CN113880833A - Biphenyl polycyclic derivative inhibitor, preparation method and application thereof - Google Patents

Biphenyl polycyclic derivative inhibitor, preparation method and application thereof Download PDF

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CN113880833A
CN113880833A CN202110744133.XA CN202110744133A CN113880833A CN 113880833 A CN113880833 A CN 113880833A CN 202110744133 A CN202110744133 A CN 202110744133A CN 113880833 A CN113880833 A CN 113880833A
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radical
alkyl
haloalkyl
amino
haloalkoxy
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曾蜜
高鹏
程宇
许�鹏
李剑
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

The invention relates to a biphenyl polycyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as an inhibitor in treating cancers, infectious diseases and autoimmune diseases, wherein each substituent in the general formula (I) is defined as the specification.

Description

Biphenyl polycyclic derivative inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a biphenyl polycyclic derivative inhibitor, and a preparation method and application thereof.
Background
The immune system plays an important role in controlling various diseases such as cancer. However, tumor cells may evade immune attack or inhibit activation of the immune system through various pathways. Blocking signaling of immunosuppressive checkpoints, such as programmed cell death receptor 1 (PD-1), has been shown to be a potential therapeutic modality.
PD-1 is a member of the CD28 superfamily and is an immunosuppressive receptor on the surface of immune cells, particularly cytotoxic T cells. PD-1 has two ligands PD-L1 and PD-L2, among which PD-L1, a programmed cell death receptor-ligand 1, is expressed in various cells such as macrophages and dendritic cells, and is universally highly expressed on tumor cells. PD-L1 exerts immunosuppressive action by binding to PD-1 and allows tumor cells to escape killing by T cells, inhibits activation of T cells and production of corresponding cytokines, attenuates infectious immunity and tumor immunity, and promotes progression of infectious diseases and tumors. The use of PD-L1 inhibitor such as antibody or small molecule inhibitor can relieve the immunosuppression effect of PD-L1, promote the immune clearance of tumor, and thus achieve the effect of treating tumor.
PD-1/PD-L1 is a hotspot of tumor immunotherapy research in recent years, the breadth, depth and persistence of monoclonal antibody drug response are quite rare, and a plurality of PD-1/PD-L1 monoclonal antibody drugs are on the market clinically at present and have great success. The PD-L1 inhibitor can be used for treating almost all major cancers such as non-small cell lung cancer, liver cancer, gastric cancer, intestinal cancer, renal cancer and the like, and has great clinical application value.
The PD-L1 inhibitor is becoming a new development trend and hot spot from large molecules to small molecules, the small molecule inhibitor has a plurality of natural advantages from the administration mode to the production cost, has the potential of replacing antibody large molecules, and the development of the PD-L1 small molecule inhibitor is actively carried out by foreign drug enterprises including BMS, Incyte and the like at present.
The oral small molecule inhibitor developed by BMS is currently in the preclinical research stage, several patents have been continuously published, the small molecule inhibitor INCB086550 developed by Incyte is in the first clinical research stage, and the small molecule inhibitor CA-170 developed by Aurigene/Curis is also in the first clinical research stage.
International applications WO2015034820, WO2015160641, WO2014151634, WO2017066227, WO2017070089, WO2017106634, WO2017112730, WO2017192961, WO2017222976, WO2018013789, WO2018044783, WO2018119224, WO2018119236, WO2018119263, WO2018119266 and WO2018119286 and the like report PD-1 or PD-L1 small molecule compound inhibitors. Furthermore, international applications WO2014151634, WO2011161699, WO2012168944, WO2013132317, WO2013144704, WO2015033299, WO2015033301, WO2015033303 and WO2015036927 report macrocyclic and peptidic compounds PD-1 or PD-L1 inhibitors. However, there is still a great need for PD-L1 small molecule inhibitors that are more potent, better pharmacokinetic and pharmaceutical properties of the PD-1/PD-L1 pathway.
The PD-L1 small molecular inhibitor has good application prospect in the pharmaceutical industry as a medicine, firstly, the PD-L1 small molecular inhibitor can be orally administrated, has the advantage of stronger compliance than intravenous administration of an antibody medicine, and can avoid serious side effects such as colitis and the like caused by long-term residence of the antibody in a body. Secondly, the PD-L1 small-molecule inhibitor has a unique action mechanism for binding and endocytosing PD-L1, and may show different efficacies from antibodies clinically. Finally, the production and quality control cost of the PD-L1 small-molecule inhibitor is lower, the price advantage of the PD-L1 small-molecule inhibitor is far lower than that of a macromolecular drug, and the PD-L1 small-molecule inhibitor can be applied to various major tumors and has huge market potential.
Disclosure of Invention
The invention aims to provide a compound shown as a general formula (III-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which has the following specific structure:
Figure BDA0003143824180000021
wherein:
R1selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-、-(CH2)n1S(O)m1NRaa-、-(CH2)n1NRaaS(O)m1-or- (CH)2)n1C(O)NRaa-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R3selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R4selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Substituted with one or more substituents of haloalkoxy;
RA1、RB1and RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
m1 is an integer of 0-2;
n1, n2 and n10 are integers of 0 to 3.
The invention also provides a compound shown as the general formula (III-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the specific structure is as follows:
Figure BDA0003143824180000031
wherein:
R1selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thioxo, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-、-(CH2)n1S(O)m1NRaa-、-(CH2)n1NRaaS(O)m1-or- (CH)2)n1C(O)NRaa-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R3selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R4selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R6selected from hydrogen, deuterium, halogen,Amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Substituted with one or more substituents of haloalkoxy;
RA1、RB1and RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-to 14-membered heteroaryl, which may optionally be further substitutedIs substituted by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
m1 is an integer of 0-2;
n1, n2 and n10 are integers of 0 to 3.
In a further preferred embodiment of the present invention, R in the compound represented by the general formula (III-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof1Selected from hydrogen, deuterium, halogen, amino, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, carboxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Substituted with one or more substituents in hydroxyalkyl; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted with hydrogen, deuterium, fluoro, chloro, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl; further preferred is
Figure BDA0003143824180000051
Figure BDA0003143824180000052
L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-or- (CH)2)n1C(O)NRaa-; preferably a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-or- (CH)2)n1NRaa(CRbbRcc)n2-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, fluorine, chlorine, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine or chlorine;
R3selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl or isopropyl;
R4selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, nOptionally further selected from hydrogen, deuterium, fluorine, chlorine, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl or isopropyl;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Substituted with one or more substituents of haloalkoxy; preferably 3-8 membered heterocyclyl, 5-8 membered heteroaryl or- (CH)2)n10NRA1RB1Said 3-8 membered heterocyclyl and 5-8 membered heteroaryl may be further substituted with hydrogen, deuterium, fluoro, chloro, carboxy, hydroxy or C1-3Substituted by one or more substituents in the alkyl group; more preferably
Figure BDA0003143824180000061
Figure BDA0003143824180000062
RA1、RB1And RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl, said C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by hydrogen, deuterium, fluoro, chloro, hydroxy, carboxy, C1-3Alkyl or C1-3Substituted with one or more substituents in the hydroxyalkyl group.
In a further preferred embodiment of the present invention, the compound represented by the general formula (III-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereofR in the acceptor salt1Selected from hydrogen, deuterium, halogen, amino, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxy, carboxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Substituted with one or more substituents in hydroxyalkyl; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted with hydrogen, deuterium, fluoro, chloro, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl; further preferred is
Figure BDA0003143824180000063
Figure BDA0003143824180000064
L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-or- (CH)2)n1C(O)NRaa-; preferably a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-or- (CH)2)n1NRaa(CRbbRcc)n2-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, fluorine, chlorine, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine or chlorine;
R3selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl or isopropyl;
R4selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further optionally selected from hydrogen, deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy; more preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl or isopropyl;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Substituted with one or more substituents of haloalkoxy; preferably 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, - (CH)2)n10C(O)RA1Or- (CH)2)n10NRA1RB1Said 3-8 membered heterocyclyl and 5-8 membered heteroaryl may be further substituted with hydrogen, deuterium, fluoro, chloro, carboxy, hydroxy or C1-3Substituted by one or more substituents in the alkyl group; more preferably
Figure BDA0003143824180000071
Figure BDA0003143824180000072
RA1、RB1And RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl, said C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by hydrogen, deuterium, fluoro, chloro, hydroxy, carboxy, C1-3Alkyl or C1-3Substituted with one or more substituents in the hydroxyalkyl group.
The invention also provides a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is shown as the general formula (IV):
Figure BDA0003143824180000081
wherein:
ring C is selected from C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl;
R7selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n5RAA、-(CH2)n5ORAA、-(CH2)n5C(O)ORAA、-(CH2)n5SRAAOr- (CH)2)n5NRAARBBSaid amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy or-C (O) RAIs substituted with one or more substituents of (1);
RAA、RBBand RCCEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6One of the haloalkoxy groupsOr substituted by a plurality of substituents;
RAselected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group;
L5selected from the group consisting of a bond, - (CH)2)n7-、-(CH2)n7(CRa2Rb2)n8-、-(CRa2Rb2)n7O(CH2)n8-、-(CH2)n7O(CRa2Rb2)n8-、-(CRa2Rb2)n7(CH2)n8NRc2-、-(CH2)n7NRa2(CRb2Rc2)n8-、-(CH2)n7C(O)(CRa2Rb2)n8-、-(CH2)n7NRa2C(O)(CRa2Rb2)n8-or- (CH)2)n7C(O)NRa2-；
Ra2、Rb2And Rc2Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heteroCyclic group, C6-10Aryl or 5-10 membered heteroaryl;
R8selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; more preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
R9each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl or-C (O) RCIs substituted with one or more substituents of (1);
RCselected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; and is
j is an integer of 0 to 6;
n5, n7 and n8 are integers of 0 to 3.
In certain embodiments of the invention, in formula (IV):
ring C is selected from C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl; preferably a cycloalkyl group,
Figure BDA0003143824180000091
Figure BDA0003143824180000092
R7Is selected from C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl, 5-8 membered heteroaryl or-CH2NRAARBBSaid amino group, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by deuterium, fluoro, chloro, amino, hydroxy, cyano, carboxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl; preference is given to
Figure BDA0003143824180000093
RAAAnd RBBEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
L5selected from the group consisting of a bond, - (CH)2)n7-or- (CH)2)n8NRc2-; preferably a bond, -CH2-or-CH2NRc2-；
Rc2Selected from hydrogen, deuterium, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, methyl, ethyl or propyl;
R8selected from hydrogen, deuterium, fluorine, chlorine, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
R9each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl and C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy or-C (O) RC(ii) a Preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, carboxyl, methyl, ethyl or-C (O) CH3；
RCSelected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or propyl; and is
j is an integer of 0 to 3; preferably 1 or 2.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of general formula (I), stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to any one of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or application of the pharmaceutical composition in preparation of PD-1 or PD-L1 inhibitor drugs.
The invention further relates to an application of the compound shown in the general formula (I), the stereoisomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof in preparing medicaments for treating cancers, infectious diseases and autoimmune diseases, wherein the cancers are selected from skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor and head and neck cancer; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ-specific autoimmune diseases and systemic autoimmune diseases, wherein the organ-specific autoimmune diseases comprise chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis and acute idiopathic polyneuritis, and the systemic autoimmune diseases comprise rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease and autoimmune hemolytic anemia.
The invention further relates to a method for preparing a compound shown in the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating cancers, infectious diseases and autoimmune diseases.
The invention also relates to a method for treating, preventing and/or treating cancers, infectious diseases and autoimmune diseases, which comprises the step of administering a therapeutically effective dose of the compound shown as the general formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient.
The invention also provides methods of using the compounds or pharmaceutical compositions of the invention to treat disease conditions, including but not limited to conditions associated with PD-1 or PD-L1.
The present invention also relates to methods of treating cancer, infectious diseases, autoimmune diseases in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the methods relate to the treatment of disorders such as cancer, infectious diseases, autoimmune diseases, and the like.
In some embodiments, the cancer to which the present methods relate is selected from skin cancer, lung cancer, urological tumors, hematological tumors, breast cancer, glioma, digestive system tumors, reproductive system tumors, lymphoma, nervous system tumors, brain tumors, head and neck cancer.
In some embodiments, the method relates to an infectious disease selected from the group consisting of a bacterial infection, a viral infection.
In some embodiments, the autoimmune disease to which the method relates is selected from the group consisting of organ-specific autoimmune disease, systemic autoimmune disease, wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include 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, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include 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 and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2)2-, "propylene" means- (CH)2)3-, "butylene" means- (CH)2)4-and the like. Term(s) for"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure BDA0003143824180000121
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure BDA0003143824180000122
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure BDA0003143824180000123
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; further preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, azetidineA group such as an oxetanyl group, an oxocyclohexyl group, an imidazolidinyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, a dihydroimidazolyl group, a dihydrofuranyl group, a dihydropyrazolyl group, a dihydropyrrolyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a homopiperazinyl group, and a pyranyl group; preferably pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl; more preferred are pyrrolidinyl, azetidinyl, oxetanyl, oxolanyl, piperidinyl, piperazinyl and pyranyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:
Figure BDA0003143824180000131
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(whereinm is a heteroatom of an integer from 0 to 2), the remaining ring atoms being carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure BDA0003143824180000132
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003143824180000133
the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, more preferably 6 to 8 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0003143824180000141
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 to 8 membered, most preferably 5 or 6 membered, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003143824180000142
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is defined as above, preferably alkyl having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" means alkenyl, also known as alkenyl, preferably alkyl containing 2 to 8 carbon atoms, more preferably alkyl of 2 to 6 carbon atoms, and most preferably alkyl of 2 to 3 carbon atoms. Wherein said alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" means (CH.ident.C-), preferably alkyl containing 2 to 8 carbon atoms, more preferably alkyl of 2 to 6 carbon atoms, and most preferably alkyl of 2 to 3 carbon atoms. Wherein said alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"fused ring group" means a polycyclic group formed by two or more carbocyclic or heterocyclic rings sharing a ring edge, the fused ring group including fused ring alkyl groups, fused ring heteroaryl groups, fused ring aryl groups, and fused ring heteroaryl groups, wherein the fused ring alkyl groups mean cycloalkyl groups and heterocyclic, aryl, and heteroaryl groups sharing a ring edge; the fused ring heterocyclic group refers to a polycyclic group formed by a heterocyclic group and cycloalkyl, aryl and heteroaryl which share a ring edge; the fused ring aryl refers to polycyclic groups formed by sharing ring edges of aryl, cycloalkyl, heterocyclic group and heteroaryl; the fused ring heteroaryl refers to heteroaryl and polycyclic radicals formed by cycloalkyl, heterocyclic radical and hetero radical in a way of sharing a ring edge; for example:
Figure BDA0003143824180000151
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. "hydroxy" refers to an-OH group. "halogen" means fluorine, chlorine, bromine or iodine. "amino" means-NH2. "cyano" means-CN. "nitro" means-NO2. "carboxy" refers to-C (O) OH. "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "DMF" refers to N, N-dimethylformamide. "DIPEA" refers to diisopropylethylamine. "TFA" refers to trifluoroacetic acid. "MeCN" refers to acetonitrile. "DMA" refers to N, N-dimethylacetamide. "Et2O "means diethyl ether. "DCE" refers to 1,2 dichloroethane. "DIPEA" refers to N, N-diisopropylethylamine. "NBS" refers to N-bromosuccinimide. "NIS" refers to N-iodosuccinimide. "Cbz-Cl" refers to benzyl chloroformate. ' Pd2(dba)3"refers to tris (dibenzylideneacetone) dipalladium. "Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene. "HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate. "KHMDS" refers to potassium hexamethyldisilazide. "LiHMDS" refers to lithium bistrimethylsilyl amide. "MeLi" refers to methyllithium. "n-BuLi" refers to n-butyllithium. "NaBH (OAc)3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"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. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The inventionThe structure of the compound(s) is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200 Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco 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. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai 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 present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
1- ((2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000171
The first step is as follows: preparation of 3-bromo-8-chloro-1, 7-naphthyridine
Figure BDA0003143824180000172
3-bromo-1, 7-naphthyridin-8-ol (13.5g,60.0mmol) was added to phosphorus oxychloride (135mL), heated to 110 ℃ under dry nitrogen blanket with stirring for 2 hours, concentrated under reduced pressure, the residue diluted with water, added ethyl acetate with stirring for 1 hour, filtered, the filter cake washed with water, the filter cake collected, and dried under reduced pressure to give the title product (9.1g, 62%).
MS m/z(ESI):243.1,245.1[M+H]+.
The second step is that: preparation of 8-chloro-3-vinyl-1, 7-naphthyridine
Figure BDA0003143824180000173
3-bromo-8-chloro-1, 7-naphthyridine (2.0g,8.2mmol), 4,4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan (1.53mL,9.04mmol), sodium carbonate (1.74g,16.4mmol) and Pd (dppf) Cl2(62mg,0.082mmol) were added to a mixed solvent of t-butanol (59mL) and water (60mL), the reaction system was evacuated and replaced with nitrogen, heated to 110 ℃ and stirred for reaction for 6 hours, cooled to room temperature, concentrated under reduced pressure to remove the organic solvent, the residue was extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate residue, filtered, concentrated, and used for the subsequent reaction without further purification.
MS m/z(ESI):191.1[M+H]+.
The third step: preparation of N- (3-bromo-2-chlorophenyl) -3-vinyl-1, 7-naphthyridin-8-amine
Figure BDA0003143824180000174
Dispersing 8-chloro-3-vinyl-1, 7-naphthyridine (3.4g,17.8mmol) in isopropanol (100mL), adding 3-bromo-2-chloroaniline (4.4g,21.4mmol) and concentrated sulfuric acid (0.96mL,17.8mmol) in this order at room temperature with stirring, heating the reaction solution to 100 deg.C, stirring for 1 hour, concentrating under reduced pressure to remove the solvent, dispersing the residue in saturated aqueous sodium carbonate solution, extracting with dichloromethane, combining dichloromethane solutions, drying over anhydrous sodium sulfate, filtering, concentrating, and separating the residue by silica gel column chromatography to obtain the title compound (5.8g, 90%).
MS m/z(ESI):360.1,362.1[M+H]+.
The fourth step: preparation of (8- ((3-bromo-2-chlorophenyl) amino) -1, 7-naphthyridin-3-yl) methanol
Figure BDA0003143824180000175
N- (3-bromo-2-chlorophenyl) -3-vinyl-1, 7-naphthyridin-8-amine (1.96g,5.74mmol) was dissolved in a mixed solvent of dioxane (60mL) and water (24mL), osmic acid dihydrate (100mg,0.28mmol) and sodium periodate (6.14g,28.8mmol) were added successively with stirring at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The organic solvent was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate, and the ethyl acetate layer was washed successively with a saturated aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in a mixed solvent of tetrahydrofuran (30mL) and anhydrous methanol (30mL), cooled to room temperature, sodium borohydride (220mg,5.74mmol) was sequentially added under stirring, the reaction solution was further stirred at 0 ℃ for 3 hours, the solvent was removed by concentration under reduced pressure, the residue was slurried with a mixed solution of water-ethanol (v/v ═ 9:1,50mL), filtered, the residue was washed with water, the filter cake was collected, and dried under reduced pressure to give the title compound (1.68g, 80%).
MS m/z(ESI):364.1,366.1[M+H]+.
The fifth step: preparation of N- (3-bromo-2-chlorophenyl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000181
Dispersing (8- ((3-bromo-2-chlorophenyl) amino) -1, 7-naphthyridin-3-yl) methanol (1.58g,4.32mmol) in DMF (50mL), adding DMP (2.75g,6.48mmol) with stirring at room temperature, reacting the reaction mixture with stirring at room temperature for 0.5 hour, concentrating under reduced pressure to remove the solvent, dispersing the residue in tetrahydrofuran (100mL), adding 3-fluoroazetidine hydrochloride (964mg,8.64mmol) and DIPEA (1.43mL,8.64mmol) in this order, reacting the reaction mixture with stirring at room temperature for 1 hour, adding sodium triacetoxyboroborate (3.66g,17.28mmol), reacting with stirring at room temperature for 16 hours, concentrating under reduced pressure to remove the solvent, dispersing the residue in ethyl acetate, washing with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentration and the residue was isolated by silica gel column chromatography to give the title compound (1.02g, 56%).
MS m/z(ESI):421.2[M+H]+.
And a sixth step: preparation of 2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000182
Adding N- (3-bromo-2-chlorophenyl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine (237mg,0.562mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile (328mg,0.842mmol), dicyclohexylphosphine palladium dichloride (46mg,0.056mmol) and carbonic acid carbenium (366mg,1.124mmol) into a mixed solvent of tert-butanol (20mL) and water (2mL), heating the reaction system to 90 ℃ under the protection of nitrogen, stirring for 16 hours, removing the solvent by concentration under reduced pressure, the residue was dispersed in methylene chloride, and the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to give the title compound (160mg, 47%).
MS m/z(ESI):605.1[M+H]+.
The seventh step: preparation of 1- ((2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000183
2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (80mg,0.132mmol) as a solvent was dissolved in dichloromethane (20mL), and sodium hydrogencarbonate (111mg,1.32mmol) and DMP (68mg,0.158mmol) were added successively under stirring at room temperature, the reaction solution was stirred at room temperature for 0.5 hour, filtered, concentrated, the residue was dispersed in tetrahydrofuran (10mL), and DIPEA (0.22mL,1.32mmol), azetidine-3-carboxylic acid (67mg,0.66mmol) and sodium triacetoxyboroborocyanide (84mg,0.396mmol), the reaction was stirred at room temperature for 2 hours, the solvent was removed by concentration under reduced pressure, and the residue was isolated by HPLC to give the title compound (23mg, 25%).
MS m/z(ESI):688.2[M+H]+.
Example 2
(R) -1- ((2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
Figure BDA0003143824180000191
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid reference is made to example 1.
MS m/z(ESI):716.2[M+H]+.
Example 3
5- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000192
Preparation of 5- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazole-7-carbonitrile reference is made to example 1.
MS m/z(ESI):700.2[M+H]+.
Example 4
2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000193
Preparation of 2- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):662.2[M+H]+.
Example 5
2- (3' - ((3- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000201
Preparation of 2- (3' - ((3- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile reference is made to example 1.
MS m/z(ESI):700.2[M+H]+.
Example 6
2- (3' - ((3- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000202
Preparation of 2- (3' - ((3- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile reference is made to example 1.
MS m/z(ESI):686.2[M+H]+.
Example 7
2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000203
Preparation of 2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):749.2[M+H]+.
Example 8
2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((((3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000211
Preparation of 2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((((3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile refers to example 1.
MS m/z(ESI):742.2[M+H]+.
Example 9
2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000212
Preparation of 2- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):728.2[M+H]+.
Example 10
2- (2,2' -dichloro-3 ' - ((3- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000213
Preparation of 2- (2,2' -dichloro-3 ' - ((3- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):749.2[M+H]+.
Example 11
2- (2,2' -dichloro-3 ' - ((3- (((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000221
Preparation of 2- (2,2' -dichloro-3 ' - ((3- (((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile refers to example 1.
MS m/z(ESI):742.2[M+H]+.
Example 12
2- (2,2' -dichloro-3 ' - ((3- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000222
Preparation of 2- (2,2' -dichloro-3 ' - ((3- ((3- (fluoromethyl) -3-hydroxyazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):728.2[M+H]+.
Example 13
1- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000223
The first step is as follows: preparation of 6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxynicotinaldehyde
Figure BDA0003143824180000224
Adding N- (3-bromo-2-chlorophenyl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine (800mg,1.9mmol), 2-methoxy-6- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) nicotinaldehyde (1.06g,2.82mmol), dicyclohexylphosphine palladium dichloride (155mg,0.19mmol) and carbonic acid cesium (1.24g,3.8mmol) into a mixed solvent of tert-butanol (40mL) and water (4mL), heating the reaction system to 90 ℃ under the protection of nitrogen, stirring for 16 hours, concentrating under reduced pressure to remove the solvent, dispersing the residue in dichloromethane, the organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by silica gel column chromatography to give the title compound (474mg, 44%).
MS m/z(ESI):568.2[M+H]+.
The second step is that: preparation of 1- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000231
6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxynicotinaldehyde (50mg,0.088mmol) and azetidine-3-carboxylic acid (14mg,0.131mmol) were dissolved in anhydrous methanol (10mL), DIPEA (0.022mL,0.131mmol) was stirred at room temperature, the reaction mixture was stirred at 40 ℃ for 2 hours, sodium triacetoxyboroborate (112mg,0.528mmol) was added, the reaction mixture was stirred at 40 ℃ for 0.5 hours, the solvent was removed by concentration under reduced pressure, and the residue was isolated by HPLC to give the title compound (36.1mg, 63%).
MS m/z(ESI):653.1[M+H]+.
Example 14
(R) -1- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000232
6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxynicotinaldehyde (36mg,0.063mmol) and (R) -pyrrolidine-3-carboxylic acid (37mg,0.317mmol) were dissolved in anhydrous methanol (10mL), DIPEA (0.052mL,0.317mmol) was stirred at room temperature, the reaction mixture was stirred at 40 ℃ for 2 hours, sodium triacetoxyborocyanide (81mg,0.38mmol) was added, the reaction mixture was stirred at 40 ℃ for 0.5 hours, the solvent was removed by HPLC concentration under reduced pressure, the residue was isolated to give the title compound (21.6mg, 53%).
MS m/z(ESI):667.1[M+H]+.
Example 15
(R) -1- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid
Figure BDA0003143824180000233
Preparation of (R) -1- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -3-methylpyrrolidine-3-carboxylic acid reference example 13.
MS m/z(ESI):681.2[M+H]+.
Example 16
N- (2-chloro-3 ' - (6-methoxy-5- ((oxetan-3-ylamino) methyl) pyridin-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000234
Preparation of N- (2-chloro-3 ' - (6-methoxy-5- ((oxetan-3-ylamino) methyl) pyridin-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine refers to example 13.
MS m/z(ESI):625.2[M+H]+.
Example 17
N- (2-chloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000241
Preparation of N- (2-chloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine refers to example 13.
MS m/z(ESI):627.2[M+H]+.
Example 18
1- (6- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one
Figure BDA0003143824180000242
Preparation of 1- (6- ((6- (2' -chloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one reference example 13.
MS m/z(ESI):692.2[M+H]+.
Example 19
N- (3' - (5- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000243
Preparation of N- (3' - (5- ((5-oxa-2-azaspiro [3.4] octan-2-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine refers to example 13.
MS m/z(ESI):665.2[M+H]+.
Example 20
N- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000244
Preparation of N- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-amine refers to example 13.
MS m/z(ESI):651.2[M+H]+.
Example 21
3- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -1, 7-naphthyridin-8-amine
Figure BDA0003143824180000251
Preparation of 3- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -N- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2-chloro-2 ' -methyl- [1,1' -biphenyl ] -3-yl) -1, 7-naphthyridin-8-amine reference example 13.
MS m/z(ESI):675.2[M+H]+.
Example 22
2- (((8- ((2,2' -dichloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) - [1,1' -biphenyl ] -3-yl) amino) -1, 7-naphthyridin-3-yl) methyl) amino) propane-1, 3-diol
Figure BDA0003143824180000252
Preparation of 2- (((8- ((2,2' -dichloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) - [1,1' -biphenyl ] -3-yl) amino) -1, 7-naphthyridin-3-yl) methyl) amino) propane-1, 3-diol reference example 13.
MS m/z(ESI):663.2[M+H]+.
Example 23
1- (6- ((6- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one
Figure BDA0003143824180000253
Preparation of 1- (6- ((6- (2,2' -dichloro-3 ' - ((3- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) -2, 6-diazaspiro [3.3] heptan-2-yl) ethan-1-one reference example 13.
MS m/z(ESI):728.2[M+H]+.
Example 24
2- (((8- ((3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) amino) -1, 7-naphthyridin-3-yl) methyl) amino) propane-1, 3-diol
Figure BDA0003143824180000254
Preparation of 2- (((8- ((3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) amino) -1, 7-naphthyridin-3-yl) methyl) amino) propane-1, 3-diol reference example 13.
MS m/z(ESI):687.2[M+H]+.
Example 25
2- (((6- (2,2' -dichloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) amino) propane-1, 3-diol
Figure BDA0003143824180000261
Preparation of 2- (((6- (2,2' -dichloro-3 ' - ((3- ((3-fluoroazetidin-1-yl) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) amino) propane-1, 3-diol reference example 13.
MS m/z(ESI):663.2[M+H]+.
Example 26
2- (((6- (2,2' -dichloro-3 ' - ((3- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) amino) propane-1, 3-diol
Figure BDA0003143824180000262
Preparation of 2- (((6- (2,2' -dichloro-3 ' - ((3- (((3-fluoro-2-methylpyridin-4-yl) amino) methyl) -1, 7-naphthyridin-8-yl) amino) - [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) amino) propane-1, 3-diol refers to example 13.
MS m/z(ESI):714.2[M+H]+.
Example 27
((2- ((3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) -L-proline
Figure BDA0003143824180000263
Preparation of ((2- ((3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) carbamoyl) -1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) -L-proline reference example 13.
MS m/z(ESI):782.2[M+H]+.
Example 28
N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -1-methyl-5- ((oxetan-3-ylamino) methyl) -1H-benzo [ d ] imidazole-2-carboxamide
Figure BDA0003143824180000271
Preparation of N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -1-methyl-5- ((oxetan-3-ylamino) methyl) -1H-benzo [ d ] imidazole-2-carboxamide reference example 13.
MS m/z(ESI):740.2[M+H]+.
Example 29
N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -5- (((((1R, 2S) -2-fluorocyclopropyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-2-carboxamide
Figure BDA0003143824180000272
Preparation of N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -5- ((((1R,2S) -2-fluorocyclopropyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-2-carboxamide reference example 13.
MS m/z(ESI):742.2[M+H]+.
Example 30
(S) -N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -5- (((2-hydroxypropyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-2-carboxamide
Figure BDA0003143824180000273
Preparation of (S) -N- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2,2' -dichloro- [1,1' -biphenyl ] -3-yl) -5- (((2-hydroxypropyl) amino) methyl) -1-methyl-1H-benzo [ d ] imidazole-2-carboxamide reference example 13.
MS m/z(ESI):742.2[M+H]+.
Example 31
N- (2-chloro-3- (1- (4-methoxy-5- ((oxetan-3-ylamino) methyl) picolinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000281
The first step is as follows: preparation of tert-butyl-2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
Figure BDA0003143824180000282
To a solution of 5- (tert-butyl) 2-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-2, 5-dicarboxylate (500mg,1.69mmol) in tetrahydrofuran (10mL) were added 3-bromo-2-chloroaniline (417mg,2.02mmol) and potassium tert-butoxide (378mg,3.38mmol) in this order, and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with saturated aqueous sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (680mg, 86%).
MS m/z(ESI):469.1[M+H]+.
The second step is that: preparation of N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000283
Tert-butyl-2- ((3-bromo-2-chlorophenyl) carbamoyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (300mg,0.64mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added thereto, and the reaction mixture was concentrated under stirring at room temperature for 30 minutes; then, tetrahydrofuran (10mL) was added to dissolve it, and an aqueous solution of formaldehyde (37 wt%, 0.48mL,6.39mmol) and sodium triacetoxyborohydride (406mg,1.92mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate solution (20mL), and then the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol 95:5) to obtain the title compound (223mg, 91%).
MS m/z(ESI):383.0[M+H]+.
The third step: preparation of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline
Figure BDA0003143824180000284
4-bromo-2, 3-dihydro-1H-indole (500mg,2.53mmol), pinacol diborate (707mg,2.78mmol), Pd (dppf) Cl2(370mg,0.506mmol) and AcOK (744mg,7.59mmol) were added to dioxane (10mL) respectively, and the temperature was raised under nitrogen protection toStirred at 100 ℃ for 2 hours. After the reaction was concentrated, the residue was isolated and purified by silica gel column chromatography to give the title compound as a brown oil (238mg, 37%).
MS m/z(ESI):246.2[M+H]+.
The fourth step: preparation of N- (2-chloro-3- (indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000291
Mixing N- (3-bromo-2-chlorophenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine-2-carboxamide (200mg,0.522mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) indoline (140mg,0.574mmol), Pd (dcypf) Cl2(86mg,0.104mmol)，Cs2CO3(340mg,1.04mmol) were added to a mixed solvent of 1, 4-dioxane (4mL) and water (0.8mL), and the mixture was heated to 100 ℃ under nitrogen and stirred for 16 hours. After the reaction solution was cooled, the fractions were separated, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (100mg, 45%).
MS m/z(ESI):422.2[M+H]+.
The fifth step: preparation of N- (2-chloro-3- (1- (5- (hydroxymethyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000292
LiHMDS (0.275mL,1.3M solution in THF) was added dropwise to a solution of N- (2-chloro-3- (indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (50mg,0.119mmol) and methyl 5- (hydroxymethyl) -4-methoxymethylpyridinate (28mg,0.143mmol) in tetrahydrofuran (1mL) at room temperature and stirred at room temperature for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride (1mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated aqueous sodium chloride (5mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (33mg, 47%).
MS m/z(ESI):587.2[M+H]+.
And a sixth step: preparation of N- (2-chloro-3- (1- (5-formyl-4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000293
To N- (2-chloro-3- (1- (5- (hydroxymethyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine-2-carboxamide (33mg,0.0564mmol) in DCM (2mL) was added with dess-Martin reagent (48mg,0.113mmol) and stirred at room temperature for 1 h. Saturated NaHCO is used for reaction liquid3Quenched with aqueous solution (1mL), extracted with DCM (5mL), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give the title compound as a brown solid (40mg, crude)
MS m/z(ESI):585.2[M+H]+.
The seventh step: preparation of N- (2-chloro-3- (1- (4-methoxy-5- ((oxetan-3-ylamino) methyl) picolinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000301
3-Oxetamine (10mg,0.137mmol) was added to a solution of N- (2-chloro-3- (1- (5-formyl-4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide (40mg,0.0564mmol) in dichloroethane (1mL), stirred at room temperature for 15 minutes, added with sodium borohydride acetate (36mg,0.17mmol) and stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate (1mL), extracted with dichloromethane (5mL), the organic layer was concentrated under reduced pressure, and the residue was isolated and purified by preparative HPLC to afford the title compound (formate salt) as a white solid (10mg, 27% yield over two steps).
MS m/z(ESI):642.2[M+H]+.
Example 32
N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000302
Preparation of N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide reference example 31.
MS m/z(ESI):660.2[M+H]+.
Example 33
N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -3-methoxy-4- ((oxetan-3-ylamino) methyl) benzamide
Figure BDA0003143824180000303
Preparation of N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -3-methoxy-4- ((oxetan-3-ylamino) methyl) benzamide refers to example 31.
MS m/z(ESI):702.2[M+H]+.
Example 34
N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- (((((1R, 2S) -2-fluorocyclopropyl) amino) methyl) -3-methoxybenzamide
Figure BDA0003143824180000311
Preparation of N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- (((((1R, 2S) -2-fluorocyclopropyl) amino) methyl) -3-methoxybenzamide refers to example 31.
MS m/z(ESI):704.2[M+H]+.
Example 35
N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- (((((3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) -3-methoxybenzamide
Figure BDA0003143824180000312
Preparation of N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- (((((3R, 4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) -3-methoxybenzamide reference example 31.
MS m/z(ESI):748.2[M+H]+.
Example 36
N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- ((3-hydroxyazetidin-1-yl) methyl) -3-methoxybenzamide
Figure BDA0003143824180000313
Preparation of N- (2-chloro-3- (1- (5- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) phenyl) -4- ((3-hydroxyazetidin-1-yl) methyl) -3-methoxybenzamide reference example 31.
MS m/z(ESI):702.2[M+H]+.
EXAMPLE 37N- (2-chloro-3- (1- (4-methoxy-5- ((oxetan-3-ylamino) methyl) picolinyl) indolin-4-yl) phenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide
Figure BDA0003143824180000321
Preparation of N- (2-chloro-3- (1- (4-methoxy-5- ((oxetan-3-ylamino) methyl) picolinyl) indolin-4-yl) phenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide reference example 31.
MS m/z(ESI):702.2[M+H]+.
Example 38
N- (3- (1- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) -2-chlorophenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide
Figure BDA0003143824180000322
Preparation of N- (3- (1- (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) -2-chlorophenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide refers to example 31.
MS m/z(ESI):769.2[M+H]+.
Example 39
N- (3- (1- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) -2-chlorophenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide
Figure BDA0003143824180000323
Preparation of N- (3- (1- (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -4-methoxymethylpyridinyl) indolin-4-yl) -2-chlorophenyl) -4- (((1, 3-dihydroxypropan-2-yl) amino) methyl) -3-methoxybenzamide refers to example 31.
MS m/z(ESI):728.2[M+H]+.
Example 44
2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000331
The first step is as follows: preparation of methyl 3-cyano-4-hydroxybenzoate
Figure BDA0003143824180000332
Methyl 4-hydroxy-3-iodobenzoate (60g,0.216mol), zinc cyanide (38g,0.324mol) and palladium tetratriphenylphosphine (12.46g,0.022mol) were suspended in N, N-dimethylformamide (300mL) under a nitrogen atmosphere, and the reaction was stirred with heating at 140 ℃ overnight. After the reaction, the reaction solution was cooled and filtered, and a saturated potassium carbonate aqueous solution was added to the filtrate to adjust the reaction solution to alkaline, followed by extraction with ethyl acetate (150 mL. times.3) to remove impurities, the filtrate was adjusted to acidic with concentrated hydrochloric acid, followed by extraction with dichloromethane (300 mL. times.3), washing with a saturated sodium chloride aqueous solution (100 mL. times.3), collection of the organic phase, drying with anhydrous sodium sulfate, filtration, and concentration of the organic phase under reduced pressure to obtain the title compound (37.2g, 97%)
MS m/z(ESI):176.1[M-H]+.
The second step is that: preparation of methyl 3-cyano-4-hydroxy-5-nitrobenzoate
Figure BDA0003143824180000333
Methyl 3-cyano-4-hydroxybenzoate (37.2g,0.210mol) was dissolved in glacial acetic acid (200mL), nitric acid (32.6mL,0.735mol) was added at room temperature, and the mixture was warmed to 70 ℃ and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into a large amount of ice water and stirred for 30 minutes, and then the aqueous phase was filtered and the filter cake was dried to obtain the title compound (24.9g, 53%).
MS m/z(ESI):221.1[M-H]+.
The third step: preparation of methyl 3-amino-4-hydroxy-5-nitrobenzoate
Figure BDA0003143824180000334
Methyl 3-cyano-4-hydroxy-5-nitrobenzoate (24.9g,0.112mol) and palladium on carbon hydrogenation catalyst (2.5g) were suspended in methanol (500mL), replaced with hydrogen three times, and then stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (16.6g, 77%).
MS m/z(ESI):191.1[M-H]+.
The fourth step: preparation of methyl 3- (3-bromo-2-methylbenzoylamino) -5-cyano-4-hydroxybenzoate
Figure BDA0003143824180000335
3-bromo-2-methylbenzoic acid (20.5g,0.095mol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (36.1g,0.095mol) and N, N-diisopropylethylamine (22.5mL,0.130mol) were dissolved in dry N, N-dimethylformamide (150mL) under a nitrogen atmosphere, stirred at room temperature for 1 hour, then methyl 3-amino-4-hydroxy-5-nitrobenzoate (16.6g,0.086mol) was added and the reaction was continued overnight with stirring at room temperature. After completion of the reaction, the reaction mixture was poured into a large amount of ice water, stirred for 30 minutes, the aqueous phase was filtered and the cake was concentrated under reduced pressure, and then the cake was slurried with petroleum ether ethyl acetate 4:1(400mL) for 1 hour, and the cake was filtered and dried to obtain the title compound (31.6g, 94%).
MS m/z(ESI):387.1[M-H]+.
The fifth step: preparation of methyl 2- (3-bromo-2-methylphenyl) -7-cyanobenzo [ d ] oxazole-5-benzoate
Figure BDA0003143824180000341
2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (35.1g,0.154mol) and triphenylphosphine (40.4g,0.154mol) were suspended in dry toluene (600mL) under a nitrogen atmosphere, stirred at room temperature for 1 hour, added with methyl 3- (3-bromo-2-methylbenzamido) -5-cyano-4-hydroxybenzoate (30g,0.077mol), and heated to 110 ℃ for stirring overnight. After the reaction was completed, the reaction solution was concentrated to remove toluene, then an aqueous solution of saturated potassium carbonate was added to adjust to alkalinity, after stirring for 30 minutes, the aqueous phase was filtered and the filter cake was concentrated under reduced pressure, then the filter cake was slurried with ethanol for 1 hour, and the filter cake was filtered and dried to obtain the title compound (26.8g, 94%).
And a sixth step: preparation of 2- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000342
Methyl 2- (3-bromo-2-methylphenyl) -7-cyanobenzo [ d ] oxazole-5-benzoate (26.8g,0.072mol) and calcium chloride (16.1g,0.144mol) were suspended in a mixed solvent of tetrahydrofuran (600mL) and ethanol (300mL) at room temperature, stirred at room temperature for 1 hour, added with sodium borohydride (8.2g,0.216mol) and heated to 55 ℃ for stirring reaction for 4 hours. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, and then the reaction solution was concentrated until a large amount of solid was precipitated, filtered and the filtrate was concentrated under reduced pressure, and then slurried with methanol for 1 hour, filtered and dried to obtain the title compound (20.7g, 84%).
MS m/z(ESI):343.1[M+H]+.
The seventh step: preparation of 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000343
2- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (20g,0.06mol), pinacol diborate (30.5g,0.12mol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (4.4g,0.006mol) and potassium acetate (17.6mg,0.18mol) were suspended in a dry 1, 4-epoxyhexacyclic (600mL) solution under nitrogen atmosphere and reacted with heating with stirring at 100 ℃ overnight. After the reaction was completed, the reaction solution was filtered, and the filtrate was decolorized with a silica gel pad, followed by beating with ethanol for 1 hour, filtration and drying to obtain the title compound (18.7g, 82%).
MS m/z(ESI):391.2[M+H]+.
Eighth step: preparation of 6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde
Figure BDA0003143824180000351
6-chloro-2-methoxynicotinaldehyde (400mg,2.34mmol), (3-bromo-2-chlorophenyl) boronic acid (600mg,2.57mmol), Pd (PPh)3)4(266mg,0.23mmol) and potassium carbonate (646mg,4.68mmol) were dissolved in a mixed solvent of dioxane (20mL) and water (2mL), purged with nitrogen, and then heated to 95 ℃ under stirring overnight. After completion of the reaction, the reaction solution was cooled, filtered, the filtrate was concentrated, and the residue was subjected to flash silica gel column chromatography (PE: EA ═ 4:1) to isolate the title compound (600mg, 78%).
MS m/z(ESI):326.7[M+H]+.
The ninth step: preparation of 1- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) azetidin-3-ol
Figure BDA0003143824180000352
6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (150mg,0.46mmol), azetidin-3-ol (150mg,1.38mmol) and N, N-diisopropylethylamine (119mg,0.92mmol) were dissolved in N, N-dimethylformamide (10mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (58mg,0.92mmol) was then added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (136mg, 77%).
MS m/z(ESI):383.1[M+H]+.
The tenth step: preparation of 2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000353
1- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) azetidin-3-ol (136mg,0.356mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile (167mg,0.427mmol), [1,1' -bis (dicyclohexylphosphine) ferrocene ] palladium dichloride (27mg,0.036mmol) and cesium carbonate (232mg,0.712mmol) were suspended in t-butanol solution (10mL) and water (2mL), displaced with nitrogen three times, heated at 100 ℃ and stirred overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (48mg, 24%).
MS m/z(ESI):567.1[M+H]+.
The eleventh step: preparation of 2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000354
2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (48mg,0.085mmol) and manganese dioxide (74mg,0.85mmol) were suspended in dichloromethane (10mL) and the reaction was stirred at 50 ℃ under reflux overnight. After completion of the reaction, the reaction mixture was concentrated by filtration, and dissolved in N, N-dimethylformamide (5mL) with 3-fluoroazetidine (28mg,0.255mmol) and N, N-diisopropylethylamine (22mg,0.17mmol), and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (10.7mg,0.17mmol) was then added and the reaction was stirred at room temperature overnight. At the end of the reaction, the reaction mixture was extracted with dichloromethane (15mL x3), washed with saturated aqueous sodium chloride (10mL x3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to give the title compound (3.9mg, 7%) by prep-HPLC.
MS m/z(ESI):624.1[M+H]+.
Example 53
1- ((2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000361
The first step is as follows: preparation of 6- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2-oxa-6-azaspiro [3.3] heptane
Figure BDA0003143824180000362
6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (500mg,0.46mmol), 2-oxa-6-azaspiro [3.3] heptane (304mg,0.92mmol) and N, N-diisopropylethylamine (119mg,0.92mmol) were dissolved in N, N-dimethylformamide (10mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (58mg,0.92mmol) was then added and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 98:2) to obtain the title compound (350mg, 56%).
MS m/z(ESI):409.1[M+H]+.
The second step is that: preparation of 2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000363
6- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) -2-oxa-6-azaspiro [3.3] heptane (350mg,0.858mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile (401mg,1.03mmol), [1,1' -bis (dicyclohexylphosphine) ferrocene ] palladium dichloride (65mg,0.086mmol) and cesium carbonate (559mg,1.716mmol) were suspended in t-butanol solution (10mL) and water (2mL), displaced with nitrogen three times, and heated with stirring at 100 ℃ overnight for reaction. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (316mg, 62%).
MS m/z(ESI):593.1[M+H]+.
The third step: preparation of 2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000371
2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (316mg,0.534mmol) and dess-martin oxidant (339mg,0.8mmol) were suspended in dichloromethane (10mL) and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with dichloromethane (15mL × 3), washed with saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (135mg, 43%).
MS m/z(ESI):624.1[M+H]+.
The fourth step: preparation of 1- ((2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000372
2- (3' - (5- ((2-oxa-6-azaspiro [3.3] heptan-6-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] oxazole-7-carbonitrile (30mg,0.05mmol), azetidine-3-carboxylic acid (15mg,0.15mmol) and acetic acid were dissolved in N, N-dimethylformamide (5mL) in one drop and stirred at room temperature for 1 hour. Sodium cyanoborohydride (6.3mg,0.1mmol) was then added and the reaction was stirred at room temperature overnight. At the end of the reaction, the reaction mixture was extracted with dichloromethane (15mL x3), washed with saturated aqueous sodium chloride (10mL x3), the organic phase collected was dried over anhydrous sodium sulfate, filtered and the organic phase concentrated under reduced pressure to give the title compound by prep-HPLC (15.0mg, 44%).
MS m/z(ESI):676.1[M+H]+.
Example 62
2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000373
Preparation of 2- (2' -chloro-3 ' - (5- ((3-hydroxyazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile reference example 1.
MS m/z(ESI):668.2[M+H]+.
Example 65
2- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000381
Preparation of 2- (3' - (5- ((6-acetyl-2, 6-diazaspiro [3.3] heptan-2-yl) methyl) -6-methoxypyridin-2-yl) -2' -chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazole-7-carbonitrile refers to example 1.
MS m/z(ESI):735.2[M+H]+.
Example 66
1- ((6- (2-chloro-3 ' - (7-cyano-5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000382
Preparation of 1- ((6- (2-chloro-3 ' - (7-cyano-5- ((((3R,4R) -3-fluorotetrahydro-2H-pyran-4-yl) amino) methyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid reference example 1.
MS m/z(ESI):696.2[M+H]+.
Example 89
2- (2,2' -dichloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) - [1,1' -biphenyl ] -3-yl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine
Figure BDA0003143824180000383
The first step is as follows: preparation of 6- (2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-methoxynicotinaldehyde
Figure BDA0003143824180000384
6- (3-bromo-2-chlorophenyl) -2-methoxynicotinaldehyde (600mg,1.83mmol), pinacolato diboron ester (607mg,2.39mol), Pd (dppf) Cl2DCM complex (149mg,0.18mmol) and potassium acetate (538mg,5.49mmol) were dissolved in dioxane (17mL), purged with nitrogen, and stirred at 95 deg.C overnight. After completion of the reaction, the reaction mixture was cooled and concentrated. The residue was subjected to flash silica gel column chromatography (PE: EA ═ 3:1) to isolate the title compound (600mg, 87%).
MS m/z(ESI):375.7[M+H]+.
The second step is that: preparation of 2- (3-bromo-2-chlorophenyl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine
Figure BDA0003143824180000391
2-bromo-5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c]Pyridine (233mg,1mmol), (3-bromo-2-chlorophenyl) boronic acid (257mg,1.1mmol), Pd (PPh)3)4(115mg,0.1mmol) and cesium carbonate (975mg,3mmol) were dissolved in a mixed solvent of dioxane (10mL) and water (1mL), purged with nitrogen, and then heated to 95 ℃ under stirring overnight. After completion of the reaction, the reaction mixture was cooled and concentrated, and the residue was subjected to flash silica gel column chromatography (PE: EA ═ 1:1), (DCM: MeOH ═ 20:1) to isolate the title compound (250mg, 73%).
MS m/z(ESI):343.2[M+H]+.
The third step: preparation of 6- (2,2' -dichloro-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) -2-methoxynicotinaldehyde
Figure BDA0003143824180000392
2- (3-bromo-2-chlorophenyl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5, 4-c)]Pyridine (250mg,0.73mmol), 6- (2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-methoxynicotinaldehyde (300mg,0.80mol), Pd (dppf) Cl2DCM complex (120mg,0.146mmol) and cesium carbonate (474mg,1.46mmol) were dissolved in a mixed solvent of dioxane (10mL) and water (1.5mL), purged with nitrogen, and stirred at 95 ℃ overnight. After completion of the reaction, the reaction mixture was cooled and concentrated. Flash column chromatography of the residue (DCM: MeOH ═ 10:1) afforded the title compound (280mg, 75%).
MS m/z(ESI):510.2[M+H]+.
The fourth step: preparation of 2- (2,2' -dichloro-3 ' - (5- ((3-fluoroazetidin-1-yl) methyl) -6-methoxypyridin-2-yl) - [1,1' -biphenyl ] -3-yl) -5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridine
Figure BDA0003143824180000393
6- (2,2' -dichloro-3 ' - (5-methyl-4, 5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) - [1,1' -biphenyl ] -3-yl) -2-methoxynicotinaldehyde (90mg,0.176mmol) and 3-fluoroazetidine hydrochloride (59mg,0.53mmol) were dissolved in methanol (3mL), neutralized by the addition of DIPEA, followed by the addition of 3 drops of acetic acid and stirring at room temperature for 3 hours. After addition of sodium cyanoborohydride (22mg,0.352mmol), stirring was continued at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by reverse phase to give the title compound (10.3mg, 10%).
MS m/z(ESI):569.2[M+H]+.
Example 98
(S) -1- ((5-chloro-6- ((4- (3- (7-cyano-5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000394
The first step is as follows: preparation of 5-formyl-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000401
Des-Martin reagent (2.49g,5.70mmol) was added to 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] n at room temperature]Oxazole-7-carbonitrile (1.51g,3.87mmol) was stirred at room temperature for 3 hours in a mixed solvent of DCM (17mL) and DMF (2 mL). Saturated NaHCO is used for reaction liquid3Aqueous solution (10mL) was quenched, extracted with DCM (50mL), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was slurried with methyl tert-butyl ether (10mL) to give the title compound as a gray solid (1.43g, 95%)
MS m/z(ESI):389.2[M+H]+.
The second step is that: preparation of 5- ((3-fluoroazetidin-1-yl) methyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000402
DIPEA (228uL,1.38mmol) was added to a solution of 5-formyl-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile (358mg,0.92mmol) and 3-fluoroazetidine hydrochloride (153mg,1.38mmol) in dichloroethane (6mL), warmed to 50 deg.C and stirred for 1 hour, sodium borohydride acetate (975mg,4.60mmol) was added, and stirred for 1 hour at 50 deg.C. The reaction was diluted with DCM (10mL) and washed with saturated aqueous sodium bicarbonate (10mL), the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give the title compound as a brown oil (372mg, 91%).
MS m/z(ESI):448.2[M+H]+.
The third step: preparation of (S) -methyl 6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinate
Figure BDA0003143824180000403
DIPEA (639mg,4.96mmol) was added to a solution of (S) -4-bromo-2, 3-dihydro-1H-inden-1-amine (500mg,2.36mmol) and methyl 6-chloro-2-methoxynicotinate (521mg,2.59mmol) in NMP (5mL) and microwave heated to 100 ℃ for 16H. The reaction was diluted with ice water (50mL), then extracted with ethyl acetate (50mL × 2), the organic layers were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography to give the title compound as a brown solid (330mg, 37%).
MS m/z(ESI):377.1[M+H]+.
The fourth step: preparation of (S) -methyl 6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-2-methoxynicotinate
Figure BDA0003143824180000404
NCS (120mg,0.878mmol) was added to a solution of (S) -methyl 6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxynicotinate (300mg,0.798mmol) in DMF (3mL) and heated to 80 ℃ for 1.5H. The reaction was diluted with ice water (30mL), then extracted with ethyl acetate (30mL × 2), the organic layers were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography to give the title compound as a brown solid (268mg, 82%).
MS m/z(ESI):411.1[M+H]+.
The fifth step: preparation of (S) - (6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-2-methoxypyridin-3-yl) methanol
Figure BDA0003143824180000411
DABAL-H (1.50mL,1.5M in toluene) was added dropwise to a solution of (S) -methyl 6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-2-methoxynicotinate (280g,0.680mmol) in tetrahydrofuran (1mL) at-78 ℃. After dropping, stirring for 1 hour under heat preservation. The reaction was quenched dropwise with methanol (3mL), warmed to room temperature, then saturated aqueous sodium tartrate solution (5mL) was added, stirred vigorously at room temperature for 1 hour, extracted with ethyl acetate (10mL), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give the title compound as a colorless oil (222mg, 85%).
MS m/z(ESI):383.1[M+H]+.
And a sixth step: preparation of (S) -2- (3- (1- ((3-chloro-5- (hydroxymethyl) -6-methoxypyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000412
Mixing (S) - (6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) amino) -5-chloro-2-methoxypyridin-3-yl) methanol (222mg,0.578mmol), 5- ((3-fluoroazetidin-1-yl) methyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d [ -d]Oxazole-7-carbonitrile (388mg,0.867mmol), Pd (dppf) Cl2(42mg,0.0578mmol)，Cs2CO3(377mg,1.16mmol) were added to a mixed solvent of 1, 4-epoxyhexacyclic compound (5mL) and water (1mL), and the mixture was heated to 100 ℃ under nitrogen and stirred for 1 hour. The reaction solution was separated, the organic layer was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the title compound as a brown oil (225mg, 62%).
MS m/z(ESI):624.2[M+H]+.
The seventh step: preparation of (S) -2- (3- (1- ((3-chloro-5-formyl-6-methoxypyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000413
Des-Martin reagent (229mg,0.541mmol) was added to (S) -2- (3- (1- ((3-chloro-5- (hydroxymethyl) -6-methoxypyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((3-fluoroazedin-1-yl) methyl) benzo [ d ] at room temperature]Oxazole-7-carbonitrile (225mg,0.361mmol) was dissolved in DCM (5mL) and stirred at room temperature for 1 hour. Saturated NaHCO is used for reaction liquid3Aqueous solution (3mL) was quenched, extracted with DCM (10mL), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown solid (139mg, 62%).
MS m/z(ESI):622.2[M+H]+.
Eighth step: preparation of (S) -1- ((5-chloro-6- ((4- (3- (7-cyano-5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazol-2-yl) -2-methylphenyl) -2, 3-dihydro-1H-inden-1-yl) amino) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000414
DIPEA (23uL,0.142mmol) was added to a mixed solution of (S) -2- (3- (1- ((3-chloro-5-formyl-6-methoxypyridin-2-yl) amino) -2, 3-dihydro-1H-inden-4-yl) -2-methylphenyl) -5- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile (22mg,0.0354mmol) and azetidine-3-carboxylic acid (14mg,0.142mmol) in dichloroethane (1mL) and DMSO (0.5mL), stirred at room temperature for 0.5H, added sodium borohydride acetate (37mg,0.177mmol) and warmed to 50 ℃ and stirred for 2H. The reaction was concentrated under reduced pressure, and the residue was isolated and purified by preparative HPLC to give the title compound (formate salt) as a pale yellow solid (2mg, 7%).
MS m/z(ESI):707.3[M+H]+.
Example 104
(R) -1- ((7-cyano-2- (3- (5- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxalylamino >) -4- (isopropylthio) thiophen-3-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000421
The first step is as follows: preparation of 3, 4-dibromo-2-nitrothiophene
Figure BDA0003143824180000422
Fuming nitric acid (41.4mL) was added dropwise to glacial acetic acid (500mL) while cooling on ice, followed by stirring for 10 minutes. A solution of 3, 4-dibromothiophene (50g,0.207mol) in acetic anhydride (78mL) was added dropwise to the above solution, gradually warmed to room temperature and stirred overnight. Crushed ice was added to the reaction solution, and the precipitated solid was filtered, washed with water and diethyl ether/n-heptane (v/v ═ 1/5), respectively, and dried in vacuo to give the title compound as a brown solid (40.2g, 68%).
1H-NMR(400MHz,CDCl3)δ7.61(s,1H).
The second step is that: preparation of 4-bromo-3- (isopropylthio) -2-nitrothiophene
Figure BDA0003143824180000423
3, 4-dibromo-2-nitrothiophene (1.0g,3.49mmol), 2-propanethiol (0.292g,3.83mmol), K2CO3(0.530g,3.83mmol) was added to a mixed solvent of EtOH (14mL) and water (2mL), respectively, and stirred at room temperature for 4 hours. The reaction was concentrated and the residue was slurried with water to give the title compound as a brown solid (0.845g, 86%).
The third step: preparation of 4-bromo-3- (isopropylthio) thiophen-2-amine
Figure BDA0003143824180000424
4-bromo-3- (isopropylthio) -2-nitrothiophene (408mg,1.45mmol), ammonium chloride (773mg,14.5mmol) and iron powder (403mg,7.23mmol) were added to a mixed solvent of EtOH (6mL) and water (3mL), respectively, and the mixture was heated to 80 ℃ and stirred overnight. The reaction was filtered through celite pad, the filtrate was concentrated under reduced pressure, and the residue was slurried with water and dried in vacuo to give the title compound as a brown solid (347mg, 95%).
MS m/z(ESI):252.0[M+H]+.
The fourth step: preparation of tert-butyl 2- ((4-bromo-3- (isopropylthio) thiophen-2-yl) carbamoyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
Figure BDA0003143824180000431
To a solution of 5- (tert-butyl) 2-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-2, 5-dicarboxylate (501mg,1.62mmol) in tetrahydrofuran (10mL) were added 4-bromo-3- (isopropylthio) thiophen-2-amine (490mg,1.94mmol), potassium tert-butoxide (363mg,3.24mmol) in that order, and the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30mL), washed with a saturated aqueous solution of sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (685mg, 82%).
MS m/z(ESI):515.1[M+H]+.
The fifth step: preparation of N- (4-bromo-3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000432
Tert-butyl 2- ((4-bromo-3- (isopropylthio) thiophen-2-yl) carbamoyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (330mg,0.64mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes and concentrated; then, tetrahydrofuran (10mL) was added to dissolve it, and an aqueous solution of formaldehyde (37 wt%, 0.48mL,6.39mmol) and sodium triacetoxyborohydride (406mg,1.92mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate solution (20mL), and then the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous sodium chloride solution (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol 100:1 to 10:1) to obtain the title compound (222mg, 81%).
MS m/z(ESI):429.1[M+H]+.
And a sixth step: preparation of methyl 3-chloro-4-hydroxy-5-nitrobenzoate
Figure BDA0003143824180000433
Methyl 3-chloro-4-hydroxybenzoate (9.47g,52.1mmol) was added to AcOH (20mL), and a solution of fuming nitric acid (6.56g,104mmol) in AcOH (20mL) was added dropwise over an ice bath. After the dripping is finished, the temperature is naturally raised to the room temperature and the mixture is stirred for 2 hours. Cooling the reaction liquid to 0-5 ℃, dropwise adding 40mL of ice water, keeping the temperature and stirring for 10 minutes after dropwise adding, filtering, and washing a filter cake with water until the pH value of the filtrate is greater than 6. The filter cake was dried under reduced pressure to give the title compound as a yellow solid (11.4g, 94%).
The seventh step: preparation of methyl 3-amino-5-chloro-4-hydroxybenzoate
Figure BDA0003143824180000441
Methyl 3-chloro-4-hydroxy-5-nitrobenzoate (11.1g,47.8mmol) was added to a mixed solvent of EtOAc (330mL) and 1, 2-dichlorobenzene (33mL) and Pd/C (740mg, 10% Pd) was added under nitrogen. The reaction solution was stirred at room temperature under 1atm hydrogen pressure for 1.5 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to 100mL under reduced pressure, and petroleum ether (100mL) was added to the filtrate, followed by concentration to 100mL under reduced pressure. The mixture was filtered and the filter cake was washed with petroleum ether and dried under reduced pressure to give the title compound as an off-white solid (6.60g, 68%).
Eighth step: preparation of methyl 2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d ] oxazole-5-carboxylate
Figure BDA0003143824180000442
Methyl 3-amino-5-chloro-4-hydroxybenzoate (1.04g,5.16mmol) and 3-bromo-2-methylbenzaldehyde (0.98g,4.92mmol) were added to absolute ethanol (25mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with anhydrous dichloromethane (25mL), and DDQ (1.12g,4.92mmol) was added portionwise at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution was filtered. The filter cake was washed with dichloromethane (10 mL). The combined organic phases were washed with saturated aqueous NaHSO3 and saturated aqueous NaHCO3, respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a grey solid (1.67g, crude).
MS m/z(ESI):380.1[M+H]+.
The ninth step: preparation of (2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d ] oxazol-5-yl) methanol
Figure BDA0003143824180000443
DABAL-H (8mL,1.2M in toluene) was added dropwise to a solution of methyl 2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d ] oxazole-5-carboxylate (1.67g,4.38mmol) in dichloromethane (30mL) at-78 ℃. After dropping, the temperature is naturally raised to 0 ℃ and stirred for 1 hour. The reaction was quenched with saturated aqueous sodium tartrate (10mL) at 0 deg.C, warmed to room temperature and stirred vigorously for 1 hour, and filtered through a pad of celite. The filter cake was washed with DCM, the filtrates were combined, the liquid was separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel to give the title compound as a pale yellow solid (645mg, 37% yield in two steps).
MS m/z(ESI):352.0[M+H]+.
The tenth step: preparation of (7-chloro-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazol-5-yl) methanol
Figure BDA0003143824180000451
Reacting (2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d]Oxazol-5-yl) methanol (226mg,0.644mmol), pinacol diborate (196mg,0.772mmol), Pd (dppf) Cl2(47mg,0.064mmol) and AcOK (158mg,1.04mmol) were added to dioxane (6mL), and the mixture was heated to 110 ℃ under nitrogen and stirred for 2 hours. After the reaction was concentrated, the residue was isolated and purified by silica gel column chromatography to give the title compound as a pale yellow solid (206mg, 80%).
MS m/z(ESI):400.1[M+H]+.
The eleventh step: preparation of 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000452
(7-chloro-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazol-5-yl) methanol (455mg,0.85mmol), potassium hexacyanoferrate trihydrate (II) (361mg,0.85mmol), potassium acetate (17mg,0.171mmol), t-BuXPhos Pd G3(68mg,0.085mmol) were added to a mixed solvent of dioxane (2mL) and water (2mL), replaced with nitrogen three times, and then heated to 100 ℃ for stirring reaction for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a yellow solid (298mg, 90%).
MS m/z(ESI):391.2[M+H]+.
The twelfth step: preparation of N- (4- (3- (7-cyano-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2-methylphenyl) -3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000453
Mixing N- (4-bromo-3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ]]Pyridine-2-carboxamide (115mg,0.268mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d]Oxazole-7-carbonitrile (115mg,0.295mmol), Pd (dppf) Cl2(20mg,0.0268mmol)，Cs2CO3(218mg,0.67mmol) was added to a mixed solvent of dioxane (1mL) and water (0.2mL), and the mixture was heated to 90 ℃ under nitrogen and stirred for 2 hours. After the reaction was concentrated, the residue was isolated and purified by silica gel column chromatography to give the title compound as a brown solid (99mg, 60%).
MS m/z(ESI):613.2[M+H]+.
The thirteenth step: preparation of N- (4- (3- (7-cyano-5-formylbenzo [ d ] oxazol-2-yl) -2-methylphenyl) -3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Figure BDA0003143824180000461
Reacting N- (4- (3- (7-cyano-5- (hydroxymethyl) benzo [ d ]]Oxazol-2-yl) -2-methylphenyl) -3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (107mg,0.175mmol) was added to DCM (2mL) and MnO was added2(305mg,3.50 mmol). The reaction solution was heated to 45 ℃ and stirred for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (105mg, 98%).
MS m/z(ESI):611.2[M+H]+.
The fourteenth step is that: preparation of (R) -1- ((7-cyano-2- (3- (5- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxalylamino) 4- (isopropylthio) thiophen-3-yl) -2-methylphenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000462
Reacting N- (4- (3- (7-cyano-5-formylbenzo [ d ]]Oxazol-2-yl) -2-methylphenyl) -3- (isopropylthio) thiophen-2-yl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridine-2-carboxamide (110mg,0.181mmol), R-pyrrolidine-3-carboxylic acid (32mg,0.27mmol), NaBH (OAc)3(58mg,0.27mmol) and DIPEA (46mg,0.362mmol) were added to DCM (2mL) respectively and stirred at room temperature overnight. The reaction was concentrated and isolated and purified by prep-HPLC to give the title compound (33mg, 26%).
MS m/z(ESI):710.2[M+H]+.
Example 105
(3R) -1- ((5-chloro-6- ((4- (5- ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -4-methylthiophen-3-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000463
The first step is as follows: preparation of 1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropane-1-amine
Figure BDA0003143824180000464
In a dry ice acetone bath, 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carbonitrile (139mg,0.79mmol) and tetraisopropyl titanate (449mg, 1.58mmol) were dissolved in anhydrous tetrahydrofuran (10mL), a solution of ethylmagnesium bromide in tetrahydrofuran (2.0M,2.37mL,4.74mmol) was added dropwise, after completion of the dropwise addition, the mixture was slowly warmed to room temperature and stirred for 1 hour, and after completion of the reaction, boron trifluoride etherate (2mL) was added and the reaction was continued with stirring for 2 hours. After the reaction was completed, dilute aqueous hydrochloric acid (1.0M,5mL) and aqueous sodium hydroxide (1.0M,10mL) were sequentially added, and then the reaction solution was extracted with ethyl acetate (15mL × 3), washed with saturated aqueous sodium chloride (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product, which was subjected to separation and purification by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (75mg, 46%).
MS m/z(ESI):207.2[M+H]+.
The second step is that: preparation of 4-bromo-N- (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) -3-methylthiophen-2-amine
Figure BDA0003143824180000471
1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropane-1-amine (75mg,0.364mmol),2, 4-dibromo-3-methylthiophene (140mg,0.546mmol), tris (dibenzylideneacetone) dipalladium (36.6mg,0.04mmol),4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (46.3mg,0.08mmol), cesium carbonate (237mg,0.728mmol) was suspended in 1, 4-epoxyhexacyclic (10mL), displaced with nitrogen three times, and heated and stirred at 110 ℃ for 2 hours. After the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with saturated aqueous sodium chloride (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (95mg, 69%).
MS m/z(ESI):381.2[M+H]+.
The third step: preparation of 6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxo) -5-chloro-2-methoxynicotinaldehyde
Figure BDA0003143824180000472
4-bromo-2, 3-dihydro-1H-inden-1-ol (213mg,1mmol) and 5, 6-dichloro-2-methoxynicotinaldehyde (247mg,1.2mmol) were dissolved in a solution of N, N-dimethylformamide (10mL), potassium tert-butoxide (224mg,2mmol) was added, and the reaction was heated to 130 ℃ with stirring overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with saturated aqueous sodium chloride (10mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (141mg, 37%).
MS m/z(ESI):382.1[M+H]+.
The fourth step: preparation of 5-chloro-2-methoxy-6- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) nicotinaldehyde
Figure BDA0003143824180000473
6- ((4-bromo-2, 3-dihydro-1H-inden-1-yl) oxo) -5-chloro-2-methoxynicotinaldehyde (141mg,0.37 mmol), pinacol diborate (139mg,0.55mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (30mg,0.04mmol) and potassium acetate (70mg,0.74mmol) were suspended in an anhydrous solution of 1, 4-epoxyhexacyclic compound (10mL), replaced with nitrogen three times, and the reaction was stirred with heating at 110 ℃ for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous solution of sodium chloride (10mL × 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 95:5) to obtain the title compound (132mg, 83%).
MS m/z(ESI):430.2[M+H]+.
The fifth step: preparation of 5-chloro-6- ((4- (5- ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -4-methylthiophen-3-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) -2-methoxynicotinaldehyde
Figure BDA0003143824180000481
4-bromo-N- (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) -3-methylthiophene-2-amine (95mg,0.25mmol), 5-chloro-2-methoxy-6- ((4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) nicotinaldehyde (129mg,0.3mmol), [1,1' -bis (dicyclohexylphosphine) ferrocene ] palladium dichloride (15mg,0.02mmol) and cesium carbonate (163mg,0.5mmol) were suspended in anhydrous 1, a solution of 4-epoxyhexacyclic compound (10mL) in water (2mL) was reacted with nitrogen three times while stirring at 100 ℃ for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous solution of sodium chloride (10mL × 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to obtain the title compound (102mg, 68%).
MS m/z(ESI):604.2[M+H]+.
And a sixth step: preparation of (3R) -1- ((5-chloro-6- ((4- (5- ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -4-methylthiophen-3-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) -2-methoxypyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000482
5-chloro-6- ((4- (5- ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -4-methylthiophen-3-yl) -2, 3-dihydro-1H-inden-1-yl) oxo) -2-methoxynicotinaldehyde (102mg,0.17mmol) was dissolved in dichloromethane (5mL), and (R) -pyrrolidine-3-carboxylic acid (97mg,0.85mmol) and N, N-diisopropylethylamine (219mg,1.7mmol) were added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (108mg,0.51mmol) was then added and stirred at room temperature overnight. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution (20mL), and then the reaction solution was extracted with ethyl acetate (15 mL. times.3), washed with saturated aqueous sodium chloride solution (10 mL. times.3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (33mg, 28%) by prep-HPLC.
MS m/z(ESI):704.1[M+H]+.
Example 106
(R) -1- ((7-cyano-2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000491
The first step is as follows: preparation of tert-butyl 2, 3-dibromo-4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate
Figure BDA0003143824180000492
Tert-butyl 4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate (2.4g,10mmol) was dissolved in dichloromethane (50mL), N-bromosuccinimide (5.4g,30mmol) was added to the reaction mixture with stirring at room temperature, and the resulting reaction mixture was further reacted with stirring at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane, washed successively with aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and chromatographed on silica gel to give the title product (3.7g, 93%).
MS m/z(ESI):398.1[M+H]+.
The second step is that: preparation of tert-butyl 3-bromo-4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate
Figure BDA0003143824180000493
Tert-butyl 2, 3-dibromo-4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate (3.5g,8.82mmol) was dissolved in dry tetrahydrofuran (60mL), cooled to-78 ℃, n-butyllithium (4.4mL, 2.4M aqueous n-hexane, 10.58mmol) was added dropwise under nitrogen protection, the reaction was stirred at-78 ℃ for 30 minutes, the reaction was quenched by addition of aqueous ammonium chloride, the reaction was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography to obtain the title compound (2.58g, 92%).
MS m/z(ESI):318.2[M+H]+.
The third step: preparation of tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate
Figure BDA0003143824180000494
Tert-butyl 3-bromo-4, 7-dihydrothieno [2,3-c]Pyridine-6 (5H) -carboxylate (2.5g,7.86mmol), pinacoldiboron ester (3.0g, 11.8mmol), Pd (dppf) Cl2(0.57g,0.78mmol) and potassium acetate (2.31g,23.56mmol) were added to a 100mL reaction flask, the reaction was evacuated and protected with nitrogen, dried epoxy hexacyclic ring (40mL) was added, the reaction was further evacuated and replaced with nitrogen 3 times, the reaction was heated to 100 ℃ under nitrogen and stirred for reaction for 15 hours, the reaction was filtered through celite, the filtrate was concentrated under reduced pressure, and the title compound (2.84g, 99%) was isolated by silica gel column chromatography.
MS m/z(ESI):366.4[M+H]+.
The fourth step: preparation of methyl 2- (3-bromo-2-fluorophenyl) -7-chlorobenzo [ d ] oxazole-5-carboxylate
Figure BDA0003143824180000501
Dissolving 3-bromo-2-fluorobenzaldehyde (2.03g,10mmol) and 5-chloro-4-hydroxy-3-aminobenzoic acid methyl ester (2.42g,12mmol) in absolute ethyl alcohol (50mL), stirring at room temperature for overnight reaction, concentrating under reduced pressure to remove the solvent, dispersing the residue in dichloromethane, adding DDQ (3.41g,15mmol) while stirring at room temperature, continuing to stir the obtained reaction solution at room temperature for 3 hours, diluting the reaction solution with dichloromethane, washing with aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating, and directly using the crude product in the subsequent reaction.
MS m/z(ESI):384.1[M+H]+.
The fifth step: preparation of (2- (3-bromo-2-fluorophenyl) -7-chlorobenzo [ d ] oxazol-5-yl) methanol
Figure BDA0003143824180000502
And (2) putting the crude methyl 2- (3-bromo-2-fluorophenyl) -7-chlorobenzo [ d ] oxazole-5-carboxylate solution into dry dichloromethane, cooling the reaction solution to-78 ℃, adding DIBAL-H (20mL, 1.5M toluene solution, 30mmol) under the protection of nitrogen, and continuously stirring the reaction solution at-78 ℃ for 2 hours. The reaction was diluted with dichloromethane, washed successively with aqueous sodium potassium tartrate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and filtered to give the title product as an off-white solid (2.27g, 64%).
MS m/z(ESI):356.1[M+H]+.
And a sixth step: preparation of tert-butyl 3- (3- (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2-fluorophenyl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate
Figure BDA0003143824180000503
(2- (3-bromo-2-fluorophenyl) -7-chlorobenzo [ d ] oxazol-5-yl) methanol (712mg,2.0mmol), tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate (1.1g,3.0mmol), 1,1' -dicyclohexylphosphinotriferrocene palladium dichloride (164mg,0.2mmol) and carbonic acid (1.3g,4.0mmol) were added to a 100mL reaction flask, the reaction system was evacuated and protected with dry nitrogen, tert-butanol (20mL) and water (2mL) were added to the reaction flask, the reaction solution was evacuated under stirring at room temperature and replaced with nitrogen three times, then heated to 100 ℃ in an oil bath under the protection of nitrogen for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by silica gel column chromatography to give the title compound (690mg, 67%).
MS m/z(ESI):515.2[M+H]+.
The seventh step: preparation of tert-butyl 3- (3- (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2- (methylthio) phenyl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate
Figure BDA0003143824180000511
Tert-butyl 3- (3- (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2-fluorophenyl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate (515g,1.0mmol) was dissolved in DMF (5mL), sodium thiomethoxide (213mg,3.0mmol) was added with stirring at room temperature, the reaction solution was heated to 50 ℃ under nitrogen protection with stirring for 4 hours, the solvent was removed by concentration under reduced pressure, the residue was dispersed in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was isolated by silica gel column chromatography to give the title product (445mg, 82%).
MS m/z(ESI):543.2[M+H]+.
Eighth step: preparation of (7-chloro-2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) benzo [ d ] oxazol-5-yl) methanol
Figure BDA0003143824180000512
Tert-butyl 3- (3- (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2- (methylthio) phenyl) -4, 7-dihydrothieno [2,3-c ] pyridine-6 (5H) -carboxylate (445mg,0.82mmol) was added to a 4M HCl solution in epoxy six rings, stirred at room temperature for 1 hour, concentrated under reduced pressure to remove the solvent, dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in NMP (4mL), DIPEA (0.42mL,2.46mmol) and 2-bromo-1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [ 4] were added with stirring at room temperature, 5-c ] pyridine (377mg,1.64mmol), heated to 150 ℃ by a microwave synthesizer, stirred for 2 hours, the reaction solution was diluted with ethyl acetate, the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to give the title compound (199mg, 41%).
MS m/z(ESI):592.1[M+H]+.
The ninth step: preparation of 2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000513
(7-chloro-2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) benzo [ d ] oxazol-5-yl) methanol (100mg, 0.17mmol), potassium ferricyanide trihydrate (85mg, 0.2mmol), t-Bu X-Phos Pd G3(14mg, 0.017mmol), and potassium acetate (3mg, 0.024mmol) were charged to a 50mL reaction flask, the reaction system was evacuated and protected with dry nitrogen, a dioxane-water mixed solvent (v/v ═ 1:1, 10mL), the reaction solution is stirred at room temperature, vacuumized and replaced by nitrogen for three times, and then heated to 100 ℃ in an oil bath under the protection of nitrogen for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to give the product (89mg, 90%).
MS m/z(ESI):583.2[M+H]+.
The tenth step: preparation of (R) -1- ((7-cyano-2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Figure BDA0003143824180000521
2- (3- (6- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) -4,5,6, 7-tetrahydrothieno [2,3-c ] pyridin-3-yl) -2- (methylthio) phenyl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (89mg, 0.15mmol) was dissolved in dichloromethane (10mL), DMP (72mg, 0.17mmol) was added with stirring at room temperature, the resulting reaction solution was further stirred at room temperature for 1 hour, insoluble materials were removed by filtration, the residue was concentrated under reduced pressure, redissolved in dichloromethane (10mL), DIPEA (0.5mL, 3.0mmol) and (R) -pyrrolidine-3-carboxylic acid (173mg, 1.5mmol) was added to the reaction mixture, the reaction mixture was stirred at room temperature for 1 hour, sodium borohydride acetate (159mg, 0.75mmol) was added, the reaction mixture was stirred at room temperature overnight, the solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (45mg, 44%).
MS m/z(ESI):680.1[M+H]+.
Example 182
1- ((6- (2-chloro-3 ' - (7-cyano-2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazol-5-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000522
The first step is as follows: preparation of 5-bromo-2-hydroxy-3-nitrobenzonitrile
Figure BDA0003143824180000523
Under the condition of ice-water bath, 5-bromo-2-hydroxybenzonitrile (20g,0.1mol) is suspended in glacial acetic acid (50mL), fuming nitric acid (8.6mL,0.2mol) is added under the condition of ice-water bath, and after dropwise addition, the temperature is slowly raised to room temperature to stir for reaction overnight. At the end of the reaction, the reaction was dropped into a large amount of ice water (500mL), and after filtration, the filter cake was concentrated under reduced pressure to give the title compound (20.9g, 86%).
MS m/z(ESI):243.1[M+H]+.
The second step is that: preparation of 3-amino-5-bromo-2-hydroxybenzonitrile
Figure BDA0003143824180000531
Under the protection of nitrogen, 5-bromo-2-hydroxy-3-nitrobenzonitrile (20.9g,86mmol) is dissolved in a mixed solvent of absolute ethanol (300mL) and water (200mL), sodium hydrosulfite (60g,344mmol) is added at room temperature, and the mixture is slowly heated to 60 ℃ and stirred for reaction for 2 hours. After completion of the reaction, the reaction mixture was concentrated to remove ethanol, and then the reaction mixture was extracted with dichloromethane (200mL × 3), washed with saturated aqueous sodium chloride (150mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (dichloromethane: methanol ═ 97:3) to obtain the title compound (6.9g, 38%).
MS m/z(ESI):213.1[M+H]+.
The third step: preparation of 5-bromo-2- (chloromethyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000532
3-amino-5-bromo-2-hydroxybenzonitrile (1g,4.72mmol), 2-chloro-1, 1, 1-trimethoxyethane (872mg,5.66mmol) and p-toluenesulfonic acid (81mg,0.47mmol) were dissolved in a solution of anhydrous tetrahydrofuran (20mL) under nitrogen protection and the reaction was stirred with heating at 60 ℃ for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous solution of sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (PE: EA ═ 10:1) to obtain the title compound (767mg, 60%).
MS m/z(ESI):271.1[M+H]+.
The fourth step: preparation of 5-bromo-2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000533
5-bromo-2- (chloromethyl) benzo [ d ] oxazole-7-carbonitrile (767mg,2.84mmol), 3-fluoroazetidine (473mg,4.26mmol) and potassium carbonate (789mg,5.72mmol) were suspended in a solution of anhydrous N, N-dimethylformamide (10mL) under nitrogen protection and the reaction was stirred with heating at 60 ℃ overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous solution of sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (PE: EA ═ 1:1) to obtain the title compound (400mg, 46%).
MS m/z(ESI):310.1[M+H]+.
The fifth step: preparation of 5- (3-bromo-2-methylphenyl) -2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000541
5-bromo-2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile (400mg,1.29mmol), (3-bromo-2-methylphenyl) boronic acid (332mg,1.55mmol), tetratriphenylphosphine palladium (149mg,0.13mmol) and potassium carbonate (356mg,2.58mmol) were suspended in a mixed solution of anhydrous 1, 4-epoxyhexacyclic ring (10mL) and water (2mL) under nitrogen protection, and the reaction was stirred with heating at 100 ℃ overnight. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with a saturated aqueous solution of sodium chloride (15mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (PE: EA ═ 3:1) to obtain the title compound (293mg, 57%).
MS m/z(ESI):400.1[M+H]+.
And a sixth step: preparation of 5- (2' -chloro-3 ' - (5-formyl-6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile
Figure BDA0003143824180000542
Under nitrogen protection, 5- (3-bromo-2-methylphenyl) -2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile (50mg,0.125mmol), 6- (2-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -2-methoxynicotinaldehyde (51mg,0.137mmol), [1,1' -bis (dicyclohexylphosphine) ferrocene ] palladium dichloride (9.5mg,0.013mmol) and cesium carbonate (81mg,0.25mmol) were suspended in t-butanol (5mL) and water (1mL), and the reaction was stirred with heating at 100 ℃ for 2 hours. After the reaction, the reaction mixture was extracted with ethyl acetate (15mL × 3), washed with saturated aqueous sodium chloride (10mL × 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (66mg, 94%).
MS m/z(ESI):567.1[M+H]+.
The seventh step: preparation of 1- ((6- (2-chloro-3 ' - (7-cyano-2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazol-5-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) -2-methoxypyridin-3-yl) methyl) azetidine-3-carboxylic acid
Figure BDA0003143824180000543
5- (2' -chloro-3 ' - (5-formyl-6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -2- ((3-fluoroazetidin-1-yl) methyl) benzo [ d ] oxazole-7-carbonitrile (30mg,0.053mmol), azetidine-3-carboxylic acid (16mg,0.16mmol) and N, N-diisopropylethylamine (14mg,0.106mmol) were dissolved in methanol (5mL) and stirred at room temperature for 1 hour. Sodium cyanoborohydride (6.7mg,0.106mmol) was then added and the reaction was stirred at room temperature overnight. At the end of the reaction, the reaction mixture was extracted with dichloromethane (15mL x3), washed with saturated aqueous sodium chloride (10mL x3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure to give the title compound (2.2mg, 6%) by prep-HPLC.
MS m/z(ESI):652.1[M+H]+.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
PD-1/PD-L1 binding assay
Test example 1: determination of the binding inhibition of the Compounds of the invention to PD-1/PD-L1
Purpose of the experiment: the purpose of this test example was to measure the activity of compounds on the inhibition of PD-1/PD-L1 binding.
An experimental instrument:
centrifuge (5810R) was purchased from Eppendorf corporation;
pipettes were purchased from Eppendorf or Rainin;
the microplate reader is purchased from BioTek company of America, and is H1MFD full-function microplate reader.
Experimental reagent:
binding Domain diluent buffer is purchased from Cisbio, and has a cargo number of 62 DLBDDF;
MAb Anti-6HIS Eu cryptate Gold, available from Cisbio under the trade designation 61HI2 KLA;
PAb Anti Human IgG-XL665 from Cisbio, cat #61 HFCXLB;
PD-L1-His protein was purchased from Abcam under the cat number ab 167713;
PD-1-Fc protein was purchased from R & D, cat # 1086-PD;
detection buffer is available from Cisbio, Inc. under the product number 62 SDBRDD;
the 384 well plates were purchased from Perkinelmer under the designation 6007290.
The experimental method comprises the following steps: in order to test the inhibitory activity of the compound on the binding of PD-1/PD-L1, the inhibition effect of the compound on the binding of PD-1/PD-L1 is tested by adopting a time-resolved fluorescence resonance energy transfer (TR-FRET) method in the experiment, and the half inhibitory concentration IC50 of the compound on the binding inhibitory activity of PD-1/PD-L1 is obtained.
The specific experimental operations were as follows:
the experiment was performed in 384 well plates with a total reaction system of 20. mu.L, the compound was diluted to different concentrations (1uM initial, 3 fold dilution, 11 doses) using the experiment buffer Binding Domain dilution buffer (Cisbio #62DLBDDF), the PD-L1-His protein (19-238 amino acids) (Abcam # ab167713) was diluted to 10nM using the experiment buffer, the PD-1-Fc protein (25-167 amino acids) (R & D #1086-PD) was diluted to 20nM using the experiment buffer, the compound, PD-L1 protein and PD-1 protein were added to 384 well plates with a total volume of 10uL, centrifuged in a centrifuge at 1000rpm for 1 minute to mix well, incubated at room temperature for 60 minutes, 10uL of MAb Ann-6 HIS Eu-cryptate Gold (Cisbio # 61A) diluted using HTRF Detection buffer and PAb Human Husbio # 665 IgG (CXLB) mixed with HFHI-61 XL), placing the mixture into a centrifuge for centrifugation at 1000rpm for 1 minute, uniformly mixing, reacting at 4 ℃ overnight, and placing into a microplate reader (BioTek Synergy H1) for reading, wherein the excitation wavelength is 340nm, and the emission wavelengths are 620nm and 665 nm.
The experimental data processing method comprises the following steps:
calculating the ratio of the fluorescence readings at 620nm and 665nm (665nm/620nm), calculating the inhibition rate, and fitting the compound concentration and the inhibition rate by nonlinear regression using Graphpad Prism software to obtain IC50The values are shown in table 1 below.
IC binding of Table 1 Compounds to human PD-1/PD-L150Value of
Figure BDA0003143824180000551
Figure BDA0003143824180000561
And (4) experimental conclusion: the compounds of the examples of the present invention showed good binding inhibition activity in the PD-1/PD-L1 inhibition assay.
Test example 2: determination of endocytosis activity of PD-L1 protein on surface of tumor cell induced by compound
Purpose of the experiment: the purpose of this test example was to test the activity of the compounds to induce endocytosis of PD-L1 on the surface of tumor cells.
An experimental instrument:
centrifuge (5702R) was purchased from Eppendorf;
pipettes were purchased from Eppendorf or Rainin
Flow cytometry was purchased from Beckman Coulter, model DxFlex.
Experimental reagent:
the PE Mouse Anti-Human CD274 antibody was purchased from BD Pharmingen, cat # 557924;
BSA was purchased from Sigma under the designation B2064-100G;
PBS, available from Gibco corporation under the cat number 10010049;
the 24 well plate was purchased from Corning corporation under the designation 3526.
The experimental method comprises the following steps: to test the activity of a compound to induce endocytosis of PD-L1, the experiment tests the activity of the compound to induce endocytosis of PD-L1 by detecting the change degree of PD-L1 on the surface of tumor cells by using a fluorescently-labeled anti-PD-L1 antibody, and obtains IC of the compound to induce endocytosis activity50。
The specific experimental operations were as follows:
collecting human breast cancer cell HCC1954, adjusting to appropriate density, spreading on 6-well plate, placing at 37 deg.C and 5% CO2Incubators adhere to the wall overnight. Preparing compounds into different concentrations with culture medium, adding into 6-well plate, setting solvent control hole, placing at 37 deg.C and 5% CO2After incubation for 16 hours in the incubator, the 6-well plate was removed, the HCC1954 cells treated differently in the plate were collected, washed once with FACS buffer (PBS containing 0.5% BSA), the cells were prepared to the appropriate density with FACS buffer, PE Mouse Anti-Human CD274 antibody (BD Pharmingen #557924) was added, the plate was incubated for 30 minutes with shaking at room temperature in the dark, the cells were washed twice with FACS buffer, resuspended with 100 μ L PBS, and the fluorescence signal on the cell surface was detected with a flow cytometer, and the isotype control was set as a negative control.
The experimental data processing method comprises the following steps:
calculating the endocytosis rate of the compound by using the fluorescence signals of different treatment groups, and carrying out nonlinear regression fitting on the concentration of the compound and the endocytosis rate by using GraphPad Prism software to obtain IC50The values are shown in Table 2.
TABLE 2 maximum endocytosis rate and IC of compounds at PD-L1 on tumor cell surface50Value of
Figure BDA0003143824180000562
Figure BDA0003143824180000571
And (4) experimental conclusion: the compound disclosed by the invention can well induce the endocytosis of PD-L1 on the surface of a tumor cell.
Test example 3 inhibition of CHO-PDL1/Jurkat-PD1 cell pathway by the inventive Compounds
Purpose of the experiment: the purpose of this test example was to test the inhibitory effect of compounds on the CHO-PDL1/Jurkat-PD1 cellular pathway.
An experimental instrument:
centrifuge (5810R) was purchased from Eppendorf corporation;
pipettes were purchased from Eppendorf or Rainin;
the microplate reader is purchased from BioTek company of America, and is H1MFD full-function microplate reader.
Experimental reagent:
CHO-PDL1 cells and NFAT-luc2/PD1 Jurkat cells were obtained from Promega under the code J1252;
RPMI 1640 was purchased from Gibco, Inc. under the cat # 22400089;
FBS is available from Gibco corporation under the product number 10091148;
One-Glo reagent available from Promega under the designation E6120;
the 96 well plate was purchased from Corning, cat 3610.
The experimental method comprises the following steps: the experiment comprises two stable transfectant cell strains, CHO-K1 cells stably transformed by PD-L1 and Jurkat cells stably transformed by PD-1 and NFAT luciferase reporter genes, after the compound is incubated with the two cells, the activation degree of the Jurkat cells is changed due to the inhibition effect of the compound on a PD-1/PD-L1 pathway, so that the NFAT level of the downstream reporter gene in the Jurkat cells is changed, and the NFAT level is represented by detecting the signal value of the luciferase, so that the inhibition effect of the test compound on the CHO-PDL1/Jurkat-PD1 pathway is represented.
The specific experimental operations were as follows:
CHO-PDL1 cells (Promega, # J1252) were cultured to appropriate cell density, resuspended to appropriate density cell suspension using complete medium after digestion, plated in 96-well plates (Corning, #3610) at 100. mu.L per well, and incubated at 37 ℃ with 5% CO2The incubator was cultured in an adherent manner overnight using an analytical medium (RPMI 1640+ 2% FBS, RPMI 1640 having a product number of Gibco, #22400089, FBS having a product number of Gibco, # 1009114)8) Compound solutions of different concentrations were prepared and NFAT-luc2/PD1 Jurkat cells (Promega, # J1252) were harvested and resuspended to the appropriate cell density using assay media. The supernatant of the CHO-PDL1 cell culture plate was aspirated, 40. mu.L of the prepared compound solution and 40. mu.L of resuspended NFAT-luc2/PD1 Jurkat cells were added, and the mixture was placed at 37 ℃ in 5% CO2The incubator is incubated for 6 hours, the cell plate is taken out, 40 mu L of One-Glo reagent (Promega, # E6120) is added into each hole, the cell plate is incubated for 10 minutes at room temperature in a dark place after being evenly mixed by oscillation, and the cell plate is placed into an enzyme labeling instrument to read the luminous value of the cell plate by using a luminous program.
The experimental data processing method comprises the following steps:
fitting EC according to Compound concentration and luminescence Signal value50Values, and maximum fold induction for each compound relative to the non-dosed signal values were calculated as shown in table 3.
TABLE 3 Compound on CHO-PDL1/Jurkat-PD1 cell EC50And maximum fold induction of compound relative to non-dosed signal values
Figure BDA0003143824180000572
And (4) experimental conclusion: the compounds of the embodiment of the invention show better inhibitory activity in the inhibition test of CHO-PDL1/Jurkat-PD1 cell pathway.
Test example 4 determination of the binding of the Compound of the present invention to improve the stability (melting temperature) of PD-L1 protein
Purpose of the experiment: the ability of the test compound to increase the stability of PD-L1 protein and to raise the melting temperature of the protein.
An experimental instrument: quantitative PCR instruments (Quantstrudio 6 Flex) were purchased from Life, pipettes from Eppendorf or Rainin.
Experimental reagent: protein Thermal ShiftTMDye Kit is available from Thermofoisher, Inc. under the product number 4461146; PD-L1 protein was purchased from Acro Biosystems under the accession number PD 1-H5229; HEPES,1M Buffer Solution available from Thermofish, cat # 15630080; NaCl was purchased from national pharmaceutical group chemical Co., Ltd under the product number 10019318.
The experimental method comprises the following steps: in the experiment, the change degree of PD-L1 protein melting temperature (Tm) before and after the compound is combined is tested by a thermal shift method to characterize the capability of the compound for improving the stability of PD-L1 protein, thereby expressing the binding capability of the compound and the PD-L1 protein.
The specific experimental operations were as follows:
a solution containing 10. mu.M HEPES, SYPRO Orange and 150mM NaCl was prepared as the experimental buffer, and human PD-L1 protein was added to the solution at a final concentration of 2. mu.M. The above reaction mixture was dispensed into 8-line PCR tubes, each with 19.5. mu.L, and 0.5. mu.L of test compound or DMSO was added, respectively, so that the total reaction system was 20. mu.L, the final concentration of compound was 10. mu.M, and 2.5% DMSO was set as a vehicle control. The PCR tube is put into a PCR instrument, and melt temperature (heated from 25 ℃ to 95 ℃ at 0.03 ℃/s) of PD-L1 protein in different treatment groups is detected by selecting melt curve function.
The experimental data processing method comprises the following steps:
the experimental data file of the PCR instrument was imported into thermal shift software to obtain the melting temperature (Tm) of each treatment group, and the Tm of the DMSO solvent control group was subtracted to obtain the variation value of the melting temperature (Δ Tm), as shown in table 4 below:
TABLE 4 change in melting temperature of the compounds
Example numbering ΔTm(℃)
2 8.5
13 12.3
14 10.5
21 10.9
31 2.9
44 14.4
50 14.2
52 11.2
53 14.3
54 11.7
55 13.2
62 14.6
65 10.3
66 13.5
And (4) experimental conclusion:
the compound shown in the invention shows the capability of improving the stability of PD-L1 protein in an experiment for improving the melting temperature of PD-L1 protein according to the scheme.
Test example 5 measurement of pharmacokinetics of Balb/C mice
1. The research aims are as follows:
Balb/C mice were used as test animals to study the pharmacokinetic behavior of the following compounds in the examples given below, administered orally at a dose of 5mg/kg in plasma in mice.
2. Test protocol
2.1 test drugs:
the embodiment of the invention is self-made.
2.2 test animals:
Balb/C Mouse 6 per example, male, Shanghai Jie Si laboratory animals Ltd, animal production license number (SCXK (Shanghai) 2013) 0006N 0.311620400001794).
2.3, preparing the medicine:
5g of hydroxyethyl cellulose (HEC, CMC-Na, viscosity: 800-1200Cps) was weighed, dissolved in 1000mL of purified water, and 10g of Tween80 was added. Mix well to get a clear solution.
2.4 administration:
Balb/C mice, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.
2.5 sample collection:
before and after administration, at 0, 0.5, 1,2, 4,6, 8 and 24 hours, the mice were bled by orbital bleeding 0.1mL, and placed in EDTA-K2The plasma was separated by centrifugation at 6000rpm for 6min at 4 ℃ in a test tube and stored at-80 ℃.
2.6 sample treatment:
1) plasma samples 40uL added 160uL acetonitrile precipitation, after mixing 3500 x g centrifugal 5 ~ 20 minutes.
2) Taking 100uL of the treated supernatant solution for LC/MS/MS analysis to analyze the concentration of the compound to be detected.
2.7 liquid phase analysis
Liquid phase conditions: shimadzu LC-20AD pump
Mass Spectrometry conditions AB Sciex API 4000 Mass Spectroscopy
Column chromatography: phenomenex Gemiu 5um C1850 x 4.6mm
The mobile phase: the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
Flow rate: 0.8mL/min
Elution time: 0-4.0 min, eluent as follows:
Figure BDA0003143824180000591
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the results of the mouse pharmacokinetic experiments are shown in table 5 below:
TABLE 5 mouse pharmacokinetic experiment results
Figure BDA0003143824180000601
4. And (4) experimental conclusion:
as can be seen from the results of the mouse pharmacokinetic experiments in the table, the compounds of the embodiment of the invention have good metabolic properties, exposure AUC and maximum blood concentration CmaxAll performed well.

Claims (10)

1. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is represented by the general formula (III-1):
Figure FDA0003143824170000011
wherein:
R1selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl group、C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-、-(CH2)n1S(O)m1NRaa-、-(CH2)n1NRaaS(O)m1-or- (CH)2)n1C(O)NRaa-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl radicals3-12 membered heterocyclic group, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R3selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R4selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl radical、C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8HalogenatedSubstituted with one or more substituents of alkoxy;
RA1、RB1and RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
m1 is an integer of 0-2;
n1, n2 and n10 are integers of 0 to 3.
2. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is represented by the general formula (III-2):
Figure FDA0003143824170000021
wherein:
R1selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-to 14-membered heteroaryl,the amino group and C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, thio, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-、-(CH2)n1S(O)m1NRaa-、-(CH2)n1NRaaS(O)m1-or- (CH)2)n1C(O)NRaa-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R3selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R4selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C2-8Alkenyl radical, C2-8Alkynyl, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, amino, nitro, hydroxy, cyano, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl, 5-14 membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Substituted with one or more substituents of haloalkoxy;
RA1、RB1and RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl, said amino, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy radical, C1-8Haloalkoxy, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-8Alkyl radical, C1-8Deuterated alkyl, C1-8Haloalkyl, C1-8Hydroxyalkyl radical, C1-8Alkoxy or C1-8Substituted with one or more substituents of haloalkoxy;
m1 is an integer of 0-2;
n1, n2 and n10 are integers of 0 to 3.
3. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is1Selected from hydrogen, deuterium, halogen, amino, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, carboxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Substituted with one or more substituents in hydroxyalkyl;
preferably, R1Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted with deuterium, fluoro, chloro, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl;
further preferably, R1Is selected from
Figure FDA0003143824170000031
L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-or- (CH)2)n1C(O)NRaa-；
Preferably, L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-or- (CH)2)n1NRaa(CRbbRcc)n2-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, fluorine, chlorine, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine or chlorine;
R3selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R3Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further selected from deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy;
more preferably, R3Selected from hydrogen, deuterium, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl;
R4selected from hydrogen, deuterium, halogen, ammoniaBase, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R4Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further selected from deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy;
more preferably, R4Selected from hydrogen, deuterium, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R6Selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl or- (CH)2)n10NRA1RB1Said 3-8 membered heterocyclyl and 5-8 membered heteroaryl may be further substituted with deuterium, fluoro, chloro, carboxy, hydroxy or C1-3Substituted by one or more substituents in the alkyl group;
more preferably, R6Is selected from
Figure FDA0003143824170000041
Figure FDA0003143824170000051
RA1、RB1And RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, RA1、RB1And RC1Each independently selected from hydrogen, deuterium, fluorine, chlorine, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl, said C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by deuterium, fluoro, chloro, hydroxy, carboxy, C1-3Alkyl or C1-3Substituted with one or more substituents in the hydroxyalkyl group.
4. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 2, wherein R is1Selected from hydrogen, deuterium, halogen, amino, hydroxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl or 5-10 membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, carboxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6In hydroxyalkyl radicalsSubstituted by one or more substituents;
preferably, R1Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl, 3-8 membered heterocyclyl and 5-8 membered heteroaryl, optionally further substituted with deuterium, fluoro, chloro, hydroxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl;
further preferably, R1Is selected from
Figure FDA0003143824170000052
L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-、-(CH2)n1NRaa(CRbbRcc)n2-、-(CH2)n1C(O)(CRaaRbb)n2-、-(CH2)n1NRaaC(O)(CRaaRbb)n2-or- (CH)2)n1C(O)NRaa-；
Preferably, L1Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1(CRaaRbb)n2-、-(CRaaRbb)n1(CH2)n2NRcc-or- (CH)2)n1NRaa(CRbbRcc)n2-；
Raa、RbbAnd RccEach independently selected from hydrogen, deuterium, fluorine, chlorine, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine or chlorine;
R3selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R3Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further selected from deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy;
more preferably, R3Selected from hydrogen, deuterium, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl;
R4selected from hydrogen, deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Haloalkoxy, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, optionally further optionally selected from deuterium, halogen, amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R4Selected from hydrogen, deuterium, fluorine, chlorine, amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3Haloalkoxy, said amino, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Haloalkoxy, optionally further selected from deuterium, fluoro, chloro, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy and C1-3Substituted with one or more substituents of haloalkoxy;
more preferably, R4Selected from hydrogen, deuterium, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl;
R6selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n10RA1、-(CH2)n10ORA1、-(CH2)n10C(O)ORA1、-(CH2)n10SRA1、-(CH2)n10NRA1RB1、-NRA1C(O)RB1、-NRA1C(O)NRB1RC1、-C(O)NRA1RB1Or- (CH)2)n10C(O)RA1Said amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Substituted with one or more substituents of haloalkoxy;
preferably, R6Selected from 3-8 membered heterocyclyl, 5-8 membered heteroaryl, - (CH)2)n10C(O)RA1Or- (CH)2)n10NRA1RB1Said 3-8 membered heterocyclyl and 5-8 membered heteroaryl may be further substituted with deuterium, fluoro, chloro, carboxy, hydroxy or C1-3Substituted by one or more substituents in the alkyl group;
more preferably, R6Is selected from
Figure FDA0003143824170000061
Figure FDA0003143824170000062
RA1、RB1And RC1Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
preferably, RA1、RB1And RC1Each independently selected from hydrogen, deuterium, fluorine, chlorine, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl, said C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by deuterium, fluoro, chloro, hydroxy, carboxy, C1-3Alkyl or C1-3Substituted with one or more substituents in the hydroxyalkyl group.
5. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (IV):
Figure FDA0003143824170000071
wherein:
ring C is selected from C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl;
R7selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-to 10-membered heteroaryl, - (CH)2)n5RAA、-(CH2)n5ORAA、-(CH2)n5C(O)ORAA、-(CH2)n5SRAAOr- (CH)2)n5NRAARBBSaid amino group, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy or-C (O) RAIs substituted with one or more substituents of (1);
RAA、RBBand RCCEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6Substituted with one or more substituents of haloalkoxy;
RAselected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group;
L5selected from the group consisting of a bond, - (CH)2)n7-、-(CH2)n7(CRa2Rb2)n8-、-(CRa2Rb2)n7O(CH2)n8-、-(CH2)n7O(CRa2Rb2)n8-、-(CRa2Rb2)n7(CH2)n8NRc2-、-(CH2)n7NRa2(CRb2Rc2)n8-、-(CH2)n7C(O)(CRa2Rb2)n8-、-(CH2)n7NRa2C(O)(CRa2Rb2)n8-or- (CH)2)n7C(O)NRa2-；
Ra2、Rb2And Rc2Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl;
R8selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; more preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
R9each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl and C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, optionally further substituted by deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Haloalkoxy, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl or-C (O) RCIs substituted with one or more substituents of (1);
RCselected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-6Alkyl radical, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Alkoxy or C1-6A haloalkoxy group; and is
j is an integer of 0 to 6;
n5, n7 and n8 are integers of 0 to 3.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, characterized in that ring C is selected from C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl or 5-8 membered heteroaryl; preferably a cycloalkyl group,
Figure FDA0003143824170000081
Figure FDA0003143824170000082
R7Is selected from C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl, 5-8 membered heteroaryl or-CH2NRAARBBSaid amino group, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl, optionally further substituted by deuterium, fluoro, chloro, amino, hydroxy, cyano, carboxy, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl or C1-3Substituted with one or more substituents in hydroxyalkyl; preference is given to
Figure FDA0003143824170000083
RAAAnd RBBEach independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
L5selected from the group consisting of a bond, - (CH)2)n7-or- (CH)2)n8NRc2-; preferably a bond, -CH2-or-CH2NRc2-；
Rc2Selected from hydrogen, deuterium, halogen, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3A haloalkoxy group; preferably hydrogen, deuteriumFluorine, chlorine, methyl, ethyl or propyl;
R8selected from hydrogen, deuterium, fluorine, chlorine, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, methyl or ethyl;
R9each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxyl and C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy radical, C1-3Haloalkoxy or-C (O) RC(ii) a Preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, carboxyl, methyl, ethyl or-C (O) CH3；
RCSelected from hydrogen, deuterium, halogen, hydroxy, cyano, C1-3Alkyl radical, C1-3Deuterated alkyl, C1-3Haloalkyl, C1-3Hydroxyalkyl radical, C1-3Alkoxy or C1-3A haloalkoxy group; preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, methyl, ethyl or propyl; and is
j is an integer of 0 to 3; preferably 1 or 2.
7. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure FDA0003143824170000091
Figure FDA0003143824170000101
Figure FDA0003143824170000111
Figure FDA0003143824170000121
Figure FDA0003143824170000131
Figure FDA0003143824170000141
Figure FDA0003143824170000151
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (la), a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7, together with one or more pharmaceutically acceptable carriers or excipients.
9. Use of a compound of general formula (la), a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8, for the preparation of a PD-1/PD-L1 inhibitor medicament.
10. Use of a compound of general formula (la), a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, or a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment of a disease selected from the group consisting of cancer, infectious disease, autoimmune disease; wherein the cancer is selected from skin cancer, lung cancer, urinary system tumor, blood tumor, breast cancer, glioma, digestive system tumor, reproductive system tumor, lymphoma, nervous system tumor, brain tumor, and head and neck cancer; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific autoimmune disease, systemic autoimmune disease; preferably, the organ-specific autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, and the systemic autoimmune disease includes rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, or autoimmune hemolytic anemia.
CN202110744133.XA 2020-07-02 2021-07-01 Biphenyl polycyclic derivative inhibitor, preparation method and application thereof Pending CN113880833A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112858459A (en) * 2021-03-11 2021-05-28 昆山聂尔精密仪器有限公司 Matrix sample preparation method and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis method
CN112858459B (en) * 2021-03-11 2022-12-20 昆山聂尔精密仪器有限公司 Matrix sample preparation method and matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis method

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