WO2021078020A1 - Composé à petites molécules - Google Patents

Composé à petites molécules Download PDF

Info

Publication number
WO2021078020A1
WO2021078020A1 PCT/CN2020/120130 CN2020120130W WO2021078020A1 WO 2021078020 A1 WO2021078020 A1 WO 2021078020A1 CN 2020120130 W CN2020120130 W CN 2020120130W WO 2021078020 A1 WO2021078020 A1 WO 2021078020A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
group
compound
tdm
alkyl
Prior art date
Application number
PCT/CN2020/120130
Other languages
English (en)
Chinese (zh)
Inventor
邢莉
李冠群
王晓磊
蔡雨婷
姜翔
潘翔
朱文浩
汪杨
王增全
Original Assignee
嘉兴特科罗生物科技有限公司
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 嘉兴特科罗生物科技有限公司 filed Critical 嘉兴特科罗生物科技有限公司
Publication of WO2021078020A1 publication Critical patent/WO2021078020A1/fr

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
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the proliferating keratinocytes also synthesize and secrete inflammatory cytokines such as IL-1b, IL-6 and TNF- ⁇ , thereby further aggravating the inflammation of the skin, forming a vicious circle .
  • Activated DCs in psoriatic lesions produce IL-21 and IL-23, the latter stimulates T cells in the epidermis to produce specific cytokines IFN ⁇ and IL-17, Th17 cells induce horns by secreting IL-17 and IL-22
  • Prion cells produce inflammatory factors that have chemotactic effects on neutrophils, such as IL-8, CCL20, GM-CSF (Granulocyte-macrophage colony stimulating factor) and anti-microbial peptides (anti-microbial peptides), resulting in neutrophils
  • This psoriasis is a characteristic pathological phenomenon that gathers in the stratum corneum of hypokeratosis.
  • cytokine-mediated signal transduction system recruits STAT (signal transmitter and activator of transcription proteins) through the activation of JAK family members JAK1, JAK2, JAK3 and TYK2 tyrosine kinases, phosphorylation of cytokine receptors, Eventually, gene expression in cells affects cell biological functions.
  • the pairing between JAK members is directly related to upstream cytokines.
  • JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2, JAK2/JAK2, and JAK1 pairing is the most common.
  • the present invention has developed a series of highly effective and specific JAK kinase inhibitors, especially for Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 dual inhibitors, and/or Tyk2/Jak2 dual inhibitors. It is suitable for the treatment of various systemic autoimmune diseases and inflammatory skin diseases, such as psoriasis or eczema as the preferred indication.
  • R when R is a substituted alkyl group, it can be several types of compounds as shown in the following structures:
  • n 1, 2, 3...a natural number; preferably within 6.
  • R 1 is a heterocycloalkyl group, such as a four-membered, five-membered, six-membered heterocyclic ring of aza, oxa, or thia.
  • One or more hydrogen atoms on the ring of the heterocycloalkyl group may be an alkyl group , Cyano, halogen, haloalkane, the specific structure can be a compound shown in the following structural formula:
  • R can also be That is, the methyl group has three substituents, which are substituted by R 2 , R 3 and -C(O)-R 1 ;
  • R can also be That is, two hydrogens on the methyl group form an alkyl ring through a bridge bond, and the other hydrogen is replaced by -C(O) -R 1;
  • the above R is a nitrogen-containing group.
  • R 1 is hydrogen or an alkyl group (e.g. generally refers to an alkyl group with carbon atoms not greater than 6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, etc.);
  • R 4 is the same as R 2 .
  • R when R is a substituted amide group, it can be several types of compounds as shown in the following structures:
  • JAK inhibitors, Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 dual inhibitors obtained in the present invention suitable for oral or intravenous administration can still be used to treat psoriasis and other autoimmunity Sexual diseases such as RA, IBD, MS, etc.
  • the compound 15f (50mg, 0.175mmol), N,N-diisopropylethylamine (52mg, 0.40mmol) and N,N-dimethylformamide (5mL) were added to a single-necked flask and stirred for 5min. Under the condition of 20°C, 15g of the compound, namely 2,2,2-trifluoroethylamine (20mg, 0.20mmol) and HATU (77mg, 0.20mmol) were added to the single-necked flask and reacted at room temperature for 16h. The reaction solution was poured into water, and a white solid precipitated out.
  • Yellow solid compound TDM-180624 is N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-1H-pyrazol-4-yl)propane -1-sulfonamide (14mg, yield: 19.8%)
  • Embodiment eleven the general method of synthesizing compound TDM-180634
  • the yellow solid compound TDM-180605 is N-(1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)ethyl Sulfonamide (38mg, yield: 28.1%)
  • TDM-180747 White solid compound 147 is 3,3,3-trifluoro-N-(3-methyl-1-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine- 4-yl)-1H-pyrazol-4-yl)propionamide (29.9 mg, yield: 26.6%).
  • Embodiment Twenty-four General method for synthesizing compound TDM-180698
  • TDM-180705 white solid compound 105 that is N-ethyl-3,3,3-trifluoro-N-(1-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-4- Yl)-1H-pyrazol-4-yl)propionamide (17.4mg, yield: 41.7%)
  • the compound 117a (50.0 mg, 0.195 mmol) was dissolved in dichloromethane (10 mL), the compound 117b (21.5 mg, 0.215 mmol) and acetic acid (0.2 mL) were added, and the mixture was stirred at room temperature for 15 minutes. Then sodium triacetylborohydride (49.6 mg, 0.234 mmol) was added. The reaction solution was stirred for another 3 hours at room temperature. The reaction solution was poured into water (20 mL), the pH was adjusted to near neutral with sodium bicarbonate, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (15 mL ⁇ 2).
  • Embodiment 28 General method for synthesizing compound TDM-180699
  • TDM-180700 Off-white solid compound 100 (3,3-difluoropyrrolidin-1-yl)(1-(4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine -4-yl)-1H-pyrazol-1-yl)cyclopropyl)methanone (85mg, yield 79%)
  • Embodiment 30 General method for synthesizing compound TDM-180737
  • Janus kinases include JAK1, JAK2, JAK3 and Tyk2, which transduce cytokine-mediated signals through the JAK-STAT pathway.
  • the size of the kinase is 120-140kDa, and there are 7 identified homology regions, JH1-JH7.
  • JH1 is an important region of enzyme activity, which contains typical tyrosine kinase characteristics. The phosphorylation of tyrosine leads to a change in the conformation of JAK protein, thereby promoting substrate binding.
  • the JAK-STAT system consists of three main parts: receptors that pass through the cell membrane, Janus kinases connected to the receptors, and signal transduction and transcription activators (STAT) that transmit signals to the nucleus and DNA.
  • STAT signal transduction and transcription activators
  • PerkinElmer's EZReader can be used to detect the phosphorylation of peptide substrates catalyzed by kinases.
  • the device is based on micro-controlled fluid separation technology and can directly detect fluorescently labeled substrates and products.
  • the separation step is achieved by controlling the pressure and electric field strength in the microfluidic chip .
  • Kinase experiments are generally controlled at a product conversion rate of 20-30%. This biological test method is used to identify the inhibitory effects of compounds on JAK kinase activity.
  • Stop Buffer 180mM HEPES buffer, 20mM ethylenediaminetetraacetic acid, 0.2% Coating Reagent 3.
  • Separation Buffer 100mM HEPES buffer, 10mM ethylenediaminetetraacetic acid, 0.0005% Tween 20, 0.1% Coating Reagent 3,1% dimethyl sulfoxide.
  • the final concentrations of JAK1, JAK2, JAK3 and Tyk2 kinases in the reaction system are 20, 1, 1, and 1 nM, respectively.
  • the graphing software Xlfit was used to make the concentration curve of the test compound and calculate the IC50 value.

Landscapes

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

Abstract

La présente invention concerne un composé à petites molécules, ayant une structure représentée par la formule générale moléculaire suivante (I), dans laquelle X1 et X2 sont choisis parmi carbone ou azote ; un ou plusieurs carbones dans A1, A2, A3, A4 et A5 sont substitués par de l'azote, du soufre ou de l'oxygène ; un cycle à cinq chaînons formé par A1, A2, A3, A4 et A5 présente des propriétés aromatiques ; un ou plusieurs atomes d'hydrogène sur le cycle à cinq chaînons sont substitués par R ; R est choisi dans un groupe constitué par l'hydrogène, halogène, alkyle, alkyle substitué, amino, amino substitué, carboxyle, acylamino, acylamino substitué, carbonyle substitué, groupe ester, groupe ester substitué, cycloalkyle, cycloalkyle substitué, hétérocycloalkyle, hétérocycloalkyle substitué, aryle, aryle substitué, hétéroaryle et hétéroaryle substitué. Le composé à petites molécules selon la présente invention peut servir d'inhibiteur efficace et spécifique de kinase Jak, en particulier, un inhibiteur de Tyk2, et/ou un inhibiteur de JAK1, et/ou un inhibiteur double de Tyk2/JAK1, et/ou un inhibiteur double de Tyk2/JAK2.
PCT/CN2020/120130 2019-10-24 2020-10-10 Composé à petites molécules WO2021078020A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911019187.9A CN110734428A (zh) 2019-10-24 2019-10-24 一种小分子化合物
CN201911019187.9 2019-10-24

Publications (1)

Publication Number Publication Date
WO2021078020A1 true WO2021078020A1 (fr) 2021-04-29

Family

ID=69271268

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/120130 WO2021078020A1 (fr) 2019-10-24 2020-10-10 Composé à petites molécules

Country Status (2)

Country Link
CN (1) CN110734428A (fr)
WO (1) WO2021078020A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264919A (zh) * 2021-05-26 2021-08-17 无锡捷化医药科技有限公司 一种1-（2-甲氧基吡啶-4-基）-1h-吡唑-4-胺的制备方法
WO2023060202A1 (fr) * 2021-10-06 2023-04-13 Aerie Pharmaceuticals, Inc. Composés de pyrazole inhibiteurs de janus kinase et leurs utilisations
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110734428A (zh) * 2019-10-24 2020-01-31 嘉兴特科罗生物科技有限公司 一种小分子化合物
CN112159394B (zh) * 2020-10-09 2021-10-22 嘉兴特科罗生物科技有限公司 一种作为jak激酶抑制剂的小分子化合物及其用途
CN114907353A (zh) * 2021-02-09 2022-08-16 明慧医药（杭州）有限公司 一种前药化合物及其制备方法和用途
WO2023001045A1 (fr) * 2021-07-20 2023-01-26 上海椿安生物医药科技有限公司 Anti-inflammatoire externe couplant un composé et un médicament, son procédé de préparation et son utilisation
CN113603677B (zh) * 2021-08-06 2022-06-14 嘉兴特科罗生物科技有限公司 一种具有高口服生物利用度的jak抑制剂

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007053776A1 (fr) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Modulateurs de kinase de type pyrimidinylthiophène
CN103298794A (zh) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 作为tyk2抑制剂的吡啶化合物及其氮杂类似物
WO2016014542A1 (fr) * 2014-07-21 2016-01-28 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'imidazolyl kinase et leurs utilisations
CN110191884A (zh) * 2016-10-14 2019-08-30 拜耳公司 取代的6-(1h-吡唑-1-基)嘧啶-4-胺衍生物及其用途
CN110627775A (zh) * 2019-10-24 2019-12-31 嘉兴特科罗生物科技有限公司 一种小分子化合物
CN110734428A (zh) * 2019-10-24 2020-01-31 嘉兴特科罗生物科技有限公司 一种小分子化合物
CN110862380A (zh) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 一种小分子化合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2832734A4 (fr) * 2012-03-28 2015-08-26 Takeda Pharmaceutical Composé hétérocyclique
EP3029031A4 (fr) * 2013-07-30 2017-01-11 Takeda Pharmaceutical Company Limited Composé hétérocyclique
AU2015300782B2 (en) * 2014-08-08 2020-04-16 Dana-Farber Cancer Institute, Inc. Uses of salt-inducible kinase (SIK) inhibitors
US11241435B2 (en) * 2016-09-16 2022-02-08 The General Hospital Corporation Uses of salt-inducible kinase (SIK) inhibitors for treating osteoporosis

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007053776A1 (fr) * 2005-11-03 2007-05-10 Sgx Pharmaceuticals, Inc. Modulateurs de kinase de type pyrimidinylthiophène
CN103298794A (zh) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 作为tyk2抑制剂的吡啶化合物及其氮杂类似物
WO2016014542A1 (fr) * 2014-07-21 2016-01-28 Dana-Farber Cancer Institute, Inc. Inhibiteurs d'imidazolyl kinase et leurs utilisations
CN110191884A (zh) * 2016-10-14 2019-08-30 拜耳公司 取代的6-(1h-吡唑-1-基)嘧啶-4-胺衍生物及其用途
CN110627775A (zh) * 2019-10-24 2019-12-31 嘉兴特科罗生物科技有限公司 一种小分子化合物
CN110734428A (zh) * 2019-10-24 2020-01-31 嘉兴特科罗生物科技有限公司 一种小分子化合物
CN110862380A (zh) * 2019-10-24 2020-03-06 嘉兴特科罗生物科技有限公司 一种小分子化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 29 July 2020 (2020-07-29), ANONYMOUS: "- /1 -(C) FILE REGISTRY RN -2451205-81-3 REGISTRY ED -Entered STN: 29 Jul 2020 CN -2-Pyrimidinamine, N-(1-methyl-1H-pyrazol-4-yl)-4-[1-(4-piperidinyl)-1H- pyrazol-4-yl]-(CA INDEX NAME", XP055805660, Database accession no. 2451205-81-3 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264919A (zh) * 2021-05-26 2021-08-17 无锡捷化医药科技有限公司 一种1-（2-甲氧基吡啶-4-基）-1h-吡唑-4-胺的制备方法
WO2023060202A1 (fr) * 2021-10-06 2023-04-13 Aerie Pharmaceuticals, Inc. Composés de pyrazole inhibiteurs de janus kinase et leurs utilisations
WO2023076161A1 (fr) 2021-10-25 2023-05-04 Kymera Therapeutics, Inc. Agents de dégradation de tyk2 et leurs utilisations

Also Published As

Publication number Publication date
CN110734428A (zh) 2020-01-31

Similar Documents

Publication Publication Date Title
WO2021078020A1 (fr) Composé à petites molécules
CN105073733B (zh) 蛋白激酶抑制剂
JP5550352B2 (ja) 有機化合物およびその使用
TWI538907B (zh) 非核苷反轉錄酶抑制劑
JP6480944B2 (ja) ブロモドメイン阻害剤としての二環式複素環誘導体
KR101530117B1 (ko) 야누스 키나제 억제제 화합물 및 방법
KR102379517B1 (ko) 세린/트레오닌 키나아제 억제제
TWI609866B (zh) 新穎吡唑衍生物
JP7397187B2 (ja) 小分子化合物
JP6424224B2 (ja) 新規ビスアミドピリジン
CN106459044A (zh) Tank‑结合激酶抑制剂化合物
KR20160003035A (ko) Fgfr 키나제 조절제로서 유용한 퀴나졸리논 유도체
JP6338665B2 (ja) 新規６−アルキニルピリジン
AU2012228090A1 (en) Pyrrolopyridineamino derivatives as Mps1 inhibitors
TW201408666A (zh) 新穎化合物
WO2022166974A1 (fr) Dérivé de pyridopyrimidinone, son procédé de préparation et son utilisation
JP2015512879A (ja) Ｓｍａｃミメチックスとしての６−アルキニルピリジン
JP2019507766A (ja) 線維症の治療のための新規化合物及びその医薬組成物
WO2021078021A1 (fr) Petit composé moléculaire
CN112457326B (zh) 一类芳香杂环并内酰胺类化合物、制备方法和用途
Xu et al. Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3, 3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors
KR20230043103A (ko) 술폰아마이드 화합물
CN110167926B (zh) 聚-adp核糖聚合酶（parp）抑制剂
AU2016346557B2 (en) Pyrimidine derivative
WO2019242689A1 (fr) Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20878954

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20878954

Country of ref document: EP

Kind code of ref document: A1