Nothing Special   »   [go: up one dir, main page]

CN114057693A - CD73 inhibitor and application thereof in medicine - Google Patents

CD73 inhibitor and application thereof in medicine Download PDF

Info

Publication number
CN114057693A
CN114057693A CN202110739012.6A CN202110739012A CN114057693A CN 114057693 A CN114057693 A CN 114057693A CN 202110739012 A CN202110739012 A CN 202110739012A CN 114057693 A CN114057693 A CN 114057693A
Authority
CN
China
Prior art keywords
compound
substituted
alkyl
halogen
radical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110739012.6A
Other languages
Chinese (zh)
Inventor
吴颢
杨晓峰
刘奇声
韩晗
李金花
蒋枫
匡翠文
夏洪峰
张洪波
兰宏
王家炳
丁列明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Betta Pharmaceuticals Co Ltd
Original Assignee
Betta Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Betta Pharmaceuticals Co Ltd filed Critical Betta Pharmaceuticals Co Ltd
Publication of CN114057693A publication Critical patent/CN114057693A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a novel compound having cancer therapeutic activity. The invention 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 invention relates to a CD73 inhibitor having cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Extracellular 5' -nucleotidase (CD 73) is a glycoprotein on the cell membrane, and is present on the surface of the cell membrane of various cell types, including endothelial cells, lymphocytes, stromal cells, tumor cells, and the like. CD73 is capable of catalyzing the production of adenosine from extracellular adenosine 5 '-phosphate (5' -AMP), which induces immunosuppressive effects and promotes 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, and CD73 has been found to be an independent prognostic factor for prostate and triple negative breast cancer patients. The invention provides a small molecule CD73 inhibitor with a novel structure, which has good anti-tumor activity.
Disclosure of Invention
The invention provides a compound shown as a general formula (I), a tautomer or a medicinal salt thereof:
Figure BDA0003140797660000011
wherein,
R1is selected from C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl radical, said C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl being unsubstituted or substituted by 1,2 or 3 substituents R3The substitution is carried out on the raw materials,
R3selected from hydroxy, amino, halogen, cyano, nitro, -ORa、-SRa、＝O、＝S、-C(O)-C0-3alkylene-Ra、-C(S)Ra、-C(O)ORa、-C(S)ORa、-C(O)N(Ra)2、-N(Ra)2、-S(O)2Ra、-O-S(O2)ORa、-O-S(O)2RaOr RaSaid R isaEach independently selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, RaUnsubstituted or further substituted by 1,2 or 3R4Substituted;
R4selected from hydroxy, amino, halogen, cyano, nitro, -ORb、-SRb、＝O、＝S、-C(O)Rb、-C(S)Rb、-C(O)ORb、-C(S)ORb、-C(O)N(Rb)2、-NHRb、-N(Rb)2、-S(O)2Rb、-O-S(O2)ORb、-O-S(O)2RbOr RbSaid R isbIs selected from C1-6Alkyl or C3-6Cycloalkyl radical, RbUnsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C1-3Alkyl or cyano;
R2selected from hydrogen, halogen, cyano, C1-3Alkyl radical, C1-3Alkoxy radical, C2-4Alkenyl, halo C2-4Alkenyl or C2-4Alkynyl.
In some embodiments, R in formula (I)1Is selected from C1-6Alkyl or C2-6Alkenyl radical, said C1-6Alkyl or C2-6Alkenyl unsubstituted or substituted by 1,2 or 3R3Substituted; the R is3Selected from halogenElement, hydroxy group, C1-3Alkyl radical, C1-3Alkoxy, -C (O) -C1-3Alkyl radical, Ra、-C(O)-Raor-C (O) -C0-3alkylene-RaSaid R isaIs selected from C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, said RaUnsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
In some embodiments, R in formula (I)1Is selected from C1-6Alkyl or C2-6Alkenyl radical, said C1-6Alkyl or C2-6Alkenyl is unsubstituted or substituted by a member selected from halogen,
Figure BDA0003140797660000021
Is substituted with a substituent of (a), said
Figure BDA0003140797660000022
Is unsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
In some embodiments, R in formula (I)1Is selected from C1-6Alkyl radical, said C1-6The alkyl radical being selected from
Figure BDA0003140797660000023
Is substituted with a substituent of (a), said
Figure BDA0003140797660000024
Is unsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
In some embodiments, R in formula (I)2Is selected from C1-3Alkyl or halogenPreferably, the element is methyl or chlorine.
In some embodiments, the compound of formula (I) is selected from:
Figure BDA0003140797660000031
in some embodiments, the method of synthesizing formula (I) comprises:
Figure BDA0003140797660000032
reacting the compound of the general formula (II) under an acidic condition to obtain a compound of the general formula (I),
wherein R is1And R2The definition of (A) is as described in formula (I).
The invention also provides a pharmaceutical composition, which is characterized by comprising at least one compound shown as the formula (I) in a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown in the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001: 1-10.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing 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, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenification, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method for treating and/or preventing diseases, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in a therapeutically effective amount.
The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the compounds of formula (I) or a pharmaceutical composition comprising the same.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain 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, "radical1-8Alkyl group "of"1-8"refers to a group comprising 1,2, 3, 4,5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
“C1-3Alkylene "refers to a straight or branched chain divalent saturated hydrocarbon group. For example methylene, 1, 2-ethylene, 1, 3-propylene or 1, 2-isopropylene.
“C2-6Alkenyl "or" C2-6Alkynyl "refers to a straight or branched chain unsaturated hydrocarbon group.
"alkoxy" refers to the oxygen ether form of the straight or branched chain alkyl group previously described, i.e., -O-alkyl.
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising carbocyclic atoms. Preferably, aryl is a 6 to 10 membered monocyclic or bicyclic aromatic ring group. Preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted stabilizing ring system of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms wherein the nitrogen or sulfur heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom to form a stable structure. Examples of such heterocyclyl 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 term "heteroaryl", in the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-or 10-membered benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system, consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms may optionally be oxidized and said heteroatoms may optionally be quaternized. The heteroaryl group may be attached at any heteroatom or carbon atom to form 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, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl, or isoquinolinyl. The heteroaryl group can 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 cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C1-8Alkyl radical, C3-12Cycloalkyl, -OR1、-SR1、＝O、＝S、-C(O)R1、-C(S)R1、＝NR1、-C(O)OR1、-C(S)OR1、-NR1R2、-C(O)NR1R2Cyano, nitro, -S (O)2R1、-O-S(O2)OR1、-O-S(O)2R1、-OP(O)(OR1)(OR2) (ii) a Wherein R is1And R2Independently selected from-H, C1-6Alkyl radical, C1-6A haloalkyl group. 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, -SCH3、-SC2H5Formaldehyde group, -C (OCH)3) Cyano, nitro, -CF3、-OCF3Amino, 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.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, 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 present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs exist of the compounds of formula (I) and pharmaceutically acceptable salts thereof, the present invention 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 can be used.
The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound shown as a formula (I) (or pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials.
Detailed Description
In order to make the above-mentioned contents clearer and clearer, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated.
The synthesis scheme is as follows:
Figure BDA0003140797660000071
reacting the compound of the general formula (II) under an acidic condition to obtain the compound of the general formula (I).
Preparation of intermediate compound M1
Figure BDA0003140797660000072
4, 6-dichloro-3-methylpyridazine (1.3g,7.98mmol), 2, 4-dimethoxy-5-pyrimidineboronic acid (1.6g,8.77mmol), Pd (dppf) Cl2-CH2Cl2(325.64mg,398.76umol) and Cs2CO3(3.75g,11.96mmol) was mixed with dioxane (25mL) and water (5mL) and the mixture was heated to 70 ℃ under nitrogen protection. After 2h, TLC monitoring indicated complete reaction. Pouring the reaction solution into a proper amount of water, mixing uniformly, extracting with ethyl acetate for three times, washing with saturated saline solution, drying and concentrating to obtain a crude product. Column chromatography purification (PE: EA: 1) gave 1.1g of a white solid, i.e. compound M1(M + H)+:267、269)。
Example 1: synthesis of Compound 1 (5- (6-chloro-5-isopentylpyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000073
Step 1: synthesis of Compound 1-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2.0g) and 4-methylpentanoic acid (3.12g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (228mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (2.45g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 1.5g of a white solid, namely the compound 1-1.
Step 2: synthesis of Compound 1-2
A50 mL single-necked flask was charged with compound 1-1(700mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (587mg) dissolved in 1, 4-dioxane (6mL) and water (2mL), and K was added2CO3(442mg) and PdCl2(dppf)(46.7mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as an organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to obtain 400mg of a crude yellow solid, i.e., compound 1-2.
And step 3: synthesis of Compound 1
A25 mL single vial was charged with Compound 1-2(400mg) dissolved in 2mol/L hydrochloric acid (5mL) and reacted at 70 ℃ for 3 hours. Cooling to room temperature, separating out solid, filtering to obtain filter cake, pulping the filter cake with DCM, and drying to obtain white solid 90mg, namely compound 1 (purity 99.45%).
LCMS：[M+H]+＝295.20
1H NMR(500MHz,DMSO-d6)δ＝11.59(s,1H),11.55(s,1H),8.34(s,1H),8.30(s,1H),2.75-2.65(m,2H),1.70–1.58(m,1H),1.55-1.45(m,2H),0.94(d,J＝6.6Hz,6H).
Example 2: synthesis of Compound 2 (5- (5-butyl-6-chloropyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000081
Step 1: synthesis of Compound 2-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2.0g) and N-pentanoic acid (2.74g), dissolved in water (50mL), and mixed with concentrated sulfuric acid (1.5mL) under N2Silver nitrate (228mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (2.45g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 1.6g of a white solid, namely the compound 2-1.
Step 2: synthesis of Compound 2-2
A50 mL single-necked flask was charged with compound 2-1(700mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (627mg) dissolved in 1, 4-dioxane (6mL) and water (2mL), and K was added2CO3(707mg) and PdCl2(dppf)(50mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as an organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to give 440mg of a crude yellow solid, i.e., compound 2-2.
And step 3: synthesis of Compound 2
Compound 2-2(440mg) was added to a 25mL single-necked flask, dissolved in 2mol/L hydrochloric acid (5mL), and reacted at 70 ℃ for 3 hours. Cooling to room temperature, separating out solid, filtering to obtain filter cake, pulping the filter cake with DCM, and drying to obtain white solid 150mg, namely compound 2 (purity 98.03%).
LCMS：[M+H]+＝281.13
1H NMR(500MHz,DMSO-d6)δ＝11.58(s,1H),11.54(s,1H),8.34(s,1H),8.30(s,1H),2.77-2.67(m,2H),,1.64-1.53(m,2H),1.43-1.32(m,2H),0.92(t,J＝7.3Hz,3H).
Example 3: synthesis of Compound 3 (5- (5- (buten-1-yl) -6-chloropyridin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000091
Step 1: synthesis of Compound 3-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2g) and cyclopropylacetic acid (1.61g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (228mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (3.12g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 670mg of a white solid, namely the compound 3-1.
Step 2: synthesis of Compound 3-2
A50 mL single vial was charged with compound 3-1(670mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (667mg) dissolved in 1, 4-dioxane (6mL) and water (2mL), and K was added2CO3(524mg) and PdCl2(dppf)(48mg)，N2The reaction is carried out for 1h at the temperature of 60 ℃ under protection. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as the organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to give 450mg of a crude yellow solid, i.e., compound 3-2.
And step 3: synthesis of Compound 3
A25 mL single vial was charged with Compound 3-2(450mg) dissolved in 2mol/L hydrochloric acid (5mL) and reacted at 70 ℃ for 3 hours. The mixture is cooled to room temperature, solid is separated out, a filter cake is obtained by suction filtration, and the filter cake is beaten and dried by DCM to obtain 209mg of white solid, namely the compound 3 (the purity is 98.25%).
LCMS：[M+H]+＝279.14
1H NMR(500MHz,DMSO-d6)δ＝11.59(d,J＝5.7Hz,1H),11.55(s,1H),8.35(d,J＝6.3Hz,1H),8.32(s,1H),5.91-5.79(m,1H),5.12-4.97(m,2H),2.82(t,J＝7.5Hz,2H),2.39(dd,J＝14.5,7.1Hz,2H).
Example 4: synthesis of Compound 4 (5- (6-chloro-5- (cyclobutylmethyl) pyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000092
Step 1: synthesis of Compound 4-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2g) and cyclobutylacetic acid (2.3g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (285mg) and an aqueous ammonium persulfate (3.8g) solution (20mL) dissolved in water (10mL) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 650mg of a white solid, namely the compound 4-1.
Step 2: synthesis of Compound 4-2
A50 mL single-necked flask was charged with compound 4-1(650mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (605mg) dissolved in 1, 4-dioxane (6mL) and water (2mL), and K was added2CO3(476mg) and PdCl2(dppf)(44mg)，N2The reaction is carried out for 1h at the temperature of 60 ℃ under protection. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the product was isolated by column chromatography (PE: EA ═ 9:1) to give 400mg of a crude product as a yellow oil, i.e., compound 4-2.
And step 3: synthesis of Compound 4
A25 mL single vial was charged with Compound 4-2(400mg) dissolved in 2mol/L hydrochloric acid (5mL) and reacted at 70 ℃ for 3 h. The mixture is cooled to room temperature, solid is separated out, a filter cake is obtained by suction filtration, and the filter cake is beaten and dried by DCM to obtain 272mg of white solid, namely the compound 4 (the purity is 98.63%).
LCMS：[M+H]+＝293.3
1H NMR(500MHz,DMSO-d6)δ＝11.59(d,J＝5.7Hz,1H),11.55(s,1H),8.35(d,J＝6.2Hz,1H),8.25(s,1H),2.83(d,J＝7.5Hz,2H),2.75-2.60(m,1H),2.08-2.00(m,2H),1.95-1.80(m,2H),1.79-1.69(m,2H).
Example 5: synthesis of Compound 5 (5- (6-chloro-5- (cyclopentylmethyl) pyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000101
Step 1: synthesis of Compound 5-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2g) and cyclopentylacetic acid (2.06g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (228mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (3.05g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 700mg of a white solid, namely the compound 5-1.
Step 2: synthesis of Compound 5-2
A50 mL single-necked flask was charged with compound 5-1(700mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (605mg) dissolved in 1, 4-dioxane (6mL) and water (2mL), and K was added2CO3(827mg) and PdCl2(dppf)(44mg)，N2The reaction is carried out for 1h at the temperature of 60 ℃ under protection. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as the organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to give 500mg of crude yellow oil, i.e., compound 5-2.
And step 3: synthesis of Compound 5
A25 mL single vial was charged with Compound 5-2(500mg) dissolved in 2mol/L hydrochloric acid (5mL) and reacted at 70 ℃ for 3 hours. After cooling to room temperature, the solid precipitated out, and the filter cake was filtered off, and the filter cake was dried by beating with DCM to obtain 352mg of a white solid, Compound 5 (purity 97.58%).
LCMS：[M+H]+＝307.19
1H NMR(500MHz,DMSO-d6)δ＝11.59(d,J＝5.9Hz,1H),11.55(s,1H),8.35(d,J＝6.3Hz,1H),8.31(s,1H),2.73(d,J＝7.4Hz,2H),2.23-2.12(m,1H),1.77-1.59(m,4H),1.51(dd,J＝6.9,4.5Hz,2H),1.27-1.15(m,2H).
Example 6: synthesis of Compound 6 (5- (6-chloro-5- (cyclopropyldifluoromethyl) pyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000111
Step 1: synthesis of Compound 6-1
A50 mL three-necked flask was charged with 2-cyclopropyl-2, 2-difluoroacetic acid (365mg) and 2, 5-dichloropyridazine (200mg), dissolved in water (10mL), and mixed with concentrated sulfuric acid (0.2mL) under N2Silver nitrate (45mg) dissolved in water (2mL) and an aqueous solution (10mL) of ammonium dithionite (920mg) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, and separating a product by column chromatography (PE: EA is 10:1) to obtain 100mg of a colorless oily substance, namely the compound 6-1.
Step 2: synthesis of Compound 6-2
A50 mL three-necked flask was charged with compound 6-1(100mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (60mg) dissolved in 1, 4-dioxane (5mL) and water (1mL), and K was added2CO3(110mg) and PdCl2(dppf)(30mg)，N2The reaction is carried out for 3h at the temperature of 40 ℃ under protection. Cooling to room temperature, adding saturated saline (50mL) into the reaction solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, separating the product by column chromatography (PE: EA is 10:1) to obtain 50mg of white solid, namely compound 6-2。
And step 3: synthesis of Compound 6
In a 25mL single-necked flask, Compound 6-2(50mg) was added and dissolved in 1M hydrochloric acid (2mL) and reacted at 70 ℃ for 3 hours. After cooling to room temperature and suction filtration, 30mg of white solid, compound 6 (purity 99.26%) was obtained.
LCMS：[M+H]+＝315.
1H NMR(500MHz,DMSO-d6)δ＝11.72(s,1H),11.64(s,1H),8.63(s,1H),8.47(s,1H),2.05-1.85(m,1H),0.82-0.73(m,4H).
Example 7: synthesis of Compound 7 (5- (6-chloro-5- (1, 1-difluoropropyl) pyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000121
Step 1: synthesis of Compound 7-1
A50 mL three-necked flask was charged with 2, 2-difluorobutyric acid (250mg) and 2, 5-dichloropyridazine (200mg) dissolved in water (10mL), and concentrated sulfuric acid (0.2mL) was added thereto and mixed well under N2Silver nitrate (45mg) dissolved in water (2mL) and an aqueous solution (10mL) of ammonium dithionite (920mg) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying an organic phase with anhydrous sodium sulfate, and separating a product by column chromatography (PE: EA is 10:1) to obtain 100mg of a colorless oily substance, namely the compound 7-1.
Step 2: synthesis of Compound 7-2
A50 mL three-necked flask was charged with compound 7-1(100mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (70mg) dissolved in 1, 4-dioxane (5mL) and water (1mL), and K was added2CO3(100mg) and PdCl2(dppf)(30mg)，N2The reaction is carried out for 3h at the temperature of 40 ℃ under protection. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as an organic phase, and the product was separated by column chromatography (PE: EA ═ 10:1) to obtain 50mg of a white solid, i.e., compound 7-2.
And step 3: synthesis of Compound 7
In a 25mL single-necked flask, Compound 7-2(50mg) was added and dissolved in 1M hydrochloric acid (2mL) and reacted at 70 ℃ for 3 hours. After cooling to room temperature, 30mg of a white solid, Compound 7 (99.36% pure) was obtained by suction filtration.
LCMS：[M+H]+＝303.
1H NMR(500MHz,DMSO-d6)δ＝11.73(s,1H),11.64(s,1H),8.62(s,1H),8.49(s,1H),2.45-2.32(m,2H),0.96(t,J＝7.4Hz,3H).
Example 8: synthesis of Compound 8 ((E) -5- (5- (2-cyclopropylvinyl) -6-methylpyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000122
Step 1: synthesis of Compound 8-1
A50 mL three-necked flask was charged with Compound M1(50mg), (E) -2- (2-cyclopropylvinyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (55mg), potassium carbonate (65mg), Pd (dppf) Cl2(15mg), dioxane (5mL), water (1mL), N2And (4) protecting, and reacting for 4h at 70 ℃. The reaction solution was directly evaporated to dryness, and the product was isolated by column chromatography (PE: EA ═ 5:1) to give 50mg of a white solid, i.e., compound 8-1.
Step 2: synthesis of Compound 8
A25 mL single vial was charged with Compound 8-1(50mg), dissolved in 1M hydrochloric acid (2mL), and reacted at 70 ℃ for 3 h. After cooling to room temperature, the mixture was filtered with suction to obtain 30mg of a white solid, i.e., Compound 8 (purity 98.36%).
LCMS：[M+H]+＝271.
Example 9: synthesis of Compound 9 (5- (6-methyl-5-vinylpyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000131
Step 1: synthesis of Compound 9-1
Compound M1(80mg), vinyl boronic acid pinacol ester (92.40mg), XantPhos (17.36mg), Pd (OAc)2(3.37mg) andCs2CO3(293.22mg) was mixed with Water (0.4mL) and Tol (2mL), and the mixture was heated to 100 ℃ under nitrogen for 3 hours. The reaction solution was mixed with water, extracted with ethyl acetate, washed with saturated brine, dried and concentrated to give a crude product, which was purified by preparative TLC (PE: EA ═ 1:1) to give 70mg of a pale yellow solid, compound 9-1.
Step 2: synthesis of Compound 9
Compound 9-1(70mg) was added to the reaction flask, and 1M hydrochloric acid (2mL) was added to the flask to conduct reaction at 70 ℃ overnight. Cool to room temperature and suction filter to give crude product, purify by prep. TLC (DCM: MeOH ═ 10:1) to give 1.7mg of yellow solid, compound 9 (96% pure).
LCMS：[M+H]+＝231.
Example 10: synthesis of Compound 10 ((E) -5- (5- (but-1-en-1-yl) -6-chloropyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000132
Step 1: synthesis of Compound 10-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2.5g) and 2-pentenoic acid (2.52g), dissolved in water (50mL), and mixed with concentrated sulfuric acid (1.5mL) to give a mixture2Silver nitrate (285mg) and an aqueous ammonium persulfate (1.9g) solution (20mL) dissolved in water (10mL) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 70mg of a white solid, namely the compound 10-1.
Step 2: synthesis of Compound 10-2
A50 mL single-necked flask was charged with compound 10-1(70mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (76mg) dissolved in 1, 4-dioxane (2mL) and water (0.5mL), and K was added2CO3(48mg) and PdCl2(dppf)(5mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. Cooling to room temperature, adding saturated saline (5mL) into the reaction solution, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and separating the product by column chromatography (PE: E)A ═ 9:1), yielding 20mg of crude yellow solid, compound 10-2.
And step 3: synthesis of Compound 10
A25 mL single vial was charged with Compound 10-2(20mg) dissolved in 2mol/L hydrochloric acid (2mL) and reacted at 70 ℃ for 3 hours. After cooling to room temperature, a solid is precipitated and filtered to obtain a filter cake, and the filter cake is beaten and dried by DCM to obtain 0.92mg of a white solid, namely the compound 10 (the purity is 97.21%).
LCMS：[M+H]+＝279.11
Example 11: synthesis of Compound 11 ((E) -5- (6-chloro-5- (3-methylbut-1-en-1-yl) pyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000141
Step 1: synthesis of Compound 11-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (2.5g) and 4-methyl-2-pentenoic acid (2.87g), dissolved in water (50mL), and mixed with concentrated sulfuric acid (1.5mL) under stirring under N2Silver nitrate (285mg) and an aqueous ammonium persulfate (1.9g) solution (20mL) dissolved in water (10mL) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 110mg of a white solid, namely the compound 11-1.
Step 2: synthesis of Compound 11-2
A50 mL single-necked flask was charged with compound 11-1(110mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (115mg) dissolved in 1, 4-dioxane (3mL) and water (0.5mL), and K was added2CO3(74mg) and PdCl2(dppf)(8mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. After cooling to room temperature, the reaction mixture was added with saturated brine (10mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as an organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to obtain 50mg of a crude yellow solid, i.e., compound 11-2.
And step 3: synthesis of Compound 11
Compound 11-2(50mg) was added to a 25mL single-necked flask, dissolved in 2mol/L hydrochloric acid (4mL) and reacted at 70 ℃ for 3 hours. Cooling to room temperature, separating out solid, filtering to obtain filter cake, pulping the filter cake with DCM, and drying to obtain white solid 12mg, namely compound 11 (purity 99.79%).
LCMS：[M+H]+＝293.18
Example 12: synthesis of Compound 12 (5- (6-chloro-5-propylpyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000151
Step 1: synthesis of Compound 12-1
A500 mL three-necked flask was charged with the compound 2, 5-dichloropyridazine (2.5g) and N-butyric acid (2.37g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (228mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (1.9g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 1.5g of a white solid, namely the compound 12-1.
Step 2: synthesis of Compound 12-2
A50 mL single-necked flask was charged with Compound 12-1(700mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (674mg) dissolved in 1, 4-dioxane (10mL) and water (1mL), and K was added2CO3(506mg) and PdCl2(dppf)(53mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as the organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to obtain 450mg of a crude yellow solid, i.e., compound 12-2.
And step 3: synthesis of Compound 12
Compound 12-2(450mg) was added to a 25mL single-neck flask, dissolved in 2mol/L hydrochloric acid (8mL), and reacted at 70 ℃ for 3 hours. Cooling to room temperature, separating out solid, filtering to obtain filter cake, pulping the filter cake with DCM, and drying to obtain white solid 150mg, namely compound 12 (purity 99.45%).
LCMS：[M+H]+＝267.16
Example 13: synthesis of Compound 13 (5- (6-chloro-5-isobutylpyridazin-3-yl) pyrimidine-2, 4(1H,3H) -dione)
Figure BDA0003140797660000152
Step 1: synthesis of Compound 13-1
A500 mL three-necked flask was charged with 2, 5-dichloropyridazine (1.5g) and 3-methylbutyric acid (2.06g), dissolved in water (50mL), and concentrated sulfuric acid (1.5mL) was added thereto and mixed well under N2Silver nitrate (117mg) dissolved in water (10mL) and an aqueous solution (20mL) of ammonium persulfate (1.84g) were added dropwise at 70 ℃ in a protective oil bath, and the reaction was carried out at 70 ℃ for 1 hour. Cooling to room temperature, dropwise adding ammonia water into the reaction solution under ice bath, adjusting the pH value to 9, extracting with ethyl acetate, drying the organic phase anhydrous sodium sulfate, and separating the product by column chromatography (PE: EA: 94:6) to obtain 500mg of a white solid, namely the compound 13-1.
Step 2: synthesis of Compound 13-2
A50 mL single-necked flask was charged with compound 13-1(500mg) and 2, 4-dimethoxypyrimidine-5-boronic acid (674mg) dissolved in 1, 4-dioxane (10mL) and water (1mL), and K was added2CO3(337mg) and PdCl2(dppf)(36mg)，N2The reaction is carried out for 1h at the protection temperature of 50 ℃. After cooling to room temperature, the reaction mixture was added with saturated brine (50mL), extracted with ethyl acetate, dried over anhydrous sodium sulfate as an organic phase, and the product was isolated by column chromatography (PE: EA ═ 9:1) to give 100mg of a crude yellow solid, i.e., compound 13-2.
And step 3: synthesis of Compound 13
A25 mL single vial was charged with Compound 13-2(100mg) dissolved in 2mol/L hydrochloric acid (5mL) and reacted at 70 ℃ for 3 hours. After cooling to room temperature, the solid precipitates out, a filter cake is obtained by suction filtration, and the filter cake is dried by beating with DCM to obtain 36mg of white solid, namely compound 13 (purity 98.40%).
LCMS：[M+H]+＝281.15
The following examples were synthesized using the methods described above, or analogous methods using the corresponding intermediates.
Figure BDA0003140797660000161
Figure BDA0003140797660000171
Comparative example 1
Comparative compound 1 was synthesized according to the procedure of example 2 of WO2019168744a1,
Figure BDA0003140797660000172
pharmacological experiments
Example 1: detection of enzymatic Activity at cellular level
Calu-6 cells were digested using TM buffer (25mM Tris,5mM MgCl)2pH 7.5) and plated at 25000 cells in 96-well plates at 100. mu.L/well. TM buffer prepares compound solutions with gradient concentrations, and 50 μ L of test compound DMSO solutions with respective concentrations are added to each well cell, respectively, with the final concentrations of the compounds being 20000, 6666.7, 2222.2, 740.7, 246.9, 82.3, 27.4, 9.1, 3.0, 1.0, 0.3, 0nM (the final concentrations of DMSO are all 0.625%). Pre-incubating for 30min by using a constant-temperature horizontal shaking table at 37 ℃, adding 50 mu L of 800 mu M AMP solution into each hole, continuously incubating for 120min by using the constant-temperature horizontal shaking table at 37 ℃, centrifuging a 96-well plate, transferring 50 mu L of supernatant into a new 96-well plate for each hole, adding 50 mu L of 130 mu M ATP solution and 100 mu L of Cell-titer Glo working solution into each hole, incubating for 10min at room temperature after uniformly mixing by shaking, reading a Luminescence value by using a multifunctional microplate reader, and converting the Luminescence value reading into inhibition percentage:
percent inhibition (1-reading/max) 100.
"maximum" is DMSO control.
Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
The enzymatic IC50 data for the compounds of the examples at the Calu-6 cell level are shown in Table 1.
TABLE 1
Name of Compound IC50(nM) Name of Compound IC50(nM)
1 40.3 11 376
2 41.3 12 131
3 32.7 13 953
4 273 31 68
5 448 32 118
6 732 36 58
7 869 39 162
8 225 D1 49.1
10 68.9 D2 7256
The compounds of the invention have good activity. In addition, R is unexpectedly1Is C1-6When alkyl, said C1-6Alkyl quilt
Figure BDA0003140797660000181
The structural substitution (representing molecules 31 and 32) is significantly more active than the direct substitution by the phenyl structure (representing molecule D2).
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims.

Claims (10)

1. A compound of formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof:
Figure FDA0003140797650000011
wherein,
R1is selected from C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl radical, said C1-6Alkyl radical, C2-6Alkenyl or C2-6Alkynyl being unsubstituted or substituted by 1,2 or 3 substituents R3The substitution is carried out on the raw materials,
R3selected from hydroxy, amino, halogen, cyano, nitro, -ORa、-SRa、＝O、＝S、-C(O)-C0-3alkylene-Ra、-C(S)Ra、-C(O)ORa、-C(S)ORa、-C(O)N(Ra)2、-N(Ra)2、-S(O)2Ra、-O-S(O2)ORa、-O-S(O)2RaOr RaSaid R isaEach independently selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, RaUnsubstituted or further substituted by 1,2 or 3R4Substituted;
R4selected from hydroxy, amino, halogen, cyano, nitro, -ORb、-SRb、＝O、＝S、-C(O)Rb、-C(S)Rb、-C(O)ORb、-C(S)ORb、-C(O)N(Rb)2、-NHRb、-N(Rb)2、-S(O)2Rb、-O-S(O2)ORb、-O-S(O)2RbOr RbSaid R isbIs selected from C1-6Alkyl or C3-6Cycloalkyl radical, RbUnsubstituted or further substituted by one or more groups selected from halogen, hydroxy, C1-3Alkyl or cyano;
R2selected from hydrogen, halogen, cyano, C1-3Alkyl radical, C1-3Alkoxy radical, C2-4Alkenyl, halo C2-4Alkenyl or C2-4Alkynyl.
2. The compound of claim 1, tautomers thereof, deuteriumA substituent or a pharmaceutically acceptable salt thereof, characterized in that R1Is selected from C1-6Alkyl or C2-6Alkenyl radical, said C1-6Alkyl or C2-6Alkenyl unsubstituted or substituted by 1,2 or 3R3Substituted; the R is3Selected from halogen, hydroxy, C1-3Alkyl radical, C1-3Alkoxy, -C (O) -C1-3Alkyl radical, Ra、-C(O)-Raor-C (O) -C0-3alkylene-RaSaid R isaIs selected from C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, said RaUnsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
3. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is1Is selected from C1-6Alkyl or C2-6Alkenyl radical, said C1-6Alkyl or C2-6Alkenyl is unsubstituted or substituted by a member selected from halogen,
Figure FDA0003140797650000012
Figure FDA0003140797650000013
Is substituted with a substituent of (a), said
Figure FDA0003140797650000014
Is unsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
4. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R is1Is selected from C1-6An alkyl group, a carboxyl group,said C is1-6The alkyl radical being selected from
Figure FDA0003140797650000021
Is substituted with a substituent of (a), said
Figure FDA0003140797650000022
Figure FDA0003140797650000023
Is unsubstituted or further substituted by 1,2 or 3R4Substituted; the R is4Selected from hydroxy, amino, halogen, cyano, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group.
5. The compound, tautomer, deuteron or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R is2Is selected from C1-3Alkyl or halogen, preferably methyl or chlorine.
6. A compound, tautomer, deuteron, or pharmaceutically acceptable salt thereof, selected from:
Figure FDA0003140797650000031
7. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and at least one pharmaceutically acceptable excipient.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 for the manufacture of a medicament.
9. 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 1-6 or a pharmaceutical composition of claim 7.
10. A process for the preparation of a compound of general formula (I), a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof, according to claim 1, comprising:
Figure FDA0003140797650000041
reacting the compound of the general formula (II) under an acidic condition to obtain a compound of the general formula (I),
wherein R is1And R2Is as defined in claim 1.
CN202110739012.6A 2020-08-03 2021-06-30 CD73 inhibitor and application thereof in medicine Pending CN114057693A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010768662 2020-08-03
CN2020107686629 2020-08-03

Publications (1)

Publication Number Publication Date
CN114057693A true CN114057693A (en) 2022-02-18

Family

ID=80233280

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110739012.6A Pending CN114057693A (en) 2020-08-03 2021-06-30 CD73 inhibitor and application thereof in medicine

Country Status (1)

Country Link
CN (1) CN114057693A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023169327A1 (en) * 2022-03-07 2023-09-14 贝达药业股份有限公司 Crystal form of pyridazine derivative, and preparation method therefor and use thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023169327A1 (en) * 2022-03-07 2023-09-14 贝达药业股份有限公司 Crystal form of pyridazine derivative, and preparation method therefor and use thereof

Similar Documents

Publication Publication Date Title
CN114761408B (en) KRAS G12C inhibitor and application thereof in medicine
ES2426482T3 (en) IGF-1R inhibitor
JP7008064B2 (en) Heterocyclic compound as an FGFR4 inhibitor
EP3333157B1 (en) Vinyl compounds as fgfr and vegfr inhibitors
EP3354653B1 (en) Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof
EP3912975A1 (en) Lysophosphatidic acid receptor antagonists and preparation method therefor
WO2015140133A1 (en) Piperidine-dione derivatives
CN114685460A (en) KRAS G12C inhibitor and application thereof in medicines
CN108069959A (en) A kind of nitrogen-containing hetero cyclics, its preparation method, pharmaceutical composition and application
CN112390796A (en) KRAS G12C inhibitor and application thereof in medicines
WO2022194066A1 (en) Kras g12d inhibitor and applications thereof in medicine
IL305046A (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
CN115785068A (en) KIF18A inhibitors
CN114685488A (en) Compounds as SOS1 inhibitors and uses thereof
TWI801394B (en) Coumarin ring-like compounds as mek inhibitor and application thereof
CN115772159A (en) KIF18A inhibitors
CN116348118A (en) CD73 inhibitor and application thereof in medicine
CN115368382A (en) KRAS G12D inhibitor and application thereof in medicines
CN115702150A (en) CD73 inhibitor and application thereof in medicine
JP2012211085A (en) Hedgehog signal inhibitor
CN114057693A (en) CD73 inhibitor and application thereof in medicine
KR102420263B1 (en) Novel quinazoline redox derivatives and their use as bet inhibitors
CN113880804A (en) Novel benzimidazole compounds
TWI676625B (en) Sulfonamide derivatives, preparation method thereof and use thereof in medicine
CN116940581A (en) Novel protein degradation agent and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40060964

Country of ref document: HK

SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination