WO2021254133A1 - Composé à petites molécules - Google Patents

Composé à petites molécules Download PDF

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WO2021254133A1
WO2021254133A1 PCT/CN2021/097367 CN2021097367W WO2021254133A1 WO 2021254133 A1 WO2021254133 A1 WO 2021254133A1 CN 2021097367 W CN2021097367 W CN 2021097367W WO 2021254133 A1 WO2021254133 A1 WO 2021254133A1
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compound
group
small molecule
follows
molecule compound
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PCT/CN2021/097367
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Chinese (zh)
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方文奎
李冠群
蔡雨婷
朱文浩
潘翔
王增全
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嘉兴特科罗生物科技有限公司
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    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention provides an active factor, and specifically relates to a small molecule compound and the application of the small molecule compound as a JAK kinase inhibitor with high efficiency and specificity.
  • JAK1 and TYK2 kinase activity can block the cytokine-mediated signal pathway involved in inflammation, thereby controlling inflammation and effectively treating autoimmune diseases and or allergic inflammation. Skin disease.
  • JAK1 and TYK2 inhibitors there are few reports on the effective inhibition of JAK1 and or TYK2 inhibitors at the same time.
  • the present invention aims to develop suitable high-efficiency and specific JAK kinase inhibitors, especially Tyk2 inhibitors, and/or JAK1 inhibitors, and/or JAK1/Tyk2 or Tyk2/JAK1 and or Tyk2/Jak2 dual inhibitors, suitable for treatment , Prevent and relieve autoimmune diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (Systemic Lupus Erythematosus, SLE), ulcerative colitis (Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS), Psoriasis (Psoriasis), Alopecia Areata (AA), Vitiligo (Vitiligo), etc. and allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis , Atopic Dermatitis (AD), eczema, neurodermatitis and other indications.
  • autoimmune diseases such as rheumatoid
  • the above X is a nitrogen-containing group
  • the above R is a fluorine-containing group
  • the above C z is connected to the nitrogen atom in the X group.
  • the aromatic group G in this embodiment can be selected from all-carbon aromatic rings or heteroaromatic rings;
  • the all-carbon aromatic ring is selected from all-carbon aromatic rings with 5-20 carbon atoms, such as: benzene ring, naphthalene ring, etc.;
  • Heteroaromatic rings are selected from heteroaromatic rings with a total of 5-20 carbon/heteroatoms, such as monocyclic rings such as furan, thiophene, pyrrole, thiazole, imidazole, pyridine, pyrazine, pyrimidine, pyridazine, etc., fused ring hetero Rings such as indole, quinoline, pteridine, acridine, etc.
  • any one or several hydrogen atoms on the above-mentioned all-carbon aromatic ring or heteroaromatic ring can also be substituted by substituents, such as any common substituent groups such as alkyl, hydroxyl, halogen, cyano, carboxyl, and ester groups.
  • the nitrogen-containing group X in this embodiment can be one of the following forms: namely, -NH-, -N(R1)-, substituted or unsubstituted nitrogen-containing alkyl, substituted or substituted nitrogen heterocycle, etc. Similar structure.
  • R1 is any substituent, such as: alkyl, aryl, etc.;
  • the substituted nitrogen-containing alkyl group is that at least one hydrogen atom on the above-mentioned nitrogen-containing alkyl group is substituted by other substituents, such as: alkyl, hydroxyl, halogen, cyano, carboxyl, ester, aryl, cycloalkyl, hetero Cycloalkyl and any common substituent groups.
  • Unsubstituted nitrogen heterocyclyl means that at least one carbon atom on the three-, four-, five- or six-membered cycloalkyl ring is replaced by nitrogen;
  • Substituted nitrogen-containing cycloalkyl means that at least one hydrogen atom on the above nitrogen heterocycle is substituted by other substituents, such as: alkyl, hydroxy, halogen, cyano, carboxy, ester, aryl, cycloalkyl, hetero Cycloalkyl and any common substituent groups.
  • the fluorine-containing group R in this embodiment can be selected from a fluorine-containing alkyl group, a fluorine-containing cycloalkyl group, a fluorine-containing heterocycloalkyl group, a fluorine-containing aryl group, a fluorine-containing heteroaryl group, etc.;
  • fluorine-containing alkyl, fluorine-containing cycloalkyl, fluorine-containing heterocycloalkyl, fluorine-containing aryl, and fluorine-containing heteroaryl refer to alkyl groups with no more than 20 carbon atoms and cycloalkanes with no more than 10 carbon atoms.
  • At least one hydrogen atom on the heteroaryl group, heterocycloalkyl group with no more than 10 carbon atoms, aryl group with no more than 10 carbon atoms, and heteroaryl group with no more than 10 carbon atoms is replaced by a fluorine atom, and other hydrogen atoms It can be alkyl, hydroxy, halogen, cyano, carboxy, ester, aryl, cycloalkyl, heterocycloalkyl and any other common substituent groups at the same time.
  • a small molecule compound provided by the present invention is also characterized in that: the above G is preferably a five-membered or six-membered aromatic ring or a heteroaromatic ring.
  • a small molecule compound provided by the present invention is also characterized in that: the above-mentioned X is preferably a substituted or unsubstituted amine, a substituted or unsubstituted nitrogen-containing cycloalkyl.
  • a small molecule compound provided by the present invention is also characterized in that: the above-mentioned R is preferably a substituted or unsubstituted fluorine-containing alkyl group, a substituted or unsubstituted fluorine-containing cycloalkyl group.
  • a small molecule compound provided by the present invention is also characterized in that the above-mentioned C z has chirality.
  • a small molecule compound provided by the present invention is also characterized in that the small molecule compound has one or more of the following uses:
  • a small molecule compound provided by the present invention is also characterized in that it is used for preparing drugs for the treatment, prevention and alleviation of autoimmune diseases;
  • autoimmune diseases are rheumatoid arthritis, Crohn's disease, ulcerative colitis, mandatory spondylitis, lupus erythematosus, psoriasis, alopecia areata, vitiligo, etc. and allergic diseases such as asthma, allergic rhinitis, allergies Conjunctivitis, atopic dermatitis, eczema, neurodermatitis or similar indications.
  • a small molecule compound provided by the present invention is also characterized in that it is manufactured by the following steps:
  • L 1 and L 1 ′ are active groups that can react with each other;
  • L 2 is an active group capable of reacting with an amino group.
  • a small molecule compound provided by the present invention is also characterized in that it is manufactured by the following steps:
  • n, m are 0 or natural numbers, R 1 is an electron withdrawing group, and pro is an amino protecting group;
  • L 1 and L 1 ′ are active groups that can react with each other;
  • the above L 2 is an amino protecting group
  • the above-mentioned L 3 is an active group capable of reacting with an amino group.
  • a small molecule compound provided by the present invention is also characterized in that the amino group on the compound 1 is protected before subsequent reactions are performed.
  • the present invention has carried out the purposeful and reasonable design of small molecule compound drugs.
  • the synthesized compound is first tested for the biochemical activity of JAK kinase, and the structure-activity relationship is established according to IC50. ), perform cytological tests on potent inhibitors with IC50 below 200nM, and determine the selectivity of the compound.
  • IC50 the biochemical activity of JAK kinase
  • IC50 the structure-activity relationship
  • the inhibitors provided by the present invention can also be used for other autoimmune-related skin diseases such as alopecia areata, vitiligo, skin-based lupus erythematosus, lichen planus, lichen lustrous, atrophic lichen sclerosus, panniculitis, and allergic diseases Such as atopic dermatitis, eczema, neurodermatitis and so on.
  • the Tyk2 inhibitor, and/or JAK1 inhibitor, and/or JAK1/Tyk2 dual inhibitor obtained in the present invention suitable for oral or intravenous administration can still be used to treat psoriasis and other autoimmune diseases such as RA , IBD, MS, etc.
  • Figure 1 384-well plate AlphaLISA SureFire test template.
  • Triethylamine (494.8 mg, 4.89 mmol) and di-tert-butyl methyl dicarbonate (852 mg, 1.406 mmol) were added to a solution of compound 368a (500 mg, 3.26 mmol) in dichloromethane (50 mL), and the reaction solution was stirred overnight at room temperature .
  • LCMS[M+H] + 416.
  • Step 4 Example 367 adds N,N-diisopropylethylamine (230mg, 1.776mmol) to compound 367f (70mg, 0.222mmol) in N,N-dimethylformamide (7mL) solution A at room temperature ,
  • N,N-dimethylformamide (7mL) solution A at room temperature
  • 2-(7-oxybenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (126.6 mg, 0.333 mmol)
  • the solutions A and B were stirred for 5 minutes, and then the solution A was added to the solution B, and the reaction was stirred at room temperature for 10 minutes.
  • compound 370c (900mg, 2.576mmol) is 3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1-(Triisopropylsilyl)-1H-pyrrole, potassium carbonate (809mg, 5.855mmol) and tetrakistriphenylphosphine palladium (270mg, 0.234mmol) were added n-butanol (10mL) and water (10mL), the water pump replaces the nitrogen 3 times. The reaction solution was heated to 100°C and stirred overnight.
  • Trifluoroacetic acid (5 mL) was added to a dichloromethane (5 mL) solution of compound 370i (100 mg, 0.195 mmol) at 0°C, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, methanol (5 mL) and diethylamine (1 mL) were added to the residue, and the mixture was stirred at room temperature for 1 hour.
  • the components are as follows: 50mM HEPES, pH 7.5, 1mM EGTA, 10mM MgCl 2 , 2mM DTT, 0.01% Tween20
  • DMSO dissolves the test compound to a 10mM stock solution, and configures it to the required concentration by 3 times the gradient dilution. Each compound has 10 concentration points.
  • the final concentration range of the test compound is: 10 ⁇ M-0.5nM
  • 1X detection buffer dissolves EDTA to 40mM (final concentration of EDTA: 10mM)
  • JAK1 reacts at room temperature for 2 hours
  • JAK2/JAK3/Tyk2 reacts at room temperature for 1 hour
  • the final concentration of each component of JAK1 reaction is: JAK1: 20nM, substrate: 50nM, ATP: 40uM, and the final concentration range of test compound is: 10 ⁇ M-0.5nM
  • the final concentration of each component of the JAK2/JAK3/Tyk2 reaction is: JAK2: 1nM, substrate: 50nM, ATP: 10 ⁇ M, and the final concentration range of the test compound is: 10 ⁇ M-0.5nM
  • the above-mentioned kinase enzyme activity inhibition test showed that the two compounds with the best effect are TDM-180967 and TDM-180970.
  • two cytological test systems to determine the effect of the compound on the cytokine in the cell. Signal conduction inhibition is tested. These two tests are based on the mechanism of cytokine signal transduction in inflammatory cells.
  • the cytokine IL-4 induced human monocyte cell line THP-1 intracellular pSTAT6 quantitative test is used to evaluate the cytological effects of JAK1 inhibitors. After IL-4 binds to cell surface receptors, JAK1 is activated, which recruits and activates STAT6 thus regulates the expression of IL-4/JAK1 downstream genes.
  • the cytokine IFN-alpha-B2 induced human osteosarcoma epithelial cell line U2OS intracellular pSTAT1 quantitative test is used to evaluate the cytological effects of Tyk2 inhibitors. After IFN-alpha-B2 binds to cell surface receptors, it mainly leads to the phosphorylation of Tyk2 The latter activates STAT1 through phosphorylation, and finally pSTAT1 enters the nucleus for gene regulation. Cytology testing is very important for the performance evaluation of molecular compounds. It not only further verifies the inhibition of in vitro enzyme activity, lays the foundation for the next step of animal testing, but also provides the initial basis for whether small molecules can enter cells smoothly. In the drug discovery stage Very important.
  • logIC50 same log units as X
  • TDM-180967 and TDM-180970 have a strong inhibitory effect on the intracellular signal transduction of JAK1 and Tyk2.
  • the experimental results of the half inhibitory concentration (IC 50 ) are listed in the following table:
  • our compound has a strong inhibitory effect on in vitro enzyme activity and cytology, especially in cell models, it has a highly effective inhibitory effect on the cytokine inflammatory pathway mediated by JAK1 and TYK2. It is well known that JAK1 and TYK2 are extremely important for the occurrence and severity of autoimmune diseases and allergic inflammatory skin diseases. Further clinical development and application of such newly-invented small molecule JAK inhibitors for treatment Such diseases offer potential possibilities.

Abstract

La présente invention concerne un composé à petites molécules, qui est caractérisé en ce qu'il est un composé représenté par la formule structurale suivante (I) ou un sel pharmaceutiquement acceptable de celui-ci, G étant un groupe ayant une aromaticité; X est un groupe contenant de l'azote; R est un groupe contenant du fluor; et Cz est relié à un atome d'azote dans le groupe X. Plusieurs composés auxquels la présente invention se rapportent ont de bonnes capacités d'inhibition pour l'activité de la kinase Jak et l'activité cytobiologique.
PCT/CN2021/097367 2020-06-15 2021-05-31 Composé à petites molécules WO2021254133A1 (fr)

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CN111704617B (zh) * 2020-06-15 2022-08-23 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
CN113735859A (zh) * 2021-08-12 2021-12-03 安徽医科大学 一种激酶抑制剂
CA3232812A1 (fr) * 2021-09-23 2023-03-30 Ian MacQuarie CATLETT Procedes de traitement de troubles de la perte des cheveux avec des inhibiteurs de tyk2
WO2023174314A1 (fr) * 2022-03-18 2023-09-21 四川科伦博泰生物医药股份有限公司 Utilisation et procédé de traitement d'un dérivé d'azétidine

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