WO2020035020A1 - 咪唑并吡啶类衍生物及其制备方法和其在医药上的用途 - Google Patents

咪唑并吡啶类衍生物及其制备方法和其在医药上的用途 Download PDF

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WO2020035020A1
WO2020035020A1 PCT/CN2019/100762 CN2019100762W WO2020035020A1 WO 2020035020 A1 WO2020035020 A1 WO 2020035020A1 CN 2019100762 W CN2019100762 W CN 2019100762W WO 2020035020 A1 WO2020035020 A1 WO 2020035020A1
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alkyl
heteroaryl
cycloalkyl
pharmaceutically acceptable
aryl
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French (fr)
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翟文强
卢勇平
程超英
云虹伟
钱文建
施正政
胡泰山
陈磊
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浙江海正药业股份有限公司
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    • 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
    • C07D471/02—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 system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • 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
    • 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

Definitions

  • the invention relates to a novel imidazole [1,2-a] pyridine derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use thereof as a therapeutic agent, particularly as an IRAK4 inhibitor.
  • Interleukin-1 receptor-related kinase 4 is a member of the IRAK family of intracellular serine-threonine kinases. Other members of the kinase family include IRAK-1, IRAK-2, and IRAK-M. IRAK-M is only expressed in monocytes and macrophages, and the expression of IRAK-1, IRAK-2 and IRAK4 is ubiquitous. IRAK4 is mainly composed of N-terminally conserved death structural region (DD), hinge region, and C-terminal central kinase domain (KD). The DD region is a region where IRAK4 binds to the adaptor protein myeloid differentiation factor primary response gene 88 (MyD88).
  • MyD88 adaptor protein myeloid differentiation factor primary response gene 88
  • the KD region is composed of 12 sub-regions and has the characteristics of a typical serine-threonine kinase domain.
  • the main function of IRAK4 is to phosphorylate its substrate through the KD region, which in turn activates downstream signaling molecules.
  • IRAK4 is a key factor downstream of the interleukin-1 receptor (IL-1R) / Toll-like receptor (TLR) -mediated inflammatory signal transduction pathway and plays a key role in the immune system. When the interleukin-1 receptor (IL-1R) or Toll-like receptor (TLR) binds to the ligand, IRAK4 can mediate signaling and activate the expression of downstream inflammatory factors.
  • IL-1R interleukin-1 receptor
  • TLR Toll-like receptor
  • TLR can receive ligand signals from the body's interaction with microorganisms or stimulation from endogenous substances, as well as the first wave of inflammatory signals and innate immune response signals caused by these stimuli. TLR plays a very important role in many diseases, including infections and auto-inflammatory diseases, as well as many other diseases in humans. Like cancer necrosis factor- ⁇ (TNF- ⁇ ) and other major cytokines, interleukin-1 (IL-1) is a key factor in the inflammation-mediated pathway that is able to spread and amplify signals.
  • TNF- ⁇ cancer necrosis factor- ⁇
  • IL-1 interleukin-1
  • TLR TLR
  • IL-1R cytokine receptor-mediated signaling pathways
  • IRAK4 a key signaling factor in the midstream of TLR and IL-1R inflammation pathways, plays a significant role in systemic inflammatory responses and can be used as An effective potential target for the treatment of various inflammation-related diseases.
  • the present inventors have unexpectedly found that a compound represented by the following formula (I) has a good IRAK4 enzyme inhibitory activity by screening a large number of compounds.
  • the present invention provides a class of imidazole [1,2-a] pyridine derivatives represented by the general formula (I) or a stereoisomer, tautomer, or a pharmaceutically Acceptable salts:
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more Substituted with a substituent selected from the group consisting of halogen, hydroxyl, amino, -CONR A R B , cyano, and haloalkyl;
  • R 2 is selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halogen, alkoxy, cyano, hydroxyl, carboxyl, -CONR A R B , -NR a R b , haloalkyl, amine Alkyl, hydroxyalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R 4 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
  • R a and R b are independently selected from a hydrogen atom, -COR E , -SO 2 R F , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, aryl or heteroaryl; wherein The aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, cyano, haloalkyl, -CONR A R B , -SO 2 NR C R D ; or R a And R b and the nitrogen atom to which it is attached form a 4- to 8-membered nitrogen-containing heterocyclic ring, condensed ring, spiro ring, or R a and R b form a 4 to 8-membered member to the nitrogen atom to which they are attached and additionally have one or more selected from nitrogen Nitrogen-containing heterocyclic ring of oxygen, oxygen and sulfur;
  • R A , R B , R C , R D are independently selected from hydrogen, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further one or more Substituted by a substituent selected from halogen, hydroxy, cyano or haloalkyl;
  • R E and R F are independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein the alkyl or cycloalkyl is optionally further selected from one or more of halogen, hydroxy, cyano Or haloalkyl.
  • the compound of formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof wherein R 1 is an aryl group or a heteroaryl group,
  • the aryl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, -CONR A R B , cyano, and haloalkyl; wherein R A , R B Is as defined in general formula (I).
  • the compound described by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof has a structure of the formula (II):
  • R 2 , R 3 , and R 4 are as defined in the general formula (I).
  • the compound described by the general formula (I) or (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof is:
  • the present invention provides a pharmaceutical composition containing an effective dose of a compound described by the general formula (I) or (II) or a stereoisomer, tautomer or pharmacy thereof.
  • the present invention provides a compound described by the general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation Use in a medicament for inhibiting the activity of IRAK4 kinase.
  • the present invention provides a compound described by general formula (I) or (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation Use in a medicament for preventing or treating an autoimmune disease, inflammatory disease or cancer, wherein the autoimmune disease, inflammatory disease or cancer is preferably selected from the group consisting of lymphoma, endometriosis, psoriasis Disease, lupus erythematosus, multiple sclerosis, or rheumatoid arthritis; wherein the lymphoma is preferably a primary central nervous system lymphoma or diffuse large B-cell lymphoma with a MYD88 L265P mutation.
  • Alkyl when taken as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group. C 1 -C 20 alkyl is preferred, and C 1 -C 6 alkyl is more preferred. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butylbutyl, 1,3-dimethylbutyl,
  • Cycloalkyl refers to saturated or partially saturated carbocyclic rings that are monocyclic, fused, bridged, and spiro. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl and the like are preferably cyclopropyl or cyclohexyl.
  • Alkoxy refers to a group of alkyl-O-. Among them, alkyl refers to the relevant provisions herein. C 1 -C 6 alkoxy is a preferred choice. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Haloalkyl means a halogen-containing alkyl group, where halogen and alkyl are specified herein.
  • C 1 -C 6 haloalkyl is a preferred choice. Examples thereof include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, and the like.
  • Aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, and examples thereof include, but are not limited to, phenyl, naphthyl, and the like.
  • Heteroaryl refers to a 5-membered monocyclic aromatic hydrocarbon group, a 6-membered monocyclic aromatic hydrocarbon group, a 9-membered bicyclic aromatic hydrocarbon group, or a 10-membered bicyclic aromatic hydrocarbon group containing at least one hetero atom (O, S, or N), and examples thereof include But not limited to thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, indium Indyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like.
  • Heterocycloalkyl refers to a structure in which at least one ring carbon atom in a cycloalkyl group is replaced with a nitrogen, oxygen, or sulfur atom.
  • Cycloalkyl is defined as described above, with 4- to 8-membered rings being the preferred choice. Examples thereof include, but are not limited to, oxetanyl, azetidinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, nitrogen methylpiperidinyl , Tetrahydrofuranyl, tetrahydropyranyl, dioxothiomorpholinyl, and the like.
  • Alkyl refers to an amine-substituted alkyl group. Among them, alkyl refers to the relevant provisions herein. Examples thereof include, but are not limited to, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, azetidinyl, piperidinyl, morpholinyl, and the like and their quaternary ammonium salt forms.
  • Hydroxyalkyl refers to a hydroxy-substituted alkyl group. Among them, alkyl refers to the relevant provisions herein. Examples thereof include, but are not limited to, 3-hydroxy-3-methylbutyl, hydroxyethyl, hydroxybutyl, hydroxycyclopentyl, hydroxycyclohexyl, and the like.
  • Fused ring refers to a cyclic structure consisting of the same or different two of a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group that share two atoms.
  • cycloalkyl, heterocycloalkyl, aryl, and heteroaryl refer to the relevant provisions herein. Examples thereof include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, and the like.
  • spiro ring refers to a cyclic structure composed of the same or different two of a cycloalkyl group or a heterocycloalkyl group that share one atom.
  • cycloalkyl and heterocycloalkyl refer to the relevant provisions herein. Examples thereof include, but are not limited to, 5-azaspiro [2.5] octyl, 6-azaspiro [2.5] octyl, 3-oxa-9azaspiro [5.5] undecyl, and the like.
  • the examples show the preparation of the representative compounds represented by formula (I) and the related structural identification data. It must be noted that the following examples are only used to illustrate the present invention and not to limit the present invention.
  • the raw materials used for synthesizing the compounds of the present invention are all derived from synthetic routes of commercial or known literatures without special instructions.
  • the present invention uses the following abbreviations:
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • the solid obtained above was added in batches to concentrated sulfuric acid under an ice bath, and the ice bath was stirred for 1 h. The reaction was continued at room temperature for 1 h, and the reaction was continued at 50 ° C. for 1 h. After the reaction was completed, the reaction solution was poured into ice, and the pH was adjusted to neutral to slightly alkaline with concentrated ammonia water. The precipitated solid was suction filtered and dried under vacuum. The obtained yellow solid was recrystallized from THF / Hex to obtain 1b (10.9 g). The total yield of the two-step reaction was 83%.
  • the second step is the synthesis of methyl 2- (3-ethoxy-3-oxycarbonylpropyl) -6-nitroimidazole [1,2-a] pyridine-7-carboxylic acid.
  • the third step is to synthesize 6-amino-2- (3-ethoxy-3-oxycarbonylpropyl) -imidazole [1,2-a] pyridine-7-carboxylic acid methyl ester.
  • Dissolve 1f (0.97g, 5.1mmol) in 40mL of dichloromethane, add HATU (2.58g, 6.8mmol), DIEA (1.32g, 10.2mmol), stir at room temperature for 1h, then add 1e, react at room temperature overnight, TLC detection After the reaction of the raw materials is completed, a saturated NaHCO 3 solution (30 mL ⁇ 2) is added for washing, and the organic phase is washed with saturated ammonium chloride (30 mL ⁇ 2), dried over anhydrous sodium sulfate, silica gel column chromatography, and dichloromethane / methanol 1 g (1.1 g, 69% yield in two steps) was obtained.
  • Step 5 Synthesis of N- (2- (3-hydroxy-3-methylbutyl) -7- (2-hydroxyprop-2-yl) imidazole [1,2-a] pyridine-6-yl) -6 -(Trifluoromethyl) pyridine-2-carboxamide
  • the second step is to synthesize 6-amino-2- (1- (tert-butoxycarbonyl) piperidin-4-yl) imidazole [1,2-a] pyridine-7-carboxylic acid methyl ester
  • Dissolve 1f (0.8g, 1.5eq) in 40mL of dichloromethane, add HATU (2.1g, 2eq), DIEA (1.1g, 3eq), stir at room temperature for 1h, then add 2c, react at room temperature overnight, and detect the reaction by TLC Complete, wash with saturated NaHCO 3 solution (30 mL ⁇ 2), wash the organic phase with saturated ammonium chloride (30 mL ⁇ 2), dry over anhydrous sodium sulfate, filter, concentrate, silica gel column chromatography, dichloromethane / methanol 2e was isolated (0.55 g, 36% yield in two steps).
  • the fourth step is to synthesize 4- (7- (2-hydroxyprop-2-yl) -6- (6- (trifluoromethyl) pyridine-2-carboxamide) imidazole [1,2-a] pyridine-2- (Tert-butyl) piperidine-1-carboxylic acid
  • Step 5 Synthesis of N- (7- (2-hydroxyprop-2-yl) -2- (piperidin-4-yl) imidazole [1,2-a] pyridin-6-yl) -6- (trifluoro (Methyl) pyridine-2-carboxamide
  • Cisbio's KinEASE-STK S1 serine / threonine kinase kits are used to determine the degree of phosphorylation of biotinylated peptide substrates, and are measured using homogeneous time-resolved fluorescence (HTRF).
  • HTRF homogeneous time-resolved fluorescence
  • the compounds of the present invention are first dissolved in DMSO to a final concentration of 10 mM. Then, the buffer solution provided in the kit is used for equal gradient dilution, so that the final concentration of the test compound in the reaction system ranges from 16000 nM to 0.008 nM, and the final concentration of DMSO is less than 2%.
  • the tested adenosine triphosphate (ATP) concentration was a pre-determined corresponding ATP Km value (300 ⁇ M).
  • Compounds, kinases, biotinylated peptide substrates and ATP were incubated at 37 ° C for 1 h for the kinase reaction, and then anti-phosphorylated silk / threonine antibodies coupled with actinide compounds and conjugates were added to the reaction system.
  • the preferred compounds of the present invention have good inhibitory effects on IRAK4 enzymes, especially compounds 3 and 4, whose IRAK4 enzyme inhibitory activity IC 50 are 0.5nM and 0.3nM, respectively.
  • compound 4 has a 28-fold increase in IRAK4 enzyme inhibitory activity, showing a more excellent IRAK4 enzyme inhibitory activity.
  • imidazole [1,2-a] pyridine derivatives as a new backbone molecule, which is completely different from the indazole skeleton of BAY-1834845.
  • Our synthetic route is simple and there is no azidoalkane derivative Problems with isomers generated by amination. Therefore, the compounds of the present invention are expected to be useful in the treatment of IRAK4 inhibitors and related diseases.

Abstract

本发明涉及具有通式(I)所示的咪唑并吡啶类衍生物或其药学上可接受的盐、及其制备方法，以及它们作为治疗剂，特别是作为IRAK4激酶抑制剂的用途。其中通式(I)中的R 1，R 2，R 3，R 4的定义与说明书中的定义相同。

Description

咪唑并吡啶类衍生物及其制备方法和其在医药上的用途 技术领域
本发明涉及一种新的咪唑[1,2-a]吡啶类衍生物，其制备方法以及含有该衍生物的药物组合物以及其作为治疗剂特别是作为IRAK4抑制剂的用途。
技术背景
白细胞介素-1受体相关激酶4(IRAK-4)是细胞内丝氨酸-苏氨酸激酶IRAK家族的成员之一。激酶家族的其他成员还包括IRAK-1、IRAK-2和IRAK-M。IRAK-M仅在单核细胞和巨噬细胞中表达，IRAK-1、IRAK-2和IRAK4的表达普遍存在。IRAK4主要由N端保守的死亡结构区域(DD)、铰链区、C端的中央激酶结构域(KD)组成。DD区是IRAK4与接头蛋白髓样分化因子初次应答基因88(MyD88)相结合的区域。KD区由12个亚区域构成，具有典型的丝氨酸-苏氨酸激酶结构域特征。IRAK4的主要功能是通过KD区域将其底物磷酸化，进而激活下游信号分子。IRAK4是白细胞介素-1受体(IL-1R)/Toll样受体(TLR)介导的炎症信号转导通路下游的关键因子，在免疫***中起关键作用。当白细胞介素-1受体(IL-1R)或者Toll样受体(TLR)与配体结合后，IRAK4能够介导信号传导，激活下游炎症因子的表达。TLR可以接受来自机体与微生物作用或者内源性物质刺激产生的配体信号，以及这些刺激引发的第一波炎症信号和先天免疫反应信号。TLR在许多疾病中，包括感染和自身炎症性疾病以及人类的许多其他疾病，起着非常重要的作用。像癌症坏死因子-α(TNF-α)和其他主要的细胞因子一样，白细胞介素-1(IL-1)是炎症介导通路中的关键因子，能够传播和放大信号。由于TLR、IL-1R和其他细胞因子受体介导的信号通路有着相互交联的作用，所以TLR和IL-1R炎症通路中游的关键信号因子—IRAK4，在全身炎症反应中作用重大，能够作为治疗各种炎症相关性疾病的一个有效潜在靶点。
目前，已经公开报到了一系列IRAK4抑制剂的专利，如专利WO2015104662、WO2016083433、WO201709798等详细描述了吲唑类衍生物作为IRAK4抑制剂的用途。然而，目前还没有针对该靶点的药物上市，而进入临床阶段的只有Pfizer  Inc的PF-06650833、Bayer AG的BAY-1834845和Aurigene的CA-4948。在Pfizer报道的一期临床结果中PF-06650833采用了缓释剂型，这不仅限制了其应用，也增加了药物开发成本。Bayer AG的BAY-1834845和Aurigene的CA-4948尚未有临床结果报道。现有技术中公开的化合物以及试验药物在有效性、安全性或适用性等方面仍不能令人满意，仍有必要继续研究和开发新的白细胞介素-1受体相关激酶4(IRAK4)抑制剂，以满足人们日益增长的医疗和健康需求。
发明内容
本发明人通过大量的化合物筛选意外地发现，下式(I)所示的化合物具有良好的IRAK4酶抑制活性。
因此，在第一个方面，本发明提供了一类通式(I)所示的咪唑[1,2-a]吡啶类衍生物或其立体异构体、互变异构体或其药学上可接受的盐：
Figure PCTCN2019100762-appb-000001
其中：
R 1选自C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、-CONR AR B、氰基、卤代烷基的取代基所取代；
R 2选自C 1-C 6烷基、C 3-C 8环烷基、卤素、烷氧基、氰基、羟基、羧基、-CONR AR B、-NR aR b、卤代烷基、胺基烷基、羟基烷基、杂环烷基、芳基或杂芳基；
R 3选自氰基、烷氧基、-NR aR b、-CONR AR B、-SO 2NR CR D、C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；其中所述的C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、氰基、卤代烷基、氧代基(O＝)、C 1-C 6烷基、-COR E、-SO 2R F、-CONR AR B、-SO 2NR CR D的取代基所取代；
R 4选自氢、卤素、C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；
R a和R b独立地选自氢原子、-COR E、-SO 2R F、C 1-C 6烷基、C 3-C 8环烷基、芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟 基、氨基、氰基、卤代烷基、-CONR AR B、-SO 2NR CR D的取代基所取代；或者R a和R b与其所连接的氮原子形成4到8元含氮杂环，稠环，螺环或者R a和R b与其所连接的氮原子形成4到8元另外具有一个或多个选自氮、氧、硫原子的含氮杂环；
R A、R B、R C、R D独立地选自氢、C 1-C 6烷基或C 3-C 6环烷基；其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基或卤代烷基的取代基所取代；
R E、R F独立地选自C 1-C 6烷基或C 3-C 6环烷基；其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基或卤代烷基的取代基所取代。
在本发明的一些优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 1为芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、-CONR AR B、氰基、卤代烷基的取代基所取代；其中，R A、R B的定义如通式(I)中所述。
在本发明的一些优选方案中，通式(I)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其具有式(II)结构：
Figure PCTCN2019100762-appb-000002
其中，R 2，R 3，R 4的定义如通式(I)中所述。
在本发明的一些优选方案中，通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 2为杂芳基、杂环烷基或羟基烷基。
在本发明的一些优选方案中，通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 3为C 1-C 6烷基、杂环烷基或杂芳基，其中所述的C 1-C 6烷基、杂环烷基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、氰基、卤代烷基、氧代基(O＝)、C 1-C 6烷基、-CONR AR B、-SO 2NR CR D、-COR E、-SO 2R F的取代基所取代；其中，R A、R B、R C、R D、R E、R F的定义如通式(I)中所述。
在本发明的一些优选方案中，通式(I)或(II)所述的化合物或其立体异构体、 互变异构体或其药学上可接受的盐，其中R 4为氢、C 1-C 6烷基或C 3-C 8环烷基。
在本发明的一些优选方案中，通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为：
Figure PCTCN2019100762-appb-000003
N-(2-(3-羟基-3-甲基丁基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
Figure PCTCN2019100762-appb-000004
N-(7-(2-羟基丙-2-基)-2-(哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
Figure PCTCN2019100762-appb-000005
N-(7-(2-羟基丙-2-基)-2-(1-甲基哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
Figure PCTCN2019100762-appb-000006
N-(2-(1-(乙磺酰基)哌啶-4-基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺。
进一步，本发明提供了一种药物组合物，所述的药物组合物含有有效剂量的通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，以及任选的可药用的载体、赋形剂或它们的组合。
另一方面，本发明提供了通式(I)或(II)所述的化合物或其立体异构体、互变 异构体或其药学上可接受的盐，或其药物组合物在制备用于抑制IRAK4激酶的活性的药物中的用途。
在又一方面，本发明提供了通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或其药物组合物在制备用于预防或治疗自身免疫性疾病、炎性疾病或癌症的药物中的用途，其中所述的自身免疫性疾病、炎性疾病或癌症优选选自淋巴瘤、子宫内膜异位症、银屑病、红斑狼疮、多发硬化症或类风湿性关节炎；其中所述的淋巴瘤优选为带有MYD88 L265P突变的原发性中枢神经***淋巴瘤或弥漫性大B细胞淋巴瘤。
本发明在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指直链或者带有支链的脂肪烃基团。优选为C 1-C 20烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正已基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C 3-C 12环烷基，更优选为C 3-C 8环烷基，最优选为C 3-C 6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选为环丙基、环己基。
“烷氧基”是指烷基-O-的基团。其中，烷基见本文有关规定。C 1-C 6的烷氧基为优选选择。其实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤素”是指氟、氯、溴和碘。
“氧代基”是指经由双键连接到碳原子上的氧原子(O＝)的基团。
“卤代烷基”是指含有卤素取代的烷基，其中卤素和烷基见本文有关规定。C 1-C 6的卤代烷基为优选选择。其实施例包括但不限于单氟甲基、二氟甲基、三氟甲基、五氟乙基等。
“芳基”是指具有6至12个碳原子的单环或双环芳族烃基，其实施例包括但 不限于苯基、萘基等。
“杂芳基”是指至少含一个杂原子(O、S或N)的5元单环芳烃基、6元单环芳烃基、9元双环芳烃基或10元双环芳烃基，其实施例包括但不限于噻吩基、呋喃基、吡咯基、噻唑基、噁唑基、咪唑基、吡唑基、***基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、吲哚基、苯并噻吩基、苯并噁唑基、苯并噻唑基、苯并咪唑基等。
“杂环烷基”是指环烷基中至少一个环碳原子被氮、氧或硫原子取代的结构。环烷基的定义如上文所述，其中4到8元环为优选选择。其实施例包括但不限于氧杂环丁烷基、氮杂环丁烷基、四氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、氮甲基哌啶基、四氢呋喃基、四氢吡喃基、二氧硫代吗啉基等。
“胺基烷基”是指胺基取代的烷基基团。其中，烷基见本文有关规定。其实施例包括但不限于二甲基胺基甲基、胺基乙基、二甲基胺基乙基、氮杂环丁烷基、哌啶基、吗啉基等及其季铵盐形式。
“羟基烷基”是指羟基取代的烷基基团。其中，烷基见本文有关规定。其实施例包括但不限于3-羟基-3-甲基丁基、羟基乙基、羟基丁基、羟基环戊基、羟基环己基等。
“稠环”是指共用两个原子的由环烷基、杂环烷基、芳基或杂芳基中相同或不同的两个构成的环状结构。其中，环烷基、杂环烷基、芳基、杂芳基见本文有关规定。其实施例包括但不限于四氢喹啉基、四氢异喹啉基、苯并***啉基等。
“螺环”是指共用一个原子的由环烷基或杂环烷基中的相同或不同的两个构成的环状结构。其中，环烷基、杂环烷基见本文有关规定。其实施例包括但不限于5-氮杂螺[2.5]辛烷基，6-氮杂螺[2.5]辛烷基，3-氧杂-9氮杂螺[5.5]十一烷基等。
具体实施方式
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，以下实施例仅用于说明本发明而不是对本发明的限制。 1H NMR化学位移用ppm表示，其中s＝单峰，d＝双重峰，t＝三重峰，q＝四重峰，m＝多重峰，br＝变宽的。若提供耦合常数时，其单位为Hz。用作合成本发明的化合物的原料无特殊说明均来源于市售或已知文献的合成路线。其市售厂家来自于上海毕得医药科技有限公司、上海韶远试剂有限公司、上海凌凯医药科技有限公司、南京药石 科技股份有限公司、上海浩鸿生物医药科技有限公司。原料1c参考专利WO2010085820合成得到。
本发明使用以下缩写：
HATU：O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐
DIEA：N,N-二异丙基乙胺
THF：四氢呋喃
Hex：正己烷
实施例1
N-(2-(3-羟基-3-甲基丁基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000007
第一步 合成2-氨基-5-硝基异烟酸甲酯
Figure PCTCN2019100762-appb-000008
在0℃下，将2-氨基异烟酸甲酯10g缓慢加到机械搅拌的100mL浓硫酸中，搅拌至溶解后再降温至-10℃，将10mL浓硝酸和6mL浓硫酸配制的混酸缓慢滴加到反应中(滴加约30min)，滴加完毕，控制反应温度在-10℃度以下，继续搅拌3h。反应结束将反应液加到大量冰中，用浓氨水调pH至中性到略碱性，搅拌析出固体，抽滤，30℃真空干燥12h。
将上面得到的固体在冰浴下分批加到浓硫酸中，冰浴搅拌1h，室温继续1h，50℃再反应1h。反应结束，将反应液倒入冰中，用浓氨水调pH至中性到略碱性，析出固体抽滤，真空干燥。得到的黄色固体，用THF/Hex重结晶得1b(10.9g)，两步反应总收率83％。
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),7.87(br,2H),6.51(s,1H),3.84(s,3H).
第二步 合成2-(3-乙氧基-3-氧羰基丙基)-6-硝基咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000009
称取1b(1g,5mmol)和1c(2.2g,10mmol)，加入THF(50mL)，100℃封管反应5天，有固体析出，反应液冷却到室温，抽滤，冷的THF洗涤得1d(1.15g,71％)。
1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),8.20(s,1H),8.13(s,1H),4.06(q,J＝8.0Hz,2H),3.09(t,J＝8.0Hz,2H),2.79(t,J＝8.0Hz,2H),1.17(t,J＝8.0Hz,3H).
第三步 合成6-氨基-2-(3-乙氧基-3-氧羰基丙基)-咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000010
称取1d(1g,3.4mmol)、铁粉(1.9g,34mmol)和氯化铵(0.55g,10.2mmol)，加入乙醇/水(100mL，体积比4/1)，90℃反应直到原料1d反应完全，硅藻土过滤，旋干滤液，乙酸乙酯溶解(100mL)，饱和NaHCO 3溶液(30mL×3)洗涤，无水Na 2SO 4干燥，过滤，浓缩得到的1e直接投入下一步反应。
第四步 合成2-(3-乙氧基-3-氧羰基丙基)-6-(6-(三氟甲基)吡啶-2-甲酰胺)咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000011
将1f(0.97g,5.1mmol)溶于40mL二氯甲烷，加入HATU(2.58g,6.8mmol)，DIEA(1.32g,10.2mmol)，室温下搅拌1h后加入1e，室温下反应过夜，TLC检测至原料反应完全，加入饱和NaHCO 3溶液(30mL×2)洗涤，有机相再用饱和氯化铵(30mL×2)洗涤，无水硫酸钠干燥，硅胶柱层析，二氯甲烷/甲醇洗脱得到1g(1.1g，两步反应69％产率)。
第五步 合成N-(2-(3-羟基-3-甲基丁基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000012
将1g(1g,2mmol)溶于超干THF(20mL)，通入N 2，将MeMgBr(20mL,1.0M的THF溶液)用注射器缓慢加入到反应中，室温反应24h，用饱和氯化铵(30mL)淬灭反应。加入乙酸乙酯100mL萃取，分出有机层，再用饱和NaHCO 3水溶液洗涤(30mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱纯化，二氯甲烷/甲醇洗脱得化合物1(171mg,19％)。
LCMS m/z(ESI):451.2[M+H] +
1H NMR(400MHz,CDCl 3)δ12.30(s,1H),9.51(s,1H),8.38(d,J＝7.6Hz,1H),8.08(t,J＝7.6Hz,1H),7.82(d,J＝7.6Hz,1H),7.42(s,1H),7.26(s,1H),2.83(t,J＝7.2Hz,2H),1.88(t,J＝7.2Hz,2H),1.68(s,6H),1.24(s,6H).
实施例2
N-(7-(2-羟基丙-2-基)-2-(哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000013
第一步 合成2-(1-(叔丁氧羰基)哌啶-4-基)-6-硝基咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000014
称取1b(1g,5mmol)、2a(2eq,3.1g)和氧化镁(2eq,0.4g)，加入THF(50mL)，100℃封管反应24h，反应液冷却到室温，抽滤，THF洗涤，滤液旋干，硅胶柱纯化，用Hex/THF洗脱得2b(1.13g,56％)。
第二步 合成6-氨基-2-(1-(叔丁氧羰基)哌啶-4-基)咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000015
称取2b(1.13g,2.8mmol)、铁粉(1.57g,10eq)和氯化铵(0.45g,3eq)，加入乙醇/水(100mL，体积比4/1)，90℃反应直到原料2b反应完全，硅藻土过滤，旋干滤液，乙酸乙酯溶解(100mL)，饱和NaHCO 3溶液(30mL×3)洗涤，无水Na 2SO 4干燥，过滤，浓缩得到的2c直接投入下一步反应。
第三步 合成2-(1-(叔丁氧羰基)哌啶-4-基)-6-(6-(三氟甲基)吡啶-2-甲酰胺)咪唑[1,2-a]吡啶-7-羧酸甲酯
Figure PCTCN2019100762-appb-000016
将1f(0.8g,1.5eq)溶于40mL二氯甲烷，加入HATU(2.1g,2eq)，DIEA(1.1g,3eq)，室温下搅拌1h后加入2c，室温下反应过夜，TLC检测至反应完全，加入饱和NaHCO 3溶液(30mL×2)洗涤，有机相再用饱和氯化铵(30mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析，二氯甲烷/甲醇洗脱得2e(0.55g，两步反应36％产率)。
第四步 合成4-(7-(2-羟基丙-2-基)-6-(6-(三氟甲基)吡啶-2-甲酰胺)咪唑[1,2-a]吡啶-2-基)哌啶-1-羧酸叔丁酯
Figure PCTCN2019100762-appb-000017
称取LiCl(40mg,3eq)溶于超干THF(5mL)，将MeMgCl(3mL,9eq,3.0M THF溶液)用注射器缓慢加入到反应中直到没有气体产生，将2e(0.55g,1mmol)溶于超干THF(10mL)，用注射器缓慢加入到上述反应中，室温反应30min，TLC显示反应完成，用饱和氯化铵(30mL)淬灭反应。加入乙酸乙酯100mL萃取，分出有机层，无水硫酸钠干燥，过滤，浓缩，硅胶柱纯化，二氯甲烷/甲醇洗脱得化合物2f(283mg,51％)。
1H NMR(400MHz,CDCl 3)δ12.17(s,1H),9.53(s,1H),8.44(d,J＝8.0Hz,1H),8.12(t,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.48(s,1H),7.29(s,1H),4.16-4.15(m,2H),2.92-2.70(m,2H),2.10-1.90(m,2H),1.75(s,6H),1.70-1.50(m,2H),1.46(s,9H).
第五步 合成N-(7-(2-羟基丙-2-基)-2-(哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000018
100mL单口瓶内加入2f(120mg,0.22mmol)，4M二氧六环/HCl(10mL)为溶剂，室温反应1小时，TLC检测至原料反应完全，减压除去溶剂，30℃真空干燥，得到化合物2(90mg，92％)
LCMS m/z(ESI):448.2[M+H] +
1H NMR(400MHz,D 2O)δ9.66(s,1H),8.35(d,J＝7.6Hz,1H),8.29(t,J＝7.6Hz,1H),8.08(d,J＝7.6Hz,1H),7.93(s,1H),7.80(s,1H),3.76(br,1H),3.66–3.58(m,2H),3.30–3.24(m,2H),2.45–2.35(m,2H),2.05–1.97(m,2H),1.73(s,6H).
实施例3
N-(7-(2-羟基丙-2-基)-2-(1-甲基哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000019
称取2(45mg,0.1mmol)溶于DMF(5mL),加入碳酸钾(27mg,2eq)，室温反应30min，加入碘甲烷(21mg,1.5eq)，TLC检测直到原料2反应完全，加入饱和食盐水(20mL)洗涤，加入乙酸乙酯100mL萃取，分出有机层，无水硫酸钠干燥，过滤，浓缩，硅胶柱纯化，二氯甲烷/甲醇洗脱得化合物3(27mg,60％)。
1H NMR(400MHz,CDCl 3)δ12.44(s,1H),9.78(s,1H),8.43(d,J＝7.8Hz,1H),8.14(t,J＝7.8Hz,1H),7.90-7.80(m,2H),7.44(s,1H),4.12(br,1H),3.90-3.80(m, 2H),2.95-2.84(m,2H),2.81(s,3H),2.35-2.25(m,2H),1.90-1.83(m,2H),1.77(s,6H).
实施例4
N-(2-(1-(乙磺酰基)哌啶-4-基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺
Figure PCTCN2019100762-appb-000020
反应瓶内加入2(100mg,0.22mmol)，30mL水溶解，碳酸钾(310mg,2.23mmol)，冰浴下加入乙基磺酰氯(145mg,1.12mmol)，室温反应1小时，TLC检测至原料反应完全，DCM(30mL×2)萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析，二氯甲烷/甲醇洗脱得化合物4(82mg，68％)。
LCMS m/z(ESI):540.2[M+H] +
1H NMR(400MHz,CDCl 3)δ12.16(s,1H),9.55(s,1H),8.45(d,J＝7.8Hz,1H),8.13(t,J＝7.8Hz,1H),7.87(d,J＝7.8Hz,1H),7.49(s,1H),7.32(s,1H),3.90-3.80(m,2H),3.05-2.85(m,5H),2.25-2.10(m,2H),1.90-1.80(m,2H),1.75(s,6H),1.38(t,J＝7.4Hz,3H).
生物学评价
IRAK4激酶活性测定
以下方法用于测定本发明优选化合物在体外条件下对IRAK4激酶活性的抑制程度。本方法使用Cisbio公司的
Figure PCTCN2019100762-appb-000021
KinEASE-STK S1丝/苏氨酸激酶试剂盒，通过测定生物素化的多肽底物磷酸化程度，以均相时间分辨荧光技术(HTRF)进行测定。
详细方法参考试剂盒说明书，将实验流程简述如下：将本发明中的化合物先 溶解于DMSO中，终浓度为10mM。接着以试剂盒中提供的缓冲液进行等梯度稀释，使受试化合物在反应体系中的终浓度范围为16000nM～0.008nM，DMSO的终浓度小于2％。
测试的三磷酸腺苷(ATP)浓度为预先测定的对应ATP Km值(300μM)。将化合物、激酶、生物素化的多肽底物和ATP在37℃下孵育进行激酶反应1h，随后向反应体系中加入偶联有铕系元素化合物的抗磷酸化丝/苏氨酸抗体和偶联有修饰化的XL665链霉亲和素以终止反应，在室温下孵育1h。孵育结束后，在酶标仪FLUOstar Omega上以HTRF模式在激发波长为337nm的条件下，读取各孔在发射波长为615nm和665nm的荧光强度，使用公式Ratio＝(665nm/615nm)×10 4算出Ratio值。通过与对照组荧光强度比值进行对比，计算化合物在各浓度下的抑制率，进而通过GraphPad Prism5以对数浓度-抑制率进行非线性曲线拟合，计算化合物的IC 50值，见下表1。
表1本发明化合物对IRAK4激酶抑制活性的IC 50值
化合物 IC 50(nM)
1 11nM
2 12nM
3 0.5nM
4 0.3nM
对照化合物BAY-1834845 8.6nM
对照化合物BAY-1834845结构式如下：
Figure PCTCN2019100762-appb-000022
从表1可以看出，本发明的优选化合物对IRAK4酶都具有良好的抑制作用，尤其是化合物3和4，其IRAK4酶抑制活性IC 50分别为0.5nM和0.3nM。与对照化合物BAY-1834845(WO2016083433实施例11)相比，化合物4对IRAK4酶抑制活性提高了28倍，显示出了更优异的IRAK4酶抑制活性。我们使用的咪唑[1,2-a]吡啶类衍生物作为一种新的骨架分子，与BAY-1834845的吲唑骨架完 全不同，我们的合成路线简洁，没有吲唑类衍生物的氮位烷基化所产生的异构体问题。因此，本发明的化合物有望用于IRAK4抑制剂及其相关疾病的治疗。

Claims (10)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体或其药学上可接受的盐：
    Figure PCTCN2019100762-appb-100001
    其中：
    R 1选自C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、-CONR AR B、氰基、卤代烷基的取代基所取代；
    R 2选自C 1-C 6烷基、C 3-C 8环烷基、卤素、烷氧基、氰基、羟基、羧基、-CONR AR B、-NR aR b、卤代烷基、胺基烷基、羟基烷基、杂环烷基、芳基或杂芳基；
    R 3选自氰基、烷氧基、-NR aR b、-CONR AR B、-SO 2NR CR D、C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；其中所述的C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、氰基、卤代烷基、氧代基(O＝)、C 1-C 6烷基、-COR E、-SO 2R F、-CONR AR B、-SO 2NR CR D的取代基所取代；
    R 4选自氢、卤素、C 1-C 6烷基、C 3-C 8环烷基、杂环烷基、芳基或杂芳基；
    R a和R b独立地选自氢原子、-COR E、-SO 2R F、C 1-C 6烷基、C 3-C 8环烷基、芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、氰基、卤代烷基、-CONR AR B、-SO 2NR CR D的取代基所取代；或者R a和R b与其所连接的氮原子形成4到8元含氮杂环，稠环，螺环或者R a和R b与其所连接的氮原子形成4到8元另外具有一个或多个选自氮、氧、硫原子的含氮杂环；
    R A、R B、R C、R D独立地选自氢、C 1-C 6烷基或C 3-C 6环烷基；其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基或卤代烷基的取代基所取代；
    R E、R F独立地选自C 1-C 6烷基或C 3-C 6环烷基；其中所述烷基或环烷基任选进一步被一个或多个选自卤素、羟基、氰基或卤代烷基的取代基所取代。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 1为芳基或杂芳基，其中所述的芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、-CONR AR B、氰基、卤代烷基的取代基所取代；其中，R A、R B的定义如权利要求1中所述。
  3. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其具有式(II)结构：
    Figure PCTCN2019100762-appb-100002
    其中，R 2，R 3，R 4的定义如权利要求1中所述。
  4. 根据权利要求1-3任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 2为杂芳基、杂环烷基或羟基烷基。
  5. 根据权利要求1-3任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 3为C 1-C 6烷基、杂环烷基或杂芳基，其中所述的C 1-C 6烷基、杂环烷基或杂芳基任选进一步被一个或多个选自卤素、羟基、氨基、氰基、卤代烷基、氧代基(O＝)、C 1-C 6烷基、-CONR AR B、-SO 2NR CR D、-COR E、-SO 2R F的取代基所取代；其中，R A、R B、R C、R D、R E、R F的定义如权利要求1中所述。
  6. 根据权利要求1-3任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其中R 4为氢、C 1-C 6烷基或C 3-C 8环烷基。
  7. 根据权利要求1-6任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，其为：
    Figure PCTCN2019100762-appb-100003
    N-(2-(3-羟基-3-甲基丁基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
    Figure PCTCN2019100762-appb-100004
    N-(7-(2-羟基丙-2-基)-2-(哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
    Figure PCTCN2019100762-appb-100005
    N-(7-(2-羟基丙-2-基)-2-(1-甲基哌啶-4-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺；
    Figure PCTCN2019100762-appb-100006
    N-(2-(1-(乙磺酰基)哌啶-4-基)-7-(2-羟基丙-2-基)咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶-2-甲酰胺。
  8. 一种药物组合物，含有有效剂量的根据权利要求1-7中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，以及任选的可药用的载体、赋形剂或它们的组合。
  9. 根据权利要求1-7中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或根据权利要求8所述的药物组合物在制备用于抑制IRAK4激酶的活性的药物中的用途。
  10. 根据权利要求1-7中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐，或根据权利要求8所述的药物组合物在制备用于预防或治疗自身免疫性疾病、炎性疾病或癌症的药物中的用途，其中所述的自身免疫性疾病、炎性疾病或癌症优选选自淋巴瘤、子宫内膜异位症、银屑病、红斑狼疮、多发硬化症或类风湿性关节炎；其中所述的淋巴瘤优选为带有MYD88 L265P突变的原发性中枢神经***淋巴瘤或弥漫性大B细胞淋巴瘤。
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020150626A1 (en) * 2019-01-18 2020-07-23 Biogen Ma Inc. Imidazo[1,2-a]pyridinyl derivatives as irak4 inhibitors
WO2020200899A1 (en) * 2019-03-29 2020-10-08 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2020200898A1 (en) * 2019-03-29 2020-10-08 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2021004533A1 (zh) * 2019-07-10 2021-01-14 南京明德新药研发有限公司 作为irak4和btk多靶点抑制剂的噁唑类化合物
WO2022135338A1 (zh) * 2020-12-25 2022-06-30 南京明德新药研发有限公司 酰胺噁唑类化合物
WO2022267673A1 (zh) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 一种亚磺酰亚胺取代的吲唑类irak4激酶抑制剂、制备方法及用途
WO2023283372A1 (en) * 2021-07-07 2023-01-12 Biogen Ma Inc. Compounds for targeting degradation of irak4 proteins
WO2023098857A1 (zh) * 2021-12-03 2023-06-08 武汉人福创新药物研发中心有限公司 Irak4抑制剂及其用途
WO2024067845A1 (zh) * 2022-09-29 2024-04-04 武汉人福创新药物研发中心有限公司 作为irak4降解剂的咪唑并吡啶类化合物及其用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220227758A1 (en) * 2019-06-26 2022-07-21 Medshine Discovery Inc. Imidazopyridine compound as irak4 inhibitor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017148902A1 (de) * 2016-03-03 2017-09-08 Bayer Pharma Aktiengesellschaft Neue 2-substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
CN107406416A (zh) * 2014-11-26 2017-11-28 拜耳医药股份有限公司 新型取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途
WO2017207481A1 (en) * 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Substituted indazoles ueful for treatment and prevention of allergic and/or inflammatory diseases in animals

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107406416A (zh) * 2014-11-26 2017-11-28 拜耳医药股份有限公司 新型取代的吲唑、其制备方法、包含其的药物制剂及其用于制备药物的用途
WO2017148902A1 (de) * 2016-03-03 2017-09-08 Bayer Pharma Aktiengesellschaft Neue 2-substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln
WO2017207481A1 (en) * 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Substituted indazoles ueful for treatment and prevention of allergic and/or inflammatory diseases in animals

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
DATABASE Chemical Catalog Aurora Fine Chemicals; 14 August 2017 (2017-08-14), retrieved from STN Database accession no. 2113260-62-9 *
DATABASE Chemical Catalog Database accession no. 2113260-74-3 *
DATABASE Chemical Catalog Database accession no. 2113260-92-5 *
DATABASE Chemical Catalog Database accession no. 2113299-24-2 *
DATABASE Chemical Catalog Database accession no. 2113299-27-5 *
DATABASE Chemical Catalog Database accession no. 2113299-35-5 *
DATABASE Chemical Catalog Database accession no. 2113299-47-9 *
DATABASE Chemical Catalog Database accession no. 2113299-49-1 *
DATABASE Chemical Catalog Database accession no. 2113299-54-8 *
GUEIFFIER, A. ET AL.: "Synthesis of lH-imidazo[l, 2-a]pyrazolo[3, 4-c]pyridines", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 38, no. 9, 30 September 1990 (1990-09-30), pages 2332 - 2356 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020150626A1 (en) * 2019-01-18 2020-07-23 Biogen Ma Inc. Imidazo[1,2-a]pyridinyl derivatives as irak4 inhibitors
WO2020200899A1 (en) * 2019-03-29 2020-10-08 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2020200898A1 (en) * 2019-03-29 2020-10-08 Galapagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2021004533A1 (zh) * 2019-07-10 2021-01-14 南京明德新药研发有限公司 作为irak4和btk多靶点抑制剂的噁唑类化合物
WO2022135338A1 (zh) * 2020-12-25 2022-06-30 南京明德新药研发有限公司 酰胺噁唑类化合物
WO2022267673A1 (zh) 2021-06-21 2022-12-29 上海勋和医药科技有限公司 一种亚磺酰亚胺取代的吲唑类irak4激酶抑制剂、制备方法及用途
WO2023283372A1 (en) * 2021-07-07 2023-01-12 Biogen Ma Inc. Compounds for targeting degradation of irak4 proteins
WO2023098857A1 (zh) * 2021-12-03 2023-06-08 武汉人福创新药物研发中心有限公司 Irak4抑制剂及其用途
WO2024067845A1 (zh) * 2022-09-29 2024-04-04 武汉人福创新药物研发中心有限公司 作为irak4降解剂的咪唑并吡啶类化合物及其用途

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