmol) and target product M-12 (1.50 g, 4.76 mmol).

[0186] (5) Synthesis of Compound M-13

[0187] Compound M-12 (1.49 g, 4.73 mmol) was added to a 100 mL reaction bottle, 50 mL of anhydrous ethanol was added to dissolve, and then 8 mL of hydrazine hydrate was slowly added dropwise, and then refluxed at 90 ° C overnight. After the reaction was completed, it was cooled to room temperature and most of the solvent was removed by vacuum distillation. The mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated by vacuum distillation, and recrystallized using ethanol as a solvent to obtain the target product M-13 (1.01 g, 3.30 mmol).

[0188] (6) Synthesis of Compound M-15

[0189] Compound M-13 (1.01 g, 3.30 mmol) was added to a 100 mL reaction bottle, dissolved with 40 mL DCM, NEt3 (1.00 g, 9.90 mmol) was added, cooled to 0°C, and then difluoroacetic anhydride (1.14 g, 6.60 mmol) was slowly added dropwise, and reacted at 0°C for 0.5 hr. After the reaction was completed, water was added to quench, and DCM was extracted 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by distillation under reduced pressure. M-14 (0.46 g, 1.22 mmol) and the target product M-15 (0.31 g, 0.87 mmol) were obtained by separation and purification by silica gel column chromatography.

[0190] (7) Synthesis of Compound M-16

[0191] Compound M-15 (310.0 mg, 0.87 mmol), Xantphos (100.7 mg, 0.17 mmol), Pd2(dba)3·CHCl3 (92.1, 0.09 mmol) were added to a 25 mL reaction bottle, replaced with nitrogen three times, 8 mL of dioxane was added to dissolve, and then BnSH (119.2 mg, 0.96 mmol), DIPEA (280.6 mg, 2.17 mmol) were added, and the reaction was carried out at 100 ° C for three hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature and concentrated directly. The target product M-16 (302.0 mg, 0.74 mmol) was separated and purified by silica gel column chromatography.

[0192] (8) Synthesis of Compound M-17

[0193] Add compound M-16 (320.0 mg, 0.74 mmol) into a 25 mL reaction bottle, add 3 mL of acetonitrile to dissolve, add a mixture of AcOH / H2O (40 μL / 80 μL) and cool to 0°C, then add DCDMH (219.9 mg, 1.11 mmol), maintain 0°C and continue the reaction for 2 hours. After the reaction, directly concentrate to remove the solvent and drain to obtain the crude product. 1-Amino-1-cyclopropyl cyanide hydrochloride (175.5 mg, 1.48 mmol) was dissolved in 5 mL of pyridine and cooled to 0°C. The crude product obtained above was then dissolved in a small amount of DCM and slowly added dropwise to the reaction system. The reaction was allowed to react overnight at room temperature. After the reaction was completed, water was added to quench the reaction. Most of the solvent was removed by vacuum concentration. A small amount of water and DCM were then added. The organic phase was separated and then extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and separated and purified by silica gel column chromatography to obtain the target product M-017 (228.1 mg, 0.53 mmol).

[0194] (9) Synthesis of Compound T-023

[0195] Compound M-17 (100.0 mg, 0.23 mmol), Cs2CO3 (149.9 mg, 0.46 mmol), and Pd-PEPPSI-IHept Cl (19.4 mg, 0.02 mmol) were added to a 8 mL microwave reaction tube, replaced with nitrogen three times, and then 4 mL of 1,4-dioxane was added to dissolve. Under nitrogen protection, microwave reaction was carried out at 100 ° C for 20 min. After the reaction was completed, it was cooled to room temperature, and the solvent was removed under reduced pressure. The target product T-023 (65.0 mg, 0.12 mmol) was obtained by separation and purification by silica gel column chromatography. 1 H NMR(400MHz, DMSO-d6)δ9.20(s,1H),8.47(d,J=1.2Hz,1H),7.63(t,J=51.3Hz,1H),7.56(d,J=1.2Hz,1H),4.53(s,3H),3.29–3.26(m,4H),2 .45–2.40(m,4H),1.64–1.57(m,1H),1.43–1.39(m,2H),1.35–1.30(m,2H),1.25–1.20(m,2H),1.03(d,J=5.7Hz,3H),0.85(t,J=7.2Hz,3H). LC-MS: MS(ESI)m / z:563.4[M+H] + .

[0196]

[0197] Referring to the synthetic route of T-023, the following compounds were synthesized:

[0198]

[0199]

[0200] Example 26: Synthesis of T-025

[0201] T-025 was synthesized from M-12 according to the synthetic route of M-01 and T-018: T-025 (65.0 mg, 0.12 mmol) 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.11 (s, 1H), 7.77 (t, J = 53.1 Hz, 1H), 6.93 (s, 1H), 4.55 (s, 3H), 3.85–3.69 (m, 4H), 3.66–3.49 (m, 4H), 2.85–2.74 (m, 1H), 1.65–1. 52(m,1H),1.39(dd,J=8.2,5.4Hz,2H),1.37–1.30(m,1H),1.28(dd,J=8.2,5.4Hz,2 H), 1.02 (d, J=6.7Hz, 3H), 0.84 (t, J=7.4Hz, 3H). LC-MS: MS (ESI) m / z: 579.3[M+H]+.

[0202]

[0203] Referring to the synthetic route of T-025, the following compounds were synthesized:

[0204]

[0205]

[0206]

[0207] Example 32: Cell anti-proliferation experiment

[0208] The PARG inhibitor compounds of the present invention were tested for their proliferation inhibitory effects on human ovarian cancer cells KURAMOCHI.

[0209] 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 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).

[0210] Experimental preparation:

[0211] 1. Cell plating

[0212] 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.

[0213] B) Remove the culture medium from the 10 cm culture dish;

[0214] C) Rinse the cells once with 10 ml 1xPBS;

[0215] D) Add 4 ml of 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;

[0216] E) Resuspend in 4 ml DMEM medium, count and adjust to 10,000 cells / ml.

[0217] 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% CO2 incubator.

[0218] 2. Compound treatment

[0219] Compound dilution

[0220] A) Preparation of test compound gradient dilution solution: Prepare the test compound into 1 mM stock solution. Then dissolve 1.5 μl of the stock solution in 1.5 ml of DMSO-free culture medium, and then perform 3-fold continuous gradient dilution with 0.1% DMSO culture medium, for a total of 9 concentrations. The compound concentrations after dilution are as follows:

[0221] 333.33nM, 111.11nM, 37.03nM, 12.35nM, 4.15nM, 1.37nM, 0.46nM, 0.15nM.

[0222] 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;

[0223] C) Transfer the cells to an incubator and incubate for 3 days.

[0224] 3. CCK8 (WST-8) cell analysis

[0225] A) Take out the cell culture plate and add 10 μl of CCK-8 (WST-8) solution to each well in a biosafety cabinet;

[0226] B) Place the cell culture plate back into the incubator and continue incubating for 3 hours;

[0227] C) Select 450 nm wavelength to measure the absorbance value on TECAN enzyme-linked immunosorbent assay instrument.

[0228] 4. Data Analysis

[0229] The cell viability (% Cell Viability) was calculated using the following formula:

[0230] Cell viability (%) = [A(drug added) - A(blank)] / [A(0 drug added) - A(blank)] × 100

[0231] A (drug added): absorbance of wells with cells, CCK8 solution and drug solution

[0232] A (blank): absorbance of wells with culture medium and CCK8 solution but no cells

[0233] A(0 drug addition): absorbance of the well with cells, CCK8 solution and no drug solution

[0234] Cell viability: Cell proliferation activity or cytotoxic activity was obtained by curve fitting using GraphPad Prism 8 software. 50 Numeric value.

[0235] As shown in Table 1, A≤0.2μM; 0.2μM <B<2μM;C≥2μM

[0236] Table 1

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245] It can be seen from the results in Table 1 that most of the compounds of the present invention have very good inhibitory effects on human pleural mesothelioma cells NCI-H226.

[0246] 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

1. A compound of formula I or II, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in, X 1 Each independently selected from the group consisting of N, S, O; X 2 Each independently selected from the following group: CY 1 , N; Y 1 Each is independently selected from the following group: hydrogen, halogen, cyano or CR, wherein R is selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-10 Haloalkyl, -CONH2, -CONH-C 1-10 Alkyl, -CH2OH, -CH2CH2O-C 1-10 Alkyl, -CH2CH2NH-C 1-10 Alkyl, -OC 1-10 Alkyl, -NHC 1-2 Alkyl, or Y 1 With R 5 and the atoms to which they are connected together form a five-membered, six-membered, or seven-membered heterocyclic ring or a heteroaromatic ring; 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 Haloalkoxy, C 1-10 Haloalkyl; R 2 and R 3 Each independently selected from the following group: C 1-10 Alkyl, or R 2 and R 3 Together with the carbon atoms connected to it, they form C 3-10 Cycloalkyl; R 4 are independently selected from the following groups: hydrogen atom, halogen, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 Haloalkyl, C 1-10 Haloalkoxy, C 1-10 Hydroxyalkyl, C 3-10 Cycloalkyl, -NR 4a R 4b 、-C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , 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 following group: hydrogen atoms, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-8 membered heterocyclic group and 5-8 membered heteroaryl, or, R 4a and R 4b Each of them together with the nitrogen atom to which they are commonly connected forms a 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, 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; R 5 Each independently selected from the following group: H, Among them, L 1 , L 2 and L 3 are the same or different and are independently selected from the following groups: hydrogen atom, cyano group, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, -C(O)R 4c 、-C(O)OR 4c 、-C(O)NR 4a R 4b 、-S(O) p R 4c , or R 5 With R 4 and the atoms connected thereto together form a five-membered, six-membered, seven-membered heterocyclic ring or heteroaromatic ring, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups are each independently optionally substituted by one or more substituents independently selected from the following groups: halogen, cyano, 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 NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; n is 0, 1, 2, 3 or 4; 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, trifluoromethyl, amide, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and C 1-6 Alkoxy.

2. The compound according to claim 1, characterized in that Ring A is selected from the following group:

3. The compound according to claim 1, characterized in that X 1 N, R 5 Each independently selected from the following group: Among them, L 1 , L 2 , L 3 are the same or different and are independently selected from the following groups: H, cyano, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, -NR 4a R 4b 、-N(C 1-3 Alkyl)2, phenyl, C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl and heteroaryl are each independently substituted by one or more substituents each independently selected from the following group: halogen, cyano, 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 、-NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; R 4a , R 4b and R 4c Each independently selected from the following group: C 1-6 alkyl; n is 0, 1, 2, 3 or 4.

4. The compound according to claim 1, 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, trifluoromethyl, amide, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl and C 1-4 Alkoxy.

5. The compound according to claim 1, characterized in that R 4 are independently selected from the following groups: hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 5-9 membered heterocyclic group, wherein one or more hydrogen atoms on the alkyl, alkoxy, cycloalkyl and heterocyclic group are substituted by a substituent 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, phenyl and C 1-3 Alkyl-substituted or unsubstituted 5-8-membered heteroaryl; Among them, R 4a , R 4b are the same or different and are independently selected from the following groups: hydrogen atoms, 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 each 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; 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 following group: halogen, oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, NH2, -N(C 1-3 Alkyl)2, nitro, hydroxyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 5-8 membered heterocyclic group, C 6-10 Aryl and 5-7 membered heteroaryl; R 4c are independently selected from the following group: hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 following groups: halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Halogenated alkoxy.

6. The compound according to claim 1, characterized in that The compound is selected from the following group:

7. The compound according to claim 1, characterized in that The compound is selected from the following group:

8. A pharmaceutical composition, characterized in that The invention comprises a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound according to claim 1.

9. Use of the compound according to claim 1 or the pharmaceutical composition according to claim 8, 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; 4) For preventing and / or treating proliferative diseases.

10. The use according to claim 9, characterized in that The PARG-related disease is selected from the group consisting of ovarian cancer, breast cancer, pancreatic cancer, lung cancer and prostate cancer.

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