CN115340586A - Nucleoside phosphoramidate analogues, preparation method and application thereof - Google Patents
Nucleoside phosphoramidate analogues, preparation method and application thereof Download PDFInfo
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- CN115340586A CN115340586A CN202210516319.4A CN202210516319A CN115340586A CN 115340586 A CN115340586 A CN 115340586A CN 202210516319 A CN202210516319 A CN 202210516319A CN 115340586 A CN115340586 A CN 115340586A
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- radical
- alkyl
- cycloalkyl
- aryl
- amino
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- 125000000217 alkyl group Chemical group 0.000 claims description 176
- 125000003118 aryl group Chemical group 0.000 claims description 143
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims description 76
- 239000001257 hydrogen Substances 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 72
- 150000002367 halogens Chemical class 0.000 claims description 72
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 71
- 150000002431 hydrogen Chemical class 0.000 claims description 71
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 69
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 66
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 65
- 229910052805 deuterium Inorganic materials 0.000 claims description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 63
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Abstract
The present invention relates to nucleoside phosphoramidate analogues, methods of preparation and uses thereof. In particular, the invention relates to a compound shown in a general formula (I) or a stereoisomer thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in preparing a medicament for treating the diseasesThe application of the medicine in treating cancer or hepatitis caused by virus and other related diseases.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a nucleoside phosphoramidate analogue, and a preparation method and application thereof.
Background
Gemcitabine (r) (Gemcitabine,
) The invention relates to a difluoro nucleoside antimetabolite chemotherapeutic drug which is designed and invented by Eli Lily company and is approved by FDA to enter the market in 1996. The traditional Chinese medicine composition is widely applied to treatment of colon cancer, lung cancer, ovarian cancer, breast cancer, pancreatic cancer and the like, and is particularly suitable for treatment of advanced or metastatic pancreatic cancer which cannot be resected by surgery and metastatic non-small cell lung cancer. Gemcitabine enters cells in vivo via a nucleoside transporter and is converted to nucleoside monophosphates (dFdCMP) by nucleotide kinases (dCK). dFdCMP is activated in vivo by pyrimidine kinases into pharmacologically active nucleoside diphosphate (dFdCDP) and nucleoside triphosphate (dFdCTP). dFdCTP blocks the normal progression of DNA synthetase by competing with deoxynucleotide triphosphates (dntps) in vivo, DNA synthesis is forcibly terminated, and the DNA strand is rendered irreparable, resulting in apoptosis. Meanwhile, dFdCDP can form covalent binding with nucleic acid reductase, so that the activity of deaminase dCTD is reduced, the concentration of dNTP is reduced, and the activity of deaminase dCTD is promotedPhosphorylation of dFdC is further promoted, resulting in a self-enhancing effect.
Gemcitabine is a very polar compound and is commonly used clinically as a hydrochloride injection. After intravenous injection into the blood, the presence of a large amount of Cytidine Deaminase (CDA) in the body degrades gemcitabine into inactive difluorine (dFdU), and thus has a short half-life, typically only a few tens of minutes. Clinically, the dosage is increased or multiple injections are needed to achieve a certain treatment effect, and meanwhile, the toxic and side effects to the body are increased. In addition, gemcitabine must pass through a specific nucleic acid transporter to enter tumor cells, and if such a nucleic acid transporter is deleted or expression is reduced, gemcitabine resistance is easily developed. In recent years, resistance to gemcitabine has been observed in a variety of tumors, such as breast and pancreatic cancers, and this has been shown in part to be due to the lack of nucleic acid delivery vectors in tumors. Furthermore, gemcitabine needs to undergo three phosphorylation events in a cell to produce an active compound, and thus, deletion of an enzyme that promotes gemcitabine phosphorylation, particularly dCK in the first step of the rate limiting step, also causes a decrease in the potency of gemcitabine.
Decitabine (DCA) is a 5-aza-2' -deoxycytidine nucleoside, a deoxynucleoside analog of cytidine. Like gemcitabine, decitabine enters cells mainly through a nucleoside transporter, is phosphorylated into a monophosphorylated derivative 5-aza-dCMP under the action of deoxycytidine kinase (dCK), and the 5-aza-dCMP is converted into an activated form 5-aza-dCTP again through phosphorylation. Decitabine is also very susceptible to irreversible catalytic hydrolysis to uridine and deoxyuridine in the blood by Cytidine Deaminase (CDA). Decitabine has significant therapeutic effects on various hematological malignancies, including myelodysplastic syndrome (MDS), acute Myelogenous Leukemia (AML), and Chronic Myelogenous Leukemia (CML).
Prodrugs, also known as prodrugs, are compounds that are not or only poorly active themselves and which are converted, chemically or biologically, in vivo to produce the active product. The parent drug is modified by chemical structure, and can release the parent drug with pharmacological activity after chemical or biological conversion in vivo, thereby playing a therapeutic role. The prodrug can improve the physicochemical property and pharmacokinetic property of parent drugs, and overcomes the defects of various drugs, such as poor water solubility, unstable chemical property, poor absorption after oral administration, difficult blood brain barrier permeation, large toxicity or local stimulation, and the like. In addition, the prodrug can also improve the targeting selectivity of the drug to tumors or specific organs.
Liposomes are vesicular structures formed by encapsulation of phospholipid bilayers, which are formed by self-assembly of lipid molecules having hydrophilic heads and hydrophobic tails, the hydrophilic heads being closely arranged to form the appearance of a membrane. A face layer and an inner surface layer, the hydrophobic tail being in the middle of the membrane. The special membrane structure enables the liposome to carry not only hydrophilic substances, but also hydrophobic substances and amphiphilic substances, and the substances are wrapped in the inner cavity of the liposome, or are inserted in the middle of a phospholipid bilayer, or are adsorbed on the surface of the liposome. Liposomes used to entrap drugs are generally 50 to 450nm in size. Compared with normal tissues, the tumor tissue has rich capillaries but poor structural integrity, and larger gap between the capillary wall and the endothelial cell wall, so that the liposome loaded with the chemotherapeutic drug can permeate into the tumor tissue through the cell wall and accumulate, the passive targeting of the liposome can be realized, and the systemic adverse reaction can be reduced. Meanwhile, according to the characteristics of less oxygen in the solid tumor, lower pH value and the like, and the modification of a specific receptor on the surface of the liposome, the active targeting and intelligent drug release of the liposome to the tumor can be realized.
Gemcitabine and decitabine share similar characteristics, namely: the protein is easy to be metabolized into inactive products in blood, a nucleic acid transporter is required to enter cells, and an enzyme is required to phosphorylate the inactive products to generate active products, so that the drug resistance is easy to generate under the condition that related proteins are deleted or the expression is reduced.
The gemcitabine/decitabine is transformed into a prodrug, so that the plasma stability of the prodrug is improved, the membrane permeability of a transporter is not depended on, and great help is brought to the improvement of curative effect, the reduction of side effect and the improvement of drug resistance. When the prodrug is further encapsulated in the liposome, the liposome can not only reduce the exposure of the drug in blood and reduce the side effect, but also better enrich the drug in local tumor to increase the curative effect, and also can play the advantage of effectively overcoming drug resistance of the prodrug, thereby having huge application prospect.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as follows:
wherein:
L 1 is an amino acid residue or a thioamino acid residue, wherein the N-terminus of the amino acid or thioamino acid is attached to a phosphorus atom;
L 2 selected from the group consisting of a bond, - (CH) 2 ) n1 -、-(CH 2 ) n1 (CR aa R bb ) n2 -、-(CR aa R bb ) n1 O(CH 2 ) n2 -、-(CH 2 ) n1 O(CR aa R bb ) n2 -、-(CR aa R bb ) n1 S(CH 2 ) n2 -、-(CH 2 ) n1 S(CR aa R bb ) n2 -、-(CR aa R bb ) n1 (CH 2 ) n2 NR cc -、-(CH 2 ) n1 NR aa (CR bb R cc ) n2 -、-(CH 2 ) n1 C(O)(CR aa R bb ) n2 -、-(CH 2 ) n1 NR aa C(O)(CR aa R bb ) n2 -、-(CH 2 ) n1 P(O)R aa -、-(CH 2 ) n1 S(O) m1 -、-(CH 2 ) n1 S(O) m1 NR aa -、-(CH 2 ) n1 NR aa S(O) m1 -or- (CH) 2 ) n1 C(O)NR aa -；
R aa 、R bb And R cc Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
or, R aa 、R bb And R cc Any two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, may be further substituted;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R a each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
or, any two R a (ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted;
R 1 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n3 (CR dd R ee ) n4 R ff 、-(CH 2 ) n3 O(CR dd R ee ) n4 R ff 、-(CH 2 ) n3 S(CR dd R ee ) n4 R ff Or- (CH) 2 ) n3 NR dd (CR ee R ff ) n4 -said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R dd 、R ee and R ff Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, R dd 、R ee And R ff Any two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, may be further substituted;
R 2 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R 3 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, halogenated alkyl, hydroxyalkylAlkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
R 6 and R 7 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
R 8 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
x is an integer of 0 to 12;
n1 to n4 are integers of 0 to 5; and is
m is 0, 1 or 2.
In a further preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (Ia) or the general formula (Ib):
in a further preferred embodiment of the present invention, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (II):
wherein:
M 1 is O or S;
m is CR or N; preferably CH or N;
r is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or5-14 membered heteroaryl, substituted with one or more substituents;
R 6 and R 7 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
R 8 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogenDeuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
R 9 and R 10 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl.
In a preferred embodiment of the present invention, R is 8 Is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
in a further preferred embodiment of the invention, R is 8 Is selected from
In a further preferred embodiment of the invention, R is 8 Is selected from
Wherein R is b Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen, C 1-8 Alkyl or C 3-8 A cycloalkyl group;
or, any two R b Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyanoRadical, nitro radical, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably, any two R b Linked to form a cyclopentyl or cyclohexyl group; and is provided with
y is an integer of 0 to 5; preferably 0, 1 or 2.
In a preferred embodiment of the present invention, R is 9 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R is 9 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl radical, C 2-3 Alkenyl radical, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
in a further preferred embodiment of the invention, R is 9 Selected from hydrogen, methyl or ethyl.
In a preferred embodiment of the invention, R 10 Is selected from C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
in a further preferred embodiment of the invention, R is 10 Is selected from C 1-6 An alkyl group,
Or
In a further preferred embodiment of the invention, R is 10 Is selected from-CH 3 、-CH 2 CH 3 、
Wherein R is c Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen or C 1-8 An alkyl group;
more preferably hydrogen, methyl, n-heptyl or 4-heptyl; and is provided with
z is an integer of 0 to 5; preferably 0, 1 or 2.
In a further preferred embodiment of the present invention, the compound represented by the general formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by the general formula (V):
wherein:
R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen, C 1-8 Alkyl or C 3-8 A cycloalkyl group;
or, any two R b Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably, any two R b Linked to form a cyclopentyl or cyclohexyl group;
R c each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen or C 1-8 An alkyl group;
more preferably hydrogen, methyl, n-heptyl or 4-heptyl;
y is an integer of 0 to 5; preferably 0, 1 or 2; and is
z is an integer of 0 to 5; preferably 0, 1 or 2.
The invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.
In another aspect, the present invention also provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a use of the pharmaceutical composition in treating and/or preventing cancer or a related disease caused by a viral infection.
In a more preferred embodiment, the cancer-related disease is selected from lung cancer, stomach cancer, colon cancer, liver cancer, ovarian cancer, breast cancer, pancreatic cancer, kidney cancer, uterine cancer, leukemia, esophageal cancer, cervical cancer, prostate cancer, rectal cancer, gastromesenchyme tumor, cholangiocarcinoma, glioma, meningioma, pituitary adenoma, schwannoma, congenital tumor, lipoma, lymphoma, melanoma, intracranial metastases; the related diseases caused by virus infection are selected from AIDS, hepatitis B or hepatitis C.
Detailed description of the invention
Unless stated to the contrary, the 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 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, most preferably an alkyl group containing 1 to 3 carbon atoms. <xnotran> , , , , , , , , ,1,1- ,1,2- ,2,2- ,1- ,2- ,3- , ,1- -2- ,1,1,2- ,1,1- ,1,2- ,2,2- ,1,3- ,2- ,2- ,3- ,4- ,2,3- , ,4- ,1- ,2- ,3- ,4- ,5- ,2,3- ,2,4- ,2,2- ,3,3- ,2- ,3- , ,2,3- ,2,4- ,2,5- ,2,2- ,3,3- ,4,4- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- ,2,2- , ,3,3- , </xnotran> 2, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and 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, n-heptyl, 4-heptyl, 1-propylbutyl, 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 "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 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 "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 monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogenOxygen or S (O) m (wherein m is an integer of 0 to 2) but does not include a cyclic 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 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-to 8-membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.
Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1, 4-diazepanyl, pyranyl, or tetrahydrothiopyranyl dioxide, and the like, preferably oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, pyrrolidinyl, morpholinyl, piperidinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azeptyl, 1, 4-diazepanyl, and piperazinyl; polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The 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 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.
Wherein the ring to which the parent structure is attached 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 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazolyl; more preferred are pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring.
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 as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, alkoxy may be optionally 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, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"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 hydroxyl group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the 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 ≡ C-) wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl 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.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" refers to-NH 2 。
"cyano" means-CN.
"nitro" means-NO 2 。
"carbonyl" means-C (O) -.
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"Ethyl acetate" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"TEA" refers to triethylamine.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "means diethyl ether.
"DCM" refers to dichloromethane.
"DMAP" refers to 4-dimethylaminopyridine.
"DCC" refers to dicyclohexylcarbodiimide.
"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.
“Pd 2 (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 bis (trimethylsilyl) amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "refers to sodium triacetoxyborohydride.
"amino acid residue" refers to a natural amino acid residue or a non-natural amino acid residue.
"Natural amino acids" refers to the 20 conventional amino acids, i.e., alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F), glycine (G), histidine (H), isoleucine (I), lysine (K), leucine (L), methionine (M), asparagine (N), proline (P), glutamine (Q), arginine (R), serine (S), threonine (T), valine (V), tryptophan (W), and tyrosine (Y).
"unnatural amino acid" refers to an amino acid that is not naturally encoded or found in the genetic code of any organism, and can be, for example, a purely synthetic compound.
"thioamino acid" refers to an amino acid in which the oxygen atom of the amino acid is replaced with a sulfur atom, which may be the oxygen atom in a carbonyl group (C = O) or a hydroxyl group (OH).
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 and 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 group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a 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, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
"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 (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was measured using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C) 18 150X 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
Preparation of 4-heptylbenzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
First step preparation of 4-heptylphenylmethyl (tert-butoxycarbonyl) -L-alanine acid ester
(4-heptylphenyl) methanol (3.1g, 15.0mmol) and (tert-butoxycarbonyl) -L-alanine (2.84g, 15.0mmol) were dissolved in DCM (40 mL), and DCC (3.71g, 18.0mmol) and DMAP (183.2mg, 1.5mmol) were added, and reacted at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and subjected to column chromatography to give the title compound, 4-heptylphenylmethyl (tert-butoxycarbonyl) -L-alanine acid ester (5.38g, 95%).
MS m/z(ESI):378.2[M+H] + .
Second step preparation of 4-heptylphenylmethyl L-alanine acid ester
4-Heptylbenzyl (tert-butoxycarbonyl) -L-alanine acid ester (5.29g, 14.0 mmol) was dissolved in DCM (15.0 mL), and TFA (15.0 mL) was slowly added dropwise at RT and stirred for 1.5h. The reaction mixture was concentrated to give the title compound 4-heptylphenylmethyl L-alanine acid ester (3.69g, 95%).
MS m/z(ESI):278.2[M+H] + .
Third step preparation of 4-heptylphenylmethyl ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine acid ester
4-heptylphenylmethyl L-alanine ester (3.05g, 11.0 mmol) was dissolved in DCM (30 mL), cooled to-78 deg.C, and cooled under N 2 TEA (3.05mL, 22.0 mmol) was added under protection, then a solution of phenyl phosphorodichlorate (2.32g, 11.0 mmol) in DCM (5 mL) was slowly added dropwise, stirred for 30 min and then slowly raised to 0 ℃ and stirring continued at that temperature for 1 h.
Perfluorophenol (2.02g, 11.0 mmol) was dissolved in DCM (10 mL), TEA (2.29mL, 16.5 mmol) was slowly added dropwise at 0 ℃ and stirred for 5 minutes, after which the solution was slowly added dropwise to the above reaction system, kept at 0 ℃ and stirred for 2 hours. The reaction was quenched by addition of water (3 mL) and DCMSeparating with water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude product (5.94g, 90%, epimer ratio is S) P /R P ＝1:1)。
Mixing the crude product (epimer ratio is S) P /R P = 1) slurried with 50mL of PE/EtOAc (3.
MS m/z(ESI):600.2[M+H] + .
Fourth step preparation of 4-heptylphenylmethyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphino) -L-alaninate
4-amino-1- ((2R, 4R, 5R) -3, 3-difluoro-4-hydroxy-5- (hydroxymethyl) tetrahydrofuran-2-yl) pyrimidin-2 (1H) -one (419.0mg, 1.4mmol) was dissolved in pyridine (15 mL), cooled to 0 ℃ under N 2 Slowly dropwise adding under protection t BuMgCl (1M in THF,4.34mL, 4.34mmol), after the addition was complete, was stirred at this temperature for 30 minutes, then warmed to room temperature and stirred for 30 minutes. The reaction was placed in an ice-water bath, and a solution of ((S) - (perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine ester (1.0 g, 1.68mmol) in THF (3.6 mL) was slowly added dropwise, maintaining the temperature and stirring continuously overnight. With saturated NH 4 The reaction was quenched with aqueous Cl (3 mL), the reaction mixture was concentrated under reduced pressure, separated with DCM from water, and the organic phase was concentrated and subjected to column chromatography to give the title compound, 4-heptylphenylmethyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphino) -L-alaninate (474mg, 50%).
1 H NMR(400MHz,CD 3 OD)δ0.84-0.93(m,3H),1.24-1.39(m,11H),1.54-4.63(m,2H),2.54-2.62(m,2H),3.96-4.06(m,2H),4.15-4.25(m,1H),4.25-4.35(m,1H),4.36-4.45(m,1H),5.07(d,J＝12.0Hz,1H),5.11(d,J＝12.0Hz,1H),5.79-5.86(m,1H),6.19-6.27(m,1H),7.11-7.27(m,7H),7.30-7.38(m,2H),7.46-7.52(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.65；
MS m/z(ESI):679.2[M+H] + .
Example 2
Preparation of S-benzyl (S) -2- (((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-ido) amino) propanesulfate
Preparation of S-benzyl (S) -2- (((S) - (((2r, 3r, 5r) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-ido) amino) propanethioate reference is made to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.16-1.30(m,3H),3.91-4.01(m,5H),4.05-4.13(m,1H),4.23-4.29(m,1H),5.72-5.79(m,1H),6.09-6.17(m,1H),7.09-7.18(m,8H),7.21-7.28(m,2H),7.37-7.49(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.47；
MS m/z(ESI):597.2[M+H] + .
Example 3
Preparation of S-isopropyl (S) -2- (((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-ido) amino) propanesulfate
Preparation of S-isopropyl (S) -2- (((S) - (((2r, 3r, 5r) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-ido) amino) propanethioate reference is made to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.13-1.25(m,9H),3.37-3.47(m,1H),3.83-3.90(m,1H),3.96-4.33(m,4H),5.75-5.84(m,1H),6.11-6.18(m,1H),7.08-7.20(m,3H),7.23-7.32(m,2H),7.39-7.53(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.50；
MS m/z(ESI):549.2[M+H] + .
Example 4
Preparation of 2-methylbenzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of 2-methylbenzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.33-1.39(m,3H),2.32(s,3H),3.95-4.05(m,2H),4.15-4.23(m,1H),4.26-4.33(m,1H),4.38-4.45(m,1H),5.14(d,J＝12.0Hz,1H),5.18(d,J＝12.0Hz,1H),5.80-5.85(m,1H),6.18-6.26(m,1H),7.11-7.24(m,6H),7.27-7.38(m,3H),7.48-7.52(m,1H)；
31 P NMR(162MHz,CD 3 OD)δ3.64；
MS m/z(ESI):595.2[M+H] + .
Example 5
Preparation of 3-methylbenzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of 3-methylbenzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
MS m/z(ESI):595.2[M+H] + .
Example 6
Preparation of 4-methylbenzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of 4-methylbenzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
MS m/z(ESI):595.2[M+H] + .
Example 7
Preparation of 2-ethylbutyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of 2-ethylbutyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
1 H NMR(400MHz,CD 3 OD)δ0.84-0.94(m,6H),1.30-1.42(m,7H),1.45-1.56(m,1H),3.92-4.10(m,4H),4.15-4.26(m,1H),4.32-4.39(m,1H),4.42-4.49(m,1H),5.82-5.88(m,1H),6.21-6.28(m,1H),7.18-7.29(m,3H),7.34-7.42(m,2H),7.48-7.54(m,1H)；
31 P NMR(162MHz,CD 3 OD)δ3.69；
MS m/z(ESI):575.2[M+H] + .
Example 8
Preparation of bicyclo [1.1.1] pentan-1-ylmethyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) -L-alaninate
Preparation of bicyclo [1.1.1] pentan-1-ylmethyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) -L-alaninate is carried out according to example 1.
MS m/z(ESI):571.2[M+H] + .
Example 9
4- (Heptane-4-yl) benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro)
Preparation of (E) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of 4- (Heptane-4-yl) benzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) -L-alaninate is carried out according to example 1.
MS m/z(ESI):679.2[M+H] + .
Example 10
Preparation of isopropyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester
Preparation of isopropyl ((S) - ((((2r, 3r, 5r) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester reference was made to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.16-1.24(m,6H),1.34(d,J＝7.2Hz,3H),2.32(s,3H),3.82-3.94(m,1H),4.01-4.09(m,1H),4.15-4.27(m,1H),4.29-4.40(m,1H),4.41-4.49(m,1H),4.92-5.02(m,1H),5.78-5.88(m,1H),6.18-6.30(m,1H),7.06-7.20(m,4H),7.49-7.56(m,1H)；
31 P NMR(162MHz,CD 3 OD)δ3.91；
MS m/z(ESI):547.2[M+H] + .
Example 11
Preparation of benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester
Preparation of benzyl ((S) - ((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester reference was made to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.34-1.38(m,3H),2.30(s,3H),3.96-4.05(m,2H),4.14-4.24(m,1H),4.25-4.33(m,1H),4.37-4.45(m,1H),5.10(d,J＝12.0Hz,1H),5.15(d,J＝12.0Hz,1H),5.79-5.83(m,1H),6.18-6.26(m,1H),7.07-7.16(m,4H),7.29-7.37(m,5H),7.48-7.52(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.78；
MS m/z(ESI):595.2[M+H] + .
Example 12
Preparation of benzyl ((S) - ((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (4-cyclopropylphenoxy) phosphoryl) -L-alanine acid ester
Preparation of benzyl ((S) - ((((2r, 3r, 5r) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (4-cyclopropylphenoxy) phosphinyl) -L-alaninate is carried out by reference to example 1.
1 H NMR(400MHz,CD 3 OD)δ0.58-0.64(m,2H),0.90-0.96(m,2H),1.35(d,J＝7.1Hz,3H),1.83-1.91(m,1H),4.96-4.06(m,2H),4.12-4.21(m,1H),4.29-4.36(m,1H),4.40-4.47(m,1H),5.09(d,J＝12.0Hz,1H),5.14(d,J＝12.0Hz,1H),5.84-5.88(m,1H),6.20-6.26(m,1H),7.00-7.10(m,4H),7.27-7.41(m,5H),7.49-7.54(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.81；
MS m/z(ESI):621.2[M+H] + .
Example 13
Preparation of benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (2, 3-dihydro-1H-inden-5-yl) oxo) phosphanyl) -L-alaninate
Preparation of benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (2, 3-dihydro-1H-inden-5-yl) oxo) phosphanyl) -L-alaninate was carried out according to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.37(d,J＝7.0Hz,3H),2.02-2.10(m,2H),2.84(t,J＝7.4Hz,4H),3.96-4.01(m,2H),4.13-4.35(m,2H),4.37-4.41(m,1H),5.10(d,J＝12.0Hz,1H),5.15(d,J＝12.0Hz,1H),5.80(d,J＝7.6Hz,1H),6.20-6.22(m,1H),6.94-6.97(m,1H),7.06(s,1H),7.13-7.15(m,1H),7.28-7.36(m,5H),7.49(d,J＝7.6Hz,1H)；
31 P NMR(162MHz,CD 3 OD)δ3.82；
MS m/z(ESI):621.2[M+H] + .
Example 14
Preparation of benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (5, 6,7, 8-tetrahydronaphthalen-2-yl) oxo) phosphanyl) -L-alaninate
Preparation of benzyl ((S) - ((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (5, 6,7, 8-tetrahydronaphthalen-2-yl) oxo) phosph-yl) -L-alaninate was carried out according to example 1.
1 H NMR(400MHz,CD 3 OD)δ1.33-1.39(m,3H),1.70-1.79(m,4H),2.64-2.73(m,4H),3.96-4.06(m,2H),4.11-4.46(m,3H),5.10(d,J＝12.0Hz,1H),5.15(d,J＝12.0Hz,1H),5.77-5.86(m,1H),6.18-6.27(m,1H),6.86-6.94(m,2H),6.96-7.02(m,1H),7.26-7.38(m,5H),7.46-7.54(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.78；
MS m/z(ESI):635.2[M+H] + .
Example 15
Preparation of benzyl ((S) - ((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (4-heptylphenoxy) phosphoryl) -L-alanine ester
Preparation of benzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (4-heptylphenoxy) phosphinyl) -L-alanine acid ester reference was made to example 1.
1 H NMR(400MHz,CD 3 OD)δ0.88(t,J＝6.7Hz,3H),1.20-1.40(m,11H),1.51-1.60(m,2H),2.54-2.61(m,2H),3.96-4.06(m,2H),4.14-4.45(m,3H),5.11(d,J＝12.0Hz,1H),5.16(d,J＝12.0Hz,1H),5.80-5.88(m,1H),6.18-6.27(m,1H),7.07-7.16(m,4H),7.27-7.37(m,5H),7.49-7.54(m,1H)；
31 P NMR(162MHz,CDCl 3 )δ3.80；
MS m/z(ESI):679.2[M+H] + .
Example 16
Preparation of benzyl ((S) - (((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (bicyclo [1.1.1] pentan-1-oxy) phosphino) -L-alaninate
Preparation of benzyl ((S) - ((((2R, 3R, 5R) -5- (4-amino-2-carbonylpyrimidin-1 (2H) -yl) -4, 4-difluoro-3-hydroxytetrahydrofuran-2-yl) methoxy) (bicyclo [1.1.1] pentan-1-oxy) phosphino) -L-alaninate is carried out by reference to example 1.
MS m/z(ESI):571.2[M+H] + .
Example 17
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
MS m/z(ESI):546.2[M+H] + .
Example 18
Preparation of 4-heptylbenzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphonium) -L-alanine acid ester
Preparation of 4-heptylphenylmethyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) -L-alanine acid ester method reference was made to example 1.
MS m/z(ESI):644.2[M+H] + .
Example 19
Preparation of S-benzyl (S) -2- (((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-ido) amino) propanethioate
Preparation of S-benzyl (S) -2- (((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) amino) propanethioate reference is made to example 1.
MS m/z(ESI):562.2[M+H] + .
Example 20
Preparation of S-isopropyl (S) -2- (((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-phoryl) amino) propanethioate
Preparation of S-isopropyl (S) -2- (((S) - (((2r, 3s, 5r) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) amino) propanethioate reference was made to example 1.
MS m/z(ESI):514.2[M+H] + .
Example 21
Preparation of 2-methylbenzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester
Preparation of 2-methylbenzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphonium) -L-alanine acid ester reference was made to example 1.
MS m/z(ESI):560.2[M+H] + .
Example 22
Preparation of 4-methylbenzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester
Preparation of 4-methylbenzyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester method reference was made to example 1.
MS m/z(ESI):560.2[M+H] + .
Example 23
Preparation of 2-ethylbutyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) -L-alanine ester
Preparation of 2-ethylbutyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester method reference was made to example 1.
MS m/z(ESI):540.2[M+H] + .
Example 24
Bicyclo [1.1.1] pentan-1-ylmethyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazine-1 (2H) -
Preparation of yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester
Preparation of bicyclo [1.1.1] pentan-1-ylmethyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alaninate the procedure is as in example 1.
MS m/z(ESI):536.2[M+H] + .
Example 25
Preparation of 4- (Heptan-4-yl) benzyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-phoryl) -L-alanine acid ester
Preparation of 4- (Heptane-4-yl) benzyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosph-yl) -L-alaninate proceeds with reference to example 1.
MS m/z(ESI):644.2[M+H] + .
Example 26
Preparation of isopropyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester
Preparation of isopropyl ((S) - (((2r, 3s, 5r) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester reference is made to example 1.
MS m/z(ESI):512.2[M+H] + .
Example 27
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosph-yl) -L-alanine acid ester
Preparation of benzyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (p-tolyloxy) phosphoryl) -L-alanine acid ester reference was made to example 1.
MS m/z(ESI):560.2[M+H] + .
Example 28
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (4-cyclopropylphenoxy) phosphinyl) -L-alanine acid ester
Preparation of benzyl ((S) - (((2r, 3s, 5r) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (4-cyclopropylphenoxy) phosphinyl) -L-alanine acid ester method reference was made to example 1.
MS m/z(ESI):586.2[M+H] + .
Example 29
3-Methylbenzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrakis
Preparation of Hydrofuran-2-yl) methoxy) (phenoxy) phospho) -L-alanine acid ester
Preparation of 3-methylbenzyl ((S) - ((((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphanyl) -L-alanine acid ester method reference was made to example 1.
MS m/z(ESI):560.2[M+H] + .
Example 30
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (2, 3-dihydro-1H-inden-5-yl) oxo) phosphanyl) -L-alanine ester
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (2, 3-dihydro-1H-inden-5-yl) oxo) phosphanyl) -L-alaninate was carried out according to example 1.
MS m/z(ESI):586.2[M+H] + .
Example 31
Preparation of benzyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (5, 6,7, 8-tetrahydronaphthalen-2-yl) oxo) phosph-enyl) -L-alanine ester
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (5, 6,7, 8-tetrahydronaphthalen-2-yl) oxo) phosphanyl) -L-alaninate the procedure was referred to example 1.
MS m/z(ESI):600.2[M+H] + .
Example 32
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (4-heptylphenoxy) phosphorus) -L-alanine acid ester
Preparation of benzyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (4-heptylphenoxy) phosphonium group) -L-alanine acid ester reference was made to example 1.
MS m/z(ESI):644.2[M+H] + .
Example 33
Preparation of benzyl ((S) - ((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (bicyclo [1.1.1] pentan-1-oxy) phosphino) -L-alanine ester
Preparation of benzyl ((S) - (((2R, 3S, 5R) -5- (4-amino-2-carbonyl-1, 3, 5-triazin-1 (2H) -yl) -3-hydroxytetrahydrofuran-2-yl) methoxy) (bicyclo [1.1.1] pentan-1-oxy) phosphino) -L-alaninate ester reference is made to example 1.
MS m/z(ESI):661.2[M+H] + .
Preparation of Compounds of the following examples reference is made to example 1
Biological test evaluation
The present invention is further described and explained below in connection with test examples, which are not intended to limit the scope of the present invention.
Test example 1 Miapaca-2 and Bxpc-3 cell proliferation inhibition experiments
1. The purpose of the experiment is as follows:
the compounds were tested for their inhibitory activity on the proliferation of Miapaca-2 cells and Bxpc-3 cells.
2. An experimental instrument:
2.1 Instrument:
pipettes were purchased from Eppendorf corp;
CO 2 incubators were purchased from Thermo, usa;
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
2.2 reagent:
cell Titer Glo, available from Promega under the cat number G7573.
3. The experimental method comprises the following steps:
the experiment adopts CTG (CELL TITER-GLO) luminescence method to detect the proliferation inhibition activity of the compound to Miapaca-2 CELLs and Bxpc-3 CELLs and obtains the half inhibition concentration IC of the compound to the CELL proliferation inhibition activity 50 。
The specific experimental operation is as follows:
on the first day, 90. Mu.L of cell suspension was plated in a 96-well assay plate, the number of cells per well was 3000, the plate was put in a 5% CO-containing cell 2 Was cultured overnight in a 37 ℃ incubator. The next day, 10 μ L of the compound solution diluted in a gradient (DMSO solvent, 0.1% DMSO final concentration) was added to each well, and the plate was incubated in a carbon dioxide incubator for 72 hours. After culturing for 72h, adding 100 μ L Cell Titer Glo into each well of the Cell plate, shaking for 5min in the dark, and standing for 10min; then detecting the luminescence value in a BioTek Synergy H1 microplate reader, calculating the inhibition rate through the chemiluminescence signal value, and calculating the inhibition rate according to different concentrationsInhibition Rate the IC of a Compound was determined by curve fitting 50 。
4. The experimental data processing method comprises the following steps:
percent inhibition data [% inhibition =100- (test compound value-negative control value)/(positive control value-negative control value) × 100 for wells treated with compound was calculated by positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
5. The experimental results are as follows:
IC of Compounds of the examples of the invention for inhibition of Miapaca-2 and Bxpc-3 cell proliferation 50 As shown in the following table:
6. and (4) experimental conclusion:
the data show that the compounds of the embodiment of the invention show good inhibitory activity in the proliferation inhibition experiment of Miapaca-2 cells and Bxpc-3 cells.
Test example 2
1. Purpose of the experiment:
the compounds were tested for their inhibitory activity on H460 cell proliferation.
2. An experimental instrument:
2.1 Instrument:
pipettors were purchased from Eppendorf corporation;
CO 2 incubators were purchased from Thermo, usa;
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
2.2 reagent:
cell Titer Glo, available from Promega, cat # G7573.
3. The experimental method comprises the following steps:
the experiment adopts CTG (CELL TITER-GLO) luminescence method to detect the proliferation inhibition activity of the compound on H460 CELLs and obtains the compoundHalf inhibitory concentration IC of compound on cell proliferation inhibitory Activity 50 。
The specific experimental operations were as follows:
on the first day, 90. Mu.L of cell suspension was plated in a 96-well assay plate, the number of cells per well was 3000, the plate was put in a 5% CO-containing cell 2 Was cultured overnight in a 37 ℃ incubator. The next day, 10 μ L of the compound solution diluted in a gradient (DMSO solvent, 0.1% DMSO final concentration) was added to each well, and the plate was incubated in a carbon dioxide incubator for 72 hours. After culturing for 72h, adding 100 μ L Cell Titer Glo into each well of the Cell plate, shaking for 5min in the dark, and standing for 10min; then detecting a luminescence value in a BioTek Synergy H1 enzyme-labeling instrument, calculating the inhibition rate through a chemiluminescence signal value, and obtaining the IC of the compound through curve fitting according to the inhibition rates of different concentrations 50 。
4. The experimental data processing method comprises the following steps:
percent inhibition data [% inhibition =100- (test compound value-negative control value)/(positive control value-negative control value) × 100 for wells treated with compound was calculated by positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
5. The experimental results are as follows:
IC of compounds of the examples of the invention for inhibition of H460 cell proliferation 50 As shown in the following table:
| examples | H460 cell proliferation inhibitory IC 50 (nM) |
| 34 | 288 |
| 36 | 278 |
| 39 | 55 |
| 40 | 259 |
| 41 | 51 |
| 42 | 107 |
6. The experimental conclusion is that:
the above data show that the compounds of the examples of the present invention show good inhibitory activity in the proliferation inhibition experiment of H460 cells.
Test example 3 inhibition of cell proliferation by pc3
1. The purpose of the experiment is as follows:
the compounds were tested for their inhibitory activity on the proliferation of PC3 cells.
2. An experimental instrument:
2.1 Instrument:
pipettors were purchased from Eppendorf corporation;
CO 2 incubators were purchased from Thermo corporation, usa;
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
2.2 reagent:
cell Titer Glo, available from Promega under the cat number G7573.
3. The experimental method comprises the following steps:
the experiment adopts CTG (CELL TITER-GLO) luminescence method to detect the proliferation inhibitory activity of the compound to PC3 CELLs and obtains the half inhibitory concentration IC of the compound to the CELL proliferation inhibitory activity 50 。
The specific experimental operations were as follows:
on the first day, 90. Mu.L of cell suspension was plated in a 96-well assay plate, the number of cells per well was 2000, the plate was put in a 5% CO-containing cell 2 Was cultured overnight in a 37 ℃ incubator. The next day, 10 μ L of a gradient diluted compound solution (DMSO as solvent, 0.1% final DMSO) was added to each well and the plate was placed in a carbon dioxide incubator and incubated for 72 hours. After culturing for 72h, adding 100 μ L Cell Titer Glo into each well of the Cell plate, shaking for 5min in the dark, and standing for 10min; then detecting a luminescence value in a BioTek Synergy H1 enzyme-labeling instrument, calculating an inhibition rate through a chemiluminescence signal value, and obtaining the IC of the compound through curve fitting according to the inhibition rates of different concentrations 50 。
4. The experimental data processing method comprises the following steps:
percent inhibition data [% inhibition =100- (test compound value-negative control value)/(positive control value-negative control value) × 100 for wells treated with compound was calculated by positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]. IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
5. The experimental results are as follows:
IC of compounds of the examples of the invention for inhibition of PC3 cell proliferation 50 As shown in the following table:
| examples | PC3 cell proliferation inhibition IC 50 (nM) |
| 34 | 217 |
| 35 | 357 |
| 36 | 171 |
| 38 | 335 |
| 39 | 185 |
6. The experimental conclusion is that:
the above data show that the compounds of the examples of the present invention show good inhibitory activity in the proliferation inhibition experiment of PC3 cells.
Test example 4
1. Purpose of the experiment:
the compounds were tested for their inhibitory activity on the proliferation of H1975 cells.
2. An experimental instrument:
2.1 Instrument:
pipettes were purchased from Eppendorf corp;
CO 2 incubators were purchased from Thermo, usa;
the microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
2.2 reagent:
cell Titer Glo, available from Promega, cat # G7573.
3. The experimental method comprises the following steps:
the experiment adopts CTG (CELL TITER-GLO) luminescence method to detect the proliferation inhibitory activity of the compound to H1975 CELLs and obtains the half inhibitory concentration IC of the compound to the CELL proliferation inhibitory activity 50 。
The specific experimental operation is as follows:
on the first day, 90. Mu.L of cell suspension was plated in a 96-well assay plate, the number of cells per well was 3000, the plate was put in a 5% CO-containing cell 2 Was cultured overnight in a 37 ℃ incubator. The next day, 10. Mu.L of the compound solution diluted in a gradient was added to each well(DMSO as solvent, final DMSO concentration of 0.1%), the plate was placed in a carbon dioxide incubator and incubated for 72 hours. After culturing for 72h, adding 100 μ L Cell Titer Glo into each well of the Cell plate, shaking for 5min in the dark, and standing for 10min; then detecting a luminescence value in a BioTek Synergy H1 enzyme-labeling instrument, calculating an inhibition rate through a chemiluminescence signal value, and obtaining the IC of the compound through curve fitting according to the inhibition rates of different concentrations 50 。
4. The experimental data processing method comprises the following steps:
percent inhibition data [% inhibition =100- (test compound value-negative control value)/(positive control value-negative control value) × 100 for wells treated with compound was calculated by positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]. IC was calculated using GraphPad prism to fit the different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50 The value is obtained.
5. The experimental results are as follows:
IC of compounds of the present examples on inhibition of H1975 cell proliferation 50 As shown in the following table:
| examples | H1975 IC for inhibition of cell proliferation 50 (nM) |
| 34 | 1252 |
| 35 | 1111 |
| 36 | 773 |
| 37 | 1148 |
| 38 | 915 |
6. The experimental conclusion is that:
the above data show that the compounds of the examples of the present invention show good inhibitory activity in the proliferation inhibition experiment of H1975 cells.
Claims (10)
1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
L 1 is an amino acid residue or a thioamino acid residue, wherein the N-terminus of the amino acid or thioamino acid is attached to the phosphorus atom;
L 2 selected from the group consisting of a bond, - (CH) 2 ) n1 -、-(CH 2 ) n1 (CR aa R bb ) n2 -、-(CR aa R bb ) n1 O(CH 2 ) n2 -、-(CH 2 ) n1 O(CR aa R bb ) n2 -、-(CR aa R bb ) n1 S(CH 2 ) n2 -、-(CH 2 ) n1 S(CR aa R bb ) n2 -、-(CR aa R bb ) n1 (CH 2 ) n2 NR cc -、-(CH 2 ) n1 NR aa (CR bb R cc ) n2 -、-(CH 2 ) n1 C(O)(CR aa R bb ) n2 -、-(CH 2 ) n1 NR aa C(O)(CR aa R bb ) n2 -、-(CH 2 ) n1 P(O)R aa -、-(CH 2 ) n1 S(O) m1 -、-(CH 2 ) n1 S(O) m1 NR aa -、-(CH 2 ) n1 NR aa S(O) m1 -or- (CH) 2 ) n1 C(O)NR aa -；
R aa 、R bb And R cc Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, R aa 、R bb And R cc Any two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, may be further substituted;
ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R a each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
or, any two R a (ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
R 1 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heteroCycloylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n3 (CR dd R ee ) n4 R ff 、-(CH 2 ) n3 O(CR dd R ee ) n4 R ff 、-(CH 2 ) n3 S(CR dd R ee ) n4 R ff Or- (CH) 2 ) n3 NR dd (CR ee R ff ) n4 -said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R dd 、R ee and R ff Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
or, R dd 、R ee And R ff Any two of which may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally, may be further substituted;
R 2 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R 3 selected from hydrogen, deuterium, halogen, aminoNitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R 4 and R 5 Each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
R 6 and R 7 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
R 8 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally being further substituted;
x is an integer of 0 to 12;
n1 to n4 are integers of 0 to 5; and is
m is 0, 1 or 2.
2. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (Ia) or formula (Ib):
3. the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (II):
wherein:
M 1 is O or S;
m is CR or N; preferably CH or N;
r is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro and C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
R 6 and R 7 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
R 8 selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
R 9 and R 10 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl.
4. The compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3,
R 8 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
preference is given to
More preferably
Wherein R is b Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen, C 1-8 Alkyl or C 3-8 A cycloalkyl group;
or, any two R b Link formation C 3-12 A cycloalkyl group, a,3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably, any two R b Linked to form a cyclopentyl or cyclohexyl group; and is
y is an integer of 0 to 5; preferably 0, 1 or 2.
5. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2 or 3, wherein R is 9 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substitutedC of (A) 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl radical, C 2-3 Alkenyl radical, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy radical, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano-substituted C 1-3 Alkyl radical, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
more preferably hydrogen, methyl or ethyl; r 10 Is selected from C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl;
preferably C 1-6 Alkyl, aryl, heteroaryl, and heteroaryl,
More preferably-CH 3 、-CH 2 CH 3 、
Wherein R is c Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-to 14-membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen or C 1-8 An alkyl group;
more preferably hydrogen, methyl, n-heptyl or 4-heptyl; and is
z is an integer of 0 to 5; preferably 0, 1 or 2.
6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein formula (II) is further represented by formula (V):
wherein:
R b each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen, C 1-8 Alkyl or C 3-8 A cycloalkyl group;
or, any two R b Link formation C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, haloElement, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably, any two R b Linked to form a cyclopentyl or cyclohexyl group;
R c each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said amino, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, cyano-substituted C 1-6 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-12 Alkyl radical, C 2-12 Alkenyl radical, C 2-12 Alkynyl, C 1-12 Deuterated alkyl, C 1-12 Haloalkyl, C 1-12 Alkoxy radical, C 1-12 Haloalkoxy, C 1-12 Hydroxyalkyl, cyano-substituted C 1-12 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
preferably hydrogen or C 1-8 An alkyl group;
more preferably hydrogen, methyl, n-heptyl or 4-heptyl;
y is an integer of 0 to 5; preferably 0, 1 or 2; and is provided with
z is an integer of 0 to 5; preferably 0, 1 or 2.
7. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
9. Use of a compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the treatment and/or prevention of cancer or a disease associated with a viral infection.
10. The use according to claim 9, wherein the cancer-related disease is selected from lung cancer, stomach cancer, colon cancer, liver cancer, ovarian cancer, breast cancer, pancreatic cancer, kidney cancer, uterine cancer, leukemia, esophageal cancer, cervical cancer, prostate cancer, rectal cancer, gastromesenchyme tumor, cholangiocarcinoma, glioma, meningioma, pituitary adenoma, schwannoma, congenital tumor, lipoma, lymphoma, melanoma, intracranial metastasis; the related diseases caused by virus infection are selected from AIDS, hepatitis B or hepatitis C.
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