CN117430651A - Nucleoside monophosphate compound and preparation method thereof - Google Patents
Nucleoside monophosphate compound and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of biological medicines, and discloses a nucleoside monophosphate compound and a preparation method thereof. The compound has a structure shown in a formula (I). The method for preparing the nucleoside compound comprises the following steps: and (3) carrying out a contact reaction I on the compound shown in the formula (I-2) and the compound shown in the formula (I-1). The nucleoside compound provided by the invention has excellent inhibitory activity on CD73, and meanwhile, the in-vivo experiment shows that the compound surface has good anti-tumor activity.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a nucleoside monophosphate compound and a preparation method thereof.
Background
CD73 is also called extracellular-5 '-Nucleotidase (Ecto-5' -Nucleotidase), which is a cell surface enzyme and is widely expressed on the surfaces of endothelial cells and lymphocytes of human bodies, such as Treg and the like. CD73 is overexpressed in tumor microenvironments, helping to convert immune-activating Adenosine Triphosphate (ATP) to adenosine, promoting tumor growth. Some tumors have up-regulation and over-expression of CD73 and, therefore, have been proposed as drug targets for cancer treatment.
In the tumor microenvironment, up-regulation of CD73 expression causes an increase in adenosine, which can promote tumor growth and disease progression, resulting in inhibition of cytotoxicity of T lymphocytes and natural killer cells, and inhibition of Antigen Presenting Cells (APC) due to inhibition of cytokine production and proliferation; it also promotes proliferation of Treg cells and suppresses immune activity, stimulating polarization of myeloid-derived suppressor cells (MDSCs) and M2-type macrophages.
CD73 is induced by transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), hepatocyte Growth Factor (HGF), interleukin-6 (IL-6), mitogen Activated Protein Kinase (MAPK), signal transduction and transcription activator 3 (STAT 3), interleukin-2 (IL-2), retinoic acid, int/Wingless (WNT), epithelial-mesenchymal transition and p53 mutations. CD73 is overexpressed in a variety of tumor types and promotes invasion, metastasis and adhesion of tumor cells. CD73 is also associated with immune tolerance and poor prognosis in cancer. CD73 is therefore a promising target in the development of anticancer drugs. Furthermore, CD73 inhibitors have potential in the treatment of other diseases mediated by adenosine and its receptors.
In preclinical in vivo studies, blocking the activity of extracellular nucleases or adenosine receptor signaling has been successful in inhibiting tumor growth and metastasis. The use of adenosine pathway blockade alone or in combination with other immunotherapies, including checkpoint inhibitors, is now in the stage of an initial phase I clinical trial in patients with advanced malignancy.
WO2017/120508 and US2017/0267710 disclose compounds that modulate AMP conversion to adenosine by extracellular-5 '-nucleotidase, compositions containing the compounds, methods of synthesizing the compounds, and the use of these compounds and compositions for the treatment and/or prevention of a variety of diseases mediated by extracellular-5' -nucleotidase; WO2015/164573 discloses purine derivatives and pharmaceutical compositions thereof which are inhibitors of CD73 and which are useful in the treatment of cancer; WO2018/049145 discloses the preparation of nucleotides as extracellular nucleotidase inhibitors and the use of these compounds in the treatment or prevention of cancer.
However, the aforementioned compounds have a disadvantage of poor inhibitory activity against CD73, and thus cannot exhibit good antitumor activity.
Disclosure of Invention
The purpose of the present invention is to overcome the defect that the compounds of the prior art have poor inhibitory activity on CD 73.
In order to achieve the above object, the first aspect of the present invention provides a nucleoside compound having a structure represented by formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite thereof,
in the case of the formula (I),
R 1 and R is 2 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, cyano, amino, azido; r is R 1 And R is 2 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 3 and R is 4 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, cyano, amino, azido; r is R 3 And R is 4 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 5 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, substituted or unsubstituted C 1-10 Alkoxy, hydroxy, cyano, amino, nitro and azido groups; r is R 5 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 6 and R is 7 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C of (2) 2-6 Alkenyl, C 2-6 Alkynyl, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Or by R 6 、R 7 And C formed by ring closure of carbon atoms to which they are attached 3-8 Cycloalkyl of (C), R 6 、R 7 And the three-to six-membered heterocyclic groups formed by cyclization of the carbon atoms connected with the three-to six-membered heterocyclic groups;
w is selected from-O-, -S-;
l is selected from substituted or unsubstituted alkylene groups, and the substituents on L are each independently selected from C 1-10 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 1-10 Alkoxy, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a);
n is 0 or 1;
G 1 、G 2 、G 3 each independently selected from N, -C (R) 12 )-，R 12 Selected from hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, C of (2) 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 1-8 Alkoxy, hydroxy, cyano, amino, nitro and five to eight membered heterocyclyl;
R 8 selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Alkoxy and five to eight membered heterocyclyl; r is R 11 Each of the substituents optionally presentIndependently selected from halogen, hydroxy;
R 9 selected from hydrogen, substituted or unsubstituted C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, substituted or unsubstituted five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a); r is R 12 The optional substituents on the above are each independently selected from halogen, hydroxy, cyano, amino, nitro, C 1-8 Alkyl, C of (2) 1-8 C substituted by at least one halogen 1-8 C substituted by at least one halogen 1-8 Alkoxy and five to eight membered heterocyclyl;
R 10 and R is 11 One of them is H and the other is selected from C 1-6 Alkyl, C of (2) 3-8 Cycloalkyl, phenyl substituted by at least one halogen, naphthyl, biphenyl, C substituted by at least one group of combination C 2-8 Alkenyl, C 6-12 Heteroaryl of (a); and said combination C consists of halogen, hydroxy, phenyl substituted by at least one halogen.
In a second aspect, the present invention provides a method for preparing a nucleoside compound according to the first aspect or a pharmaceutically acceptable salt thereof, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, or a metabolite thereof, comprising:
the method comprises the steps of (1) carrying out a contact reaction I on a compound shown in a formula (I-2) and a compound shown in a formula (I-1), wherein the temperature is 0-60 ℃ and the time is 1-72h;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 10 、R 11 、G 1 、G 2 、G 3 The definition of W, L, n is as described in the first aspect.
In a third aspect, the present invention provides an application of the nucleoside compound organism described in the first aspect and the second aspect in preparing a medicament serving as a CD73 inhibitor.
In a fourth aspect, the present invention provides an application of the nucleoside compound organism described in the first aspect, the second aspect and the third aspect in preparing a medicament for preventing and treating tumors.
The nucleoside compound provided by the invention has excellent inhibitory activity on CD73, and meanwhile, the in-vivo experiment shows that the compound surface has good anti-tumor activity.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
In the present invention, the "halogen" represents at least one of fluorine, chlorine, bromine and iodine.
In the present invention, the "C 1-10 Alkyl "of (C) refers to a straight chain alkyl, branched alkyl group having a total of 1 to 10 carbon atoms, illustratively 1-10 The alkyl group of (2) may be C 1 Straight-chain alkyl, branched alkyl, C 2 Straight-chain alkyl, branched alkyl, C 3 Straight-chain alkyl, branched alkyl, C 4 Straight-chain alkyl, branched alkyl, C 5 Straight-chain alkyl, branched alkyl, C 6 Straight-chain alkyl, branched alkyl, C 7 Straight-chain alkyl, branched alkyl, C 8 Straight-chain alkyl, branched alkyl, C 9 Straight-chain alkyl, branched alkyl, C 10 Straight chain alkyl, branched alkyl, and the like. And, H in the alkyl group may be optionally substituted or unsubstituted with at least one group in combination a, preferred groups in combination a are:halogen, hydroxy, C 3-8 Cycloalkyl radicals as described under "C 1-10 Is substituted C 1-10 Is "C substituted with at least one group of combination A 1-10 And the number of carbon atoms of the substituent is not counted in the total number of carbon atoms of 1 to 10. "C 1-n Is substituted by at least one halogen 1-8 Definition of "alkyl" and "C 1-10 Is defined similarly, except that the total number of carbon atoms is different, where n is an integer greater than 1 and less than 10.
In the present invention, the "C 1-10 Alkoxy "of (C) refers to a straight chain alkoxy, branched alkoxy or cycloalkoxy group having a total number of carbon atoms of 1 to 10, and is exemplified by 1-10 Alkoxy "of (C) may be 1 Straight-chain alkoxy, branched alkoxy, C 2 Straight-chain alkoxy, branched alkoxy, C 3 Straight-chain alkoxy, branched alkoxy, C 4 Straight-chain alkoxy, branched alkoxy, C 5 Straight-chain alkoxy, branched alkoxy, C 6 Straight-chain alkoxy, branched alkoxy, C 7 Straight-chain alkoxy, branched alkoxy, C 8 Straight-chain alkoxy, branched alkoxy, C 9 Straight-chain alkoxy, branched alkoxy, C 10 Straight chain alkoxy, branched alkoxy, and the like. And, H in the alkoxy group may be optionally substituted or unsubstituted with at least one halogen, when the "C" is 1-10 Alkoxy "of (2) is substituted C 1-10 Is "C substituted by at least one halogen 1-10 Alkoxy groups of (a). "C 1-n Definition of "alkoxy" and "C 1-10 Is defined similarly, except that the total number of carbon atoms is different, where n is an integer greater than 1 and less than 10.
In the present invention, the "C 2-8 Alkenyl "of (C) refers to a straight-chain alkenyl, branched alkenyl group having a total of 2 to 8 carbon atoms, and is exemplified by 2-8 Alkenyl "of (2) may be C 2 Straight chain alkenyl, branched alkenyl, C 3 Straight chain alkenyl, branched alkenyl, C 4 Straight chain alkenyl, branched chainAlkenyl, C 5 Straight chain alkenyl, branched alkenyl, C 6 Straight chain alkenyl, branched alkenyl, C 7 Straight chain alkenyl, branched alkenyl, C 8 Straight chain alkenyl, branched alkenyl, and the like. And, H in the alkenyl group may be optionally substituted with at least one group in combination C, preferred groups in combination C are: halogen, hydroxy, phenyl substituted by at least one halogen, when said "C 2-8 Alkenyl "of (2) is substituted C 2-8 Is "C substituted with at least one group of combination C 2-8 Alkenyl ", and the number of carbon atoms of the substituent is not counted in the total number of carbon atoms of 2 to 8. The invention is directed to "C 2-n Alkenyl group of "and" C 2-8 Alkenyl groups of (C) are defined similarly, except that the total number of carbon atoms is different, and therefore the invention is not repeated for "C" hereinafter 2-n Detailed description of specific definitions of alkenyl groups "those skilled in the art should not be construed as limiting the invention wherein n is an integer greater than 2 and less than 8.
In the present invention, the "C 2-8 Alkynyl "of (C) refers to straight-chain alkynyl, branched alkynyl having a total of 2 to 8 carbon atoms, illustratively 2-8 Alkynyl groups of (2) may be C 2 Straight chain alkynyl, branched chain alkynyl, C 3 Straight chain alkynyl, branched chain alkynyl, C 4 Straight chain alkynyl, branched chain alkynyl, C 5 Straight chain alkynyl, branched chain alkynyl, C 6 Straight chain alkynyl, branched chain alkynyl, C 7 Straight chain alkynyl, branched chain alkynyl, C 8 Straight chain alkynyl, branched alkynyl, and the like. And, the invention is directed to "C 2-n Alkynyl group of (C) 2-8 The definition of "alkynyl" is similar, except that the total number of carbon atoms is different, and therefore, the present invention is not repeated for "C" hereinafter 2-n Detailed description of the specific definition of "alkynyl", where n is an integer greater than 2 and less than 8, should not be construed as limiting the invention to those skilled in the art.
In the present invention, the "five-to eight-membered heterocyclic group" means a heterocyclic group having 5 to 8 total ring atoms and containing at least one hetero atom in the atoms constituting the ring, and the hetero atom may be N, O orAt least one of S and the remaining ring atoms is C, including a saturated or unsaturated heterocyclic group, which may contain at least one saturated or unsaturated heterocyclic ring, or at least two saturated or unsaturated heterocyclic rings, and when two or more saturated or unsaturated heterocyclic rings are contained, the connection manner of each ring is not particularly limited, and examples thereof include furyl, thienyl, thiazolyl, imidazolyl, and the like, and any position in the heterocyclic group that can be substituted may be optionally substituted with at least one group in the combination B, and preferred groups in the combination B are: hydroxy, C 1-8 C substituted by at least one halogen 1-8 The combination C consists of halogen, hydroxyl and phenyl substituted by at least one halogen, when the five-membered to eight-membered heterocyclic group is substituted, the combination C is the five-membered to eight-membered heterocyclic group substituted by at least one group in the combination B, and the atom number of the substituent is not counted in the total number of ring atoms of 5-8. "three to six membered heterocyclic group", "four to ten membered heterocyclic group", "six to ten membered heterocyclic group" is similar to the definition of "five to eight membered heterocyclic group", except that the total number of ring atoms is different.
In the present invention, the "C 6-12 The term "aryl" as used herein refers to an aryl group having a total of 6 to 12 carbon atoms and containing at least one unsaturated aromatic ring, and optionally containing at least two unsaturated aromatic rings.
In the present invention, the "C 6-12 Heteroaryl "of (a) refers to an aryl group having a total of 6 to 12 carbon atoms, which contains at least one unsaturated aromatic ring, and may also contain at least two unsaturated aromatic rings, and at least one heteroatom, which may be, for example, at least one of N, O or S, is contained in the atoms constituting the aromatic rings, and the remaining ring atoms are C.
In the present invention, the "C 2-6 The "acyl group" refers to an acyl group having 2 to 6 carbon atoms in total, and the structural formula may be-NHCO-C 1-5 Is a hydrocarbon group. And, the invention is directed to "C 2-n Definition of "acyl" and "C 2-6 The definition of "acyl" is similar, except that the total number of carbon atoms is different, and therefore the present invention is not repeated"C" in the text 2-n The specific definition of "acyl" is detailed, and those skilled in the art should not be construed as limiting the invention, where n is an integer greater than 2 and less than 6.
In the present invention, the "C 3-8 Cycloalkyl "of (C) refers to a ring of 3 to 8 carbon atoms, and is exemplified by the term" C 3-8 The cycloalkyl group "of (a) may be cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. And, the invention is directed to "C 3-n Definition of cycloalkyl group of (C) and C 3-8 Is defined similarly to cycloalkyl ", except that the total number of carbon atoms is different, and therefore the invention is not repeated for" C "hereinafter 3-n The specific definition of "cycloalkyl" is detailed herein and those skilled in the art should not be construed as limiting the invention, wherein n is an integer greater than 3 and less than 8.
The present invention will be described in detail by examples.
In the examples below, the various starting materials used were all commercially available in chemical purity, unless otherwise specified. The room temperature was 25.+ -. 2 ℃.
Example 1: preparation of(((2 r,3s,4r,5 r) -5- (4- (2- ((E) -benzylidene) hydrazino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl)) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
Step 1): preparation of di-tert-butyl (hydroxymethyl) phosphonate.
To a 250mL single neck round bottom flask was added di-tert-butylphosphite (9.72 g,48 mmol), triethylamine (8.0 mL,57.7 mmol), water (3.0 mL), 37% aqueous formaldehyde (3.6 mL,48 mmol), and the reaction was allowed to react overnight at room temperature, the reaction mixture was concentrated by azeotropic distillation with methanol to give a white solid powder 10.5g, Y=98.1%. The crude solid was used in the next reaction without further purification.
Step 2): preparation of methyl (di-tert-butoxyphosphoryl) 2-nitrobenzenesulfonate.
Di-tert-butyl (hydroxymethyl) phosphonate (10.0 g,59.5 mmol), dichloromethane (100 mL), pyridine (9.41 g,11.90 mmol), 2-nitrobenzenesulfonyl chloride (15.8 g,71.4 mmol) were added sequentially to a 250mL single-neck round bottom flask, reacted at room temperature for 2h, the reaction mixture concentrated under reduced pressure, and column chromatographed (petroleum ether: ethyl acetate=1.1, R f =2.0) to yield 15.1g of a yellow oil, y=71%.
Step 3): preparation of tert-butyl 2- (6-chloro-1- ((3 r,4r,6 r) -6- (((di-tert-butoxyphosphoryl) methoxy) methyl) -2, 2-dimethyltetrahydrofuran [3,4-d ] [1,3] dioxazol-4-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-yl) hydrazine-1-carboxylic acid.
To a 250mL single neck round bottom flask was added methyl (di-tert-butoxyphosphoryl) 2-nitrobenzenesulfonate (5.0 g,13.3 mmol) and tert-butyl 2- (6-chloro-1- ((3 aR,4R,6 aR) -6- (hydroxymethyl) -2, 2-dimethyltetrahydrofuran [3, 4-d)][1,3]Dioxa-4-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-yl) hydrazine-1-carboxylate (4.3 g,9.4mmol, prepared in the same manner as in example 1, steps 1-4), N, N-dimethylformamide (80 mL), magnesium tert-butoxide (6.8 g,39.9 mmol). After the addition was completed, the reaction was allowed to proceed to 70 ℃ for 2h, after completion of the tlc monitoring, the reaction mixture was poured into ice water, diluted hydrochloric acid was used to adjust PH to neutral, extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue, and the residue was purified by column chromatography (petroleum ether: ethyl acetate=1.1, r f =1.5) to give 3.6g of a white foam solid, y=40.9%.
Step 4): preparation of(((2 r,3s,4r,5 r) -5- (6-chloro-4-hydrazino-1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonate.
To a 50mL single neck round bottom flask was added tert-butyl 2- (6-chloro-1- ((3R, 4R, 6R) -6- (((di-tert-butoxyphosphoryl) methoxy) methyl) -2, 2-dimethyltetrahydrofuran [3, 4-d) sequentially][1,3]Dioxazol-4-yl) -1H-pyrazolo [3,4-d]Pyrimidine-4-yl) hydrazine-1-carboxylic acid (1.0 g,1.5 mmol), methanol (6.0 mL), water(1.5 mL), concentrated hydrochloric acid (1.5 mL,18 mmol), after 3 hours of reaction at room temperature, concentrated under reduced pressure to obtain a yellow gum, acetonitrile (10.0 mL) was added to the yellow gum to precipitate a white solid, suction filtration was performed, the filter cake was washed with acetonitrile, dried to obtain the title compound 400mg, Y=60%, 1 HNMR(400MHz,DMSO-d 6 )δ9.77(s,1H),8.38(s,1H),6.04(d,J＝4.0Hz,1H),4.50(t,J＝4.6Hz,1H),4.20(t,J＝5.2Hz,1H),4.03(q,J＝5.2Hz,1H),3.72(dd,J＝10.8,4.2Hz,1H),3.63–3.45(m,3H).
step 5): preparation of(((2 r,3s,4r,5 r) -5- (4- (2- ((E) -benzylidene) hydrazino) -6-chloro-1H-pyrazolo [3,4-d ] pyrimidin-1-yl)) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
To a 10mL single neck round bottom flask was added ((((2R, 3S,4R, 5R) -5- (6-chloro-4-hydrazino-1H-pyrazolo [3, 4-d))]Pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl-methoxy) methyl phosphonate (50 mg,0.11 mmol), ethanol (2.0 mL), water (1.0 mL) and benzaldehyde (14.8 mg,0.14 mmol), and after the addition was completed, the temperature was raised to 45℃for one night. After the reaction is detected to be complete by HPLC, the mixture is concentrated under reduced pressure to obtain a residue, a small amount of ethanol is added into the residue to precipitate solid, the solid is filtered by suction, a filter cake is dried in vacuum to obtain white powder of 20mg, 1 H NMR(600MHz,DMSO-d 6 )δ12.65(s,1H),8.50(s,1H),8.28(s,1H),7.90–7.74(m,2H),7.53–7.36(m,3H),6.12(d,J＝3.9Hz,1H),4.52(t,J＝4.5Hz,1H),4.25(t,J＝5.1Hz,1H),4.06(q,J＝6.0Hz,1H),3.74(dd,J＝10.8,4.2Hz,1H),3.61–3.49(m,3H).
example 2: preparation of(((2R, 3S,4R, 5R) -5- (6-chloro-4- (2- ((E) -2, 4-dichlorobenzylidene) hydrazino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation was the same as in example 1, except that the benzaldehyde in step 1 was replaced with an equimolar amount of 2, 4-dichlorobenzaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.78(s,1H),8.57(s,1H),8.45(s,1H),8.22–8.07(m,1H),7.74–7.66(m,1H),7.58–7.40(m,1H),6.09(d,J＝3.9Hz,1H),4.51(t,J＝4.5Hz,1H),4.23(t,J＝4.8Hz,1H),4.06–3.96(m,1H),3.71(dd,dd,J＝10.8,4.2Hz,1H),3.59–3.34(m,3H).
example 3: preparation of((((2R, 3S,4R, 5R) -5- (4- (2- ((E) - [1,1' -biphenyl ] -4-ylmethylene) hydrazino) -6-chloro-1H-pyrazoline)) 3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation was the same as in example 1, except that the benzaldehyde in step 1 was replaced with an equimolar amount of p-phenylbenzaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.66(s,1H),8.50(s,1H),8.29(s,1H),7.95–7.85(m,2H),7.81–7.74(m,2H),7.70(d,J＝7.6Hz,2H),7.54–7.44(m,2H),7.41–7.33(m,1H),6.10(d,J＝3.9Hz,1H),4.50(t,J＝4.5Hz,1H),4.23(t,J＝5.2Hz,1H),4.04(q,J＝5.2Hz,1H),3.73(dd,J＝10.8,4.2Hz,1H),3.66–3.46(m,3H).
example 4: preparation of(((2R, 3S,4R, 5R) -5- (6-chloro-4- (2- ((E) -naphthalen-1-ylmethylene) hydrazino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation was the same as in example 1, except that the benzaldehyde in step 1 was replaced with an equimolar amount of 1-naphthaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.73(s,1H),9.06(s,1H),8.49(s,1H),8.46(d,J＝8.7Hz,1H),8.19(d,J＝7.2Hz,1H),8.07(dd,J＝17.1,8.1Hz,2H),7.80–7.53(m,3H),6.13(d,J＝3.9Hz,1H),4.53(t,J＝4.4Hz,1H),4.24(t,J＝5.2Hz,1H),4.06(q,J＝5.2Hz,1H),3.74(dd,J＝10.8,4.2Hz,1H),3.62–3.48(m,3H).
example 5: preparation of(((2R, 3S,4R, 5R) -5- (6-chloro-4- (2- ((E) -quinolin-8-ylmethylene) hydrazino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation was the same as in example 1, except that the benzaldehyde in step 1 was replaced with an equimolar amount of quinoline-8-carbaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.78(s,1H),9.55(s,1H),8.98(d,J＝4.0Hz,1H),8.66–8.29(m,3H),8.09(d,J＝8.2Hz,1H),7.75(t,J＝7.7Hz,1H),7.62(dd,J＝8.3,4.2Hz,1H),6.11(d,J＝3.9Hz,1H),4.51(t,J＝4.4Hz,1H),4.24(t,J＝5.4Hz,1H),4.04(q,J＝5.4Hz,1H),3.73(dd,J＝10.8,4.2Hz,1H),3.62–3.45(m,3H).
example 6: preparation of(((2 r,3s,4r,5 r) -5- (6-chloro-4- (2- ((E) - (4-oxo-4H-chrome-3-yl) methylene) hydrazino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation was the same as in example 1, except that the benzaldehyde in step 1 was replaced with an equimolar amount of chromone-3-carbaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.57(s,1H),9.04(s,1H),8.75(s,1H),8.30(s,1H),8.11(d,J＝7.8Hz,1H),7.81(t,J＝7.8Hz,1H),7.68(d,J＝8.4Hz,1H),7.58–7.46(m,1H),6.08(d,J＝3.9Hz,1H),4.50(t,J＝4.5Hz,1H),4.23(t,J＝5.4Hz,1H),4.03(q,J＝5.4,5.2Hz,1H),3.83–3.67(m,1H),3.63–3.45(m,3H).
example 7: preparation of((((2R, 3S,4R, 5R) -5- (6-chloro-4- (2- ((1E, 2E) -3- (4-fluorophenyl) allyl) hydrazino) -1H-pyrazolin [3,4-d ] pyrimidin-1-yl) -3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) methyl) phosphonic acid.
The preparation process is the same as in example 1, except that the benzaldehyde in step 1 is replacedChanging into equimolar p-fluoro cinnamaldehyde, 1 H NMR(600MHz,DMSO-d 6 )δ12.51(s,1H),8.53(s,1H),8.01(d,J＝9.3Hz,1H),7.69(t,J＝6.9Hz,2H),7.35–7.18(m,3H),7.08(d,J＝16.0Hz,1H),6.06(d,J＝3.9Hz,1H),4.49(t,J＝4.5Hz,1H),4.21(t,J＝5.2Hz,1H),4.02(q,J＝5.2Hz,1H),3.71((dd,J＝10.8,4.2Hz,1H),3.59–3.49(m,3H).
CD73 in vitro enzyme bioassay test
1.1 Experimental materials
Multifunctional enzyme-labeled instrument (Bio-TEK); 96-well plate centrifuge-MPC 2000 (Beijing tripod source); tris (hydroxymethyl) aminomethane (Sigma-Aldrich); magnesium chloride (aledine); adenosine 5' -triphosphate (ATP) (Sigma-Aldrich); adenine ribonucleotide (AMP) (Sigma-Aldrich) CellTiter-Glo kit (prolog biotechnology limited); constant temperature incubator ZDP-A2080A (Shanghai Zhhengjingsheng); deuterated dimethyl sulfoxide (aledine).
1.2 preparation of reagents
Compound preparation:
1. the compound mother liquor (10 mM) was diluted 10-fold, 2. Mu.L of the diluted mother liquor was taken, and 18. Mu.L of DMSO was added.
2. Then, 5. Mu.L of the compound mother solution mixed with DMSO was diluted 3-fold by adding 10. Mu.L. mu.L of diluted compound mother liquor is taken and 997 mu.L of Tris-MgCl is added 2 。
hCD73 formulation process:
mu.L of mother liquor (1.45 mg/ml) was taken and 99. Mu.L of Tris-MgCl was added 2 Dilution was performed to give a dilution of 14.5. Mu.g/mL of hCD 73.
AMP formulation process:
14uL of AMP mother liquor (100 mM) was taken and added with 1986. Mu.L of Tris-MgCl 2 And diluting to obtain diluted AMP mother liquor.
1.3 test methods
1. The CD73 solution prepared above was added to a 96-well plate at 20. Mu.L/well.
2. The formulated compound was then added to the plate containing the CD73 solution at 20. Mu.L/well. After mixing, incubation was carried out at room temperature for 30min. Positive (no compound added) and negative control wells (no CD73 added) were set simultaneously.
3. The prepared AMP solution was then added to the plate mixed with CD73 and compound at 20. Mu.L/well. After the mixed solution is evenly mixed, the mixture is incubated for 60min at 37 ℃ and then the next operation is carried out.
4. The prepared ATP solution was added to the plate of step 3 at a concentration of 10. Mu.L/well, and the mixture was homogenized.
5. Finally, the prepared CellTiter-Glo reagent (Promega REF: G7573) was added to the plate of step 4 at 70. Mu.l/well, and the mixture was mixed and examined.
Inhibition ratio (IC) 50 ) Is calculated by the following steps: determined by compound dose response curves fitted using standard four parameter fitting equations.
The present invention provides a half maximal Inhibitory Concentration (IC) of a compound of formula (I) on CD73 50 ) See table 1:
table 1: the invention provides the inhibitory activity of the compound on CD73
| Numbering of compounds | IC 50 ,nM |
| Compound 1 | 130.2 |
| Compound 2 | 113.6 |
| Compound 3 | 5.8 |
| Compound 4 | 194.3 |
| Compound 5 | 168.2 |
| Compound 6 | >1000 |
| Compound 7 | >1000 |
As shown in table 1, the compounds provided by the present invention all showed excellent inhibitory activity against CD 73.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (6)
1. A nucleoside compound with a structure shown in a formula (I) or pharmaceutically acceptable salt thereof, or stereoisomer, geometric isomer, tautomer, oxynitride, hydrate, solvate and metabolite thereof,
in the case of the formula (I),
R 1 and R is 2 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, cyano, amino, azido; r is R 1 And R is 2 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 3 and R is 4 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-10 Alkyl, substituted or unsubstituted C 1-10 Alkoxy, cyano, amino, azido; r is R 3 And R is 4 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 5 selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, substituted or unsubstituted C 1-10 Alkoxy, hydroxy, cyano, amino, nitro and azido groups; r is R 5 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 6 and R is 7 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C of (2) 2-6 Alkenyl, C 2-6 Alkynyl, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Or by R 6 、R 7 And C formed by ring closure of carbon atoms to which they are attached 3-8 Cycloalkyl of (C), R 6 、R 7 And the three-to six-membered heterocyclic groups formed by cyclization of the carbon atoms connected with the three-to six-membered heterocyclic groups;
w is selected from-O-, -S-;
l is selected from substituted or unsubstituted alkylene groups, and the substituents on L are each independently selected from C 1-10 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 1-10 Alkoxy, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a);
n is 0 or 1;
G 1 、G 2 、G 3 each independently selected from N, -C (R) 12 )-，R 12 Selected from hydrogen, halogen, substituted or unsubstituted C 1-8 Alkyl, C of (2) 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted C 1-8 Alkoxy, hydroxy, cyano, amino, nitro and five to eight membered heterocyclyl;
R 8 selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Alkoxy and five to eight membered heterocyclyl; r is R 11 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 9 selected from hydrogen, substituted or unsubstituted C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, substituted or unsubstituted five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a); r is R 12 The optional substituents on the above are each independently selected from halogen, hydroxy, cyano, amino, nitro, C 1-8 Alkyl, C of (2) 1-8 C substituted by at least one halogen 1-8 C substituted by at least one halogen 1-8 Alkoxy and five to eight membered heterocyclyl;
R 10 and R is 11 One of them is H and the other is selected from C 1-6 Alkyl, C of (2) 3-8 Cycloalkyl, phenyl substituted by at least one halogen, naphthyl, biphenyl, C substituted by at least one group of combination C 2-8 Alkenyl, C 6-12 Heteroaryl of (a); and said combination C consists of halogen, hydroxy, phenyl substituted by at least one halogen.
2. The compound according to claim 1, wherein, in formula (I),
R 1 and R is 2 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, amino, azido, and R 1 And R is 2 Not simultaneously H; r is R 1 And R is 2 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 3 and R is 4 Each independently selected from H, deuterium, hydroxy, halogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Alkoxy, cyano, amino, azido, and R 3 And R is 4 Not simultaneously H; r is R 3 And R is 4 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 5 selected from hydrogen, deuterium;
R 6 and R is 7 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-6 Alkyl, C of (2) 2-4 Alkenyl, C 2-4 Alkynyl, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Or by R 6 、R 7 And C formed by ring closure of carbon atoms to which they are attached 3-6 Cycloalkyl of (C), R 6 、R 7 And the three-to six-membered heterocyclic groups formed by cyclization of the carbon atoms connected with the three-to six-membered heterocyclic groups;
w is selected from-O-, -S-;
l is selected from substituted or unsubstituted alkylene groups, and the substituents on L are each independently selected from C 1-10 Alkyl, halogen, amino, nitro, cyano, hydroxy, C 1-10 Alkoxy, five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a);
n is 0 or 1;
G 1 、G 2 、G 3 each independently selected from N, -C (R) 12 )-，R 12 Selected from hydrogen, halogen, substituted or unsubstituted C 1-6 Alkyl, C of (2) 2-4 Alkenyl, C 2-4 Alkynyl, substituted or unsubstituted C 1-6 Alkoxy, hydroxy, cyano, amino, nitro and five to eight membered heterocyclyl;
R 8 selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, C 1-10 Alkoxy and five to eight membered heterocyclyl; r is R 11 The optional substituents on the above are each independently selected from halogen, hydroxy;
R 9 selected from hydrogen, substituted or unsubstituted C 1-10 Alkyl, C of (2) 2-8 Alkenyl, C 2-8 Alkynyl, substituted or unsubstituted five-to eight-membered heterocyclyl, C 6-12 Aryl and C of (2) 6-12 Heteroaryl of (a); r is R 12 The optional substituents on the above are each independently selected from halogen, hydroxyCyano, amino, nitro, C 1-8 Alkyl, C of (2) 1-8 C substituted by at least one halogen 1-8 C substituted by at least one halogen 1-8 Alkoxy and five to eight membered heterocyclyl;
R 10 and R is 11 One of them is H and the other is selected from C 1-3 Alkyl, C of (2) 3-6 Cycloalkyl, phenyl substituted by at least one halogen, naphthyl, biphenyl, C substituted by at least one group of combination C 2-8 Alkenyl, C 6-12 Heteroaryl of (a); and said combination C consists of halogen, hydroxy, phenyl substituted by at least one halogen.
3. The compound according to claim 1 or 2, wherein, in formula (I),
R 1 、R 2 、R 3 and R is 4 Each independently selected from H, deuterium, hydroxy, halogen, and R 1 And R is 2 Not simultaneously H, R 3 And R is 4 Not simultaneously H;
R 5 、R 6 、R 7 each independently selected from H, deuterium;
w is-O-;
l is absent;
G 1 、G 2 、G 3 each independently selected from-N-, -CH-;
R 8 selected from H, hydroxy, F, cl, br;
R 9 selected from H, deuterium;
R 10 and R is 11 One of which is H, the other is selected from phenyl, phenyl substituted with at least one halogen, naphthyl, biphenyl, quinolinyl, C substituted with at least one group of combination C 2-6 Alkenyl, 4-benzopyronyl; and said combination C consists of halogen, hydroxy, phenyl substituted by at least one halogen.
4. A compound according to any one of claims 1-3, wherein, in formula (I),
R 1 and R is 2 One of them is H, and the other is hydroxyl;
R 3 and R is 4 One of them is H, and the other is hydroxyl;
R 5 、R 6 、R 7 、R 12 all are H;
w is-O-;
l is absent;
G 1 and G 2 One of them is-N-, and the other is-CH-;
G 3 selected from-N-, -CH-;
R 8 is Cl;
R 10 and R is 11 One of which is H, the other is selected from phenyl, phenyl substituted with at least one chlorine atom, naphthyl, biphenyl, quinolinyl, C substituted with at least one group of combination C 2-4 Alkenyl, 4-benzopyronyl; and said combination C consists of halogen, hydroxy, phenyl substituted by at least one halogen.
5. The compound according to any one of claims 1 to 4, wherein the nucleoside compound is selected from the group consisting of a specific compound or a pharmaceutically acceptable salt thereof, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite thereof,
compound I-1:
compound I-2:
compound I-3:
compound I-4:
compound I-5:
compound I-6:
compound I-7:
6. a process for preparing a nucleoside compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite thereof, comprising:
the method comprises the steps of (1) carrying out a contact reaction I on a compound shown in a formula (I-2) and a compound shown in a formula (I-1), wherein the temperature is 0-60 ℃ and the time is 1-72h;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 10 、R 11 、G 1 、G 2 、G 3 W, L, n are defined as in any one of claims 1 to 5.
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