CN118027066A - Thienopyrimidinone compound, preparation method and application thereof - Google Patents

Thienopyrimidinone compound, preparation method and application thereof Download PDF

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CN118027066A
CN118027066A CN202310329899.0A CN202310329899A CN118027066A CN 118027066 A CN118027066 A CN 118027066A CN 202310329899 A CN202310329899 A CN 202310329899A CN 118027066 A CN118027066 A CN 118027066A
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alkyl
cycloalkyl
deuterium
halogen
substituted
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张国锋
陶志刚
郭淑春
郭海兵
胡贺
梁超
蔡金娜
陈春麟
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Xiamen Baotai Biotechnology Co ltd
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Xiamen Baotai Biotechnology Co ltd
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Abstract

The invention discloses a thienopyrimidinone compound, a preparation method and application thereof. Specifically, a compound shown as a formula (I) has excellent Cdc7 kinase inhibitor activity and can be used for treating tumors mediated by Cdc7 kinase.

Description

Thienopyrimidinone compound, preparation method and application thereof
Technical Field
The invention relates to the field of medicines, in particular to a thienopyrimidinone compound which can be used as a Cdc7 kinase inhibitor and can be used for treating Cdc7 mediated or related tumor and other proliferative diseases.
Background
Cyclin 7 (Cdc 7) is a highly conserved serine/threonine kinase expressed by the ubiquitously essential gene Cdc7 and is widely found in almost all tissue cells. Cdc7 is activated by interaction with subunit DBF 4. The initiation of DNA replication in the cell cycle is critical and plays an important role in the normal apoptosis process.
In recent years, people observe abnormally high expression of Cdc7 in a plurality of clinical tumors such as cancer cell lines, breast cancer, colorectal cancer, lung cancer and the like, and the abnormally high expression of Cdc7 has high correlation with abnormal proliferation and metastasis of the tumors. Meanwhile, the abnormally high expression of Cdc7 has high correlation with anti-chemotherapy drugs. Several preclinical experiments have demonstrated that Cdc7 inhibitors can produce better synergistic therapeutic effects when used in combination with other antitumor agents.
Recent research results indicate that Cdc7 and cyclin-dependent kinase (Cdk 1) act to complement each other in promoting the transition of the mammalian cell cycle from G1 phase to S phase. For different human and mouse cell types, at least one of the two kinases Cdc7 and Cdk1 must be present to allow for normal synthesis of DNA in the cell. Thus, the development of Cdc7 inhibitors has a higher safety window than the development of other pan-essential gene inhibitors.
Aiming at Cdc7 targets, no successful medicine is developed at present. The fastest growing Cdc7 inhibitor worldwide is TAK-931 (CAS: 1330782-76-7) reported by the Wuta-tsu corporation, and clinical stage II is currently completed. Therefore, developing a new drug with higher efficiency, lower toxicity, high selectivity and better DMPK (drug metabolism and pharmacokinetics) characteristics can provide new treatment options for tumor patients, and has great clinical value.
Disclosure of Invention
The invention aims to provide a novel Cdc7 kinase inhibitor, a preparation method thereof, a pharmaceutical composition containing the same and application of the novel Cdc7 kinase inhibitor in medicines, and particularly, the novel Cdc7 kinase inhibitor can be widely applied to preparation of medicines for treating tumor diseases mediated by Cdc7 kinase and is hopeful to be developed into a novel generation of Cdc7 kinase inhibitor. Specifically, the invention provides the following technical scheme:
In one aspect, the present invention provides a compound of formula (I), stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
Wherein,
X 1 is S, O or CH 2;
X 2 is S, O or C;
R 1 is selected from halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8;
When X 2 is S or O, R 2 is absent; when X 2 is C, R 2 is selected from halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 cycloalkyl, 3-12 membered heterocyclyl, C 2-10 aryl, 5-10 membered heteroaryl 2-10 and-N (R 2-10 optionally further substituted with one or more carbon atoms selected from deuterium, halogen, cyano, nitro, azido, C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 2-10 alkyl, deuterium substituted C 2-10 alkyl, C 2-10 cycloalkyl, 3-12 membered heterocyclyl, C 2-10 aryl, 5-10 membered heteroaryl 2-10 and-N (substituted with R 2-10 substituents or any two of the same or different substituents on R 2-10 form a C 2-10 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which it is directly attached; R 2-10 is selected from deuterium, halogen, cyano, nitro, azido, C 2-10 alkyl, substituted C 2-10 alkyl, halo C 2-10 alkyl, C 2-10 cycloalkyl, C 2-10 alkenyl, C 2-10 aryl, C 2-10 heteroaryl, 5-10 membered heteroaryl and-N (substituted with R 2-10 substituents on R 2-10 or two of 3-12 membered heterocyclyl, R 2-10 is attached directly to the C 2-10 cycloalkyl, C 2-10 cycloalkyl or C 2-10 -3 membered heterocyclyl);
Ring a is C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein Y is CR 5 or N, Z is CR 5' or N; r 4、R5、R5' is each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, deuterated C 1-10 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8, or ring A and either R 4 or R 5 together form a C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl;
With the proviso that when Y is selected from-C (R 5) -, and Z is selected from N, ring A is connected with R 4 to form a C 7-12 bridged cycloalkyl group, Z is a bridgehead atom, or ring A is connected with R 5 to form a 7-12 membered bridged heterocyclic group, Y is a bridgehead atom;
Each R 6 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 9R10;
Each R 7 is independently selected from the group consisting of hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 9R10;
Each R 8 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 9R10;
Each R 9 and each R 10 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, sulfamoyl, dimethylaminosulfonyl, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl, said groups being independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, mono C438 alkylamino and di C65343 alkylamino;
Or R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl, said 4-10 membered heterocyclyl or 4-10 membered heteroaryl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl;
each r is independently selected from 0, 1 or 2;
n is selected from 0,1, 2 or 3.
In a further preferred embodiment of the present invention,Is C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein Y is CR 5 or N; z is CR 5' or N; r 4、R5、R5' is each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, deuterated C 1-10 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8, or R 5 is C 1-4 alkylene, Y is connected to the ring atom of ring A through R 5,Is C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl; or R 4 is C 1-4 alkylene, Z is attached to the ring atom of ring A by R 4,/>Is C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl;
Provided that when Y is CR 5 and Z is N, Is C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl, wherein R 5 is C 1-4 alkylene, Y is connected to the ring atom of ring A via R 5, or R 4 is C 1-4 alkylene, Z is connected to the ring atom of ring A via R 4.
Preferably selected from the group consisting of compounds of formula (II):
Wherein,
R 1 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8;
R 2 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、-SF5、-S(O)rR6、-P(O)R8R9、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8 optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8 being substituted with any two substituents on R 2 which are the same or different, or with the carbon atom to which they are directly attached, form C 3-6 cycloalkyl or 3-6 membered heterocyclyl);
R 3 is selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl);
Ring a is C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein Y is CR 5 or N, Z is CR 5' or N; r 4、R5、R5' is each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8, or ring A and either R 4 or R 5 together form a C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl;
With the proviso that when Y is selected from-C (R 5) -, and Z is selected from N, ring A is connected with R 4 to form a C 7-12 bridged cycloalkyl group, Z is a bridgehead atom, or ring A is connected with R 5 to form a 7-12 membered bridged heterocyclic group, Y is a bridgehead atom;
R 6、R7、R8、R9、R10, R and n are as defined previously.
As a further preferred embodiment, each R 6 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-10 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 9R10;
Each R 7 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 9R10;
Each R 8 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 9R10;
Each R 9 and each R 10 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, sulfamoyl, dimethylaminosulfonyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and C 1-4 alkanoyl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and di C9832 alkanoyl;
Or R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group optionally being further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered hetero epoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered hetero aryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl.
Preferably selected from the group consisting of compounds of formula (IIIA):
Wherein R 11 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10, and-N (R 9)-C(O)R8).
The rings A, Y, Z, R 2、R3、R4、R6、R7、R8、R9、R10, r and n are as previously defined.
As a still further preferred embodiment, R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl;
r 6、R7、R8、R9、R10 and R are as defined previously.
Preferably selected from the compounds of the following formula (IVA) or (IVB):
Wherein,
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10;
R 3 is selected from deuterium, halogen, cyano, nitro, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(O)NR9R10 and-N (R 9)-C(O)R8, or two R 3 atoms directly attached thereto form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
R 4 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl;
The rings A, Z, R 6、R7、R8、R9、R10, r and n are as previously defined.
As a further preferred embodiment, R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10;
r 3 is selected from deuterium, =o, =ch 2, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-R 7, or two atoms to which R 3 are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
R 4 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl;
Ring a is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl.
As a still further preferred embodiment, R 2 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, alkoxy;
r 4 is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, tridentate methyl, dideuteromethyl, monodeuteromethyl;
R 11 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, preferably from the group:
n is selected from 0.
Preferably selected from the compounds of the following formulae (IVC) or (IVD):
In formula (IVC), ring A is linked to R 4 to form a 7-10 membered bridged heterocyclic group, the nitrogen atom on ring A directly linked to R 4 being a bridgehead atom;
In formula (IVD), ring A is linked to R 5 to form a 7-10 membered bridged heterocyclyl, the carbon atom on ring A directly linked to R 5 being the bridgehead atom;
R 2、R3、R11 and n are as defined above.
As a further preferred embodiment, R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
R 3 is selected from deuterium, =o, =ch 2, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-8 cycloalkyl, -O-R 7, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl.
As a still further preferred embodiment, R 2 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, alkoxy;
R 3 is selected from =o, =ch 2, hydroxy, deuterium, methyl, ethyl, propyl, isopropyl, mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-fluoromethyl, di-fluoromethyl, tri-fluoromethyl, fluoro, chloro, bromo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
R 11 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
ring a is further linked to R 4 or R 5 to form the following group:
preferably, the compound is selected from the following compounds of formula (VA):
Wherein R 2 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、-SF5、-S(O)rR6、-P(O)R8R9、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10, and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10, and-N (R 9)-C(O)R8).
R 6、R7、R8、R9、R10 and R are as defined above
As a further preferred embodiment, R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and C 3-8 cycloalkyl.
As a still further preferred embodiment, R 2 is selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from the group consisting of halogen, -O-R 7、-NR9R10;
R 11 is selected from hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl.
As a still further preferred embodiment, R 2 is selected from the group consisting of fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, optionally further substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, alkoxy; r 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Preferably selected from the group consisting of compounds of the following formula (IIIB):
R 1 is selected from halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
R 6、R7、R8、R9、R10, R and n are as defined previously.
As a further preferred embodiment, R 1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl;
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10.
As a still further preferred embodiment, R 1 is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridinyl,The above groups are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl
R 2 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, alkoxy.
As a most preferred embodiment, the following compounds are selected:
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In another aspect, the present invention provides a method for preparing the above-described compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, comprising the steps of:
Wherein PG is a protecting group such as benzyl, and the other groups are as defined in formula (II)
Halogenating the compound A and removing the protecting group to obtain the compound in the formula (II)
Wherein PG is a protecting group such as benzyl, and the other groups are as defined in formula (II)
And reacting the compound A with benzyl alcohol and the like to obtain a compound B or a compound B 'or a mixture of the compound B and the compound B', carrying out halogenation and metal catalysis reaction to obtain a compound C or a compound C 'or a mixture of the compound C and the compound C', and finally removing a protecting group to obtain the compound in the formula (II).
The various starting materials, intermediates and compounds described herein may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatography. These compounds can be characterized using conventional methods such as by melting point, mass spectrometry, nuclear magnetic resonance, and various spectroscopic analyses.
The invention also relates to a pharmaceutical composition comprising the above compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention also relates to the use of the above compound, a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and/or prevention of diseases mediated by Cdc7 kinase, including but not limited to, blood cancer, cervical cancer, lung cancer, prostate cancer, mesothelioma, thyroid cancer, renal cancer, biliary tract cancer, bladder cancer, breast cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, sarcoma, skin cancer, ovarian cancer, liver cancer, colorectal cancer and pancreatic cancer.
The invention also relates to application of the compound, the stereoisomer or the pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating tumors.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 shows the inhibition of colorectal cancer COLO 205 cell xenograft tumor growth.
Detailed Description
Through extensive and intensive studies, the inventor provides a Cdc7 kinase inhibitor with a novel structure through a large number of screening and testing. The present invention has been completed on the basis of this finding.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …", or "consisting of …".
"Alkyl" refers to straight or branched chain saturated aliphatic hydrocarbon groups, preferably straight and branched chain alkyl groups comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof, and the like. "C 1-10 alkyl" refers to straight chain and branched alkyl groups comprising from 1 to 10 carbon atoms, and "C 1-4 alkyl" refers to straight chain and branched alkyl groups comprising from 1 to 4 carbon atoms.
The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) selected independently from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituent of R 9)-C(O)R8).
"Alkylene" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent hydrocarbon group. The two groups attached to the alkylene group may be attached to the same or different atoms on the alkylene group. For example, the linear alkylene group may be a divalent group of- (CH 2)n -where n is 1, 2, 3, or 4-representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene.
"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, and cycloalkyl is classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, e.g., "C 3-12 cycloalkyl" refers to cycloalkyl including 3 to 12 carbon atoms, and "C 3-6 cycloalkyl" refers to cycloalkyl including 3 to 6 carbon atoms, wherein:
Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more (preferably 1,2 or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single-, double-, or multiple-spirocycloalkyl groups according to the number of common spiro atoms between rings, and include, but are not limited to:
"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups including, but not limited to:
"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms that are not directly attached, and which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of constituent rings, include, but are not limited to:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by substituents of R 9)-C(O)R8).
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which refers to a cyclic hydrocarbon that may contain one or more (preferably 1,2, or 3) double bonds, but no ring has a fully conjugated pi electron system, heterocyclyl wherein one or more (preferably 1,2,3 or 4) ring atoms are selected from nitrogen, oxygen or heteroatoms of S (O) r (where r is an integer 0, 1, 2) but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferred is a heterocyclic group including 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclic group" means a ring group including 3 to 6 ring atoms, "4-6 membered heterocyclic group" means a ring group including 4 to 6 ring atoms, "4-10 membered heterocyclic group" means a ring group including 4 to 10 ring atoms, "3-12 membered heterocyclic group" means a ring group including 3 to 12 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as the spiro atom) in common between monocyclic rings, wherein one or more (preferably 1,2,3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) r (wherein r is an integer 0,1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1,2 or 3), but none of the rings has a fully conjugated pi-electron system. The spiroheterocyclyl groups are classified as single spiroheterocyclyl groups, double spiroheterocyclyl groups or multiple spiroheterocyclyl groups according to the number of common spiro atoms between rings. Spiroheterocyclyl groups include, but are not limited to:
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"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more (preferably 1,2, 3 or 4) of which may contain one or more (preferably 1,2 or 3) double bonds, but none of which has a fully conjugated pi electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integer 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, they may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclylalkyl groups, including but not limited to:
"bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly attached, which may contain one or more (preferably 1,2, or 3) double bonds, but none of which have a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3, or 4) ring atoms are selected from nitrogen, oxygen, or a heteroatom of S (O) r (where r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclyl groups that may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic include, but are not limited to:
The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, including but not limited to:
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by R 9)-C(O)R8).
"Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., ring with adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group of 5-10 or 5-8 carbons, e.g., "C 6-10 aryl" refers to an all-carbon aryl group of 6-10 carbons, including but not limited to phenyl and naphthyl, "C 6-8 aryl" refers to an all-carbon aryl group of 6-8 carbons, which aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
The "aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by substituents of R 9)-C(O)R8).
"Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2,3 or 4) heteroatoms including nitrogen, oxygen and S (O) r (where r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 or 5 to 6 ring atoms, e.g., 5 to 6 membered heteroaryl refers to a heteroaromatic system containing 5 to 6 ring atoms, 5 to 8 membered heteroaryl refers to a heteroaromatic system containing 5 to 8 ring atoms, 5 to 10 membered heteroaryl refers to a heteroaromatic system containing 5 to 10 ring atoms including, but not limited to, furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, including but not limited to:
"heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituents of R 9)-C(O)R8).
"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2 to 10 or 2 to 4 carbons, e.g., C 2-10 alkenyl refers to a straight or branched alkenyl group containing 2 to 10 carbons, and C 2-4 alkenyl refers to a straight or branched alkenyl group containing 2 to 4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
"Alkenyl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted with R 9)-C(O)R8 substituents).
"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched alkynyl group containing 2 to 10 or 2 to 4 carbons, e.g., C 2-10 alkynyl refers to a straight or branched alkynyl group containing 2 to 10 carbons, and C 2-4 alkynyl refers to a straight or branched alkynyl group containing 2 to 4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituent of R 9)-C(O)R8).
"Alkoxy" refers to an-O-alkyl group wherein alkyl is as defined above, e.g., "C 1-10 alkoxy" refers to an alkyloxy group containing 1 to 10 carbons, and C 1-4 alkoxy "refers to an alkyloxy group containing 1 to 4 carbons, including but not limited to methoxy, ethoxy, propoxy, butoxy, and the like.
"Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituent of R 9)-C(O)R8).
"Cycloalkoxy" refers to-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C 3-12 Cycloalkoxy" refers to cycloalkyloxy of 3-12 carbons, and "C 3-6 Cycloalkoxy" refers to cycloalkyloxy of 3-6 carbons, including but not limited to cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituent of R 9)-C(O)R8).
"Heteroepoxy" refers to an-O-heterocyclic group wherein the heterocyclic group is defined as described above and includes, but is not limited to, azetidinyloxy, oxetyloxy, azetidinyloxy, nitrogen, oxetyloxy, and the like.
"Heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted by the substituents of R 9)-C(O)R8).
The definition of R 6、R7、R8、R9、R10 is as described above.
"C 1-10 alkanoyl" refers to a monovalent radical remaining after removal of the hydroxyl group of a C 1-10 alkyl acid, also commonly referred to as "C 0-9 alkyl-C (O) -", e.g., "C 1 alkyl-C (O) -" refers to acetyl; "C 2 alkyl-C (O) -" refers to propionyl; "C 3 alkyl-C (O) -" refers to butyryl or isobutyryl.
"Halo-substituted C 1-10 alkyl" refers to 1-10 carbon alkyl groups on the alkyl groups optionally substituted with fluorine, chlorine, bromine, iodine atoms, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"Deuterium substituted C 1-10 alkyl" refers to 1-10 carbon alkyl groups where the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-, di-, tri-deuteromethyl, and the like.
"Halogen" means fluorine, chlorine, bromine or iodine.
"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not, i.e., instances where it is substituted or unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"Substituted" means that one or more "hydrogen atoms" in the group are substituted independently of each other with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, in line with the theory of chemical valence, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., olefins).
"Stereoisomer" is named stereoisomer, and refers to an isomer produced by the different spatial arrangements of atoms in a molecule, and can be classified into cis-trans isomers and enantiomers, and also into enantiomers and diastereomers. Stereoisomers due to rotation of single bonds are known as conformational isomers (conformational stereo-isomers), sometimes also known as rotamers (rotamer). Stereoisomers due to bond length, bond angle, double bonds in the molecule, rings, etc. are called configurational isomers (configuration stereo-isomers) which are classified into two types. Wherein the isomer due to the inability of the double bond or single bond of the ring-forming carbon atom to rotate freely becomes the geometric isomer (geometric isomer), also known as cis-trans isomer (cis-trans isomer), and is classified into two configurations of Z, E. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers with different optical properties due to the lack of trans-axisymmetry in the molecule are called optical isomers (optical isomers) and are classified into R, S configurations. "stereoisomers" as used herein, unless otherwise indicated, are understood to include one or more of the enantiomers, configurational isomers and conformational isomers described above.
"Tautomer" refers to structural isomers having different energies that can be converted to each other by a low energy barrier. For example proton tautomers include tautomers by proton transfer, valence tautomers include interconversions by recombination of some of the bond-forming electrons. For exampleAnd/>Are tautomers. In the present invention, unless otherwise indicated, "tautomers" and all tautomeric forms of the compounds are within the scope of the invention.
By "pharmaceutically acceptable salts" is meant in the present invention pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts may be prepared by methods known in the art.
"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as tritium (3 H), iodine-125 (125 I) or C-14 (14 C). For another example, deuterium can be formed by substituting deuterium for hydrogen. All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
The main advantages of the invention include:
The compound of the invention has excellent inhibitory activity on Cdc7/DBF4 and strong inhibitory activity on tumor cells. In addition, compared with a control compound TAK-931, the compound disclosed by the invention has better absorption and bioavailability in mice, and has a remarkable inhibition effect on tumors in the mice. The results show that the compound is expected to become a Cdc7 kinase inhibitor which is more efficient and has lower toxicity than similar products, and provides a new choice for treating proliferative diseases such as tumors and the like.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using a Bruker AVANCE-400/500 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3) as solvents and Tetramethylsilane (TMS) as internal standard.
The LC-MS measurement was performed by using an Agilent 6120 mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being dry solvent and the reaction temperature being in degrees celsius (°c) without specific description.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In the invention, when SFC chiral resolution is involved, the first component is marked as A, and the later component is marked as B. For example, a pair of enantiomers of compound 1 were chiral resolved by SFC to give two enantiomers, designated compound 1A and compound 1B, respectively. The retention time is Rt.
Intermediate preparation intermediate A1: synthesis of 7-bromo-2- (quinuclidin-2-yl) -6- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one
Intermediate A1 was synthesized by the following route
The first step: synthesis of Compound A1-1
Methyl 3-amino-5-bromothiophene-2-carboxylate (5 g,21 mmol) was dissolved in 1, 4-dioxane (50 mL) and water (10 mL), and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.52 g,2.1 mmol) and potassium carbonate (5.8 g,42 mmol) were added and the reaction stirred in an oil bath at 90℃under nitrogen overnight. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (ethyl acetate: petroleum ether=0% -50%) to give compound A1-1.
LC-MS(ESI+)m/z:308.1(M+H)+。
And a second step of: synthesis of Compound A1-2
Compound A1-1 (5 g,16.3 mmol) was dissolved in acetonitrile (50 mL), triethylamine solution (16 mL,124.9 mmol) and quinuclidine-2-carbonyl chloride (3.2 g,18.7 mmol) were added and the reaction stirred at room temperature overnight. After monitoring that the reaction of the raw material A1-1 is complete, the reaction solution is cooled to room temperature. Extraction was performed using a mixed solvent (dichloromethane: methanol=10:1), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column (ethyl acetate: petroleum ether=0% -100%) to give compound A1-2.
LC-MS(ESI+)m/z:445.2(M+H)+。
And a third step of: synthesis of Compounds A1-3
A1-2 (4.5 g,10.1 mmol) was dissolved in N, N-dimethylacetamide (27 mL), potassium tert-butoxide (5.7 g,50.6 mmol) and formamide (180 mL) were added and the reaction stirred in an oil bath at 70deg.C for 1h. The reaction solution was cooled to room temperature and purified using a reverse phase column to give compounds A1-3.
LC-MS(ESI+)m/z:412.1(M+H)+。
Fourth step: synthesis of Compound A1
In a three-necked flask equipped with an internal temperature thermometer, methylene chloride (10.0 mL), compound A1-3 (1.00 g), N-bromosuccinimide (0.87 g) was added in portions, and the mixture was stirred at 25℃for 2 hours. LCMS monitored completion of the reaction. The reaction solution was concentrated to dryness and purified by flash column chromatography (methanol/dichloromethane=0-10%) to give compound a1 7-bromo-2- (quinuclidin-2-yl) -6- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one.
LC-MS(ESI+)m/z:490.1,492.1(M+H)+。
Preparation of specific Compounds
Example 1: synthesis of Compound 1A and Compound 1B
Compounds 1A and 1B were synthesized by the following route:
In a three-necked flask equipped with an internal temperature thermometer, 1, 4-dioxane (8.0 mL), compound A1 (0.75 g), dioxane hydrochloride solution (4M, 4.0 mL) was added and stirred at 25℃for 2h. LCMS monitored completion of the reaction. The reaction solution was concentrated to dryness, dissolved in anhydrous methanol (200 mL), added with sodium carbonate (2.0 g), stirred at 25℃for 5min, filtered, the filter cake was rinsed with anhydrous methanol (80 mL), and the filtrate was concentrated to give compound 1.
Chiral resolution of compound 1 (100 mg) by Supercritical Fluid Chromatography (SFC) gave compound 1A (R or S) -7-bromo-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =1.60 min) and compound 1B (S or R) -7-bromo-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =2.82 min) as enantiomers.
Separation conditions:
Chromatographic column: DAICEL CHIRALPAK IH,40MM,I.D..times.250 mm, 10. Mu.m; mobile phase a: supercritical CO2, mobile phase B: meOH (+0.1% 7.0mol/L Ammonia in MeOH), mobile phase a: mobile phase b=50:50; the flow rate was 120mL/min. Detection wavelength: 254nm/214nm.
Compound 1A:
LC-MS(ESI+)m/z:406.0,408.0(M+H)+；
1H NMR(400MHz,DMSO-d6):δ8.30(s,2H),4.01(t,J＝8.0Hz,1H),3.13-3.01(m,1H),2.97-2.89(m,1H),2.73-2.67(m,2H),2.42-2.31(m,1H),1.98-1.89(m,1H),1.89-1.79(m,1H),1.65-1.45(m,4H).
Compound 1B:
LC-MS(ESI+)m/z:406.0,408.0(M+H)+；
1H NMR(400MHz,DMSO-d6):δ8.33(s,2H),4.02(t,J＝8.0Hz,1H),3.11-3.04(m,1H),2.93-2.88(m,1H),2.69-2.65(m,2H),2.38-2.27(m,1H),1.96-1.88(m,1H),1.87-1.77(m,1H),1.65-1.45(m,4H).
Example 2: synthesis of Compound 2A and Compound 2B
Compound 2 was synthesized by the following route:
The first step: synthesis of Compound 2-1:
In a three-necked flask equipped with an internal temperature thermometer, methylene chloride (10.0 mL), compound A1-3 (240.0 mg), and N-chlorosuccinimide (155.3 mg) were added in portions, and the mixture was stirred at 25℃for 20 hours. LCMS monitored completion of the reaction. The reaction solution was concentrated to dryness and purified by flash column chromatography (methanol/dichloromethane=0-10%) to give compound 2-1.
LC-MS(ESI+)m/z:446.1(M+H)+；
And a second step of: synthesis of Compound 2:
1, 4-Dioxa-ring (2.0 ml), compound 2-1 (106.0 mg), and dioxane hydrochloride solution (4M, 1.0 ml) were added to a three-necked flask equipped with an internal temperature thermometer, and stirred at 25℃for 2 hours. LCMS monitored completion of the reaction. The reaction mixture was concentrated to dryness, anhydrous methanol (4 mL) was added, stirred at 25℃for 5min, filtered, the filter cake was rinsed with anhydrous methanol (1 mL), and the filter cake was lyophilized to give compound 2 7-chloro-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one.
Chiral resolution of compound 2 (50 mg) by Supercritical Fluid Chromatography (SFC) gave the inter-enantiomeric compound 2A (R or S) -7-chloro-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =6.71 min) and 2B (S or R) -7-chloro-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =8.60 min).
Separation conditions:
Chromatographic column: DAICEL CHIRALPAK IG 250X 30mm,10 μm;
Mobile phase a MeOH (+0.2% Ammonia in MeOH (V/V)), mobile phase B EtOH (+0.2% 4.0mol/LAmmonia in MeOH), mobile phase a mobile phase b=50:50; the flow rate was 25mL/min. Detection wavelength: 254nm/214nm.
Compound 2A:
LC-MS(ESI+)m/z:361.9(M+H)+；
1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),4.02(t,J＝8.4Hz,1H),3.18-3.07(m,1H),2.99-2.89(m,1H),2.74-2.68(m,2H),2.40-2.32(m,1H),1.95-1.88(m,1H),1.88-1.79(m,1H),1.71-1.54(m,2H),1.53-1.39(m,2H).
Compound 2B:
LC-MS(ESI+)m/z:361.9(M+H)+；
1H NMR(400MHz,DMSO-d6):δ8.28(s,2H),4.02(t,J＝8.4Hz,1H),3.14–3.11(m,1H),2.96–2.93(m,1H),2.75–2.71(m,2H),2.40–2.35(m,1H),1.96–1.89(m,1H),1.89–1.84(m,1H),1.64–1.57(m,2H),1.54–1.48(m,2H).
example 3: synthesis of Compound 3A and Compound 3B
Compound 3 was synthesized by the following route:
The first step: synthesis of Compound 3-1:
Tetrahydrofuran (7.0 ml), compound A1 (1.34 g), benzyl alcohol (0.35 g), triphenylphosphine (1.08 g) were added to a three-necked flask equipped with an internal temperature thermometer under the protection of nitrogen, cooled to 0℃and diisopropyl azodicarboxylate (0.83 g) was added dropwise, and stirring was continued at 25℃for 16 hours. LCMS monitored completion of the reaction. The reaction solution was concentrated to dryness and purified by flash column chromatography (methanol/dichloromethane=0 to 10%), to give compound 3-1.
LC-MS(ESI+)m/z:580.13(M+H)+；
And a second step of: synthesis of Compound 3-2:
1, 4-Dioxahexacyclic ring (3.0 mL), compound 3-1 (200 mg), pinacol cyclopropylborate (116 mg), potassium carbonate (143 mg), water (0.6 mL) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (25 mg) were added to a three-necked flask equipped with an internal temperature thermometer under nitrogen and stirring was continued at 100℃for 5 hours. LCMS monitored completion of the reaction, the reaction was quenched with water, extracted with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, filtered to remove solids, the filtrate concentrated to dryness and purified by column chromatography (dichloromethane/methanol=10:1) to give compound 3-2.
LC-MS(ESI+)m/z:542.2(M+H)+；
And a third step of: synthesis of Compound 3-3:
in a single-necked flask, methanol (2.0 mL), compound 3-2 (100 mg), palladium on charcoal (5%) was added, and stirring was continued under hydrogen at 20℃and 1 atm for 16h. LCMS monitored completion of the reaction. The reaction solution was filtered to remove solids, and the filtrate was concentrated to give compound 3-3.
LC-MS(ESI+)m/z:452.2(M+H)+；
Fourth step: synthesis of Compound 3:
1, 4-Dioxa-ring (1.0 mL), compound 3-3 (20 mg), 1, 4-Dioxa-ring solution of hydrochloric acid (2 mol/L,1.0 mL) was added to a 50mL single-necked flask under nitrogen atmosphere, and the mixture was stirred at 25℃for 1h. LCMS monitored completion of the reaction, and the reaction mixture was concentrated and purified using reverse phase preparation to give the hydrochloride salt of compound 3 7-cyclopropyl-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one.
Chiral resolution of compound 3 (15 mg) by Supercritical Fluid Chromatography (SFC) gave the hydrochloride salt of the inter-enantiomeric compound 3A (R or S) -7-cyclopropyl-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =4.87 min) and 3B (S or R) -7-cyclopropyl-6- (1H-pyrazol-4-yl) -2- (quinuclidin-2-yl) thieno [3,2-d ] pyrimidin-4 (3H) -one (R t =6.44 min).
Separation conditions:
Chromatographic column: DAICEL CHIRALPAK IG 250X 30mm,10 μm;
Mobile phase a MeOH (+0.2% Ammonia in MeOH (V/V)), mobile phase B EtOH (+0.2% 4.0mol/LAmmonia in MeOH), mobile phase a mobile phase b=50:50; the flow rate was 25mL/min. Detection wavelength: 254nm/214nm.
Compound 3A:
LC-MS(ESI+)m/z:368.1(M+H)+；
1H NMR(400MHz,DMSO-d6)δ8.08(s,2H),3.89(t,J＝8.0Hz,1H),3.05-3.02(m,1H),2.88-2.82(m,1H),2.60-2.53(m,1H),2.30-2.26(m,1H),2.09-2.02(m,1H),1.89-1.86(m,1H),1.55-1.44(m,4H),1.38-1.31(m,1H),1.27-1.21(m,1H),0.96-0.93(m,2H).
Compound 3B:
LC-MS(ESI+)m/z:368.1(M+H)+；
1H NMR(400MHz,DMSO-d6)δ8.08(s,2H),3.89(t,J＝8.0Hz,1H),3.05-3.02(m,1H),2.88-2.82(m,1H),2.60-2.53(m,1H),2.30-2.26(m,1H),2.09-2.02(m,1H),1.89-1.86(m,1H),1.55-1.44(m,4H),1.38-1.31(m,1H),1.27-1.21(m,1H),0.96-0.93(m,2H).
Compounds 4 to 9 can be obtained by reference to the preparation method of example 3:
biological test evaluation
1. Inhibitory Effect on Cdc7/DBF4 enzymatic Activity
1. Experimental materials
Name of the name Branding
ADP-GLO Kit Promega
Cdc7/DBF4 SignalChem
PDK tide SignalChem
5X Enzymatic buffer Cisbio
DTT Sigma
MgCl2 Sigma
DMSO Sigma
2. Detection instrument
EnVision 2104 multifunctional enzyme labelling instrument (PERKIN ELMER).
3. Experimental method
Enzymes, substrates, adenosine triphosphate and inhibitors were diluted with Cisbio kinase buffer. A5 Xtest compound concentration gradient was prepared and a double multiplex well assay was set up with a row gun for 3-fold dilution to the 10 th concentration, i.e., from 2.5. Mu.M to 0.13nM, and 0.5% (v/v) DMSO. To the microplate was added 2. Mu.L of 5X inhibitor at each concentration gradient, 4. Mu. LCdc7/DBF4 enzyme (1 ng), 4. Mu.L of 2.5X substrate and ATP mixture (2.5. Mu.M substrate and 12. Mu.M ATP) at which point the final concentration gradient of the compound was 500nM diluted to 0.025nM. The reaction system was allowed to react at 37℃for 4h. After the reaction is finished, the operation is carried out according to the specification of the ADP-GLO kit, namely 10 mu L of ADP-GLO Reagent is added into each hole, the reaction is carried out for 40min at room temperature, 20 mu L of Detection Reagent is added into each hole, and the reaction is carried out for 30min at room temperature; chemiluminescence was read using an EnVision2104 multi-label analyzer with an integration time of 0.1 seconds.
4. Data analysis
The raw data was converted to inhibition rate using the equation (Sample-Min)/(Max-Vin) 100%, and IC 50 values were obtained by curve fitting four parameters (Log (inhibitor) vs. response-Variable slope mode) in GRAPHPAD PRISM analysis software, and the experimental results are shown in table 1.
Table 1: inhibitory Activity against Cdc7/DBF4 enzyme
Numbering of compounds IC50(nM) Numbering of compounds IC50(nM)
Compound 1 0.258 Compound 4 1.431
Compound 1B 0.099 Compound 4B 0.320
Compound 2 0.156 Compound 5 0.205
Compound 2A 0.138 Compound 5B 0.168
Compound 3 0.180 TAK-931 0.296
Compound 3A 0.246
As can be seen from the results in Table 1, the compounds of the present invention strongly inhibit Cdc7/DBF4 enzymatic activity, which is comparable to or better than the known compound TAK-931.
2. Inhibitory Effect on COLO205 cell proliferation
1. Experimental materials
1640 Medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Life Invitrogen.
CellTiter-Glo chemiluminescent cell viability assay reagents were purchased from Promega.
COLO205 cell line was purchased from ATCC.
2. Detection instrument
EnVision 2104 multifunctional enzyme labelling instrument (PERKIN ELMER).
3. Experimental method
COLO205 cells (colon cancer cells) were seeded in white 384-well plates, 45. Mu.L of cell suspension per well, containing 2000 COLO205 cells. The cell plates were incubated overnight at 37℃in a carbon dioxide incubator. The test compounds were diluted 3-fold to the 10 th concentration, i.e. from 10mM to 152.4nM, with a DMSO concentration of 100% using a row gun, and a double multiplex well experiment was set up. 99. Mu.L of medium was added to the intermediate plate, and 1. Mu.L of gradient diluted compound per well was transferred to the intermediate plate at the corresponding position, and after thoroughly mixing, 5. Mu.L of compound per well was transferred to the cell plate at a concentration ranging from 10. Mu.M to 1.52nM and DMSO concentration of 0.1% (v/v). The cell plates were placed in a carbon dioxide incubator for 3 days. To each well of this plate, 25. Mu.L of chemiluminescent cell viability assay reagent was added and incubated at room temperature for 10min. After the luminescence signal is stable, the EnVision 2104 multifunctional enzyme-labeled instrument is adopted for reading.
4. Data analysis
The raw data is converted to inhibition ratio according to the following formula:
cell growth inhibition% = (1-RLUs/RLUv) ×100%.
RLUs: absorbance of sample-treated cells (cells+celltiter-glo+ compounds).
RLUv: absorbance of solvent-treated cells (cells+CellTiter-glo+DMSO).
EC 50 values can be obtained by curve fitting four parameters (Log (inhibitor) vs. response-Variable slope mode) in GRAPHPAD PRISM analysis software. Table 2 provides the inhibitory activity of the compounds of the present invention on COLO205 cell proliferation, the experimental results are shown in table 2:
table 2: inhibitory Effect of certain compounds of the invention on COLO-205 cell proliferation
Numbering of compounds EC50(nM)
Compound 1 20.4
Compound 1B 11.5
Compound 2A 25.2
Compound 3 16.9
Compound 3A 12.7
Compound 5 29.3
Compound 5B 14.7
TAK-931 46.1
As can be seen from the results in Table 2, the compound of the present invention can significantly inhibit COLO-205 cell proliferation, and the activity of inhibiting COLO-205 cell proliferation is significantly superior to that of the known compound TAK-931.
3. Pharmacokinetic experiments in mice
Healthy male CD-1 mice were selected for pharmacokinetic experiments. Some of the compounds of the invention are administered in a single dose after vortexing using a suitable vehicle.
Intravenous injection uses solvent, 5% DMSO/95% (v/v) (10% (v/v) hydroxypropyl-beta-cyclodextrin), and the solvent is administered at a dose of 2mg/kg (administration concentration of 0.4mg/mL, administration volume of 5 mL/kg), and blood is collected from the vein after 5min,15min,30min,1h,2h,4h,8h, and 24h, and plasma is obtained by treatment, and plasma drug concentration is calculated.
The vehicle used for oral gavage was 5% DMSO/95% (v/v) (10% (v/v) hydroxypropyl-. Beta. -cyclodextrin) or 0.5% methylcellulose (v/v) and was administered at a dose of 10mg/kg (administration concentration 1mg/mL, administration volume 10 mL/kg). After the administration, blood is collected for 15min,30min,1h,2h,4h,6h,8h and 24h respectively, plasma is obtained through treatment, and the plasma drug concentration is calculated.
Pharmacokinetic parameters were calculated using Phoenix WinNonlin. The results are shown in tables 3 and 4.
Table 3: pharmacokinetics of intravenous administration (2 mg/kg)
Compounds of formula (I) t1/2(h) AUCinf(ng.h/mL) Vz(mL/kg) Cl(mL/min/kg)
TAK-931 0.53 1076.58 1434.66 31.11
Compound 1B 1.26 2482.58 1461.48 13.44
Compound 3A 1.09 595.47 6324.10 56.63
Compound 5B 1.44 1358.87 3045.72 24.54
Table 4: pharmacokinetics of intragastric administration (10 mg/kg)
Compounds of formula (I) t1/2(h) Cmax(ng/mL) AUCinf(ng.h/mL) F(％)
TAK-931 1.52 1290.84 2723.97 49.56
Compound 1B 2.47 5415.83 18434.63 136.59
Compound 3A 1.27 3366.91 5876.76 197.41
Compound 5B 1.80 1934.35 4185.11 59.36
As can be seen from tables 3 and 4, the compounds of the present invention exhibited better absorption and pharmacokinetic profile in mice, and had higher exposure and bioavailability than the control compound TAK-931.
4. Research on inhibition effect of COLO 205 cell xenograft tumor growth of colon cancer by using compound of the invention
The antitumor activity of the test subjects administered alone was evaluated using a colon cancer COLO205 cell nude mouse xenograft tumor model.
BALB/c Nude mice, females, 8-10 weeks old, weight 18-20g. COLO 205 cells (purchased from AMERICAN TYPE Culture Collection, ATCC) were cultured in MEM medium containing 10% fetal bovine serum and maintained in a 37℃saturated humidity cell incubator containing 5% CO 2. COLO 205 cells in the logarithmic growth phase were collected and resuspended in MEM basal medium containing 50% matrigel, and the cell concentration was adjusted to 5X 10 7/mL. Under sterile conditions, 0.1mL of the cell suspension was inoculated subcutaneously into the right dorsal portion of the mice at a concentration of 2X 10 6/0.1 mL/mouse. When the average tumor volume reached about 150mm 3, animals were randomly grouped by tumor volume, 7 animals per group.
TAK-931 (40 mg/kg) and test compound 1B (5 mg/kg,10mg/kg,20 mg/kg) were dissolved in 0.5% (v/v) methylcellulose, respectively, as a negative control group, and orally administered, grouped as Day 0, and started to administer according to animal body weight. The administration was carried out orally twice daily for 21 days. Animal body weight and tumor volume were measured 2 times per week during the experiment. The experimental mice were euthanized 21 days after dosing and weighed for tumor removal.
The Tumor Volume (TV) is calculated as: 1/2 Xa x b 2, where a, b are the length and width of the tumor measurement, respectively;
the tumor growth inhibition (% TGI TV) was calculated as: (1-TV T/TVC)×100％,TVC is the average tumor volume of the negative control group, TV T is the average tumor volume of the treatment group;
The relative tumor volume (Relative Tumor Volume, RTV) was calculated as: vt/V 0, where V 0 is the tumor volume at the time of grouping and Vt is the tumor volume at each measurement.
The relative tumor proliferation rate (% T/C RTV) was calculated as: t RTV/CRTV X100%, wherein T RTV is RTV of the treatment group and C RTV is RTV of the negative control group.
The tumor inhibition (% TGI TW) was calculated as: (TW C-TWT)/TWC X100%, where TW C is the average tumor weight of the negative control group and TW T is the average tumor weight of the treatment group.
The experimental results are shown in Table 5 and FIG. 1.
Table 5: results of inhibition of colorectal cancer COLO 205 cell xenograft tumor growth by the Compounds of the invention
From Table 5, it can be seen that the compounds of the present invention have a remarkable inhibitory effect on COLO 205 cell xenograft tumor growth, and the ability to inhibit tumor growth in mice is remarkably superior to TAK-931.
From the above test evaluation results, it can be seen that the compounds of the present invention show a strong inhibitory effect on Cdc7/DBF4, while showing a good inhibitory activity on COLO-205 cells. In addition, the compound of the invention has better absorption and bioavailability in mice, and has obvious inhibition effect on in vivo tumor. The results show that the compound is expected to become a Cdc7 kinase inhibitor which is more efficient and has lower toxicity than similar products, and provides a new treatment option for proliferative diseases such as tumors and the like.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (24)

1. A compound of formula (I), a stereoisomer, a tautomer thereof or a pharmaceutically acceptable salt thereof,
Wherein,
X 1 is S, O or CH 2;
X 2 is S, O or C;
R 1 is selected from halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8;
When X 2 is S or O, R 2 is absent; when X 2 is C, R 2 is selected from halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-P(O)R8R9、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8 optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (substituted with R 9)-C(O)R8 or any two substituents on the same or different R 2 form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl with the carbon atom to which they are directly attached;
R 3 is selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, deuterated C 1-10 alkyl, halogenated C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl);
Ring a is C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein Y is CR 5 or N, Z is CR 5' or N; r 4、R5、R5' is each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogenated C 1-10 alkyl, deuterated C 1-10 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8, or ring A and either R 4 or R 5 together form a C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl;
With the proviso that when Y is selected from-C (R 5) -, and Z is selected from N, ring A is connected with R 4 to form a C 7-12 bridged cycloalkyl group, Z is a bridgehead atom, or ring A is connected with R 5 to form a 7-12 membered bridged heterocyclic group, Y is a bridgehead atom;
Each R 6 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 9R10;
Each R 7 is independently selected from the group consisting of hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 9R10;
Each R 8 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl oxy, and-NR 9R10;
Each R 9 and each R 10 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, sulfamoyl, dimethylaminosulfonyl, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl, said groups being independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, mono C438 alkylamino and di C65343 alkylamino;
Or R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 4-10 membered heteroaryl, said 4-10 membered heterocyclyl or 4-10 membered heteroaryl optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heteroaryl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 alkylamino, di C 1-10 alkylamino and C 1-10 alkanoyl;
each r is independently selected from 0, 1 or 2;
n is selected from 0,1, 2 or 3.
2. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (ii):
Wherein,
R 1 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8;
R 2 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、-SF5、-S(O)rR6、-P(O)R8R9、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8 optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8 being substituted with any two substituents on R 2 which are the same or different, or with the carbon atom to which they are directly attached, form C 3-6 cycloalkyl or 3-6 membered heterocyclyl);
R 3 is selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl);
Ring a is C 3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein Y is CR 5 or N, Z is CR 5' or N; r 4、R5、R5' is each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8, or ring A and either R 4 or R 5 together form a C 7-12 bridged cycloalkyl or 7-12 membered bridged heterocyclyl;
With the proviso that when Y is selected from-C (R 5) -, and Z is selected from N, ring A is connected with R 4 to form a C 7-12 bridged cycloalkyl group, Z is a bridgehead atom, or ring A is connected with R 5 to form a 7-12 membered bridged heterocyclic group, Y is a bridgehead atom;
R 6、R7、R8、R9、R10, R and n are as defined in claim 1.
3. A compound according to claim 2, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-10 aryloxy, 5-8 membered heteroaryloxy, and-NR 9R10;
Each R 7 is independently selected from the group consisting of hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, and 5-8 membered heteroaryl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR 9R10;
Each R 8 is selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 9R10, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryl, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl oxy, and-NR 9R10;
Each R 9 and each R 10 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, sulfamoyl, dimethylaminosulfonyl, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and C 1-4 alkanoyl, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroaryloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino, and di C9832 alkanoyl;
Or R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, said 4-8 membered heterocyclic group optionally being further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 alkyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered hetero epoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered hetero aryloxy, amino, mono C 1-4 alkylamino, di C 1-4 alkylamino and C 1-4 alkanoyl.
4. The compound of claim 2, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (iiia):
Wherein R 11 is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8;
the rings A, Y, Z, R 2、R3、R4、R6、R7、R8、R9、R10, r and n are as defined in claim 2.
5. The compound of claim 4, wherein R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl;
r 6、R7、R8、R9、R10 and R are as defined in claim 2.
6. The compound of claim 4, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (iva) or formula (ivb):
Wherein,
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10;
R 3 is selected from deuterium, halogen, cyano, nitro, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(O)NR9R10 and-N (R 9)-C(O)R8, or two atoms to which R 3 is directly attached form C 3-6 cycloalkyl or 3-6 membered heterocyclyl; R 4 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7、-C(O)OR7、-C(O)R8、-O-C(O)R8;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl;
the rings A, Z, R 6、R7、R8、R9、R10, r and n are as defined in claim 4.
7. The compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to claim 6,
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10;
r 3 is selected from deuterium, =o, =ch 2, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -O-R 7, or two atoms to which R 3 are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
R 4 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, -O-R 7;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, C 3-8 cycloalkyl;
Ring a is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl.
8. A compound according to claim 7, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, the foregoing optionally further substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, alkoxy;
r 4 is selected from hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, monofluoromethyl, tridentate methyl, dideuteromethyl, monodeuteromethyl;
R 11 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
ring a is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, preferably from the group:
n is 0.
9. The compound of claim 4, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formulas (ivc) and (ivd) as follows:
In formula (IVC), ring A is linked to R 4 to form a 7-10 membered bridged heterocyclic group, the nitrogen atom on ring A directly linked to R 4 being a bridgehead atom;
In formula (IVD), ring A is linked to R 5 to form a 7-10 membered bridged heterocyclyl, the carbon atom on ring A directly linked to R 5 being the bridgehead atom;
R 2、R3、R11 and n are as defined in claim 4.
10. The compound of claim 9, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 3 is selected from deuterium, =o, =ch 2, halogen, C 1-4 alkyl, deuterated C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-8 cycloalkyl, -O-R 7, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or a 3-6 membered heterocyclyl.
11. A compound according to claim 10, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, the foregoing optionally being further substituted with one or more substituents selected from fluoro, chloro, bromo, iodo, hydroxy, amino, alkoxy;
R 3 is selected from =o, =ch 2, hydroxy, deuterium, methyl, ethyl, propyl, isopropyl, mono-deuteromethyl, di-deuteromethyl, tri-deuteromethyl, mono-fluoromethyl, di-fluoromethyl, tri-fluoromethyl, fluoro, chloro, bromo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or two atoms to which R 3 is directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
R 11 is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
ring a is further linked to R 4 or R 5 to form the following group:
12. A compound according to claim 9, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (va):
Wherein R 2 is selected from halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、-SF5、-S(O)rR6、-P(O)R8R9、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10, and-N (R 9)-C(O)R8, which is optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 11 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-SF5、-S(O)rR6、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10、-C(＝NR9)R8、-N(R9)-C(＝NR10)R8、-C(O)NR9R10 and-N (R 9)-C(O)R8,
R 6、R7、R8、R9、R10 and R are as defined in claim 4.
13. The compound of claim 12, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 11 is selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and C 3-8 cycloalkyl.
14. A compound according to claim 13, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10;
R 11 is selected from hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl.
15. A compound according to claim 14, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, the foregoing optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, alkoxy;
R 11 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
16. The compound of claim 2, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (iiib):
R 1 is selected from halogen, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10, and-C (O) NR 9R10;
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl 、＝O、＝CH2、-O-R7、-C(O)OR7、-C(O)R8、-O-C(O)R8、-NR9R10 and-C (O) NR 9R10;
r 6、R7、R8、R9、R10, R and n are as defined in claim 2.
17. The compound of claim 16, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 6-10 aryl, 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl;
R 2 is selected from halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, -S (O) rR6、-P(O)R9R10、-C(O)R8, optionally further substituted with one or more substituents selected from halogen, -O-R 7、-NR9R10.
18. The compound of claim 17, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of pyrazolyl, pyrimidinyl, pyridinyl,The above groups are optionally further substituted with one or more substituents selected from deuterium, halogen, amino, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl
R 2 is selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, spiro [2.3] hex-5-yl, 1-bicyclo [1, 1] pentyl, -C (O) CH 3、-S(O)CH3、-S(O)2CH3、-P(O)(CH3)CH3, optionally further substituted with one or more substituents selected from fluorine, chlorine, bromine, iodine, hydroxy, amino, alkoxy.
19. The compound of claim 1, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
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20. a process for the preparation of a compound according to any one of claims 2 to 19, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprising the steps of:
And (3) reacting the compound A with benzyl alcohol to obtain a compound B or a compound B 'or a mixture of the compound B and the compound B', carrying out halogenation and metal catalysis reaction to obtain a compound C or a compound C 'or a mixture of the compound C and the compound C', and finally removing a protecting group to obtain the compound in the formula (II).
Wherein PG is a protecting group such as benzyl, and the other groups are as defined in formula (II).
21. A pharmaceutical composition comprising a compound according to any one of claims 1-19, a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. Use of a compound according to any one of claims 1-19, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 for the manufacture of a medicament for the treatment and/or prophylaxis of a disease mediated by Cdc7 kinase.
23. Use of a compound according to any one of claims 1-19, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 for the manufacture of a medicament for the prevention and/or treatment of a tumor.
24. Use of a compound according to any one of claims 1-19, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 21 for the manufacture of a medicament for the prevention and/or treatment of blood cancer, cervical cancer, lung cancer, prostate cancer, mesothelioma, thyroid cancer, renal cancer, biliary tract cancer, bladder cancer, breast cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, sarcoma, skin cancer, ovarian cancer, liver cancer, colorectal cancer or pancreatic cancer.
CN202310329899.0A 2022-11-11 2023-03-30 Thienopyrimidinone compound, preparation method and application thereof Pending CN118027066A (en)

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