WO2023103898A1 - Composé ayant des activités inhibitrices de clk et de dyrk, son procédé de préparation et son utilisation - Google Patents

Composé ayant des activités inhibitrices de clk et de dyrk, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023103898A1
WO2023103898A1 PCT/CN2022/136149 CN2022136149W WO2023103898A1 WO 2023103898 A1 WO2023103898 A1 WO 2023103898A1 CN 2022136149 W CN2022136149 W CN 2022136149W WO 2023103898 A1 WO2023103898 A1 WO 2023103898A1
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alkyl
preparation
oxy
halogenated
alkoxy
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PCT/CN2022/136149
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English (en)
Chinese (zh)
Inventor
阳安乐
何权鸿
王志
张德伟
李泽睿
余攀
池哲鑫
杨旭东
胡东杰
鲜嘉陵
沈欢
孟江
唐元清
唐军
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赛诺哈勃药业（成都）有限公司
成都倍特药业股份有限公司
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Publication of WO2023103898A1 publication Critical patent/WO2023103898A1/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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • X 1 and X 2 are each independently CH 2 , O, NH, or S;
  • X 3 , X 4 , X 5 , X 6 , X 7 are each independently CR 6 or N;
  • R 10 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, or hydroxy substituted C 1 -C 6 alkyl;
  • W 1 and W 2 are each independently CR 12 R 13 , O, or S;
  • R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, -C(O)NH 2 , or -NHC(O)R 10 , R 10 is C 1 -C 3 alkyl, or halogenated C 1 -C 3 alkyl.
  • W 1 and W 2 are each independently CR 12 R 13 , O, S;
  • CR 12 R 13 , O, S, R 12 and R 13 are each independently H, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, halogenated C 1 to C 3 alkyl, or -C (O) NH2 ;
  • R a and R b are each independently H, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, a halogenated C 1 to C 3 alkyl, or the carbon atom to which R a and R b are connected form three- to six-membered rings;
  • n 1, 2, or 3.
  • X 1 , X 6 , X 8 , R 1 , L are as defined above;
  • R 14 is H, halogen, hydroxyl, amino, -C(O)NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, or hydroxyl Substitute C 1 -C 6 alkyl.
  • the CLK inhibitor is selected from one or more of CLK1, CLK2 and CLK4 inhibitors.
  • the fibrotic disease is selected from pulmonary fibrosis, cutaneous fibrosis, scleroderma, progressive systemic fibrosis, glomerulosclerosis, glomerulonephritis, hypertrophic scarring, uterine Fibrosis, renal fibrosis, cirrhosis, hepatic fibrosis, abdominal adhesions, pelvic adhesions, spinal adhesions, tendon adhesions, chronic obstructive pulmonary disease, fibrosis after myocardial infarction, fibrosis associated with diffuse or interstitial lung disease, and Scarring, central nervous system fibrosis, post-stroke fibrosis, fibrosis associated with neurodegenerative diseases such as Alzheimer's or multiple sclerosis, fibrosis associated with proliferative vitreoretinopathy, restenosis, intrauterine Membranous disease, ischemic disease, and radiation fibrosis.
  • pulmonary fibrosis cutaneous fibrosis, scleroderma
  • the metabolic disease is selected from one or more of type I and type II diabetes, abnormal metabolism of folic acid and methionine, Duchenne muscular dystrophy, and gout.
  • One or more embodiments of the present application provide a preparation method of a compound of formula (II), comprising the following steps:
  • Y 2 is H, 4-methoxybenzyl, tetrahydropyranyl, or benzyl;
  • the base is cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, or sodium tert-butoxide.
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , W 1 , W 2 , m1 are as defined above;
  • Y is H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl, benzoyl, pivaloyl, tert-butoxycarbonyl, or benzyloxycarbonyl;
  • Y is H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, or benzoyl;
  • Y3 is H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, or methyl sulfone.
  • One or more embodiments of the present application provide the compound represented by formula (I'), or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, Diastereomers or their mixtures, or their pharmaceutically acceptable salts, deuterated substances:
  • CR 12 R 13 O, S, R 12 and R 13 are each independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, -C( O) NH 2 ;
  • R a and R b are each independently selected from H, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, halogenated C 1 to C 3 alkyl or R a and R b with The connected carbon atoms together form a three- to six-membered ring; m2, m3, m4, n1, n2, and n3 are selected from 0, 1, 2, and 3; further, W 1 and W
  • CR 12 R 13 , O, S, R 12 and R 13 are each independently selected from H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, -C( O) NH 2 ;
  • R a and R b are each independently selected from H, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, halogenated C 1 to C 3 alkyl or R a and R b with
  • the connected carbon atoms together form a three- to six-membered ring;
  • m2, m3, m4, n1, n2, and n3 are selected from 0, 1,
  • X 1 , X 3 , X 4 , X 5 , X 6 , X 8 , R 1 , W 1 , W 2 , R a , R b , and m1 are as defined above.
  • One or more embodiments of the present application provide the compound of the following structure, or its tautomers, cis-trans isomers, mesoforms, racemates, enantiomers, diastereoisomers body or its mixture, or its pharmaceutically acceptable salt, deuterated substance:
  • One or more embodiments of the present application provide the use of the compound of the present application in the preparation of DYRK1a and/or CLK inhibitor drugs.
  • One or more embodiments of the present application provide a synthetic method of the compound of the present application, comprising the following steps:
  • Y is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy;
  • Y is selected from H, 2-(trimethylsilyl)ethoxymethyl, 4-methylbenzenesulfonyl;
  • the organic solvent is selected from N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, acetonitrile;
  • X1 is NH or O
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b , W 1 , W 2 , m1 are as defined above;
  • Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, benzoyl;
  • Y2 is selected from H, 4-methoxybenzyl, tetrahydropyranyl, benzyl, tert-butyldimethylsilyl, benzoyl;
  • Y is selected from H, halogen, methylsulfonyloxy, 4-methylbenzenesulfonyloxy, trifluoromethanesulfonyloxy, 4-nitrobenzenesulfonyloxy, trifluoroethoxy, methyl Sulfone group.
  • ring refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heterocycloalkyl), aryl), non-aromatic (such as cycloalkyl or heterocycloalkyl). Rings may be optionally substituted and may be monocyclic or polycyclic. Typical polycyclic rings generally include bicyclic and tricyclic rings.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.
  • heterocycloalkyl groups can also be represented by commonly understood structural formulas, for example
  • cyano refers to -CN.
  • aryl refers to a 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered) all-carbon monocyclic or fused polycyclic ring (also are ring) groups sharing adjacent pairs of carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl. Phenyl is more preferred.
  • Treatment is intended to alleviate or eliminate the disease state or disorder being addressed. If the subject has received a therapeutically effective amount of the compound, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof according to the method described in this application , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and the subject shows an observable and/or detectable reduction or improvement in one or more of the signs and symptoms, the subject is Successfully "cured”. It should also be understood that reference to treatment of a disease state or disorder includes not only complete treatment, but also incomplete treatment while achieving some biologically or medically relevant result.
  • KSAc represents potassium thioacetate
  • H 2 O means water
  • PPTS means pyridinium 4-methylbenzenesulfonate
  • NaSMe sodium methyl mercaptide
  • XPhos means 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl
  • Xantphos means 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
  • KBr represents potassium bromide
  • NaOH sodium hydroxide
  • TLC means thin layer chromatography
  • Prep-HPLC refers to the preparation of high performance liquid chromatography
  • M refers to the molar concentration unit mol/L, for example, 2M refers to 2mol/L;
  • N refers to the equivalent concentration, for example, 1N HCl refers to hydrochloric acid with a concentration of 1mol/L; 2N NaOH refers to sodium hydroxide with a concentration of 2mol/L.
  • Step 1 Preparation of methyl (5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methylsulfonate
  • Step 1 Preparation of 3-(azidomethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyridine
  • Step 2 Preparation of ethyl 6-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyrazine-2-carboxylate
  • Step 3 N 4 -((4-((tert-butyldimethylsilyloxy)methyl)pyrimidin-2-yl)methyl)-5-(3-((4-methoxybenzyl) Preparation of oxy)quinolin-6-yl)-N 2 -methyl-7-p-tolyl-7H-pyrrole[2,3-d]pyrimidine-2,4-diamine
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.
  • Step 1 6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy)-2-chloro-7 -((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-((tetrahydro-2H-pyran -2-yl)oxyl)quinoline preparation
  • Step 3 2-((5-(((2-(methylamino)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)quinolin-6-yl)-7 -((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl) Preparation of oxy)ethan-1-ol
  • Step 1 (2-(2-((6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)oxy ) ethoxy) pyridin-4-yl) the preparation of methanol
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials, and using a preparation method similar to that of Preparation Example 28 above.
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 33.
  • Step 4 Preparation of N-(5-iodo-4-(methylsulfonyl)-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide
  • Step 5 N-(4-(((5-hydroxypyridin-3-yl)methyl)amino)-5-iodo-7-tolyl-7H-pyrrolo[2,3-d]pyrimidine-2- Base) the preparation of cyclopropanecarboxamide
  • N-(5-iodo-4-(methylsulfonyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide (100.0 mg) was dissolved in N,N-Dimethylformamide (1 mL), triethylamine (36.0 mg) and 5-(aminomethyl)pyridin-3-ol (43.0 mg) were added and reacted at room temperature for 2 hours.
  • Step 6 N-(4-((5-hydroxypyridin-3-yl)methyl)amino)-5-(3-((4-methoxybenzyl)oxy)quinolin-6-yl) - Preparation of 7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)cyclopropanecarboxamide
  • Step 1 3-(Benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy
  • Step 2 3-(Benzyloxy)-6-(4-((5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)pyridin-3-yl)methoxy Base)-2-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)quinoline preparation of
  • Step 3 2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethan-1-ol
  • Step 4 2-((5-(((5-(3-(benzyloxy)quinolin-6-yl)-2-methoxy-7-((2-(trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)methyl)pyridin-3-yl)oxy)ethyl methanesulfonate
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.
  • the title compound was prepared by using the corresponding commercial reagents and the product in the aforementioned Preparation Example as raw materials and using a similar preparation method to the aforementioned Preparation Example 31.
  • Step 3 Preparation of ethyl 2-(6-((4-methoxybenzyl)oxy)quinolin-3-yl)acetate
  • Step 7 (5-(4-(6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Preparation of pyrimidin-5-yl)quinolin-3-yl)butyl)pyridin-3-yl)methanol
  • Step 3 Preparation of ethyl 2-(6-(benzyloxy)quinolin-3-yl)acetate

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  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé ayant une structure macrocyclique. De façon spécifique, l'invention concerne un composé ayant une structure macrocyclique de formule (I), ou un sel pharmaceutiquement acceptable ou une forme deutérée de celui-ci, ainsi qu'un procédé de préparation de tels composés. Ce type de composés a des effets inhibiteurs sur DYRK et/ou CLK.
PCT/CN2022/136149 2021-12-07 2022-12-02 Composé ayant des activités inhibitrices de clk et de dyrk, son procédé de préparation et son utilisation WO2023103898A1 (fr)

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CN202111482108 2021-12-07

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020006115A1 (fr) * 2018-06-26 2020-01-02 Betty Tam Méthodes de traitement du cancer à l'aide d'un inhibiteur de clk
WO2020150552A2 (fr) * 2019-01-17 2020-07-23 Samumed, Llc Procédés de traitement de troubles du cartilage par inhibition de clk et dyrk
WO2021091982A1 (fr) * 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020006115A1 (fr) * 2018-06-26 2020-01-02 Betty Tam Méthodes de traitement du cancer à l'aide d'un inhibiteur de clk
WO2020150552A2 (fr) * 2019-01-17 2020-07-23 Samumed, Llc Procédés de traitement de troubles du cartilage par inhibition de clk et dyrk
WO2021091982A1 (fr) * 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IWAI KENICHI; YAGUCHI MASAHIRO; NISHIMURA KAZUHO; YAMAMOTO YUKIKO; TAMURA TOSHIYA; NAKATA DAISUKE; DAIRIKI RYO; KAWAKITA YOICHI; M: "Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability.", EMBO MOLECULAR MEDICINE (ONLINE), WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 10, no. 6, 31 May 2018 (2018-05-31), DE , pages 1 - 15, XP009535850, ISSN: 1757-4684, DOI: 10.15252/emmm.201708289 *

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