WO2022007677A1 - Inhibiteur de cd73 et son application en utilisation pharmaceutique - Google Patents

Inhibiteur de cd73 et son application en utilisation pharmaceutique Download PDF

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Publication number
WO2022007677A1
WO2022007677A1 PCT/CN2021/103508 CN2021103508W WO2022007677A1 WO 2022007677 A1 WO2022007677 A1 WO 2022007677A1 CN 2021103508 W CN2021103508 W CN 2021103508W WO 2022007677 A1 WO2022007677 A1 WO 2022007677A1
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WIPO (PCT)
Prior art keywords
compound
alkyl
synthesis
reaction
mixed
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PCT/CN2021/103508
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English (en)
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
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贝达药业股份有限公司
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Priority to CN202180043145.8A priority Critical patent/CN115702150A/zh
Publication of WO2022007677A1 publication Critical patent/WO2022007677A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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

Definitions

  • the present invention relates to a CD73 inhibitor having cancer therapeutic activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
  • Extracellular 5'-nucleotidase is a cell membrane glycoprotein that exists on the cell membrane surface of a variety of cell types, including endothelial cells, lymphocytes, stromal cells, and tumor cells Wait.
  • CD73 can catalyze the production of adenosine from extracellular 5'-phosphate adenosine (5'-AMP), and adenosine can induce immunosuppressive effects and promote tumor proliferation and/or metastasis.
  • CD73 can also promote tumorigenesis through non-immune-related mechanisms, such as promoting tumor angiogenesis and promoting tumor cell adhesion to extracellular matrix proteins.
  • CD73 has been found to be an independent prognostic factor in prostate cancer and triple-negative breast cancer patients.
  • the present invention will provide a novel structure of small molecule CD73 inhibitor with good antitumor activity.
  • the present invention provides a compound represented by general formula (I), its tautomer or pharmaceutically acceptable salt:
  • R 1 is selected phenyl or 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl unsubstituted or substituted with 1, 2 or 3 substituents substituted by R 3,
  • R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
  • the Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  • R 1 in formula (I) is selected from phenyl or 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl optionally contains 1 or 2 independently selected A heteroatom from N, O or S, and the heteroaromatic ring group is unsubstituted or substituted with 1, 2 or 3 substituents R 3 ; preferably R 1 is selected from Said R 1 is unsubstituted or substituted with 1, 2 or 3 substituents R 3 .
  • R 3 in formula (I) is meta-substituted.
  • R 2 in formula (I) is selected from halogen, C 1-3 alkyl or C 1-3 alkoxy; preferably chloro, methyl or methoxy.
  • the compound of formula (I) is selected from the compounds of general formula (IA):
  • X 1 is selected from N or CH;
  • X 2 is selected from N or CH;
  • R 3 is selected from C 1-6 alkyl, -(C 1-4 alkylene) 0-1 -Cyc, -O-(C 1-4 alkylene) 0-1 -Cyc, -S-(C 1-4 alkylene) 0-1 -Cyc, -NH-(C 1-4 alkylene) 0-1 -Cyc, -NH-C 1-6 alkyl, -N(C 1-6 alkyl ) 2 , -OC 1-6 alkyl or -SC 1-6 alkyl, R 3 is optionally unsubstituted or further substituted by one or more R 4 substituents;
  • the Cyc is selected from C 3-10 cycloalkyl, 3-10-membered heterocyclic group, C 6-10 aryl or 5-10-membered heteroaryl, the C 3-10 cycloalkyl, 3-10-membered Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents R 5 ;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, halogenated C 2-4 alkenyl or C 2-4 alkynyl.
  • formula (I) is selected from:
  • the method of synthesizing formula (I) comprises:
  • R 1 and R 2 are defined as described in formula (I).
  • the present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
  • the present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
  • the present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
  • the application is in the preparation of a drug for treating and/or preventing cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cells tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes 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-hexyl, 2-methylpentyl, etc.
  • a "C1-8 alkyl group” in the "1-8” refers to a straight or branched chain radical form with 7 or 8 carbon atoms arranged group.
  • C 1-3 alkylene refers to a linear or branched divalent saturated hydrocarbon group.
  • methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene For example methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • C 2-6 alkenyl or “C 2-6 alkynyl” refers to a straight or branched chain unsaturated hydrocarbon group.
  • Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring.
  • the aryl group is a 6- to 10-membered monocyclic or bicyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable ring system consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S, which is Saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents comprising 3 to 20 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively quaternized .
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • heteroaryl in the present invention, unless otherwise specified, 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
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, 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.
  • 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 .
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby 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 and pharmaceutically acceptable salts thereof.
  • substitution of compounds of formula (I) with heavier isotopes may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention. In addition, some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • step 1
  • reaction solution was poured into an appropriate amount of water and mixed, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain a brown solid (136 mg), namely compound 16-1 (M+H + : 298, 454). Used directly in the next step without purification.
  • Example 15 Synthesis of Compound 15 (5-(5-(1-(4-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 18 Synthesis of Compound 18 (5-(5-(1-(3-methoxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 28 Synthesis of Compound 28 (5-(6-methyl-5-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-pyrrol-3-yl) Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione)
  • Example 30 Synthesis of Compound 30 (5-(6-methyl-5-(1-((5-methylpyridin-2-yl)methyl)-1H-pyrrol-3-yl)pyridazine-3 -yl)pyrimidine-2,4(1H,3H)-dione)
  • Example 33 Compound 33 (5-(5-(1-(4-hydroxybenzyl)-1H-pyrrol-3-yl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H Synthesis of ,3H)-diketone)
  • Example 37 Synthesis of Compound 37 (5-(5-(3-(4-methoxybenzyl)-1H-pyrrol-1-yl)-6-methylpyridazin-3-yl)pyrimidine-2 ,4(1H,3H)-dione)
  • Example 40 Synthesis of Compound 40 (5-(5-(1-(4-methoxybenzyl)-1H-pyrazol-3-yl)-6-methylpyridazin-3-yl)pyrimidine- 2,4(1H,3H)-dione)
  • Example 41 Synthesis of Compound 41 (5-(6-methyl-5-(1-(2-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
  • Example 42 Synthesis of Compound 42 (5-(6-methyl-5-(1-(3-(trifluoromethoxy)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl )pyrimidine-2,4(1H,3H)-dione)
  • Example 44 Synthesis of Compound 44 (3-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)benzoic acid methyl ester)
  • Example 47 Synthesis of Compound 47 (5-(5-(1-(3-(difluoromethyl)benzyl)-1H-pyrrol-3-yl)-6-methylpyridin-3-yl)pyrimidine -2,4(1H,3H)-dione)
  • Example 50 Synthesis of compound 50 (6-((3-(6-(2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methylpyridazine -4-yl)-1H-pyrrol-1-yl)methyl)nicotinonitrile)
  • Example 51 Synthesis of Compound 51 (5-(6-methyl-5-(1-(3-methylbenzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione)
  • Example 54 Synthesis of Compound 54 (5-(6-methyl-5-(1-(4-(methylsulfonyl)benzyl)-1H-pyrrol-3-yl)pyridazin-3-yl)pyrimidine -2,4(1H,3H)-dione)
  • Example 1 Detection of enzymatic activity at the cellular level
  • Calu-6 cells were digested, resuspended in TM buffer (25 mM Tris, 5 mM MgCl 2 , pH 7.5), and plated in a 96-well plate at 25,000 cells and 100 ⁇ L/well.
  • TM buffer was used to prepare compound solutions with gradient concentrations, and 50 ⁇ L of DMSO solutions of the compounds to be tested were added to the cells in each well. 0.3, 0 nM (the final concentration of DMSO is 0.625%).
  • Pre-incubate for 30 min on a constant temperature horizontal shaker at 37 °C add 50 ⁇ L of 800 ⁇ M AMP solution to each well, and continue to incubate at 37 °C for 120 min on a constant temperature horizontal shaker, then centrifuge the 96-well plate and transfer 50 ⁇ L of supernatant per well to a new 96-well plate. , add 50 ⁇ L of 130 ⁇ M ATP solution and 100 ⁇ L of Cell-titer Glo working solution to each well, shake and mix, incubate at room temperature for 10 min, read the Luminescence luminescence value with a multi-function microplate reader, and convert the luminescence value reading into inhibition percentage:
  • Max is the DMSO control.
  • R & inter-group substituents of the present invention is 3-substituted compound of the ortho-substituted compound, significantly enhanced activity (Table 2).

Abstract

L'invention concerne un nouveau composé ayant une activité curative contre le cancer. L'invention concerne également un procédé de préparation du composé et une composition pharmaceutique contenant le composé.
PCT/CN2021/103508 2020-07-07 2021-06-30 Inhibiteur de cd73 et son application en utilisation pharmaceutique WO2022007677A1 (fr)

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CN202180043145.8A CN115702150A (zh) 2020-07-07 2021-06-30 Cd73抑制剂及其在医药上的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2017120508A1 (fr) * 2016-01-08 2017-07-13 Arcus Biosciences, Inc. Modulateurs de l'ecto-5 '-nucléotidase et leur utilisation
WO2019168744A1 (fr) * 2018-03-01 2019-09-06 Eli Lilly And Company Inhibiteurs de cd73

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017120508A1 (fr) * 2016-01-08 2017-07-13 Arcus Biosciences, Inc. Modulateurs de l'ecto-5 '-nucléotidase et leur utilisation
WO2019168744A1 (fr) * 2018-03-01 2019-09-06 Eli Lilly And Company Inhibiteurs de cd73

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YA-PING GONG, WAN REN-ZHONG, LIU ZHAO-PENG: "Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 28, no. 2, 1 February 2018 (2018-02-01), GB , pages 167 - 171, XP055584044, ISSN: 1354-3776, DOI: 10.1080/13543776.2018.1407756 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

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