CN116768866A - CD73 inhibitor and application thereof in medicine - Google Patents

CD73 inhibitor and application thereof in medicine Download PDF

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Publication number
CN116768866A
CN116768866A CN202310238802.5A CN202310238802A CN116768866A CN 116768866 A CN116768866 A CN 116768866A CN 202310238802 A CN202310238802 A CN 202310238802A CN 116768866 A CN116768866 A CN 116768866A
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alkylene
pharmaceutically acceptable
substituted
alkyl
compound
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吴颢
杨晓峰
韩晗
杜亚军
王维
兰宏
王家炳
丁列明
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Betta Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The present application relates to a novel compound having cancer therapeutic activity. The application also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.

Description

CD73 inhibitor and application thereof in medicine
Technical Field
The present application relates to a CD73 inhibitor having cancer therapeutic activity. The application also relates to a preparation method of the inhibitors and a pharmaceutical composition containing the inhibitors.
Background
Extracellular 5' -nucleotidase (CD 73) is a glycoprotein on the cell membrane and is present on the surface of cell membranes of various cell types, including endothelial cells, lymphocytes, stromal cells, tumor cells, and the like. CD73 is capable of catalyzing extracellular adenosine 5 '-phosphate (5' -AMP) to form adenosine, which can induce immunosuppressive effects, promoting tumor proliferation and/or metastasis. In addition, CD73 can also promote tumorigenesis by non-immune related mechanisms, such as promoting tumor angiogenesis, promoting adhesion of tumor cells to extracellular matrix proteins, and the like. Clinically, high levels of CD73 expression are associated with lymph node metastasis and poor prognosis for a variety of cancer types, CD73 has been found to be an independent prognostic factor in prostate and triple negative breast cancer patients.
Drugs targeting CD73 are one of the current areas of drug development hotspots, and existing varieties enter the clinical stage. The varieties under investigation include both large molecular antibodies and small molecular drugs. The application provides a novel-structure small-molecule CD73 inhibitor which has good anti-tumor activity.
Disclosure of Invention
The application provides a compound shown in a general formula (I), or stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts thereof:
wherein,,
x is selected from C or N; preferably N;
R 1 selected from H, halogen, cyano, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl;
R 2 each independently selected from H, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 A haloalkyl group;
R 3 selected from OR a 、-OC(O)N(R a ) 2 、-N(R a ) 2 、-NR b C(O)R a 、-NR a C(O)N(R a ) 2 、-NR a S(O)R a 、-NR a S(O) 2 R a 、-S(＝O)R a 、-S(＝O) 2 R a 、-SR a 、-S(R a ) 5 、-C(＝O)R a 、-C(＝O)OR a 、-C(＝O)N(R a ) 2 、C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl or C 5-14 Heteroaryl, said C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl or C 5-14 Heteroaryl is optionally further substituted with one or more R 5 Substitution;
R 4 selected from H, halogen or C 1-6 An alkyl group;
R 5 selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=O)OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionally may also be substituted with 1 or more R a Substituted;
each R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; the C is 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl optionally may also be substituted with 1 or more R b Substituted;
each R b Each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 An alkoxy group;
m is selected from 0, 1,2, 3 or 4.
n is selected from 1 or 2.
In some embodiments, the compound of formula (I), or a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds of formula (IA) or formula (IA-1):
R 1 、R 2 、R 3 、R 4 m is defined as in formula (I).
In some embodiments, X in formula (I) is selected from N.
In some embodiments, R in formula (I) 1 Selected from halogen, cyano, C 1-3 Alkyl or C 1-3 Alkoxy, preferably chloro, cyano, methyl or methoxy.
In some embodiments, R in formula (I) 2 Selected from halogen, preferably F.
In some embodiments, R in formula (I) 3 Selected from-OR a 、-OC(O)N(R a ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The R is a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl.
In some embodiments, R in formula (I) 3 Selected from the group consisting of
In some embodiments, R in formula (I) 4 Selected from H, halogen or methyl, preferably H.
In some embodiments, the compound in formula (I) is selected from:
the application also provides a pharmaceutical composition which is characterized by comprising a therapeutically effective amount of at least one compound shown as a formula (I) and at least one pharmaceutically acceptable auxiliary material.
The application further provides a pharmaceutical composition which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown as the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001:1-10.
The application provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of medicines.
The application further provides a preferable technical scheme of the application:
preferably, the use is in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
Preferably, the use is the use for the manufacture of a medicament for the treatment of a CD73 mediated disease. Preferably, the disease is cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell cancer, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, bryoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The application also provides a method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
The application also provides a method for treating and/or preventing a CD 73-mediated disease comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
The application also provides a method of treating cancer comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
Preferably, in the above method, the CD 73-mediated disease is cancer.
Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.
For example, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine unless otherwise indicated.
In the present application, unless otherwise indicated, "alkyl" includes straight or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "base 1-8 "in" alkyl group " 1-8 "refers to a group comprising an array of straight or branched chain forms of 1,2, 3, 4, 5, 6, 7 or 8 carbon atoms.
In the present application, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", in the present application, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising atoms of a carbon ring having a fully conjugated pi-electron system. Preferably aryl is a 6 to 14 membered monocyclic or polycyclic aromatic ring group. Phenyl and naphthyl are preferred. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
The term "heterocyclyl", unless otherwise indicated, in the present application refers to an unsubstituted or substituted 3-to 14-membered stable ring system consisting of carbon atoms and 1 to 3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms, wherein the nitrogen or sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom that results in the formation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.
The term "heteroaryl", in the present application, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14 membered benzofused heteroaromatic ring system or polycyclic heteroaromatic ring system consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. Heteroaryl groups may be attached to any heteroatom or carbon atom that results in the formation of a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferably C 3-10 Cycloalkyl radicals, where "C 3-10 "means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9 or 10 ring members. Cycloalkyl groups may include monocyclic and polycyclic (e.g., having 2,3, or 4 fused rings, spiro rings, bridged rings, etc.). Some embodiments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl groups may also be fused to aryl, heterocyclyl or heteroaryl rings, wherein the ring attached to the parent structure is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in the group are eachSubstituted with the same or different substituents. Typical substituents include, but are not limited to, H, =ch 2 (O), =s, acyl, cyano, halo, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 alkylene-OR 1 、-C 0-3 alkylene-N (R) 1 ) 2 、-C 0-3 alkylene-S (=o) R 1 、-C 0-3 alkylene-S (=o) 2 R 1 、-C 0-3 alkylene-SR 1 、-C 0-3 alkylene-S (R) 1 ) 5 、-C 0-3 alkylene-C (=o) R 1 、-C 0-3 alkylene-C (=o) OR 1 、-C 0-3 alkylene-C (=O) N (R) 1 ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, substituted or unsubstituted-C 0-3 alkylene-C 3-14 Cycloalkyl, substituted or unsubstituted-C 0-3 Alkylene- (3-14 membered heterocycloalkyl), substituted or unsubstituted-C 0-3 alkylene-C 6-14 Aryl or substituted or unsubstituted-C 0-3 Alkylene- (5-14 membered heteroaryl), each R 1 H, C independently 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 A haloalkyl group. In some embodiments of the present application, in some embodiments, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
Examples of substituted alkyl groups include, but are not limited to, 2, 3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2, 3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compounds provided herein are acids, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (both higher and lower), ferric, ferrous, lithium, magnesium, manganese (both higher and lower), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases capable of derivatizing into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituent-containing amines, such as naturally occurring and synthetic substituent-containing amines. Other pharmaceutically acceptable non-toxic organic bases capable of salt formation include ion exchange resins as well as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compounds provided by the present application are bases, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharin acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably formic acid and hydrochloric acid.
Since the compounds of formula (I) will be used as pharmaceuticals, it is preferable to use a purity, for example, of at least 60%, more suitably at least 75%, and particularly suitably at least 98% (% by weight).
Prodrugs of the compounds of the present application are included within the scope of the present application. Typically, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the application or a pharmaceutically active metabolite or residue thereof. Particularly preferred derivatives or prodrugs are those compounds that enhance the bioavailability of the compounds of the application when administered to a patient (e.g., may make oral compounds more readily absorbable into the blood), or promote delivery of the parent compound to a biological organ or site of action (e.g., the brain or lymphatic system). Thus, the term "administration" in the methods of treatment provided herein refers to the administration of a compound disclosed herein that is capable of treating a different disease or, although not explicitly disclosed, of being converted in vivo to a compound disclosed herein upon administration to a subject.
The compounds of the present application may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present application includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
Substitution of the compounds of formula (I) with heavier isotopes (e.g., deuterium) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When the compound of formula (I) and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphs, the present application includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like may be used.
The term "composition" is meant to include within the present application products comprising the specified amounts of each of the specified ingredients, as well as any product that is produced directly or indirectly from combinations of the specified amounts of each of the specified ingredients. Thus, pharmaceutical compositions containing the compounds of the present application as active ingredients and methods of preparing the compounds of the present application are also part of the present application.
The pharmaceutical composition provided by the application comprises a compound (or a pharmaceutically acceptable salt thereof) shown in a formula (I) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular subject being administered, the nature of the subject and the severity of the condition. The pharmaceutical compositions of the present application may be conveniently presented in unit dosage form well known in the art and prepared by any of the methods of manufacture well known in the pharmaceutical arts.
Detailed Description
In order to make the above matters clearer and more obvious, the following examples are provided to further illustrate the technical aspects of the present application. The following examples are presented only to illustrate specific embodiments of the application so that those skilled in the art can understand the application and are not intended to limit the scope of the application. In the specific embodiment of the present application, technical means, methods, and the like not specifically described are conventional technical means, methods, and the like in the art.
All parts and percentages herein are by weight and all temperatures are in degrees celsius unless otherwise indicated.
The following abbreviations are used in the examples:
PE, EA: ratio of petroleum ether to ethyl acetate;
Pd(dppf)Cl 2 : [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride;
Pre-TLC, thin layer chromatography silica gel plate;
DMSO: n, N-dimethylformamide;
DCM: dichloromethane;
DCE:1, 2-dichloroethane;
B 2 Pin 2 : pinacol ester of biboron acid;
THF: tetrahydrofuran;
ACN: acetonitrile;
DIEA: n, N-diisopropylethylamine;
example 1: synthesis of the compound (S) -1- (3-chloro-6- (2, 4-dihydroxypyrimidin-5-yl) pyridazin-4-yl) -4, 4-difluoropyrrolidin-3-yl-tert-butylcarbamate
Step 1: synthesis of Compound 1-1
(S) -3, 3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g) was dissolved in DCM (10 mL), and hydrochloric acid (4M/dioxane) (5.6 mL) was added dropwise to the reaction solution at room temperature, after the dropwise addition, the reaction was completed at room temperature for 4 hours, and TLC monitored the completion of the reaction. The reaction solution was directly concentrated to obtain 0.7g of a white powder, namely, compound 1-1. The compound was directly subjected to the next reaction without purification.
Step 2: synthesis of Compounds 1-2
1-1 (0.6 g), 3-amino-4-bromo-6-chloropyridazine (0.79 g), DIEA (1.25 mL) were added sequentially to DMSO (3 mL), reacted at 110℃and LCMS monitored for reaction completion. Adding water into the reaction solution for dilution, precipitating brown solid, carrying out suction filtration, washing a filter cake with water, and drying to obtain 0.9g of brown powder, namely the compound 1-2.ESI-MS m/z 251[ M+H ]] + 。
Step 3: synthesis of Compounds 1-3
1-2 (0.50 g), 2, 4-dimethoxy-5-pyrimidine boron ester (0.80 g), potassium carbonate (0.55 g), pd (dppf) Cl 2 (0.16 g) dioxane (10 mL), H was added sequentially 2 O (2 mL), under nitrogen, at 100deg.C, LCMS monitors the completion of the reaction. The reaction was concentrated directly and purified by column chromatography (DCM-MeOH, 5% MeOH off-peak) to give 0.7g of a brown powder, compound 1-3.ESI-MS m/z 355[ M+H ]] + 。
Step 4: synthesis of Compounds 1-4
Cuprous chloride (0.49 g) was added to ACN (10 mL), isoamyl nitrite (0.85 mL) and 1-3 (0.70 g) were added dropwise to the reaction solution under nitrogen protection in an ice bath, and after the addition, the reaction solution was reacted at 70 ℃ for 2 hours, and LCMS monitored the completion of the reaction. The reaction was concentrated directly and purified by column chromatography (DCM-MeOH, 6% MeOH off-peak) to give 0.6g of a brown powder, compound 1-4.ESI-MS m/z 374[ M+H ]] + 。
Step 5: synthesis of Compounds 1-5
1-4 (0.60 g) was added to DCE (10 mL), followed by DIEA (2.65 mL), stirred at room temperature for 10 minutes, then tert-butyl isocyanate (0.91 mL) was added dropwise to the reaction solution, the reaction solution was reacted at 70℃for 6 hours after the dropwise addition, and LCMS monitored the completion of the reaction. The reaction was concentrated directly and purified by column chromatography (DCM-MeOH, 2% MeOH off-peak) to give 0.6g of a reddish brown powder, compound 1-5.ESI-MS m/z 473[ M+H ]] + 。
Step 6: synthesis of Compound 1
1-5 (0.10 g) was dissolved in MeOH (2 mL) and then 1M hydrochloric acid (2 mL) was added and reacted at 50℃with LCMS monitoring the reaction completion. The reaction was adjusted to ph=7 with saturated sodium bicarbonate solution, filtered with suction, and purified by column chromatography on a filter cake (DCM-MeOH, 2% MeOH off peak) to give 40mg of compound 1 as a yellow powder. ESI-MS m/z 445[ M+H ]] + 。 1 H NMR(500MHz,DMSO)δ11.53(s,2H),8.32(s,1H),7.67(s,1H),7.42(s,1H),5.39(s,1H),4.26-4.00(m,3H),3.66(d,J＝11.5Hz,1H),1.23(s,9H)。
The following examples were synthesized using the methods of the examples described above, or similar methods using the corresponding intermediates.
Comparative example 1
Comparative compound 1 (D1) was synthesized according to the procedure of example 2 of WO2019168744A1, LCMS: [ M+H ]] + ＝287。
Pharmacological experiments
Example 1: enzymatic Activity detection at cellular level
Calu-6 cells were digested using TM buffer (25mM Tris,5mM MgCl) 2 pH 7.5) resuspended cells, and plated in 96-well plates at 25000 cells, 100. Mu.L/well. The compound solutions of gradient concentration were prepared by TM buffer, 50 μl of each concentration of DMSO solution of test compound was added to each well cell, and the final concentrations of the compounds were 20000, 6666.7, 2222.2, 740.7, 246.9, 82.3, 27.4, 9.1, 3.0, 1.0, 0.3, 0nM (DMSO final concentrations were 0.625%). Pre-incubating for 30min by a constant temperature horizontal shaking table at 37 ℃, adding 50 mu L of 800 mu M AMP solution into each well, continuously incubating for 120min by a constant temperature horizontal shaking table at 37 ℃, centrifuging a 96-well plate, transferring 50 mu L of supernatant to a new 96-well plate, adding 50 mu L of 130 mu M ATP solution and 100 mu L of Cell-timer Glo working solution into each well, shaking and uniformly mixing, incubating for 10min at room temperature, and reading the Luminescence value by a multifunctional enzyme-labeling instrument, wherein the Luminescence value reading is converted into inhibition percentage:
percent inhibition = (1-reading/maximum) ×100.
"maximum" is DMSO control.
Curve fitting was performed with GraphPad Prism software and IC was obtained 50 Values.
Example Compounds enzymatic IC at Calu-6 cellular level 50 See table 1 for data. The compound of the application has better activity.
TABLE 1
Names of Compounds IC 50 (nM)
1 0.5
D1 49.1
While the present application has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such variations and modifications are intended to be included within the scope of the appended claims.

Claims (12)

1. A compound of formula (I), or a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof:
wherein,,
x is selected from C or N; preferably N;
R 1 selected from H, halogen, cyano, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl;
R 2 each independently selected from H, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 A haloalkyl group;
R 3 selected from OR a 、-OC(O)N(R a ) 2 、-N(R a ) 2 、-NR b C(O)R a 、-NR a C(O)N(R a ) 2 、-NR a S(O)R a 、-NR a S(O) 2 R a 、-S(＝O)R a 、-S(＝O) 2 R a 、-SR a 、-S(R a ) 5 、-C(＝O)R a 、-C(＝O)OR a 、-C(＝O)N(R a ) 2 、C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl or C 5-14 Heteroaryl, said C 3-8 Cycloalkyl, C 3-8 Heterocyclyl, C 6-14 Aryl or C 5-14 Heteroaryl is optionally further substituted with one or more R 5 Substitution;
R 4 selected from H, halogen or C 1-6 An alkyl group;
R 5 selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=o) OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 0-6 Alkylene, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 Alkylene group-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionally may also be substituted with 1 or more R a Substituted;
each R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl; the C is 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl optionally may also be substituted with 1 or more R b Substituted;
each R b Each independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 An alkoxy group;
m is selected from 0, 1,2, 3 or 4.
n is selected from 1 or 2.
2. A compound according to claim 1, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formula (IA) or formula (IA-1):
R 1 、R 2 、R 3 、R 4 m is defined as in formula (I).
3. A compound according to claim 1, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein X is selected from N.
4. A compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogenCyano, C 1-3 Alkyl or C 1-3 Alkoxy, preferably chloro, cyano, methyl or methoxy.
5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein R 2 Selected from halogen, preferably F.
6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein R 3 Selected from-OR a 、-OC(O)N(R a ) 2 The method comprises the steps of carrying out a first treatment on the surface of the The R is a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl.
7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein R 3 Selected from the group consisting of
8. The compound according to any one of claims 1 to 7, or a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof, wherein R 4 Selected from H, halogen or methyl, preferably H.
9. A compound, or a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
10. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.
11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 in the manufacture of a medicament.
12. A method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-9 or a pharmaceutical composition of claim 10.
CN202310238802.5A 2022-03-18 2023-03-14 CD73 inhibitor and application thereof in medicine Pending CN116768866A (en)

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