CN111925367A - Fused ring derivative inhibitor, preparation method and application thereof - Google Patents
Fused ring derivative inhibitor, preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a fused ring derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to compounds of formula (I), a process for their preparation and pharmaceutical compositions containing them, and their use as inhibitorsThe preparation is used for treating cancers, infectious diseases and autoimmune diseases, wherein each substituent in the general formula (I) is defined as the specification.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a fused ring 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 in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(RaaRbb)n2-、-(CH2)n1S(CH2)n2C(O)O-、-(CH2)n1S(CRaaRbb)n2C(O)NRcc-、-(CH2)n1C(O)(CH2)n2-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-、-N(Raa)(CRbbRcc)n1(CH2)n2NRdd-or- (CH)2)n1S(CH2)n2C(O)NRaa-；
L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(CH2)n2-、-(CH2)n1S(CH2)n2C(O)-、-(CH2)n1S(CH2)n2C(O)NRaa-、-(CH2)n1C(O)(CH2)n2-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-、-N(Raa)(CRbbRcc)n1(CH2)n2NRdd-or- (CH)2)n1S(CH2)n2C(O)NRaa-；
L3Selected from a bond or- (CH)2)n1-；
X is selected from halogen, preferably chlorine;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cyano group, alkenyl group, alkynyl group, heterocyclylalkyl group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, - (CH)2)n1Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaS(O)m1RbbOr- (CH)2)n1N(Raa)(CH2)n2RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R2a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are optionally further substituted by one or more substituents selected from the group consisting of a hydrogen atom, a deuterium atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted deuterated alkyl group, a substituted or unsubstituted haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted haloalkoxy group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl groupSubstitution;
R3selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, halogen, amino, nitro, cyano, hydroxyl, carboxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R4selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group;
Raa、Rbb、Rccand RddThe same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.Generation;
or, Raa、Rbb、RccAnd RddAny two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, haloalkyl groups, halogen, amino groups, oxo groups, nitro groups, cyano groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups;
x is an integer of 0, 1,2, 3, 4,5 or 6;
y is an integer of 0, 1,2, 3, 4,5 or 6;
n1 is an integer of 0, 1 or 2; and is
n2 is an integer of 0, 1 or 2.
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I) is a compound shown in a general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring C is selected from cycloalkyl, heterocyclyl, aryl or heterocyclyl;
R5selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, hydroxyalkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaS(O)m1RbbOr- (CH)2)n1N(Raa)(CH2)n2Rbb；
z is an integer of 0, 1 or 2;
ring A, ring B, L1～L3、X、R1、R2、R4、Raa～RccX, y, n1, n2 and m1 are as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (II) is a compound shown in a general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring A, ring B, L1～L3、R1、R2、R5X, y and z are as described in formula (II).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (III) is a compound shown in general formulas (IV-A), (IV-B) and (IV-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
M1～M11the same or different and each is independently selected from O, N, S, CRaaOr NRaa；
R6Selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, halogenated alkyl group, alkoxy group, halogenated alkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, and carboxyl groupA group, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B, ring C, L1～L3、R1、R5X and z are as described in formula (III).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (III) is a compound shown in general formulas (V-A) and (V-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring A, ring B, L1、L2、R1、R2X and y are as described in formula (III).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I) is a compound shown in a general formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
g is selected from oxygen, sulfur or NRaa；
Ring B, L1、R1、NRaaAnd x is as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I) is a compound shown in a general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring B, L1、L2、R1And x is as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I) is a compound shown in a general formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring B, L1、L2、R1And x is as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in the general formula (I) is a compound shown in a general formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
R7selected from hydrogen atoms, hydroxyl groups, alkyl groups or hydroxyalkyl groups;
n is an integer of 0, 1 or 2;
ring A, ring B, L1～L3、、R2、R5X, y and z are as described in formula (I).
The invention also provides a preferable scheme, wherein the compound shown in each general formula, the stereoisomer or the pharmaceutically acceptable salt thereof:
ring a is selected from the following groups:
ring B is selected from the following groups:
ring C is selected from the following groups:
the invention also provides a preferable scheme, wherein the compound shown in each general formula, the stereoisomer or the pharmaceutically acceptable salt thereof:
L1selected from the group consisting of a bond, - (CH)2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2C(O)NRcc-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-or-N (R)aa)(CRbbRcc)n1(CH2)n2NRdd-；
L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O-、-(CH2)n1S(CH2)n2-、-(CH2)n1C(O)(CH2)n2-or- (CH)2)n1N(Raa)C(O)(CH2)n2-；
R1Selected from hydrogen atoms, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-to 10-membered heterocyclyl, 3-to 10-membered heterocyclylalkyl,-(CH2)n1NRaaRbbOr- (CH)2)n1N(Raa)(CH2)n2RbbWherein said C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-10 membered heterocyclyl and 3-10 membered heterocyclylalkyl groups optionally further substituted by a group selected from hydrogen atom, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl and heterocyclyl, substituted with one or more substituents;
R2selected from hydrogen atoms, C1-6Alkyl radical, C1-6Alkoxy or cyano;
R3selected from hydrogen atoms, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl or 3-to 10-membered heterocyclyl, wherein said C is1-6Alkyl radical, C1-6Hydroxyalkyl and 3-to 10-membered heterocyclyl being optionally further selected from hydrogen atom, C1-6Alkyl, hydroxyl and carboxyl;
R4is selected from C1-6Alkyl, preferably methyl;
R5selected from a hydrogen atom or a carboxyl group;
R6selected from a hydrogen atom, an alkoxy group or a cyano group;
Raa、Rbb、Rccand RddAre the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy, cyano, hydroxy or 3-10 membered heterocyclyl wherein said C is1-6Alkyl radical, C1-6Alkoxy and 3-to 10-membered heterocyclic group optionally further substituted by a group selected from hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl, cyano, hydroxy or oxo;
or, Raa、Rbb、RccAnd RddAny two of which may be linked to form a C3-8Cycloalkyl or 3-10 membered heterocyclyl, wherein said C is3-8Cycloalkyl and 3-12 membered heterocyclyl being optionally further selected from hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl, cyano, hydroxy or oxo;
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, 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. The term "alkenyl" refers to 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, cyclohexyl, cyclopentyl 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:
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
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:
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, 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. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
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 heterocyclyl groups include pyrrolidinyl, azetidinyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like; preference is given to azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl and pyranyl; more preferably azetidinyl, oxetanyl, piperidinyl, piperazinyl and pyranyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein spiro, fused and bridged rings are involvedThe heterocyclic group of (a) is optionally linked to other groups by a single bond, or is 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:
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(wherein m is an integer of 0 to 2) and the remaining ring atoms are 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:
the term "bridged heterocyclyl" refers to 5 to 14 membered rings, any two rings sharing two rings which are not straightPolycyclic heterocyclic radicals, which are linked by atoms and may contain one or more double bonds, but no ring has a completely conjugated pi-electron system, 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. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
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:
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:
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:
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:
"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 structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts () 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 1200Infinity 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
(R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of tert-butyl-1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
To a solution of 1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine (2g,14.58mmol) in methylene chloride (50mL) were added di-tert-butyl dicarbonate (3.49g,16.04mmol) and triethylamine (2.21g,21.87mmol) in this order, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution (50mL), and then the reaction solution was extracted with ethyl acetate (30mL × 3), washed with saturated aqueous sodium chloride solution (20mL × 3), the collected organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound (3.19g, 92%).
MS m/z(ESI):238.2[M+H]+.
The second step is that: preparation of 5- (tert-butyl) 2-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-2, 5-dicarboxylate
To a solution of tert-butyl-1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (3.19g,13.41mmol) in anhydrous tetrahydrofuran (50mL) in a dry ice acetone bath under nitrogen protection was slowly added dropwise a solution of n-butyllithium in n-hexane (2.5M,8mL,20.11mmol), after completion of the dropwise addition, methyl chloroformate (2.5g,26.82mmol) was added after stirring for 10 minutes, and the reaction was continued for 1 hour. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution (50mL), and then the reaction solution was extracted with ethyl acetate (30mL × 3), washed with saturated aqueous sodium chloride solution (20mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (3.54g, 89%).
MS m/z(ESI):296.3[M+H]+.
The third step: preparation of tert-butyl 2- (1-hydroxycyclopropyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
Isopropyl titanate (96mg,0.339mmol) was added dropwise to a solution of (500mg,1.69mmol) in anhydrous THF (5mL) at 0 deg.C, stirred for 10 minutes at incubation, then warmed to 10-15 deg.C and ethyl magnesium bromide (1.24mL,3M in Et at that temperature was added dropwise2O,3.72 mmol). After the reaction was stirred at 25 ℃ for 30 min, it was quenched with water (0.5mL), filtered, the filtrate was concentrated under reduced pressure, and the residue was column chromatographed on silica gel to give the title compound as a white solid (173mg, 35%).
MS m/z(ESI):294.2[M+H]+.
The fourth step: preparation of 3-bromo-2-chlorobenzenethiol
At-10 deg.C or belowAt the temperature, NaNO is added2To 3-bromo-2-chloroaniline (50.0g,245mmol) in aqueous HCl (3N,200mL) was added dropwise (20.2g,293mmol, dissolved in 100mL of water) and reacted at low temperature for 1 hour after dropwise addition. The orange-colored solution was added dropwise to an aqueous solution of potassium ethylxanthate (66.4g,414mmol, dissolved in 120mL of water) at 80 ℃ for about 1 hour. Cooling to room temperature after dropping, layering, and using saturated NaHCO for organic layer3The aqueous solution and water were washed and then added portionwise to a hot KOH solution (68.4g,1220mmol, dissolved in 52mL of water and 280mL of ethanol). After the addition, the mixture was refluxed at elevated temperature for 21 hours. The reaction was cooled to 0 ℃, diluted with ice water (500mL), adjusted to pH 2 with hydrochloric acid to give an oil, which was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown liquid (43.5g, 80%).
The fifth step: preparation of tert-butyl 2- (1- ((3-bromo-2-chlorophenyl) thio) cyclopropyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
MsCl (60mg,0.512mmol) was added dropwise to a solution of TEA (103mg,1.02mmol) and tert-butyl 2- (1-hydroxycyclopropyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (100mg,0.341mmol) in anhydrous DCM (5mL) at-10 deg.C, then warmed to room temperature and stirred for 30 min, a solution of 3-bromo-2-chlorobenzenethiol (114mg,0.512mmol) in anhydrous DCM (0.5mL) was added and stirred for 4H. The reaction was poured into ice water and extracted with DCM (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and 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 (89mg, 55%).
MS m/z(ESI):472.1[M+H]+.
And a sixth step: preparation of 2- (1- ((3-bromo-2-chlorophenyl) thio) cyclopropyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine
Reacting tert-butyl 2- (1- ((3-bromo-2-chlorophenyl) thio) cyclopropyl) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ]]Pyridine-5-carboxylate (326mg,0.654mmol) was added to a solution of HCl in dioxane (5mL,4M) and stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, and the residue was diluted with MeOH (6mL) and 37% aqueous formaldehyde (0.25mL), NaBH, respectively3CN (62mg,0.98mmol) and AcOH (20 uL). The reaction was stirred overnight at room temperature. The reaction was diluted with DCM and then with saturated NaHCO respectively3The aqueous solution, water, dried over anhydrous sodium sulfate, filtered and 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 (229mg, 85%).
MS m/z(ESI):412.1[M+H]+.
The seventh step: preparation of methyl 3-chloro-4-hydroxy-5-nitrobenzoate
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%).
Eighth step: preparation of methyl 3-amino-5-chloro-4-hydroxybenzoate
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%).
The ninth step: preparation of methyl 2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d ] oxazole-5-carboxylate
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 tenth step: preparation of (2- (3-bromo-2-methylphenyl) -7-chlorobenzo [ d ] oxazol-5-yl) methanol
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 eleventh 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
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 twelfth 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
(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 thirteenth step: preparation of 2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
Reacting 2- (1- ((3-bromo-2-chlorophenyl) thio) cyclopropyl) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine (111mg,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, 62%).
MS m/z(ESI):596.2[M+H]+.
The fourteenth step is that: preparation of 2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
2- (2 '-chloro-3' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl]-3-yl) -5- (hydroxymethyl) benzo [ d]Oxazole-7-carbonitrile (104mg,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 (102mg, 98%).
MS m/z(ESI):594.1[M+H]+.
The fifteenth step: preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
2- (2 '-chloro-3' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl]-3-yl) -5- (hydroxymethyl) benzo [ d]Oxazole-7-carbonitrile (54mg,0.0903mmol), R-pyrrolidine-3-carboxylic acid (16mg,0.135mmol), NaBH (OAc)3(29mg,0.135mmol) and DIPEA (23mg,0.181mmol) were added to DCM (1mL) respectively, and stirred at room temperature overnight. The reaction was concentrated and isolated and purified by prep-HPLC to give the title compound (23mg, 25%).
MS m/z(ESI):693.2[M+H]+.
Example 2
(R) -1- ((2- (2' -chloro-3 ' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of tert-butyl 2-bromo-1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
NBS (0.789g,4.43mmol) was added portionwise to a solution of tert-butyl 1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (1.0g,4.22mmol) in DCM (10mL) at room temperature. After the addition, the mixture was stirred at room temperature until the reaction was completed. After the reaction solution was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography to give the title compound as a white solid (1.06g, 80%).
MS m/z(ESI):317.2[M+H]+.
The second step is that: preparation of tert-butyl 2- ((3-bromo-2-chlorophenyl) thio) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate
Tert-butyl 2-bromo-1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (500mg,1.58mmol), 3-bromo-2-chlorobenzenethiol (426mg,1.90mmol) and cesium carbonate (1.55g,4.74mmol) were added to DMF (5mL) respectively, and the mixture was heated to 100 ℃ and stirred until the reaction was complete. The reaction solution was cooled to room temperature and poured into 40mL of ice water, and the precipitated solid was filtered, the filter cake was washed with water, dried in vacuo, and the title compound was isolated and purified by silica gel column chromatography as a brown solid (493mg, 68%).
MS m/z(ESI):458.1[M+H]+.
The third step: preparation of 2- ((3-bromo-2-chlorophenyl) thio) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine
Tert-butyl 2- ((3-bromo-2-chlorophenyl) thio) -1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (300mg,0.654mmol) was added to a solution of HCl in dioxane (5mL,4M), stirred at room temperature for 1 hour, the reaction was concentrated under reduced pressure, and the residue was diluted with MeOH (6mL) and 37% aqueous formaldehyde (0.25mL), NaBH3CN (62mg,0.98mmol) and AcOH (20uL) were added, respectively. The reaction was stirred overnight at room temperature. The reaction was diluted with DCM, then washed with saturated aqueous NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and 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 (171mg, 70%).
MS m/z(ESI):372.0[M+H]+.
The fourth step: preparation of 2- (2' -chloro-3 ' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
2- ((3-bromo-2-chlorophenyl) thio) -1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c)]Pyridine (100mg,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 (89mg, 60%).
MS m/z(ESI):556.2[M+H]+.
The fifth step: preparation of 2- (2' -chloro-3 ' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] oxazole-7-carbonitrile
2- (2 '-chloro-3' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4, 5-c))]Pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl]-3-yl) -5- (hydroxymethyl) benzo [ d]Oxazole-7-carbonitrile (80mg,0.144mmol) was added to DCM (2mL) and MnO was added2(250mg,2.88 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 (72mg, 90%)
MS m/z(ESI):554.1[M+H]+.
And a sixth step: preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
2- (2 '-chloro-3' - ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazole)Azolo [4,5-c]Pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl]-3-yl) -5-formylbenzo [ d]Oxazole-7-carbonitrile (50mg,0.0903mmol), R-pyrrolidine-3-carboxylic acid (16mg,0.135mmol), NaBH (OAc)3(29mg,0.135mmol) and DIPEA (23mg,0.181mmol) were added to DCM (1mL) respectively, and stirred at room temperature overnight. The reaction mixture was concentrated and isolated and purified by prep-HPLC to give the title compound (27mg, 30%).
MS m/z(ESI):653.2[M+H]+.
Example 3
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of tert-butyl 4- (4-iodo-1H-imidazol-1-yl) piperidine-1-carboxylate
DEAD (1.56mL,9.95mmol) was added dropwise to a solution of 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (2.0g,9.95mmol), 4-iodoimidazole (0.965g,4.98mmol) and triphenylphosphine (2.61g,9.95mmol) in tetrahydrofuran (40mL) under ice-cooling. After the dripping is finished, the temperature is naturally raised to the room temperature and the reaction is stirred for 2 hours. After the reaction was concentrated, the residue was purified by silica gel column chromatography to give the title compound as a brown solid (1.61g, 86%).
MS m/z(ESI):378.1[M+H]+.
The second step is that: preparation of tert-butyl 4- (4- ((3-bromo-2-chlorophenyl) thio) -1H-imidazol-1-yl) piperidine-1-carboxylate
Tert-butyl 4- (4-iodo-1H-imidazol-1-yl) piperidine-1-carboxylate (80mg,0.212mmol), (71mg,0.318 mmol))，Pd2(dba)3(19mg,0.0212mmol)，XantPhos(25mg,0.0424mmol)，K2CO3(59mg,0.424mmol) was added to DMF (1.5mL), and the mixture was purged with nitrogen and heated to 160 ℃ for 1 hour. After the reaction solution was cooled, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown solid (60mg, 60%).
MS m/z(ESI):472.1[M+H]+.
The third step: preparation of 4- (4- ((3-bromo-2-chlorophenyl) thio) -1H-imidazol-1-yl) -1-methylpiperidine
Tert-butyl 4- (4- ((3-bromo-2-chlorophenyl) thio) -1H-imidazol-1-yl) piperidine-1-carboxylate (309mg,0.654mmol) was added to HCl/dioxane (5mL,4M), stirred at room temperature for 1 hour, the reaction was concentrated under reduced pressure, the residue was diluted with MeOH (6mL), and 37% aqueous formaldehyde (0.25mL), NaBH, and methanol were added3CN (62mg,0.98mmol) and AcOH (20 uL). Stir at room temperature overnight. The reaction was diluted with DCM and then with saturated NaHCO respectively3The aqueous solution, water, dried over anhydrous sodium sulfate, filtered and 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 (159mg, 63%).
MS m/z(ESI):386.1[M+H]+.
The fourth step: preparation of 2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile
4- (4- ((3-bromo-2-chlorophenyl) thio) -1H-imidazol-1-yl) -1-methylpiperidine (104mg,0.268mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] 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, 65%).
MS m/z(ESI):570.2[M+H]+.
The fifth step: preparation of 2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] oxazole-7-carbonitrile
2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] oxazole-7-carbonitrile (82mg,0.144mmol) was added DCM (2mL) and MnO2(250mg,2.88mmol) was added. The reaction solution was heated to 45 ℃ and stirred for 30 minutes. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (78mg, 95%).
MS m/z(ESI):568.2[M+H]+.
And a sixth step: preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
2- (2' -chloro-2-methyl-3 ' - ((1- (1-methylpiperidin-4-yl) -1H-imidazol-4-yl) thio) - [1,1' -biphenyl]-3-yl) -5-formylbenzo [ d]Oxazole-7-carbonitrile (100mg,0.176mmol), R-pyrrolidine-3-carboxylic acid (30mg,0.264mmol), NaBH (OAc)3(56mg,0.264mmol) and DIPEA (45mg,0.352mmol) were added to DCM (2mL) respectively and stirred at room temperature overnight. The reaction mixture was concentrated and isolated and purified by prep-HPLC to give the title compound (41mg, 23%).
MS m/z(ESI):667.2[M+H]+.
Example 4
(R) -1- ((7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of 1-tert-butyl-4-ethyl-4- (2-chloropyridin-4-yl) piperidine-1, 4-dicarboxylate
NaHMDS (2.3mL,2M, THF solution) was added dropwise to 1-Boc-4-piperidinecarboxylic acid ethyl ester (1.0g,3.89mmol) in anhydrous tetrahydrofuran (5mL) while cooling on ice, and after dropwise addition, the mixture was stirred for 0.5 hour while maintaining ice bath conditions, and a solution of 2-chloro-4-iodopyridine (1.0g,4.18mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise to the solution. The mixture was naturally warmed to room temperature and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (5mL), extracted with ethyl acetate (10mL × 2), the organic phases combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, the organic solvent concentrated under reduced pressure, and the residue was isolated by silica gel column chromatography to give the title compound as a brown oil (1.07g, 75%).
MS m/z(ESI):369.2[M+H]+.
The second step is that: preparation of tert-butyl 4- (2-chloropyridin-4-yl) piperidine-1-carboxylate
1-tert-butyl 4-ethyl 4- (2-chloropyridin-4-yl) piperidine-1, 4-dicarboxylate (1.07g,2.90mmol) was added to a mixed solvent of sodium hydroxide (0.383g,9.57mmol) of ethanol (0.8mL) and water (4.7mL), and stirred at 85 ℃ for 1 hour. The reaction solution was concentrated to half volume under reduced pressure, diluted with water (5mL), and the impurities were extracted with methyl tert-butyl ether (5 mL). The aqueous phase was adjusted to pH 2 with hydrochloric acid (4N) while cooling on ice, followed by extraction with ethyl acetate (10 mL). The organic layer was washed with saturated brine (5mL), dried over anhydrous sodium sulfate, filtered, the organic solvent was concentrated under reduced pressure, and the residue was redissolved in DMSO (2mL) and reacted at 120 ℃ for 1 hour under microwave heating. The reaction mixture was concentrated under reduced pressure, and the title compound was isolated by silica gel column chromatography as a brown oil (0.534g, 62%).
MS m/z(ESI):296.2[M+H]+.
The third step: preparation of tert-butyl 4- (2- ((3-bromo-2-chlorophenyl) thio) pyridin-4-yl) piperidine-1-carboxylate
NaH (88mg,2.22mmol, 60%) was added to a solution of 3-bromo-2-chlorobenzenethiol (452mg,2.02mmol) in DMF (2mL) while cooling on ice, warmed to room temperature and stirred for 10 min. A solution of tert-butyl 4- (2-chloropyridin-4-yl) piperidine-1-carboxylate (300mg,1.01mmol) in DMF (2mL) was added dropwise to the above solution and the reaction was heated to 140 ℃ with a microwave for 14 hours. The reaction solution was poured into ice water (30mL) and extracted with ethyl acetate (30 mL. times.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 column chromatographed on silica gel to give the title compound as a brown oil (283mg, 58%).
MS m/z(ESI):483.1[M+H]+.
The fourth step: preparation of 2- ((3-bromo-2-chlorophenyl) thio) -4- (1-methylpiperidin-4-yl) pyridine
Tert-butyl 4- (2- ((3-bromo-2-chlorophenyl) thio) pyridin-4-yl) piperidine-1-carboxylate (283mg,0.585mmol) was added to a mixed solution of HCl/dioxane (4mL,4M) and methanol (4mL) at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with methanol (10mL), followed by addition of acetic acid (20uL), formalin solution (0.219mL,2.92mmol) and sodium cyanoborohydride (105mg,1.76mmol), and stirring at room temperature for 16 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10mL), extracted with ethyl acetate (50mL × 2), the organic phases combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was isolated by column chromatography on silica gel to give the title compound as a brown oil (83mg, 36%).
MS m/z(ESI):397.1[M+H]+.
The fifth step: preparation of (7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazol-5-yl) methanol
2- ((3-bromo-2-chlorophenyl) thio) -4- (1-methylpiperidin-4-yl) pyridine (83mg,0.209mmol), (7-chloro-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazol-5-yl) methanol (92mg,0.229mmol), tetratriphenylphosphine palladium (24mg,0.0209mmol), cesium carbonate (136mg,0.418mmol) was added to DMF (0.75mL), and after nitrogen substitution, the temperature was raised to 100 ℃ for 1 hour. The reaction was diluted with water (5mL), extracted with ethyl acetate (10mL × 2), the organic phases combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give the title compound as a brown oil (43mg, 35%).
MS m/z(ESI):590.1[M+H]+.
And a sixth step: preparation of 7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazole-5-carbaldehyde
Sodium bicarbonate (61mg,0.728mmol) and dess-martin reagent (46mg,0.109mmol) were added to dichloromethane (2mL) of (7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazol-5-yl) methanol (43mg,0.0728mmol), respectively, and stirred at room temperature for 1 hour. The reaction was concentrated and used directly in the next step.
MS m/z(ESI):588.2[M+H]+.
The seventh step: preparation of (R) -1- ((7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
DIPEA (575mg,0.583mmol) was added to a solution of 7-chloro-2- (2' -chloro-2-methyl-3 ' - ((4- (1-methylpiperidin-4-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazole-5-carbaldehyde (43mg,0.0728mmol) and (R) -pyrrolidine-3-carboxylic acid (42mg,0.364mmol) in dichloromethane (4mL) and stirred at room temperature for 10 minutes, followed by addition of sodium borohydride acetate (46mg,0.219mmol) and stirring at room temperature for 16 hours. The reaction was concentrated under reduced pressure and isolated and purified by preparative HPLC to give the title compound as a white solid (7.0mg, 14% yield over two steps).
MS m/z(ESI):687.2[M+H]+.
Example 5
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((2- (methyl (1-methylpiperidin-4-yl) amino) -2-carbonylethyl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of tert-butyl 4- (2-chloro-N-methylacetamido) piperidine-1-carboxylate
DIPEA (662mg,5.14mmol) was added dropwise to a solution of 1-Boc-4- (methylamino) piperidine (1.0g,4.67mmol) and chloroacetyl chloride (0.686g,6.07mmol) in DCM (40mL) at RT and stirred for 16 h. The reaction was washed with saturated aqueous sodium bicarbonate (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a brown oil (1.38g, 100%).
MS m/z(ESI):291.1[M+H]+.
The second step is that: preparation of tert-butyl 4- (2- ((3-bromo-2-chlorophenyl) thio) -N-methylacetamido) piperidine-1-carboxylate
DIPEA (1.08g,8.38mmol) was added dropwise to a solution of tert-butyl 4- (2-chloro-N-methylacetamido) piperidine-1-carboxylate (1.22g,4.19mmol) and 3-bromo-2-chlorobenzenethiol (1.13g,5.03mmol) in DCM (20mL) at room temperature and stirred at room temperature for 16 h. The reaction solution was washed with water (10mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the title compound as a brown oil (0.76g, 38%).
MS m/z(ESI):477.1[M+H]+.
The third step: preparation of 2- ((3-bromo-2-chlorophenyl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide
Tert-butyl 4- (2- ((3-bromo-2-chlorophenyl) thio) -N-methylacetamido) piperidine-1-carboxylate (760mg,1.59mmol) was added to a mixed solution of HCl/dioxane (5mL,4M) and methanol (10mL) at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with methanol (5mL), followed by addition of acetic acid (50uL), formalin solution (0.645mL,7.95mmol) and sodium cyanoborohydride (286mg,4.77mmol), and stirring at room temperature for 1 hour. The reaction was diluted with dichloromethane (50mL), washed with saturated aqueous sodium bicarbonate (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give the title compound as a brown oil (380mg, 61%).
MS m/z(ESI):391.1[M+H]+.
The fourth step: preparation of 2- ((2-chloro-3 ' - (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide
2- ((3-bromo-2-chlorophenyl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide (380mg,0.955mmol), (7-chloro-2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] oxazol-5-yl) methanol (401mg,1.00mmol), tetratriphenylphosphine palladium (110mg,0.0955mmol), cesium carbonate (622mg,1.91mmol) was added to DMF (8mL), and after nitrogen substitution, the temperature was raised to 100 ℃ for 1 hour. The reaction was diluted with water (40mL), extracted with ethyl acetate (50mL × 2), the organic phases combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to give the title compound as a brown oil (300mg, 54%).
MS m/z(ESI):584.2[M+H]+.
The fifth step: preparation of 2- ((2-chloro-3 ' - (7-cyano-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide
2- ((2-chloro-3 ' - (7-chloro-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide (284mg,0.485mmol), potassium hexacyanoferrate (II) trihydrate (205mg,0.485mmol), potassium acetate (100mg,1.02mmol), t-BuXPhos Pd G3(193mg,0.243mmol) were added to a mixed solvent of dioxane (7mL) and water (7mL), replaced with nitrogen three times, and the mixture was heated to 100 ℃ and stirred 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 (147mg, 53%). Simultaneously, 2- ((2-chloro-3 ' - (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide was isolated (30mg, 11%).
MS m/z(ESI):575.2[M+H]+.
And a sixth step: preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((2- (methyl (1-methylpiperidin-4-yl) amino) -2-carbonylethyl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Manganese dioxide (410mg,4.71mmol) was added to a solution of 2- ((2-chloro-3 ' - (7-cyano-5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide (270mg,0.471mmol) in dichloromethane (4mL) and stirred at 45 ℃ for 8 hours. The reaction mixture was filtered, and (R) -pyrrolidine-3-carboxylic acid (271mg,2.36mmol) and DIPEA (486mg,3.77mmol) were added to the filtrate, followed by stirring at room temperature for 1 hour, and sodium borohydride acetate (300mg,1.41mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction was isolated and purified by prep-HPLC to give the title compound as a white solid (44mg, 14%).
MS m/z(ESI):672.1[M+H]+.
Example 6
(R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine
Tert-butyl-1-methyl-1, 4,6, 7-tetrahydro-5H-imidazo [4,5-c ] pyridine-5-carboxylate (4g,16.88mmol) was dissolved in dichloromethane (50mL), trifluoroacetic acid (5mL) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes and concentrated; then, tetrahydrofuran (50mL) was added to dissolve it, and an aqueous solution of formaldehyde (37 wt%, 12.68mL, 168.8mmol) and sodium triacetoxyborohydride (10.7g,50.63mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with a saturated sodium bicarbonate solution (50mL), and then the reaction solution was extracted with ethyl acetate (30mL × 3), washed with a saturated aqueous sodium chloride solution (20mL × 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 (2.11g, 83%).
MS m/z(ESI):152.1[M+H]+.
The second step is that: preparation of 2-bromo-1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine
1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine (2.11g,13.97mmol) is dissolved in chloroform (50mL), N-bromosuccinimide (3.73g,20.95mmol) and azobisisobutyronitrile (458mg,2.79mmol) are added in this order, and the reaction is stirred at 50 ℃ for 12 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (30mL × 3), washed with saturated aqueous sodium sulfite (20mL × 3), washed with saturated aqueous sodium chloride (20mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (2.47g, 78%).
MS m/z(ESI):230.1[M+H]+.
The third step: preparation of 1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carbonitrile
2-bromo-1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine (230mg,1mmol),1,1' -bis (diphenylphosphino) ferrocene (110mg,0.2mmol), tris (dibenzylideneacetone) dipalladium (90mg,0.1mmol), zinc powder (7.8mg,0.12mmol), and zinc cyanide (140mg,1.2mmol) were suspended in N, N-dimethylaniline (10mL), displaced with nitrogen three times, and the reaction was stirred with heating at 120 ℃ for 3 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 (139mg, 79%).
MS m/z(ESI):177.2[M+H]+.
The fourth step: preparation of 1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropane-1-amine
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 fifth step: preparation of 3-bromo-2-chloro-N- (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) aniline
1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropane-1-amine (75mg,0.364mmol), 2-chloro-1, 3-dibromobenzene (147mg,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 (119mg, 83%).
MS m/z(ESI):395.2[M+H]+.
And a sixth step: preparation of methyl 7-cyanobenzo [ d ] thiazole-5-carboxylate
To a solution of sodium sulfide nonahydrate (120mg,1.25mmol) and sulfur (18mg,0.07mmol) in methanol (20mL) was added methyl 4-chloro-3-cyano-5-nitrobenzoate (240mg,1mmol), and the mixture was stirred at 60 ℃ overnight. After the reaction, the reaction mixture was concentrated, washed with water (30 mL. times.3), filtered, dissolved in ethanol (20mL), and formic acid (0.5mL) was added, and after reaction with stirring at 70 ℃ for 10 minutes, zinc powder (13mg,0.2mmol) was added, and the reaction was continued with stirring at 100 ℃ for 1 hour. 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 (100mg, 46%).
MS m/z(ESI):219.1[M+H]+.
The seventh step: preparation of methyl 2- (3-bromo-2-methylphenyl) -7-cyanobenzo [ d ] thiazole-5-carboxylate
To a solution of methyl 7-cyanobenzo [ d ] thiazole-5-carboxylate (100mg,0.46mmol) in anhydrous tetrahydrofuran (10mL) in a dry ice acetone bath under nitrogen atmosphere, an n-hexane solution of n-butyllithium (2.5M,0.28mL,0.69mmol) was slowly added dropwise, and after completion of the dropwise addition, stirring was carried out for 10 minutes, 2, 6-dibromotoluene (172mg,0.69mmol) was added, and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution 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 (ethyl acetate: petroleum ether ═ 1:1) to obtain the title compound (103mg, 58%).
MS m/z(ESI):387.1[M+H]+.
Eighth step: preparation of 2- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) benzo [ d ] thiazole-7-carbonitrile
To a solution of methyl 2- (3-bromo-2-methylphenyl) -7-cyanobenzo [ d ] thiazole-5-carboxylate (103mg,0.27mmol) in dichloromethane (10mL) was slowly added dropwise a solution of diisobutylaluminum hydride in dichloromethane (1.0M,0.4mL,0.4mmol) in a dry ice acetone bath under nitrogen atmosphere, and the reaction was completed for 1 hour after the dropwise addition. 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 (75mg, 78%).
MS m/z(ESI):359.1[M+H]+.
The ninth step: preparation of 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] thiazole-7-carbonitrile
2- (3-bromo-2-methylphenyl) -5- (hydroxymethyl) benzo [ d ] thiazole-7-carbonitrile (75mg,0.21mmol), pinacol diboron (79mg,0.31mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (15mg,0.02mmol) and potassium acetate (40mg,0.42mmol) were suspended in an anhydrous solution of 1, 4-epoxyhexacyclic ring (10mL), replaced with nitrogen three times, and the reaction was stirred with heating 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: 95:5) to obtain the title compound (109mg, 76%).
MS m/z(ESI):407.2[M+H]+.
The tenth step: preparation of 2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] thiazole-7-carbonitrile
3-bromo-2-chloro-N- (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) aniline (91mg,0.23mmol), 5- (hydroxymethyl) -2- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [ d ] thiazole-7-carbonitrile (109mg,0.27mmol), [1,1' -bis (dicyclohexylphosphine) ferrocene ] palladium dichloride (15mg,0.02mmol) and cesium carbonate (150mg,0.46mmol) were suspended in an anhydrous solution of 1, 4-epoxyhexacyclic compound (10mL) and water (2mL), the reaction was carried out under nitrogen three times with heating and 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 (105mg, 77%).
MS m/z(ESI):595.2[M+H]+.
The eleventh step: preparation of 2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] thiazole-7-carbonitrile
To a solution of 2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (hydroxymethyl) benzo [ d ] thiazole-7-carbonitrile (105mg,0.18mmol) in dichloromethane (5mL) were added sodium bicarbonate (151mg,1.8mmol) and dess-martin oxidant (112mg,0.27mmol) in that order, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, the organic phase was filtered and concentrated under reduced pressure to give the title compound (86mg, 81%).
MS m/z(ESI):593.2[M+H]+.
The twelfth step: preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-formylbenzo [ d ] thiazole-7-carbonitrile (86mg,0.14mmol) was dissolved in dichloromethane (5mL), and (R) -pyrrolidine-3-carboxylic acid (80mg,0.7mmol) and N, N-diisopropylethylamine (181mg,1.4mmol) were added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (89mg,0.42mmol) 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 (29mg, 30%) by prep-HPLC.
MS m/z(ESI):692.1[M+H]+.
Example 7
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((2- (methyl (1-methylpiperidin-4-yl) amino) -2-carbonylethyl) thio) - [1,1' -biphenyl ] -3-yl) benzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Manganese dioxide (47mg,0.55mmol) was added to a solution of 2- ((2-chloro-3 ' - (5- (hydroxymethyl) benzo [ d ] oxazol-2-yl) -2' -methyl- [1,1' -biphenyl ] -3-yl) thio) -N-methyl-N- (1-methylpiperidin-4-yl) acetamide (30mg,0.055mmol) in dichloromethane (4mL) and the temperature was raised to 45 ℃ and stirred for 8 hours. The reaction mixture was filtered, and (R) -pyrrolidine-3-carboxylic acid (31mg,0.27mmol) and DIPEA (56mg,0.44mmol) were added to the filtrate, followed by stirring at room temperature for 1 hour, and sodium borohydride acetate (35mg,0.16mmol) was added thereto, followed by stirring at room temperature for 2 hours. The reaction was isolated and purified by preparative HPLC to afford the title compound as a white solid (5mg, 14%).
MS m/z(ESI):647.2[M+H]+.
Example 8
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of (R) -1- ((2-chloropyridin-4-yl) methyl) pyrrolidin-3-ol
2-chloropyridine-4-carbaldehyde (1.41g, 10mmol) and (R) -pyrrolidin-3-ol (958mg, 11mmol) were dissolved in methylene chloride (20mL) and stirred at room temperature for 1 hour, sodium borohydride acetate (3.18g, 15mmol) was added, the resulting reaction solution was stirred at room temperature overnight, the solvent was removed by concentration under reduced pressure, and the residue was isolated by silica gel column chromatography to give the title compound (1.84g, 87%).
MS m/z(ESI):213.2[M+H]+.
The second step is that: preparation of (R) -1- ((2- ((3-bromo-2-chlorophenyl) amino) pyridin-4-yl) methyl) pyrrolidin-3-ol
(R) -1- ((2-Chloropyridin-4-yl) methyl) pyrrolidin-3-ol (1.0g, 4.7mmol), 3-bromo-2-chloroaniline (1.46g, 7.05mmol) were dissolved in dry dioxane (15mL), sodium hydride (564mg, 23.5mmol) was added with stirring at room temperature, and the reaction mixture was warmed to 60 ℃ and stirred for 5 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 separated by silica gel column chromatography to give the title compound (1.5g, 83%)
MS m/z(ESI):382.1[M+H]+.
The third step: preparation of (R) -5- ((2' -chloro-3 ' - ((4- ((3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile
(R) -1- ((2- ((3-bromo-2-chlorophenyl) amino) pyridin-4-yl) methyl) pyrrolidin-3-ol (381mg, 1.0mmol), 5- ((2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxo) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile (605mg, 1.5mmol), 1,1' -dicyclohexylphosphinocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocerrocelldium (82mg,0.1 mmol) and carbonic acid (652mg, 2.0mmol) were added to a 100mL reaction flask, the reaction was evacuated and protected with dry nitrogen, tert-butanol (, then 10 drops of water are added, the reaction solution is vacuumized and replaced by nitrogen for three times under the stirring of room temperature, and then the reaction solution is 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 (388mg, 67%).
MS m/z(ESI):579.2[M+H]+.
The fourth step: preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
(R) -5- ((2' -chloro-3 ' - ((4- ((3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile (100mg, 0.172mmol) and (R) -pyrrolidine-3-carboxylic acid (198mg, 1.72mmol) were dispersed in dichloromethane (10mL), DIPEA (0.57mL, 3.44mmol) was added with stirring at room temperature, the resulting reaction mixture was stirred at room temperature for 1 hour, sodium borohydride acetate (183mg, 0.86mmol) was added, the resulting reaction mixture was stirred at room temperature for overnight, the solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (57mg, 49%).
MS m/z(ESI):678.3[M+H]+.
Example 9
(R) -1- ((R) -5- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
The first step is as follows: preparation of (1- ((6-bromo-2-chloropyridin-3-yl) methyl) azetidin-3-yl) methanol
6-bromo-2-chloronicotinaldehyde (2.2g, 10mmol) and azetidin-3-ylmethanol (958mg, 11mmol) were dissolved in dichloromethane (20mL), the reaction was stirred at room temperature for 1 hour, sodium borohydride acetate (3.18g, 15mmol) was added, the resulting reaction solution was stirred at room temperature overnight, the solvent was removed by concentration under reduced pressure, and the residue was isolated by silica gel column chromatography to give the title compound (2.07g, 71%).
MS m/z(ESI):290.1[M+H]+.
The second step is that: preparation of (1- ((6-bromo-2-methoxypyridin-3-yl) methyl) azetidin-3-yl) methanol
(1- ((6-bromo-2-chloropyridin-3-yl) methyl) azetidin-3-yl) methanol (2.0g, 7mmol) was dissolved in anhydrous methanol (15mL), sodium methoxide (3.78g, 70mmol) was added, the mixture was stirred at room temperature, and the mixture was heated to 60 ℃ to react for 5 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 compound (1.35g, 67%).
MS m/z(ESI):287.1[M+H]+.
The third step: preparation of (1- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) azetidin-3-yl) methanol
Will (1- ((6-bromo-2-methoxypyridin-3-yl)Methyl) azetidin-3-yl) methanol (1.0g, 3.48mmol), 3-bromo-2-chlorobenzoic acid (0.8g, 3.40mmol), Pd (dppf) Cl2(256mg, 0.35mmol) and cesium carbonate (2.21g, 6.80mmol) were charged into a 100mL reaction flask, the reaction was evacuated and protected with dry nitrogen, dry dioxane (30mL) and water (0.5mL) were added to the reaction flask, the reaction was evacuated under stirring at room temperature and replaced with nitrogen three times, and then heated to 100 ℃ in an oil bath under nitrogen protection for 15 hours. Celite was filtered, the celite layer was washed with ethyl acetate, the filtrates were combined, the solvent was removed by concentration under reduced pressure, and the residue was isolated by silica gel column chromatography to give the title compound (1.21g, 90%).
MS m/z(ESI):397.1[M+H]+.
The fourth step: preparation of 5- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile
Adding (1- ((6- (3-bromo-2-chlorophenyl) -2-methoxypyridin-3-yl) methyl) azetidin-3-yl) methanol (398mg, 1.0mmol), 5- ((2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) oxo) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile (605mg, 1.5mmol), 1,1' -dicyclohexylphosphinocarbane palladium dichloride (82mg,0.1 mmol) and carbonic acid (652mg, 2.0mmol) to a 100mL reaction flask, evacuating the reaction system and protecting with dry nitrogen, adding tert-butanol (20mL) to the reaction flask, then 10 drops of water are added, the reaction solution is vacuumized and replaced by nitrogen for three times under the stirring of room temperature, and then the reaction solution is 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 (374mg, 63%).
MS m/z(ESI):594.2[M+H]+.
The fifth step: preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Dispersing 5- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -1-carbonyl-2, 3-dihydro-1H-indene-4-carbonitrile (100mg, 0.168mmol) and (R) -pyrrolidine-3-carboxylic acid (194mg, 1.68mmol) in dichloromethane (10mL), adding DIPEA (0.55mL, 3.36mmol) with stirring at room temperature, stirring the resulting reaction mixture at room temperature for 1 hour, adding sodium borohydride (178mg, 0.84mmol) and stirring the resulting reaction mixture at room temperature for overnight, the solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (48mg, 41%).
MS m/z(ESI):693.2[M+H]+.
Example 10
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((3- (methyl (1-methylpiperidin-4-yl) carbamoyl) oxetan-3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((3- (methyl (1-methylpiperidin-4-yl) carbamoyl) oxetan-3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 1.
MS m/z(ESI):714.2[M+H]+.
Example 11
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1-methyl-3- (methyl (1-methylpiperidin-4-yl) carbamoyl) azetidin-3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1-methyl-3- (methyl (1-methylpiperidin-4-yl) carbamoyl) azetidin-3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 1.
MS m/z(ESI):727.2[M+H]+.
Example 12
(R) -1- ((2- (2' -chloro-3 ' - ((1- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 1.
MS m/z(ESI):706.2[M+H]+.
Example 13
(3R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1' -methyl- [1,4' -bipiperidin ] -3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1' -methyl- [1,4' -bipiperidin ] -3-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):684.2[M+H]+.
Example 14
(3R) -1- ((2- (2' -chloro-3 ' - ((1- (1- (2-hydroxyethyl) azetidin-3-yl) piperidin-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((2- (2' -chloro-3 ' - ((1- (1- (2-hydroxyethyl) azetidin-3-yl) piperidin-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):686.2[M+H]+.
Example 15
(3R) -1- ((2- (2' -chloro-3 ' - ((1- (1- (2-hydroxyethyl) azetidin-3-yl) pyrrolidin-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((2- (2' -chloro-3 ' - ((1- (1- (2-hydroxyethyl) azetidin-3-yl) pyrrolidin-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):672.2[M+H]+.
Example 16
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- (5-methyl-4, 5,6, 7-tetrahydrooxazolo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- (5-methyl-4, 5,6, 7-tetrahydrooxazolo [4,5-c ] pyridin-2-yl) cyclopropyl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 1.
MS m/z(ESI):680.2[M+H]+.
Example 17
(R) -1- ((2- (2' -chloro-3 ' - ((5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 2.
MS m/z(ESI):683.2[M+H]+.
Example 18
(R) -1- ((2- (2' -chloro-3 ' - ((5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 2.
MS m/z(ESI):686.2[M+H]+.
Example 19
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((4- (4-methylpiperazin-1-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((4- (4-methylpiperazin-1-yl) pyridin-2-yl) thio) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 4.
MS m/z(ESI):679.2[M+H]+.
Example 20
(R) -1- ((2- (2' -chloro-3 ' - ((4- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((4- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):666.2[M+H]+.
Example 21
(R) -1- ((2- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] oxazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):680.2[M+H]+.
Example 22
(R) -N- (2' -chloro-3 ' - ((4- ((3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Preparation of (R) -N- (2' -chloro-3 ' - ((4- ((3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide reference is made to example 3.
MS m/z(ESI):673.2[M+H]+.
Example 23
N- (2' -chloro-3 ' - ((4- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Preparation of N- (2' -chloro-3 ' - ((4- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -1-methyl-5- (tetrahydro-2H-pyran-4-yl) -4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide reference is made to example 3.
MS m/z(ESI):659.2[M+H]+.
Example 24
(S) -N- (2' -chloro-3 ' - ((1- ((1- (2-hydroxyethyl) azetidin-3-yl) methyl) -1H-imidazol-4-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (2-hydroxypropyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide
Preparation of (S) -N- (2' -chloro-3 ' - ((1- ((1- (2-hydroxyethyl) azetidin-3-yl) methyl) -1H-imidazol-4-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5- (2-hydroxypropyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine-2-carboxamide reference is made to example 3.
MS m/z(ESI):650.2[M+H]+.
Example 25
(R) -1- ((6- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((6- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):678.2[M+H]+.
Example 26
(R) -1- ((2- (3- (3-chloro-4- ((3- (((R) -3-hydroxypyrrolidin-1-yl) methyl) phenyl) thio) pyridin-2-yl) -2-methylphenyl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (3- (3-chloro-4- ((3- (((R) -3-hydroxypyrrolidin-1-yl) methyl) phenyl) thio) pyridin-2-yl) -2-methylphenyl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):678.2[M+H]+.
Example 27
(R) -1- ((2- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-cyanoindolizin-7-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-cyanoindolizin-7-yl) methyl) pyrrolidine-3-carboxylic acid reference example 3.
MS m/z(ESI):600.2[M+H]+.
Example 28
(3R) -1- ((1- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 9.
MS m/z(ESI):714.2[M+H]+.
Example 29
(3R) -1- ((1- ((2' -chloro-3 ' - (6-methoxy-5- ((((((S) -5-carbonylpyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - (6-methoxy-5- ((((((S) -5-carbonylpyrrolidin-2-yl) methyl) amino) methyl) pyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 3.
MS m/z(ESI):741.2[M+H]+.
Example 30
(3R) -1- ((1- ((2' -chloro-3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - (5- (2-hydroxyethyl) -4,5,6, 7-tetrahydrothiazolo [5,4-c ] pyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) thio) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 2.
MS m/z(ESI):690.2[M+H]+.
Example 31
(3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 8.
MS m/z(ESI):683.2[M+H]+.
Example 32
(3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) oxo) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) oxo) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 8.
MS m/z(ESI):684.2[M+H]+.
Example 33
(3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (3R) -1- ((1- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) oxo) -4-methoxy-2, 3-dihydro-1H-inden-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 8.
MS m/z(ESI):700.2[M+H]+.
Example 34
(R) -1- ((2- (2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):708.2[M+H]+.
Example 35
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((3- ((methyl (1-methylpiperidin-4-yl) amino) methyl) oxetan-3-yl) amino) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((3- ((methyl (1-methylpiperidin-4-yl) amino) methyl) oxetan-3-yl) amino) - [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):699.2[M+H]+.
Example 36
(R) -1- ((2- (2' -chloro-3 ' - ((3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((3- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyanobenzo [ d ] thiazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):735.2[M+H]+.
Example 37
(R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):689.2[M+H]+.
Example 38
(R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- ((methyl (1-methylpiperidin-4-yl) amino) methyl) cyclopropyl) amino) - [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-2-methyl-3 ' - ((1- ((methyl (1-methylpiperidin-4-yl) amino) methyl) cyclopropyl) amino) - [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):680.2[M+H]+.
Example 39
(R) -1- ((2- (2' -chloro-3 ' - ((1- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (5- ((3-hydroxyazetidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -7-cyano-1-methyl-1H-benzo [ d ] imidazol-5-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):702.2[M+H]+.
Example 40
(R) -1- ((6- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((6- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 9.
MS m/z(ESI):676.2[M+H]+.
EXAMPLE 41
(R) -1- ((2- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 9.
MS m/z(ESI):676.2[M+H]+.
Example 42
(R) -1- ((2- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-cyanoindolizin-7-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) -5-cyanoindolizin-7-yl) methyl) pyrrolidine-3-carboxylic acid refers to example 9.
MS m/z(ESI):676.2[M+H]+.
Example 43
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid reference example 8.
MS m/z(ESI):695.2[M+H]+.
Example 44
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((5- (2-hydroxyethyl) -1-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid reference example 8.
MS m/z(ESI):698.2[M+H]+.
Example 45
(R) -1- ((R) -5- (((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methyl) thio) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- (((2' -chloro-3 ' - (5- ((3- (hydroxymethyl) azetidin-1-yl) methyl) -6-methoxypyridin-2-yl) -2-methyl- [1,1' -biphenyl ] -3-yl) methyl) thio) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid reference example 9.
MS m/z(ESI):709.2[M+H]+.
Example 46
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):691.2[M+H]+.
Example 47
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid reference example 1.
MS m/z(ESI):724.2[M+H]+.
Example 48
(R) -1- ((R) -5- ((2' -chloro-3 ' - (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropoxy) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - (1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropoxy) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid refers to example 1.
MS m/z(ESI):692.2[M+H]+.
Example 49
(R) -1- ((R) -5- ((2' -chloro-3 ' - ((1- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - ((1- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) thio) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid refers to example 1.
MS m/z(ESI):735.2[M+H]+.
Example 50
(R) -1- ((R) -5- ((2' -chloro-3 ' - (1- ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxo) cyclopropyl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - (1- ((1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxo) cyclopropyl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid refers to example 8.
MS m/z(ESI):692.2[M+H]+.
Example 51
(R) -1- ((R) -5- ((2' -chloro-3 ' - (1- ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -1-methyl-1H-imidazol-2-yl) thio) cyclobutyl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((R) -5- ((2' -chloro-3 ' - (1- ((4- (((R) -3-hydroxypyrrolidin-1-yl) methyl) -1-methyl-1H-imidazol-2-yl) thio) cyclobutyl) -2-methyl- [1,1' -biphenyl ] -3-yl) methoxy) -4-cyano-2, 3-dihydro-1H-inden-1-yl) pyrrolidine-3-carboxylic acid refers to example 8.
MS m/z(ESI):752.2[M+H]+.
Example 52
(R) -1- ((7- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) imidazo [1,2-a ] pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((7- (2' -chloro-3 ' - ((1- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) imidazo [1,2-a ] pyridin-3-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):650.2[M+H]+.
Example 53
(R) -1- ((6- (2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((6- (2' -chloro-3 ' - ((3- (1, 5-dimethyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridin-2-yl) oxetan-3-yl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -3-cyanoindolizin-1-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):690.2[M+H]+.
Example 54
(R) -1- ((2- (2' -chloro-3 ' - ((1- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid
Preparation of (R) -1- ((2- (2' -chloro-3 ' - ((1- (5- (((R) -3-hydroxypyrrolidin-1-yl) methyl) pyridin-2-yl) cyclopropyl) amino) -2-methyl- [1,1' -biphenyl ] -3-yl) -8-cyanoindolizin-6-yl) methyl) pyrrolidine-3-carboxylic acid reference example 6.
MS m/z(ESI):701.2[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: the centrifuge (5810R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a H1MFD full-function microplate reader.
The experimental method comprises the following steps: to test the inhibitory activity of compounds on PD-1/PD-L1 binding, this experiment was tested using time-resolved fluorescence resonance energy transfer (TR-FRET)The compound has the inhibition effect on the binding of PD-1/PD-L1, and the half inhibition concentration IC of the compound on the binding inhibition activity of PD-1/PD-L1 is obtained50。
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
And (4) experimental conclusion:
the scheme shows that the compound shown in the invention shows good binding inhibition activity in a PD-1/PD-L1 inhibition test.
2. Tumor cell surface PD-L1 endocytosis 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, pipettor from Eppendorf or Rainin, and flow cytometer from Beckman Coulter, model DxFlex.
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 value is obtained.
And (4) experimental conclusion:
the above protocol shows that the compounds of the present invention show about 0.10nM to 1000nM (IC) in the tumor cell surface PD-L1 endocytosis assay50) The biological activity of (1).
In some embodiments, the compounds of the invention have IC for tumor cell surface endocytosis of PD-L150Less than about 1000nM, more preferably less than about 500nM, more preferably less than about 100nM, and most preferably less than 10nM or even less than about 1 nM. In some other embodiments, preferred compounds of the compounds shown herein exhibit induced PD-L1 endocytic activity and are capable of an IC of less than about 1000nM, less than about 500nM, less than about 100nM, less than about 10nM, or even less than about 1nM50Biological activity of the value.
Claims (15)
1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
L1selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(RaaRbb)n2-、-(CH2)n1S(CH2)n2C(O)O-、-(CH2)n1S(CRaaRbb)n2C(O)NRcc-、-(CH2)n1C(O)(CH2)n2-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-、-N(Raa)(CRbbRcc)n1(CH2)n2NRdd-or- (CH)2)n1S(CH2)n2C(O)NRaa-；
L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(CH2)n2-、-(CH2)n1S(CH2)n2C(O)-、-(CH2)n1S(CH2)n2C(O)NRaa-、-(CH2)n1C(O)(CH2)n2-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-、-N(Raa)(CRbbRcc)n1(CH2)n2NRdd-or- (CH)2)n1S(CH2)n2C(O)NRaa-；
L3Selected from a bond or- (CH)2)n1-；
X is selected from halogen, preferably chlorine;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R1selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cyano group, alkenyl group, alkynyl group, heterocyclylalkyl group, cycloalkyl group, heterocyclylalkyl group, aryl group, heteroaryl group, - (CH)2)n1Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaS(O)m1RbbOr- (CH)2)n1N(Raa)(CH2)n2RbbWherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, halogen, substituted or unsubstituted amino, nitro, hydroxyl, cyano, oxo, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R2selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, halogen, amino, nitro, cyano, hydroxyl, carboxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R3selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, hydroxyalkyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atom, deuterium atom, substituted or unsubstituted alkyl, substituted or unsubstituted deuterated alkyl, substituted or unsubstituted haloalkyl, halogen, amino, nitro, cyano, hydroxyl, carboxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R4selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group;
Raa、Rbb、Rccand RddThe same or different and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a haloalkoxy group, a halogen, a cyano group, a nitro group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, substituted or unsubstituted alkyl, halogen, hydroxyl, substituted or unsubstituted amino, oxo, nitro, cyano, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
alternatively, the first and second electrodes may be,Raa、Rbb、Rccand RddAny two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of hydrogen atoms, deuterium atoms, alkyl groups, haloalkyl groups, halogen, amino groups, oxo groups, nitro groups, cyano groups, hydroxy groups, hydroxyalkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups;
x is an integer of 0, 1,2, 3, 4,5 or 6;
y is an integer of 0, 1,2, 3, 4,5 or 6;
n1 is an integer of 0, 1 or 2; and is
n2 is an integer of 0, 1 or 2.
2. The compound of formula (I) according to claim 1, which is a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring C is selected from cycloalkyl, heterocyclyl, aryl or heterocyclyl;
R5selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, hydroxyalkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, - (CH)2)n1Raa、-(CH2)n1ORbb、-(CH2)n1NRaaRbb、-NRaaC(O)Rbb、-NRaaC(O)NRbbRcc、-C(O)NRaaRbb、-NRaaS(O)m1Rbb、-(CH2)n1S(O)m1NRaaRbb、-(CH2)n1C(O)Raa、-(CH2)n1C(O)ORaa、-NRaaC(O)ORbb、-(CH2)n1S(O)m1Raa、-(CH2)n1NRaaS(O)m1RbbOr- (CH)2)n1N(Raa)(CH2)n2Rbb；
z is an integer of 0, 1 or 2;
ring A, ring B, L1～L3、X、R1、R2、R4、Raa～RccX, y, n1, n2 and m1 are as described in claim 1.
3. The compound of formula (II) according to claim 2, which is a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring A, ring B, L1～L3、R1、R2、R5X, y and z are as defined in claim 2.
4. The compound of formula (III) according to claim 3, which is a compound of formula (IV-a), (IV-B) and (IV-C), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
M1～M11same orAre different from and each independently selected from O, N, S, CRaaOr NRaa；
R6Selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amino group, nitro group, hydroxyl group, cyano group, carboxyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;
ring B, ring C, L1～L3、R1、R5X and z are as defined in claim 3.
5. The compound of formula (III) according to claim 3, which is a compound of formulae (V-a) and (V-B), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
ring A, ring B, L1、L2、R1、R2X and y are as defined in claim 3.
6. The compound of formula (I) according to claim 1, which is a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
g is selected from oxygen, sulfur or NRaa；
Ring B, L1、R1、NRaaAnd x is as defined in claim 1.
7. The compound of formula (I) according to claim 1, which is a compound of formula (VII):
wherein:
ring B, L1、L2、R1And x is as defined in claim 1.
8. The compound of formula (I) according to claim 1, which is a compound of formula (VIII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
ring B, L1、L2、R1And x is as defined in claim 1.
9. The compound of formula (I) according to claim 1, which is a compound of formula (IX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
wherein:
R7selected from hydrogen atoms, hydroxyl groups, alkyl groups or hydroxyalkyl groups;
n is an integer of 0, 1 or 2;
ring A, ring B, L1～L3、R2、R5X, y and z are as defined in claim 1.
10. The compound of any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
ring a is selected from the following groups:
ring B is selected from the following groups:
ring C is selected from the following groups:
11. the compound of any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
L1selected from the group consisting of a bond, - (CH)2)n1NRaa-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O(CH2)n2-、-(CRaaRbb)n1NRcc-、-(CH2)n1S(CRaaRbb)n2-、-(CRaaRbb)n1S(CH2)n2-、-(CH2)n1S(CRaaRbb)n2C(O)NRcc-、-(CH2)n1C(O)N(Raa)(CRbbRcc)n2-、-N(Raa)(CRbbRcc)n1-、-(CH2)n1N(Raa)C(O)(CH2)n2-or-N (R)aa)(CRbbRcc)n1(CH2)n2NRdd-；
L2Selected from the group consisting of a bond, - (CH)2)n1-、-(CH2)n1O(CRaaRbb)n2-、-(CRaaRbb)n1O-、-(CH2)n1S(CH2)n2-、-(CH2)n1C(O)(CH2)n2-or- (CH)2)n1N(Raa)C(O)(CH2)n2-；
R1Selected from hydrogen atoms, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, - (CH)2)n1NRaaRbbOr- (CH)2)n1N(Raa)(CH2)n2RbbWherein said C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy, 3-10 membered heterocyclyl and 3-10 membered heterocyclylalkyl groups optionally further substituted by a group selected from hydrogen atom, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl and heterocyclyl, substituted with one or more substituents;
R2selected from hydrogen atoms, C1-6Alkyl radical, C1-6Alkoxy or cyano;
R3selected from hydrogen atoms, C1-6Alkyl, hydroxy, C1-6Hydroxyalkyl or 3-to 10-membered heterocyclyl, wherein said C is1-6Alkyl radical, C1-6Hydroxyalkyl and 3-to 10-membered heterocyclyl being optionally further selected from hydrogen atom, C1-6Alkyl, hydroxyl and carboxyl;
R4is selected from C1-6Alkyl, preferably methyl;
R5selected from a hydrogen atom or a carboxyl group;
R6selected from a hydrogen atom, an alkoxy group or a cyano group;
Raa、Rbb、Rccand RddAre the same or different and are each independently selected from the group consisting of a hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy, cyano, hydroxy or 3-10 membered heterocyclyl wherein said C is1-6Alkyl radical, C1-6Alkoxy and 3-to 10-membered heterocyclic group optionally further substituted by a group selected from hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl, cyano, hydroxy or oxo;
or, Raa、Rbb、RccAnd RddAny two of which may be linked to form a C3-8Cycloalkyl or 3-10 membered heterocyclyl, wherein said C is3-8Cycloalkyl and 3-12 membered heterocyclyl being optionally further selected from hydrogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl, cyano, hydroxy or oxo.
12. The compound of any one of claims 1 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
13. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 12, in association with one or more pharmaceutically acceptable carriers, diluents or excipients.
14. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13 for the preparation of a PD-1/PD-L1 inhibitor medicament.
15. Use of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 13 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 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.
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