CN-117229224-B - Quinazoline-4 (3H) -ketone compound, preparation method, composition and application

Abstract

The invention discloses a quinazoline-4 (3H) -ketone compound, a preparation method, a pharmaceutical composition and application thereof, wherein the structure of the compound is shown as a formula (I), and the compound comprises an isomer, pharmaceutically acceptable salt or a mixture thereof. The compound and the pharmaceutical composition thereof have high-efficiency inhibition effect on PARP7, the inhibition activity reaches nanomolar concentration level, and the compound and the pharmaceutical composition thereof can also obviously promote the release of immune factors, can be used for the immunotherapy of tumors, and can play good effects on molecular level and cell level. In addition, the preparation method of the compounds is simple, convenient and feasible.

Inventors

• XU YUNGEN
• WANG YONG
• YAN WENXIN
• LIU BEIBEI
• ZOU YI
• GU HONGFENG
• XU WENBO
• YANG JIEPING
• ZHU QIHUA

Assignees

• 中国药科大学

Dates

Publication Date

20260508

Application Date

20220607

Claims (8)

1. 1. A quinazolin-4 (3H) -one compound, characterized by having the structure of formula (I), said compound comprising a pharmaceutically acceptable salt thereof: (I), Wherein: n is selected from 0,1, 2, 3, 4 or 5; m is selected from 0 or 1; R 1 is selected from hydrogen; R 2 or R 3 are each independently selected from hydrogen or methyl; R 4 is selected from ; R 5 is selected from methyl; A 1 is selected from-NH-; A 2 is selected from-CH 2 -; A 3 is selected from 。
2. 2. A quinazolin-4 (3H) -one compound, characterized in that it is selected from any one of the following compounds: 2-methyl-8- ((6-oxo-6- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) hexyl) amino) quinazolin-4 (3H) -one (I-1), 2-Methyl-8- ((2-oxo-2- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) ethyl) amino) quinazolin-4 (3H) -one (I-2), 2-Methyl-8- ((1-oxo-1- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propan-2-yl) amino) quinazolin-4 (3H) -one (I-3), 2-Methyl-8- ((3-oxo-3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) propyl) amino) quinazolin-4 (3H) -one (I-4), 2-Methyl-8- ((4-oxo-4- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) butyl) amino) quinazolin-4 (3H) -one (I-5), 2-Methyl-8- ((5-oxo-5- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazin-1-yl) pentyl) amino) quinazolin-4 (3H) -one (I-6), 2-Methyl-8- ((3- (4- (5- (trifluoromethyl) pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) amino) quinazolin-4 (3H) -one (I-7), 8- ((4- (4- (5-Fluoropyrimidin-2-yl) piperazin-1-yl) -4-oxybutyl) amino) -2-methyl quinazolin-4 (3H) -one (I-8), 2-Methyl-8- ((4-oxo-4- (4- (5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) butyl) amino) quinazolin-4 (3H) -one (I-9), 2-Methyl-8- ((5- (4- (5-methylpyrimidin-2-yl) piperazin-1-yl) -5-oxopentyl) amino) quinazolin-4 (3H) -one (I-10), 8- ((5- (4- (5-Fluoropyrimidin-2-yl) piperazin-1-yl) -5-oxopentyl) amino) -2-methylquinazolin-4 (3H) -one (I-11), 8- ((5- (4- (5-Methoxypyrimidin-2-yl) piperazin-1-yl) -5-oxopentyl) amino) -2-methylquinazolin-4 (3H) -one (I-12), 2-Methyl-8- ((5-oxo-5- (4- (pyrimidin-2-yl) piperazin-1-yl) pentyl) amino) quinazolin-4 (3H) -one (I-13), 2-Methyl-8- ((5-oxo-5- (4- (5- (trifluoromethyl) pyridin-2-yl) piperazin-1-yl) pentyl) amino) quinazolin-4 (3H) -one (I-14), 8- ((5- (4- (2, 2-Difluorobenzo [ d ] [1,3] dioxol-5-yl) piperazin-1-yl) -5-oxopentyl) amino) -2-methylquinazolin-4 (3H) -one (I-15).
3. 3. The quinazolin-4 (3H) -one compound of claim 1 or 2, wherein said pharmaceutically acceptable salt is a salt of said compound with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid or ferulic acid.
4. 4. A method for preparing a quinazoline-4 (3H) -one compound according to any one of claims 1 to 3, wherein the method comprises the steps of: the compound (II) and the compound (III) are subjected to substitution, hydrolysis, acylation and deprotection reaction to obtain a compound (I); ; wherein m, n, A 1 、A 2 、R 1 、R 2 、R 3 、R 5 are as defined in claim 1, Is defined as A 3 in claim 1, Is defined as R 4 in claim 1; and (3) salifying the corresponding acid with the compound (I) prepared by the method to obtain pharmaceutically acceptable salts of the compound.
5. 5. A pharmaceutical composition comprising a quinazolin-4 (3H) -one compound according to any one of claims 1-3 and a pharmaceutically acceptable carrier.
6. 6. Use of a quinazolin-4 (3H) -one compound of any of claims 1-3 or a pharmaceutical composition of claim 5 in the preparation of a PARP7 inhibitor medicament.
7. 7. The use according to claim 6, wherein the medicament is an anti-tumor medicament.
8. 8. The use according to claim 7, wherein the medicament is an anti-squamous carcinoma of the lung, colon or breast.

Description

Quinazoline-4 (3H) -ketone compound, preparation method, composition and application Technical Field The invention relates to a quinazoline-4 (3H) -ketone compound and a preparation method, a pharmaceutical composition and application thereof, in particular to a quinazoline-4 (3H) -ketone compound which can be prepared into PARP7 inhibitor medicines and has anti-tumor activity, and a preparation method, a pharmaceutical composition and application thereof. Background Most PARP family members in humans exhibit monoADP ribotransferase activity. The MonoPARP family of proteins is closely related to the occurrence and progression of cancer, inflammation and neurodegenerative diseases. PARP7 is one of the members of the monoPARP protein family, a novel negative regulator of nucleic acid sensors in cells, which is overexpressed in a variety of tumor cells. Since cancer cells can "harbor" the immune system by inhibiting interferon signaling with PARP-7, many cancer cells rely on PARP-7 to survive. It was found that inhibiting PARP7 restores intracellular interferon signaling, restores the innate and adaptive immunity of the body, and thereby inhibits the growth of cancer cells. PARP7 inhibitors exhibit a durable tumor growth inhibiting effect in cancer models such as lung cancer, colorectal cancer and the like. No PARP-7 inhibitor is approved to be marketed, RBN-2397 developed by Ribon company is the first compound with strong inhibition activity on PARP-7, and clinical phase I research (NCT 04053673) is currently carried out. Aiming at the current target, no inhibitors with other structure types exist, therefore, a series of PARP7 inhibitors with brand new structure types are designed and synthesized and biological activity evaluation is carried out, and a foundation is provided for further research of the target. Disclosure of Invention Aiming at the problems of single structure type, limited activity and the like of the existing compounds, the invention aims to provide a quinazoline-4 (3H) -ketone compound with excellent anti-tumor activity, and a preparation method, a pharmaceutical composition and application thereof. According to the technical scheme, as a first aspect related to the invention, the quinazoline-4 (3H) -ketone compound has a structure shown in a formula (I), and the compound comprises an isomer, a pharmaceutically acceptable salt or a mixture thereof: Wherein: n is selected from 0,1, 2, 3, 4 or 5; m is selected from 0 or 1; r 1 is selected from hydrogen, halogen, cyano, trifluoromethyl, C 1～C6 alkyl, C 1～C6 alkoxy, methylthio, methylsulfonyl or carbamoyl; R 2 or R 3 are each independently selected from hydrogen, C 1～C6 alkyl, C 3～C6 cycloalkyl, heterocycloalkyl, cyano, halogen, difluoromethyl or trifluoromethyl, or R 2 and R 3 together with the carbon atom to which they are attached form C 3～C6 cycloalkyl, said C 3～C6 cycloalkyl being substituted with one or more of hydrogen, methyl, trifluoromethyl, 2-difluoroethyl, methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxy, acetoxy, carboxyl or methoxycarbonyl; r 4 is selected from aryl, heteroaryl, or 1, 3-benzodioxan substituted with one or more of hydrogen, halogen, cyano, trifluoromethyl, 2, -difluoroethyl, C 1～C6 alkyl, C 1～C6 alkoxy, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxy, methoxycarbonyl, or nitro; R 5 is selected from hydrogen, cyano, trifluoromethyl, C 1～C6 alkyl, C 1～C6 alkoxy or methanesulfonyl; A 1 is selected from-NH-, -O-, -S-or-N (CH 3) -; a 2 is selected from-NH-, -O-, -CH 2-、C3～C6 cycloalkyl, C 3～C6 heterocycloalkyl or 5-8 membered aromatic or heteroaromatic ring, wherein any position of the C 3～C6 cycloalkyl, heterocycloalkyl or 5-8 membered aromatic or heteroaromatic ring is substituted by one or more of hydrogen, halogen, methyl, ethyl, isopropyl, difluoromethyl sulfonyl, trifluoromethyl, trifluoromethylsulfonyl, methylsulfonyl, cyano, hydroxy, amino, methylamino, dimethylamino, diethylamino, acetamido, formylamino, nitro, methoxy or ethoxy; a 3 is selected from: Wherein R 6、R7 or R 8 are each independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxy, methoxy, amino, methylamino, dimethylamino, acetamido, carboxy or methoxycarbonyl. Preferably, in the above structure: n is selected from 0,1, 2, 3 or 4; r 1 is selected from hydrogen or halogen; R 2 or R 3 are each independently selected from hydrogen, methyl, fluoro or ethyl, and when R 2、R3 is different, the carbon atom connected with R 2、R3 is in racemized configuration, R configuration or S configuration; r 4 is selected from: wherein Y 1 and Y 2 each independently represent N, CH or CH-R 9, R9 is selected from hydrogen, trifluoromethyl, methyl, fluoro, chloro, bromo, cyano, methoxy, methanesulfonyl, 2-difluoroethyl or 4-trifluoromethylphenyl; R 5 is selected from hydrogen, methyl or trifluoromethyl; A 1 is selected from-NH-or-O-; a 2 is selected from the group consisting of-NH-, -C