CN115707708A - Wee1 kinase inhibitors - Google Patents
Wee1 kinase inhibitors Download PDFInfo
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- CN115707708A CN115707708A CN202110952817.9A CN202110952817A CN115707708A CN 115707708 A CN115707708 A CN 115707708A CN 202110952817 A CN202110952817 A CN 202110952817A CN 115707708 A CN115707708 A CN 115707708A
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a dihydropyrazolopyrimidinone Wee1 kinase inhibitor shown in a formula (I), pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof,
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a dihydropyrazolopyrimidinone Wee1 kinase inhibitor, pharmaceutically acceptable salts and stereoisomers thereof, a pharmaceutical composition and a preparation containing the compound, the pharmaceutically acceptable salts and the stereoisomers thereof, a method for preparing the compound, the pharmaceutically acceptable salts and the stereoisomers thereof, and application of the compound, the pharmaceutically acceptable salts and the stereoisomers thereof.
Background
Cancer is a malignant disease which is difficult to treat all over the world, and has high treatment difficulty and high mortality rate. The recent global tumor statistics in 2018 show that, to date, 1819 ten thousand new cases of cancer and 960 ten thousand cases of cancer death are estimated globally. In 2019, month 1, the national cancer center released the latest national cancer statistics for the first phase. About 392.9 million people develop national malignancies each year, with an average of over 1 million diagnosed cancers per day and 7.5 diagnosed cancers per minute. Cancer has become a major disease affecting the health of residents in China, and the prevention and treatment of cancer also faces a severe form.
Currently, radiotherapy and chemotherapy are the most effective means of treating cancer in addition to surgical resection, while radiotherapy is the most effective non-surgical treatment for malignant tumors. Both radiation and a considerable number of anticancer drugs can cause DNA damage. After DNA damage, a series of cellular responses such as damaged DNA repair can be initiated to improve the survival of tumor cells, which is also one of the mechanisms of tumor cells against chemoradiotherapy. If the damaged DNA is not repaired in time and intact, the tumor cells die due to apoptosis or/and mitotic disorders. Therefore, by inhibiting the repair of such DNA damage, the sensitivity of cancer cells to radiotherapy and chemotherapy can be improved, and the proliferation of cells can be inhibited.
Wee1 protein kinase is a member of the serine/threonine protein kinase family, and was first isolated by Nurse et al in fission yeast cells (S.pombe). In humans, wee1 contains 647 amino acids with a molecular weight of 96 kDa. In the DNA single-strand damage repair channel, wee1 is positioned at the downstream of an ATR signal channel, after the ATR signal channel is activated, CHK1 is phosphorylated, activated CHK1 can activate Wee1, CDC25 is inhibited (the phosphorylation of CDK1/Cyclin B complex is relieved, the activity of regulating and controlling the cell cycle is recovered), CDK1/Cyclin B is further phosphorylated, the CDK1/Cyclin B complex enters an inactive state, the cell cycle is blocked in a G2/M phase, and the time is gained for DNA damage repair; in addition, weel can regulate the repair of DNA double strand breaks that occur during DNA replication by phosphorylating CDK2, retarding the S phase of the cell cycle.
Among the entire DDR (DNA damage repair) pathway, wee1 plays a role mainly at the G2/M checkpoint. For p53 mutant tumor cells, the G2/M phase checkpoint is more dependent on the G1/S checkpoint defect itself to repair DNA damage, and the Wee1 inhibitor is more sensitive to p53 mutant tumor cells in terms of mechanism.
In conclusion, the Wee1 kinase inhibitor can not only synergistically enhance the effects of radiotherapy and chemotherapy, effectively inhibit tumor growth, but also reduce damage to normal cells and reduce side effects. At present, the research on the target medicine is still in the clinical experimental stage, and no medicine is on the market. Therefore, the development of a high-efficiency Wee1 kinase inhibitor has important clinical significance, and has wide market prospect in single use or combined application of other medicines.
Disclosure of Invention
The invention aims to provide a dihydropyrazolopyrimidinone compound which has a novel structure and has inhibition activity on Wee 1. Furthermore, the compounds can be used for inhibiting the activity of Wee1 kinase, thereby enhancing the immunity of organisms to tumors. Further, such compounds may also be useful in the treatment of one or more diseases mediated by Wee1, particularly cancer. The compounds have good inhibition effect on various cancer cells, and have higher exposure and better in-vivo drug effect in organisms.
The technical scheme of the invention is as follows:
in one aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
wherein X 1 、X 2 Are each independently selected from C, C (R) 3 ) Or N;
l is selected from-C (R) 4 )(R 5 )-、-O-、-N(R 6 ) -or-S-;
R 1 selected from C optionally substituted by substituents 1-6 Alkyl radical, C 2-6 Alkenyl or C 2-6 Alkynyl, the substituents are respectively and independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl、C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heteroaryl, optionally substituted with 1-3 of Q1;
ring B is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heteroaryl, optionally substituted with 1-3 of Q2;
ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with 1-3Q 3;
each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
each R 3 、R 4 、R 5 Each independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 1-6 Alkylcarbonyl or C 1-6 Alkoxy radical C 1-6 An alkyl group;
R 6 each independently selected from hydrogen and C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-6 Alkoxy radicalC 1-6 An alkyl group;
m is selected from 0, 1,2 or 3.
In some of the above embodiments, X 1 、X 2 Each independently selected from C, CH or N;
l is selected from-CH 2 -, -O-, -NH or-S-;
R 1 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl or C 2-6 An alkynyl group;
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring A is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl, optionally substituted with 1-2 of Q1;
ring B is selected from phenyl or 5-6 membered monocyclic heteroaryl optionally substituted with 1-2Q 2;
ring C is selected from the group consisting of 5-7 membered monocyclic cycloalkyl, 8-10 membered fused cyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 8-10 membered fused cyclic heterocyclyl, phenyl, naphthyl, 5-7 membered monocyclic heteroaryl or 8-10 membered fused heteroaryl optionally substituted with 1-2Q 3;
each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
m is selected from 0, 1 or 2.
In certain embodiments, X 1 、X 2 Each independently selected from C, CH or N;
l is selected from-CH 2 -, -O-, -NH or-S-;
R 1 is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl or C 2-4 An alkynyl group;
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl optionally substituted with 1-2Q 2S or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O) or S (O) 2 ；
Ring C is selected from the group consisting of 5-6 membered monocyclic cycloalkyl, 8-10 membered fused cyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, 8-10 membered fused cyclic heterocyclyl containing 1-3 heteroatoms or groups, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl containing 1-3 heteroatoms or groups, each independently selected from the group consisting of N, NH, O, S (O), or S (O) 2 ；
Each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
m is selected from 0, 1 or 2.
In certain embodiments, X 1 、X 2 Each independently selected from CH or N;
l is selected from-CH 2 -, -O-, -NH or-S-;
R 1 selected from methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl or propynyl;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 2;
ring C is selected from cyclopentyl, cyclohexyl, phenyl, a 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms or groups, or a 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O), optionally substituted with 1-2Q 3S 2 ；
Each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
m is selected from 0 or 1.
In certain embodiments, X 1 、X 2 Are respectively N; l is NH; r is 1 Is propenyl group;
each R 2 Each independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or halo C 1-6 An alkoxy group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in the contraposition of the ring B;
ring C is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0, 1 or 2.
In certain embodiments, X 1 、X 2 Are respectively N;
l is NH;
R 1 is propenyl group;
R 2 selected from halogen, hydroxy, amino, carboxyl, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino group,Halogen substituted C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in para position of the ring B;
ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, oxazolidinyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0 or 1.
In certain embodiments, X 1 、X 2 Are respectively N;
l is NH;
R 1 is propenyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in para position of the ring B;
ring C is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0.
In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in the following general formula (I-1):
each R 2 Each independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or halo C 1-6 An alkoxy group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in para position of the ring B;
ring C is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0, 1 or 2.
In certain of the embodiments described above, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (II) below:
wherein, ring A, ring C, Q, Q2, Q3, X 1 、X 2 、L、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 M is as defined in any of the above schemes; n is selected from 0, 1 or 2.
In certain of the embodiments described above, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (III) below:
wherein, ring A, ring C, Q, Q2, Q3, X 1 、X 2 、L、R 2 、R 3 、R 4 、R 5 、R 6 M is as defined in any of the above schemes; n is selected from 0, 1 or 2.
In some of the above embodiments, the compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has the structure represented by the following general formula (IV):
wherein, ring A, ring C, Q, Q2, Q3, R 2 M is as defined in any of the above schemes; n is selected from 0, 1 or 2.
In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (IV) below:
wherein the content of the first and second substances,
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring C is selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 3;
each Q1, each Q2, and each Q3 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0 or 1;
n is selected from 0 or 1.
In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure of formula (IV):
wherein, the first and the second end of the pipe are connected with each other,
ring a is selected from the following optionally substituted with 1-2Q 1:
ring C is selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is 0;
n is 0.
In certain embodiments, the compounds of the present invention, pharmaceutically acceptable salts thereof, or stereoisomers thereof, have the structure shown in formula (IV) below:
wherein the content of the first and second substances,
ring a is selected from the following optionally substituted with 1-2Q 1:
ring C is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is 0;
n is 0.
In some of the above embodiments, R 1 Is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl or C 2-4 Alkynyl. In some of the above embodiments, R 1 Selected from methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl or propynyl. In certain of the above embodiments, R 1 Selected from propyl, propenyl or propynyl. In some of the above embodiments, R 1 Selected from the group consisting of propenyl.
In certain of the above embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
X 1 is selected from C, -CH-or-N-;
each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 An alkyl group,Amino group C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
each Q1 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
each Q1 is independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain of the above embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
in certain of the above embodiments, ring a is selected from the following groups optionally substituted with 1-2Q 1:
in certain of the above embodiments, ring a is selected from the following optionally substituted with 1-2Q 1:
in certain of the above embodiments, each Q1 is independently selected from halogen, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy or halo C 1-6 An alkoxy group.
In certain of the above embodiments, each Q1 is independently selected from C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy or halo C 1-6 An alkoxy group.
In certain of the above embodiments, each Q1 is independently selected from methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, methoxymethyl, methoxyethyl, ethoxymethyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethyl, or trifluoromethoxy.
In certain of the above embodiments, ring B is selected from phenyl optionally substituted with 1-2Q 2 or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O) 2 ；
Each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxyl, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring B is selected from phenyl optionally substituted with 1-2Q 2 or 5-6 membered monocyclic heteroaryl containing 1-2 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O) 2 (ii) a Each Q2 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring B is selected from phenyl or a 5-6 membered monocyclic heteroaryl group containing 1-2 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O) 2 Preferably, L and X 2 In alignment with ring B.
In certain of the above embodiments, ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 2;
each Q2 is independentlyThe site is selected from halogen, hydroxyl, amino, nitro, cyano, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, preferably, L and X 2 In alignment with ring B.
In certain of the above embodiments, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, optionally substituted with 1-2Q 2, preferably, L and X 2 Is in the contraposition of the ring B;
each Q2 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain of the above embodiments, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 In alignment with ring B.
In certain of the above embodiments, ring B is selected from phenyl.
In certain of the above embodiments, ring C is selected from the group consisting of 5-6 membered monocyclic cycloalkyl optionally substituted with 1-2Q 3, 8-10 membered fused ring cycloalkyl, 5-6 membered monocyclic heterocyclyl, 1-3 heteroatoms or groups8-10 membered fused ring heterocyclic group of (1), phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O) or S (O) 2 ；
Preferably, ring C is selected from 5-6 membered monocyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, phenyl or 5-6 membered monocyclic heteroaryl, optionally substituted with 1-2 of Q3;
preferably, ring C is selected from cyclopentyl, cyclohexyl, phenyl, a 5-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms or groups, or a 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O), optionally substituted with 1-2Q 3S 2 ；
Preferably, ring C is selected from cyclopentyl, cyclohexyl, phenyl, a 5-6 membered monocyclic heterocyclic group containing 1-2 heteroatoms or groups, or a 5-6 membered monocyclic heteroaryl group containing 1-2 heteroatoms or groups, each independently selected from N, NH, O, S (O), or S (O), optionally substituted with 1-2Q 3 2 ；
Each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, oxazolidinyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 3;
each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group.
In certain of the above embodiments, ring C is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 3;
each Q3 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain of the above embodiments, ring C is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 3;
each Q3 is independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In some of the embodiments described above, eachQ3 is independently selected from C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group.
In certain of the above embodiments, each Q3 is independently selected from C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-6 Alkoxy radical C 1-6 An alkyl group.
In some of the above embodiments, X 1 、X 2 Each independently selected from C, CH or N. In some of the above embodiments, X 1 、X 2 Each independently selected from CH or N. In some of the above embodiments, X 1 、X 2 Are all N.
In certain of the above embodiments, L is selected from-CH (R) 5 )-、-O-、-N(R 6 ) -or-S-; r is 5 Selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 Alkoxy radical C 1-6 An alkyl group; r 6 Selected from hydrogen, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-6 Alkoxy radical C 1-6 An alkyl group.
In certain of the above embodiments, L is selected from-CH (R) 5 )-、-O-、-N(R 6 ) -or-S-; r 5 Selected from hydrogen, halogen, hydroxy, amino, methyl, ethyl, isopropyl, methoxy or trifluoromethyl; r is 6 Selected from hydrogen, methyl, ethyl or isopropyl.
In certain of the above embodiments, L is selected from-CH 2 -, -O-) -NH-or-S-. In some of the embodiments described above, the first and second, L is selected from-O-, -NH-or-S-. In some of the above embodiments, L is-NH-.
In certain of the above embodiments, each R is 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkyl carbonyl group.
In certain of the above embodiments, each R is 2 Each independently selected from halogen, hydroxy, amino, C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or halo C 1-6 An alkoxy group.
In certain of the above embodiments, each R is 2 Are each independently selected from halogen C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkyl or halo C 1-6 An alkoxy group.
In certain of the above embodiments, m is selected from 0, 1 or 2. In certain of the above embodiments, m is selected from 0 or 1. In certain of the above embodiments, m is selected from 0.
In certain of the above embodiments, n is selected from 0 or 1. In certain of the above embodiments, n is selected from 0.
The technical solutions of the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.
In certain embodiments, the compound of formula (I), formula (I-1), formula (II), formula (III), or formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, is selected from the group consisting of:
the invention also provides a pharmaceutical preparation which contains the compound shown in the general formula (I), the general formula (I-1), the general formula (II), the general formula (III) or the general formula (IV), the pharmaceutically acceptable salt or the stereoisomer thereof, and one or more medicinal carriers and/or diluents; the pharmaceutical preparation can be prepared into any clinically or pharmaceutically acceptable dosage form.
The present invention also provides a pharmaceutical composition comprising a compound of the aforementioned general formula (I), general formula (I-1), general formula (II), general formula (III) or general formula (IV), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more second therapeutically active agents selected from the group consisting of mitotic inhibitors, anticancer alkylating agents, anticancer metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors, interferons, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal anti-cancer agents, angiogenesis inhibitors, aromatase inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors and protein prenyltransferase inhibitors.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent used in the art of pharmaceutical formulation, and the selection of a particular carrier and/or diluent will depend on the mode of administration or the type and state of the disease used to treat a particular patient.
In another aspect, the present invention also relates to the use of a compound of the aforementioned formula (I), formula (I-1), formula (II), formula (III) or formula (IV), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, for the manufacture of a medicament for the prevention and/or treatment of diseases and related disorders mediated by Wee1, selected from cancers, including carcinoma in situ and metastatic cancers.
Furthermore, the invention also relates to the application of a pharmaceutical preparation containing the compound shown in the general formula (I), the general formula (I-1), the general formula (II), the general formula (III) or the general formula (IV), the pharmaceutically acceptable salt thereof or the stereoisomer thereof in preparing medicines, wherein the diseases and related symptoms are selected from cancers, and the cancers comprise carcinoma in situ and metastatic cancer.
Further, the present invention also relates to the use of a pharmaceutical composition comprising a compound of the aforementioned formula (I), formula (I-1), formula (II), formula (III) or formula (IV), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more second therapeutically active agents for the manufacture of a medicament for the treatment and/or prevention of diseases and related conditions mediated by Wee1, selected from the group consisting of cancer, including carcinoma in situ and metastatic cancer.
In the above embodiment, the cancer includes, but is not limited to, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, cancer of the female genital tract, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.
In the above embodiment, the second therapeutically active agent is selected from the group consisting of mitotic inhibitors, anticancer alkylating agents, anticancer metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors, interferons, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal anti-cancer agents, angiogenesis inhibitors, aromatase inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and protein prenyltransferase inhibitors.
In certain embodiments, the ingredients to be combined (e.g., the compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and the second therapeutically active agent) may be administered simultaneously or separately, sequentially and separately. For example, the second therapeutically active agent may be administered before, simultaneously with, or after the administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the components to be combined may also be administered in combination in the same formulation or in separate and distinct formulations.
In another aspect, the present invention also provides a method for treating diseases mediated by Wee1 and related disorders, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I), formula (I-1), formula (II), formula (III) or formula (IV), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, a formulation thereof or a pharmaceutical composition; the diseases and related conditions mediated by Wee1 are as defined above.
By "effective amount" is meant a dosage of a drug that reduces, delays, inhibits or cures a condition in a subject. The size of the administered dose is determined by the administration mode of the drug, the pharmacokinetics of the medicament, the severity of the disease, the individual physical signs (sex, weight, height, age) of the subject, and the like.
The medicine containing the compound of the general formula (I), the general formula (I-1), the general formula (II), the general formula (III) or the general formula (IV), the pharmaceutically acceptable salt or the stereoisomer thereof can be combined with radiotherapy to improve the treatment effect of the radiotherapy, and can be used as a radiotherapy sensitizer.
In another aspect, the compounds of the invention may also be used as sensitizers for other anticancer agents (second therapeutically active agents) in the field of cancer therapy. The second therapeutically active agent is as previously described. The sensitizer means a drug which enhances the therapeutic effect of radiotherapy and/or chemotherapy by being used in combination with radiotherapy and/or chemotherapy using an anticancer agent, additively or synergistically, in the field of cancer treatment.
[ detailed description of the invention ]
In the present invention, unless otherwise specified, scientific and technical terms used herein have meanings commonly understood by those skilled in the art, however, definitions of some terms are provided below for better understanding of the present invention. To the extent that the definitions and explanations of terms provided herein do not conform to the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
"C" according to the invention 1-6 Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C 1-4 Alkyl group "," C 1-3 Alkyl group "," C 1-2 Alkyl group "," C 2-6 Alkyl group "," C 2-5 Alkyl group "," C 2-4 Alkyl group "," C 2-3 Alkyl group "," C 3-6 Alkyl group and C 3-5 Alkyl group "," C 3-4 Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, and the like. "C" according to the invention 1-4 Alkyl "means C 1-6 Specific examples of the alkyl group having 1 to 4 carbon atoms.
"C" according to the invention 1-6 Alkoxy "means" C 1-6 alkyl-O- ", said" C 1-6 Alkyl "is as defined above. "C" according to the invention 1-4 Alkoxy "means" C 1-4 alkyl-O- ", said" C 1-4 Alkyl "is as defined above.
"C" according to the invention 1-6 Alkylthio "means" C 1-6 alkyl-S- ", said" C 1-6 Alkyl "is as defined above. "C" according to the invention 1-4 Alkylthio "means" C 1-4 alkyl-S- ", said" C 1-4 Alkyl "is as defined above.
The "hydroxy group C" of the present invention 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl "means C 1-6 One or more hydrogens of the alkyl group are each replaced by one or more hydroxyl groups, amino groups or halogens. C 1-6 Alkyl is as previously defined
The "hydroxy group C" of the present invention 1-6 Alkoxy, amino C 1-6 Alkoxy, halo C 1-6 Alkoxy "means" C 1-6 One or more hydrogens of "alkoxy" are replaced with one or more hydroxyl, amino, or halogen.
The "hydroxy group C" of the present invention 1-6 Alkylthio, amino C 1-6 Alkylthio, halo C 1-6 Alkylthio "means" C 1-6 Alkylthio "is one in which one or more hydrogens are replaced with one or more hydroxy, amino, or halogen.
"C" according to the invention 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino "means independently C 1-6 alkyl-NH-),
"C" according to the invention 2-6 Alkenyl "means a straight, branched or cyclic alkenyl group having 2 to 6 carbon atoms containing at least one double bond, and includes, for example," C 2-4 Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl and the like.
"C" according to the invention 2-6 Alkynyl "refers to a straight or branched chain alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, for example," C 2-4 Alkynyl "and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methyl-2-hexynyl and the like.
The term "3-to 10-membered cycloalkyl" as used herein is meant to include "3-to 8-membered monocycloalkyl" and "8-to 10-membered fused ring alkyl".
The "3-to 8-membered monocyclic alkyl" as used herein means a saturated or partially saturated monocyclic cyclic alkyl group having 3 to 8 carbon atoms and having no aromaticity, and includes "3-to 8-membered saturated monocyclic alkyl" and "3-to 8-membered partially saturated monocyclic alkyl"; preferred are "3-to 4-membered monocycloalkyl", "3-to 5-membered monocycloalkyl", "3-to 6-membered monocycloalkyl", "3-to 7-membered monocycloalkyl", "4-to 6-membered monocycloalkyl", "4-to 7-membered monocycloalkyl", "4-to 8-membered monocycloalkyl", "5-to 6-membered monocycloalkyl", "5-to 8-membered monocycloalkyl", "6-to 7-membered monocycloalkyl", "6-to 8-membered monocycloalkyl", "7-to 8-membered monocycloalkyl", "3-to 6-membered saturated monocycloalkyl", "5-to 8-membered saturated monocycloalkyl", "5-to 7-membered saturated monocycloalkyl", "5-to 6-membered saturated monocycloalkyl", and the like. Specific examples of said "3-to 8-membered saturated monocycloalkyl" include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl; specific examples of said "3-to 8-membered partially saturated monocycloalkyl" include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl-1,3-diene, cyclohexenyl-1,4-diene, cycloheptenyl, cycloheptyl-1,3-dienyl, cycloheptyl-1,4-dienyl, cycloheptyl-1,3,5-trienyl, cyclooctenyl, cyclooctyl-1,3-dienyl, cyclooctyl-1,4-dienyl, cyclooctyl-1,5-dienyl, cyclooctyl-1,3,5-trienyl, cyclooctatetraenyl.
The 8-10-membered fused ring group is a saturated or partially saturated non-aromatic cyclic group containing 8-10 ring atoms, which is formed by two or more cyclic structures sharing two adjacent carbon atoms, wherein one ring in the fused ring can be an aromatic ring, but the fused ring does not have aromatic property as a whole; including "8-9-membered fused ring group", "9-10-membered fused ring group", etc., the fusion mode may be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl and the like. Examples include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentanyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl, bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3 a-tetrahydropentanyl, 2, 3a,4,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6, 8a-octanaphthyl, 1,2,4a,5,6, 8a-hexahydronaphthyl, 8978-hexadecyl, benzocyclopentenyl, benzo (benzocyclopentyl), etc.
The "3-to 10-membered heterocyclic group" described in the present invention includes "3-to 8-membered monocyclic heterocyclic group" and "8-to 10-membered fused heterocyclic group".
The "3-to 8-membered heteromonocyclic group" as referred to herein means a saturated or partially saturated monocyclic cyclic group having at least one hetero atom or group (e.g., 1,2,3,4 or 5 hetero atoms, which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and which may have oxo group in the cyclic structure, and having 3 to 8 ring atoms, and which does not have aromaticity. The "3-to 8-membered heteromonocyclic group" described in the present invention includes "3-to 8-membered saturated heteromonocyclic group" and "3-to 8-membered partially saturated heteromonocyclic group". Preferably, the "3-8 membered heteromonocyclic group" described herein contains 1-3 heteroatoms or groups; preferably, the "3-to 8-membered heteromonocyclic group" of the present invention contains 1 to 2 heteroatoms or groups, and the heteroatoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered heteromonocyclic group" described herein contains 1-2 nitrogen atoms. The "3-to 8-membered heteromonocyclic group" is preferably "3-to 7-membered heteromonocyclic group", "3-to 6-membered heteromonocyclic group", "4-to 7-membered heteromonocyclic group", "4-to 6-membered heteromonocyclic group", "6-to 8-membered heteromonocyclic group", "5-to 7-membered heteromonocyclic group", "5-to 6-membered heteromonocyclic group", "3-to 6-membered saturated nitrogen-containing heteromonocyclic group", "5-to 6-membered saturated nitrogen-containing heteromonocyclic group", and the like. For example, containing only 1 or 2 nitrogen atoms, or, alternatively, containing one nitrogen atom and 1 or 2 other heteroatoms (e.g., oxygen and/or sulfur atoms). Specific examples of "3-8 membered heteromonocyclic group" include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, 3H-diazacyclopropenyl, azetidinyl, 1,4-dioxanyl, 3524 zxft 3424-dioxanyl, 3584 zxft 3523-dihydrothienyl, 3584-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, tetrahydrothienyl, etc piperidinonyl, tetrahydropyridonyl, dihydropiperidinonyl, piperazinyl, morpholinyl, 4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, and the like.
The "8-to 10-membered fused heterocyclic group" according to the present invention refers to a saturated or partially saturated, nonaromatic cyclic group containing 8 to 10 ring atoms, at least one ring atom of which is a heteroatom or a group, which is formed by two or more cyclic structures sharing two adjacent atoms with each other, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, and a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo, and includes, but is not limited to, "8-to 9-membered fused heterocyclic group", "9-to 10-membered fused heterocyclic group", and the like, in a fused manner including, but not limited to: 5-6 membered heterocyclo 5-6 membered heterocyclyl, 5-6 membered heterocyclo 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclyl, benzo 5-6 membered saturated heterocyclyl, 5-6 membered heteroarylo 5-6 membered saturated heterocyclyl; 5-6 membered heteroaryl is as previously defined; specific examples of the "8-to 10-membered fused heterocyclic group" include, but are not limited to: <xnotran> , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ; </xnotran> Tetrahydroimidazo [4,5-c ] pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 3724 zxft 24-dihydro-1H-thieno [ 4924 zxft 49624924-d ] imidazolyl, 3742 xzft 42-dihydro-1H-pyrrolo [ 8583 zxft 83-d ] pyridyl, 5383-d ] octreoyl, octahydroquinoxalinyl, hexahydrobenzo [ H-2-chromenyl ] imidazolyl, hexahydrobenzo [ 987H-4-chromenyl, 4H-4-oxo-1H-naphtho-3282-benzoxazinyl, 3438-pyridyl, 3724 zxft 3534-dihydrobenzo [ 3534-H-1H-yl ] imidazolyl, 3524-H-thieno [ 3538-yl ] imidazolyl, 3524-H-3524-yl, and the like.
The term "benzocyclopentyl", the structure of which refers to
(also known as 2,3-dihydro-1H-indenyl); the term "benzo-pyrrolidine" structurally includes
Etc.; the term "pyridotetrahydrofuranyl" structurally includes
Other of the other definitions defined aboveSpecific examples of the fused heterocyclic group "have a similar cyclic structure thereto.
The "6-to 10-membered aryl" as referred to herein includes "6-to 8-membered monocyclic aryl" and "8-to 10-membered fused-ring aryl".
The "6-to 8-membered monocyclic aryl" as referred to herein means a monocyclic aryl group containing 6 to 8 ring carbon atoms, examples of which include, but are not limited to: phenyl, cyclooctatetraenyl, and the like; phenyl is preferred.
The "8-to 10-membered fused ring aryl" as referred to herein means an unsaturated aromatic cyclic group having 8 to 10 ring carbon atoms, formed by two or more ring structures sharing two adjacent atoms with each other, and is preferably a "9-to 10-membered fused ring aryl", and specific examples thereof are naphthyl and the like.
The "5-to 10-membered heteroaryl" as referred to herein includes "5-to 8-membered monoheteroaryl" and "8-to 10-membered fused heteroaryl".
The "5-to 8-membered monoheteroaryl group" according to the present invention means a monocyclic cyclic group having aromaticity, which contains 5 to 8 ring atoms, at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom. The ring atoms (e.g., carbon atom, nitrogen atom, or sulfur atom) in the cyclic structure may be oxo. The "5-to 8-membered monoheteroaryl group" includes, for example, "5-to 7-membered monoheteroaryl group", "5-to 6-membered nitrogen-containing monoheteroaryl group", "6-membered nitrogen-containing monoheteroaryl group", and the like, in which the hetero atom contains at least one nitrogen atom, for example, contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom), or contains 2 nitrogen atoms and the other 1 or 2 hetero atoms (for example, oxygen atom and/or sulfur atom). Specific examples of "5-8 membered monocyclic heteroaryl" include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepinyl, 1,3-diazepanyl, azepinyl, and the like. The "5-6 membered monoheteroaryl" refers to a specific example containing 5 to 6 ring atoms in a 5-8 membered heteroaryl.
The "8-to 10-membered fused heteroaryl group" as used herein refers to an unsaturated aromatic cyclic structure having 8 to 10 ring atoms (at least one of which is a heteroatom such as nitrogen atom, oxygen atom or sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms with each other. Optionally, a ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo. Including "9-to 10-membered fused heteroaryl", "8-to 9-membered fused heteroaryl", and the like, which can be fused in a benzo-5-to 6-membered heteroaryl, 5-to 6-membered heteroaryl and 5-to 6-membered heteroaryl, and the like; specific examples include, but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furothiophene, pyrazoloxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, and the like.
The "carbon atom, nitrogen atom or sulfur atom is oxo" in the present invention means that C = O, N = O, S = O or SO is formed 2 The structure of (1).
The term "optionally substituted" as used herein means both the case where one or more hydrogen atoms on a substituent may be "substituted" or "unsubstituted" by one or more substituents.
"pharmaceutically acceptable salt" as used herein refers to an acidic functional group (e.g., -COOH, -OH, -SO) present in a compound 3 H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compounds (e.g. -NH2, etc.) with suitable inorganic or organic groupsSalts with anions (acids) include salts with inorganic or organic acids (e.g., carboxylic acids, etc.).
"isomers" as used herein refers to compounds of the present invention when they contain one or more asymmetric centers and thus may be present as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention may have asymmetric centers that each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. The compounds of the present invention, if they contain an olefinic double bond, include cis-isomers and trans-isomers, unless otherwise specified. The compounds of the invention may exist in tautomeric (one of the functional group isomers) forms having different points of attachment of hydrogen through one or more double bond shifts, e.g., a ketone and its enol form are keto-enol tautomers. The compounds of the present invention contain a spiro ring structure, and substituents on the ring may be present on both sides of the ring to form the opposite cis (cis) and trans (trans) isomers, depending on the steric structure of the ring. Each tautomer and mixtures thereof are included within the scope of the present invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.
The compounds of the invention may be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers in such a way as to give the individual enantiomers. Conventional resolution techniques include the formation of salts of the free base of each of the enantiomers of an enantiomeric pair using optically active acids (followed by fractional crystallization and regeneration of the free base), the formation of salts of the acid form of each of the enantiomers of an enantiomeric pair using optically active amines (followed by fractional crystallization and regeneration of the free acid), the formation of esters or amides of each of the enantiomers of an enantiomeric pair using optically pure acids, amines or alcohols (followed by chromatographic separation and removal of the chiral auxiliary), or the resolution of mixtures of the enantiomers of the starting materials or final products using various well-known chromatographic methods.
When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. The optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.
The "dosage form" of the present invention refers to a form prepared from the drug suitable for clinical use, including, but not limited to, powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injections and concentrated solutions for injections), sprays, aerosols, powders, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.
Advantageous effects of the invention
1. The compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof has excellent Wee1 activity inhibition effect and anti-tumor cell proliferation activity, has good pharmacokinetic property in organisms, has lasting effect and high exposure and bioavailability, and can treat and/or prevent diseases mediated by Wee 1.
2. The compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof has better inhibition and treatment effects on Wee1 mediated cancer in vivo and in vitro.
3. The compound, the pharmaceutically acceptable salt thereof or the stereoisomer thereof can synergistically enhance the effects of radiotherapy and chemotherapy, effectively inhibit the growth of tumors, and can reduce the damage to normal cells and reduce side effects.
4. The compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
Detailed description of the preferred embodiments
The technical solutions of the present invention will be described below in conjunction with the specific embodiments, and the above-mentioned contents of the present invention will be further described in detail, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1: preparation of 2-allyl-6- ((4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (preparation of Compound 1)
1. Preparation of 2- (4-nitrophenyl) octahydropyrrolo [1,2-a ] pyrazine
1-fluoro-4-nitrobenzene (338mg, 2.4mmol) was dissolved in DMSO (10 mL) and K was added 2 CO 3 (662mg, 4.8mmol), octahydropyrrolo [1,2-a]Pyrazine (300mg, 2.4 mmol) was reacted at 70 ℃ for 16h. After the reaction was completed, EA and water were added to the reaction solution, liquid-separation extraction was carried out three times, the organic phase was spin-dried, and preparative isolation was carried out in the forward direction (PE: EA = 1:5) to obtain a product (480 mg, yield 81.6%).
2. Preparation of 4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) aniline
2- (4-Nitrophenyl) octahydropyrrolo [1,2-a ] pyrazine (470mg, 1.9mmol) is dissolved in methanol (10 mL), palladium carbon (40 mg) is added, then the mixture is placed at the lower reaction temperature of 25 ℃ for reaction for 1h, suction filtration is carried out, and the filtrate is concentrated to obtain a crude product (400 mg).
3. Preparation of 2-allyl-6- ((4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one
2-allyl-1- (6- (2-hydroxyprop-2-yl) pyridin-2-yl) -6- (methylsulfinyl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (76 mg) was dissolved in toluene (3 mL), 4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) aniline (130 mg crude) and DIEA (129mg, 1mmol) were added and reacted at 25 ℃ for 10H. After the reaction, the reaction solution was spin-dried and purified by reverse phase chromatography (water: acetonitrile = 1:3) to obtain a product (25 mg).
Molecular formula C 29 H 34 N 8 O 2 Molecular weight 526.6LC-MS (M/e): 527.2 (M + H) + )
1 H-NMR(400MHz,MeOD)δ:10.1(s,1H),8.95(s,1H),8.10(t,1H),7.75(m,1H),7.65(m,1H),7.50–7.60(m,2H),6.90-7.00(m,2H),5.60–5.70(m,1H),5.30(s,1H),5.00(d,1H),4.83(d,1H),4.67(d,2H),3.75(m,1H),3.55(m,1H),3.05(m,2H),2.65(t,1H),2.35(t,1H),2.25(t,1H),2.05(m,2H),1.85(m,1H),1.70(m,2H),1.46(s,6H),1.40(m,1H).
Example 2: preparation of (R) -2-allyl-6- ((4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 1-2)
1. Preparation of (R) -2- (4-nitrophenyl) octahydropyrrolo [1,2-a ] pyrazine
1-fluoro-4-nitrobenzene (350mg, 2.5 mmol) was dissolved in DMSO (6 mL), K was added 2 CO 3 (685mg, 5.0mmol), (R) -octahydropyrrolo [1,2-a)]Pyrazine (313mg, 2.5 mmol) was reacted at 70 ℃ for 7 hours. The reaction was completed, extracted with water (20 mL) and ethyl acetate (20mL x2), the organic phase was washed with water (20mL x3), and the crude product was purified by silica gel column chromatography (PE: EA = 1:4) to obtain a product (400 mg, yield 65.2%).
2. Preparation of (R) -4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) aniline
(R) -2- (4-nitrophenyl) octahydropyrrolo [1,2-a ] pyrazine (400mg, 1.6 mmol) was dissolved in methanol (40 mL), palladium on carbon (120 mg) was added, the gas was replaced with hydrogen three times, reaction was carried out at 30 ℃ for 1h under a hydrogen atmosphere, the solid was removed by filtration, and the mixture was concentrated to give a crude product (350 mg).
3. Preparation of (R) -2-allyl-6- ((4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one
2-allyl-1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -6- (methylthio) -1,2-dihydro-3H-pyrazolo [3,4-d]Pyrimidin-3-one (100mg, 0.28mmol) was dissolved in toluene (15 mL), and m-chloroperoxybenzoic acid (63mg, 0.31mmol) was added thereto and reacted at 25 ℃ for 0.5 hour. The reaction was complete. N, N-diisopropylethylamine (180mg, 1.39mmol) and (R) -4- (hexahydropyrrolo [1,2-a) were added]Pyrazin-2 (1H) -yl) aniline (67mg, 0.31mmol) was reacted at 25 ℃ for 16H. The crude product was extracted with ethyl acetate (20 mL) and saturated sodium bicarbonate solution (15 mL) and purified by reverse phase chromatography (water: acetonitrile = 1:2) to give the product (42 mg, yield 28.5%). Molecular formula C 29 H 34 N 8 O 2 Molecular weight 526.6LC-MS (M/e): 527.2 (M + H) + )
1 H-NMR(400MHz,MeOD)δ:10.20-10.05(brs,1H),8.82(s,1H),8.12-8.03(m,1H),7.81-7.75(m,1H),7.65-7.46(m,3H),6.93(d,J＝8.8Hz,2H),5.71-5.60(m,1H),5.32(s,1H),5.00(d,J＝9.2Hz,1H),4.90-4.80(m,1H),4.68-4.67(m,2H),3.80-3.70(m,1H),3.65-3.55(m,1H),3.06-3.01(m,2H),2.75-2.65(m,1H),2.40-2.32(m,1H),2.27-2.20(m,1H),2.10-1.99(m,2H),1.90-1.80(m,1H),1.78-1.65(m,2H),1.46(s,6H),1.44-1.35(m,1H)。
Example 3: preparation of (S) -2-allyl-6- ((4- (hexahydropyrrolo [1,2-a ] pyrazin-2 (1H) -yl) phenyl) amino) -1- (6- (2-hydroxypropan-2-yl) pyridin-2-yl) -1,2-dihydro-3H-pyrazolo [3,4-d ] pyrimidin-3-one (Compound 1-1)
The compound 1-1 is prepared by referring to the preparation method of the compound 1-2, and the raw material (R) -octahydropyrrolo [1,2-a ] pyrazine is replaced by (S) -octahydropyrrolo [1,2-a ] pyrazine.
Compounds 2 to 4 were prepared in the same manner as or similar to examples 1 to 3.
Experimental protocol
An exemplary experimental scheme of a portion of the compounds of the invention is provided below to show the advantageous activity and advantageous technical effects of the compounds of the invention. It should be understood, however, that the following experimental protocols are only illustrative of the present disclosure and are not intended to limit the scope of the present disclosure.
Experimental example 1 inhibition of cell proliferation Activity by Compounds of the present invention
The test method comprises the following steps: cellTiter-Glo
Test article: the structural formula and the preparation method of the partial compound are shown in the preparation examples of the invention.
AZD1775, prepared according to the method disclosed in prior art WO2007126128, and having the structure shown below:
experimental method
1. Test materials and reagents
| Name(s) | Source | Goods number |
| DMEM high-sugar medium | Gibco | 11995-065 |
| RPMI-1640 medium | Gibco | A10491-01 |
| MEM medium | Gibco | 10370-021 |
| FBS (fetal bovine serum) | Gibco | 10099-141C |
| Horse serum | Solarbio | S9050 |
| Pyruvic acid sodium salt | Gibco | 11360-070 |
| Glutamine | Gibco | 35050-061 |
| Penicillin streptomycin double antibody | Gibco | 1507-063 |
| 0.25% Trypsin | Gibco | 25200-072 |
| 10 XDPBS (Du's phosphate buffer) | Gibco | 14200-075 |
| 96-hole bottom transparent white board | Corning | 3610 |
| Gemcitabine (Guitar decitabine) | MCE | HY-B0003 |
| CTG | Promega | G7571 |
2. Cell culture medium proportion and plating number
| Cell lines | Cell type | Growth characteristics | Plank Density/hole | Culture medium |
| MIAPaCa2 | Human pancreatic cancer | Wall-attached type | 2000 | DMEM+10％FBS+2.5％HS+1％P.S |
| A431 | Squamous cell carcinoma | Wall-attached type | 3000 | DMEM+10％FBS+1％P.S |
| SK-MES-1 | Human squamous cell lung carcinoma | Wall-attached type | 2000 | EMEM+10％FBS+1％P.S |
| LoVo | Human colorectal cancer cell | Wall-attached type | 2000 | DMEM+10％FBS+1％P.S |
| OVCAR-3 | Ovarian cancer cells | Wall-attached type | 2000 | RPMI-1640+20％FBS+1％P.S |
3. Procedure of experiment
3.1 preparation of Compounds
Test compounds in 10mM DMSO, diluted in DMSO 3-fold gradient, 8 concentrations. Test compounds were 10mM DMSO solutions, prepared in DMSO as 1000-fold solutions at the combined concentrations, i.e., 300. Mu.M, 100. Mu.M, 30. Mu.M.
A stock solution of Gemcitabine (Gemcitabine) 10mM is prepared, diluted 1000-fold to the highest final concentration, i.e., 100. Mu.M, and then diluted 5 concentrations with a DMSO 3-fold gradient.
3.2 test procedure
Culturing cells according to the recommended conditions of the source, removing the culture medium, washing with PBS, digesting with 0.25% trypsin, collecting cells after the complete culture medium is terminated, resuspending to the appropriate concentration, inoculating to 96-well plate, culturing at 37 deg.C and 5% CO in each well 2 The incubator was incubated for 24 hours.
The compound is used alone: compound solution at a final concentration of 1000 times, medium diluted 100 times, 10. Mu.L per well, 37 ℃,5% CO 2 And (5) detecting after the incubator is cultured for 72 hours.
Combination of compound and gemcitabine: gemcitabine final concentration 1000-fold solution, medium diluted 100-fold, 10. Mu.L per well, 37 ℃,5% CO 2 The incubator continues to incubate for 24 hours. Compound solution at a final concentration of 1000 times, dilution of the medium by 20 times, addition of 5. Mu.L per well, 37 ℃,5% CO 2 The incubator is used for detection after 24 hours of continuous culture.
The culture plate is placed at room temperature in advance, 60 mu L of CTG detection solution is added into each hole, the plate is protected from light, the plate is shaken on an orbital shaker for 2 minutes to crack cells, and after the reaction lasts for 20 minutes, the cold light value is read by a multifunctional microplate reader.
4. Data processing
Fitting the data using nonlinear S-curve regression to derive a dose-effect curve and calculating IC therefrom 50 The value is obtained.
Results of the experiment
TABLE 1 in vitro cell inhibitory Activity of Compounds of the invention alone
TABLE 2 in vitro cell inhibitory Activity of the Compounds of the invention in combination with Gemcitabine
Note that: IC showing gemcitabine as data in combination 50 The value is obtained.
Conclusion of the experiment
The compound disclosed by the invention has a good inhibition effect on a test cell strain when used alone, and has a remarkable synergistic effect on inhibition of the proliferation activity of the MIAPaCa2 cell when used together with gemcitabine.
Claims (11)
1. A compound shown as a formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof,
wherein the content of the first and second substances,
X 1 、X 2 are each independently selected from C, C (R) 3 ) Or N;
l is selected from-C (R) 4 )(R 5 )-、-O-、-N(R 6 ) -or-S-;
R 1 selected from C optionally substituted by substituents 1-6 Alkyl radical, C 2-6 Alkenyl or C 2-6 Alkynyl, the substituents are respectively and independently selected from halogen, hydroxyl, amino, carboxyl, cyano, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring A is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heteroaryl, optionally substituted with 1-3 of Q1;
ring B is selected from 5-7 membered monocyclic cycloalkyl, 5-7 membered monocyclic heterocyclyl, 6-8 membered monocyclic aryl or 5-8 membered monocyclic heteroaryl, optionally substituted with 1-3 of Q2;
ring C is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl optionally substituted with 1-3Q 3;
each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
each R 3 、R 4 、R 5 Each independently selected from hydrogen, halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy radical, C 1-6 Alkylcarbonyl or C 1-6 Alkoxy radical C 1-6 An alkyl group;
R 6 selected from hydrogen, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl or C 1-6 Alkoxy radical C 1-6 An alkyl group;
m is selected from 0, 1,2 or 3.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X 1 、X 2 each independently selected from C, CH or N;
l is selected from-CH 2 -, -O-, -NH or-S-;
R 1 is selected from C 1-4 Alkyl radical, C 2-4 Alkenyl or C 2-4 Alkynyl;
each R 2 Each independently selected from halogen, hydroxyl, amino, carboxyl and C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl optionally substituted with 1-2Q 2S or 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O) or S (O) 2 ；
Ring C is selected from the group consisting of 5-6 membered monocyclic cycloalkyl, 8-10 membered fused cyclic cycloalkyl, 5-6 membered monocyclic heterocyclyl, 8-10 membered fused cyclic heterocyclyl containing 1-3 heteroatoms or groups, phenyl, naphthyl, 5-6 membered monocyclic heteroaryl, or 8-10 membered fused heteroaryl containing 1-3 heteroatoms or groups, each independently selected from the group consisting of N, NH, O, S (O), or S (O) 2 ；
Each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
m is selected from 0, 1 or 2.
3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X 1 、X 2 each independently selected from CH or N;
l is selected from-CH 2 -, -O-, -NH-or-S-;
R 1 selected from methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl or propynyl;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 2;
ring C is selected from the group consisting of cyclopentyl, cyclohexyl, phenyl, a 5-6 membered monocyclic heterocyclic group containing 1-3 heteroatoms or groups, or a 5-6 membered monocyclic heteroaryl group containing 1-3 heteroatoms or groups, each independently selected from N, NH, O, S (O) or S (O), optionally substituted with 1-2Q 3S 2 ；
Each Q1, each Q2, each Q3 is independently selected from halogen, hydroxy, amino, nitro, cyano, carboxy, C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylthio, halogeno C 1-6 Alkoxy, halo C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 An alkylthio group;
m is selected from 0 or 1.
4. The compound of claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X 1 、X 2 are respectively N;
l is NH;
R 1 is propenyl;
R 2 selected from halogen, hydroxy, amino, carboxy, C 1-6 Alkyl radical, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkoxy or C 1-6 An alkylcarbonyl group;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in para position of the ring B;
ring C is selected from cyclopentyl, cyclohexyl, phenyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydropyrazolyl, oxazolidinyl, thiazolidinyl, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyranyl, thiopyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0 or 1.
5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,
X 1 、X 2 are respectively N;
l is NH;
R 1 is propenyl;
ring a is selected from the following optionally substituted with 1-2Q 1:
ring B is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl, preferably, L and X 2 Is in para position of the ring B;
ring C is selected from phenyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazole, 1,2,4-triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is selected from 0.
6. The compound of any one of claims 1-5, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having a structure represented by the following general formula (II):
wherein, ring A, ring C, Q, Q2, Q3, X 1 、X 2 、L、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 M is as defined in any one of claims 1 to 5; n is selected from 0, 1 or 2.
7. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having a structure represented by the following general formula (IV):
wherein the content of the first and second substances,
ring a is selected from the following optionally substituted with 1-2Q 1:
ring C is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl optionally substituted with 1-2Q 3;
each Q1 and each Q3 is independently selected from halogen, hydroxyl, amino and C 1-6 Alkyl radical, C 1-6 Alkylamino radical, di (C) 1-6 Alkyl) amino, halo C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy, hydroxy C 1-6 Alkoxy or amino C 1-6 An alkoxy group;
m is 0;
n is 0.
8. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the following compounds:
9. a pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in a pharmaceutically acceptable dosage form, wherein the pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising a compound of any one of claims 1-8, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, comprising one or more second therapeutically active agents selected from the group consisting of mitotic inhibitors, anticancer alkylating agents, anticancer metabolic antagonists, anticancer platinum coordination compounds, anticancer camptothecin derivatives, antitumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, anticancer tyrosine kinase inhibitors, interferons, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormonal anticancer agents, angiogenesis inhibitors, aromatase inhibitors, cell growth inhibitors, targeting antibodies, HMG-CoA reductase inhibitors, and protein prenyltransferase inhibitors.
11. Use of a compound of any one of claims 1-8, a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical formulation of claim 19, or a pharmaceutical composition of claim 10 in the manufacture of a medicament for the treatment and/or prevention of a Wee 1-mediated disease and related conditions selected from cancer;
preferably, the cancer is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, cancer of the female reproductive tract, lymphoma, neurofibromas, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.
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| WO2023138362A1 (en) * | 2022-01-18 | 2023-07-27 | 江苏天士力帝益药业有限公司 | Wee1 inhibitor, preparation therefor, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023138362A1 (en) * | 2022-01-18 | 2023-07-27 | 江苏天士力帝益药业有限公司 | Wee1 inhibitor, preparation therefor, and use thereof |
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