WO2023098857A1 - Irak4 inhibitor and use thereof - Google Patents

Irak4 inhibitor and use thereof Download PDF

Info

Publication number
WO2023098857A1
WO2023098857A1 PCT/CN2022/136130 CN2022136130W WO2023098857A1 WO 2023098857 A1 WO2023098857 A1 WO 2023098857A1 CN 2022136130 W CN2022136130 W CN 2022136130W WO 2023098857 A1 WO2023098857 A1 WO 2023098857A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
lymphoma
alkyl
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2022/136130
Other languages
French (fr)
Chinese (zh)
Inventor
张学军
李金平
臧杨
陈浩民
贾一民
刘礼飞
李杨
张博
程智逵
杨成兵
杨俊�
李莉娥
Original Assignee
武汉人福创新药物研发中心有限公司
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 武汉人福创新药物研发中心有限公司 filed Critical 武汉人福创新药物研发中心有限公司
Publication of WO2023098857A1 publication Critical patent/WO2023098857A1/en

Links

Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D471/02—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

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the invention relates to an IRAK4 inhibitor. More specifically, the invention relates to an imidazopyridine compound capable of inhibiting IRAK4 kinase, a preparation method thereof, and an application thereof in preparing medicine.
  • IRAK4 interleukin-1 receptor-associated kinase 4 belongs to the IRAK family. Family members also include IRAK1, IRAK2, IRAKM (I-RAK3) and so on.
  • the human IRAK-4 gene is located in the p11.12 region of the x chromosome and encodes a 52KDa protein.
  • IRAK4 protein like other family members, contains a serine-threonine kinase domain (KD) and a conserved death domain (DD) at the N-terminus.
  • TLRs Toll-like receptor
  • IL-1Rs interleukin 1 receptor
  • TLRs are a family of transmembrane pattern recognition receptors that play a central role in innate immune signaling.
  • the IL-1Rs family can initiate immune responses under the stimulation of various IL-1 cytokines.
  • myeloid differentiation factor 88 acts as an adapter protein to bind to these receptors, and the IRAK4 protein is subsequently recruited to the TLRs/IL-1R complex.
  • IRAK4 can combine with MyD88 and IRAK2 through the shared death domain to form a protein complex Myddosome, activate the kinase activity of IRAK4, and lead to the phosphorylation of downstream IRAK1 and/or IRAK2.
  • IRAK1 Phosphorylation of IRAK1 causes a change in its own conformation, prompting it to bind to tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby activating serine-threonine kinase TAK1, activating downstream NF- ⁇ B, and activating IL-1, IL-8 and Transcription and expression of pro-inflammatory factors such as IL-33, causing inflammatory response.
  • TRAF6 tumor necrosis factor receptor-associated factor 6
  • the JNK signaling pathway is also activated by TRAF6 to regulate the transcription of genes related to inflammation, apoptosis and cell proliferation.
  • IRAK4 Due to the key role of IRAK4 in the cytokine signaling network, abnormally high expression or silencing of IRAK4 will induce abnormalities in the body's immune system. Among them, the abnormally high expression of IRAK4 will lead to excessive activation of the TRL/IL-1R pathway, which will cause the long-term secretion of high levels of pro-inflammatory factors in the body, cause persistent inflammatory responses, and eventually induce autoimmune diseases, including rheumatoid arthritis, silver Psoriasis, systemic lupus erythematosus, multiple sclerosis, etc.
  • TLR4 can reduce the secretion of IL-1 and prevent joint inflammation in mouse models (Abdollahi-Roodsaz S, et al.2007; 56(9):2957-67.)
  • Activation of TLR7 and TLR9 It can stimulate the production of IFN ⁇ in pDC cells, which is also considered as a potential cause of systemic lupus erythematosus (Chiang EY, et al.
  • IRAK4 has also been reported to play a key role in the occurrence and development of a variety of malignant tumors, including melanoma, Waldenstrom's macroglobulinemia (WM), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (T-ALL), ABC diffuse large B-cell lymphoma (ABC-DLCBL) and so on.
  • WM Waldenstrom's macroglobulinemia
  • CLL chronic lymphocytic leukemia
  • T-ALL acute lymphoblastic leukemia
  • ABC-DLCBL ABC diffuse large B-cell lymphoma
  • FLT3 Fms-like tyrosine kinase
  • IRAK1/4 signal-induced activation of the TLR pathway leads to autoimmune response activation, and experiments to knock down IRAK4 or inhibit IRAK4 activity have confirmed the necessity of IRAK1/4 in the process of adaptive resistance in FLT3-ITD mutants (Melgar K, et al.Sci Transl Med 2019; 508(11)), suggesting that simultaneous inhibition of FLT3 signal transduction and IRAK1/4 compensatory activation has the potential to treat patients with FLT3-mutant AML.
  • the invention aims to propose a new IRAK4 inhibitor, which can be used to prepare medicines for treating tumor-related diseases.
  • the present invention proposes a kind of compound, it is the stereoisomer of the compound shown in formula (II) or the compound shown in formula (II), tautomer, nitrogen oxide, solvent compounds, metabolites, pharmaceutically acceptable salts or prodrugs,
  • R 1 is independently selected from C 1 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 13s , the R 13s are the same or different;
  • R 11 and R 12 are each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or R 11 and R 12 together with the N they are connected to form a 3-6 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclic groups may be optionally substituted by one or more R 121 , each of which R 121 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 121 , said R 121 are the same or different;
  • R 2 is independently selected from C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl, and the C 1 -C 6 alkyl and 4-8 membered heterocycloalkyl can optionally be replaced by one or more R 21 is substituted, and the R 21 are each independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, and when there are multiple R 21 , the R 21 are the same or different;
  • R 3 is independently selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl may be optionally substituted by one or more R 31 , each of said R 31 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano, when there are multiple R 31 , said R 31 are the same or different;
  • n 1, 2, 3 or 4;
  • n 1, 2, 3, 4, 5 or 6;
  • hetero of the "5-8 membered heteroaryl", “3-6 membered heterocyclic group” and “4-8 membered heterocycloalkyl” is a heteroatom or a heteroatom group; the heteroatom or heteroatom group The number of is 1 or more, which are independently N, -O-, -NH-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O) 2 -; when there are multiple heteroatoms or heteroatom groups, the heteroatoms or heteroatom groups are the same or different.
  • the present invention proposes a compound, which is a compound represented by formula I,
  • R 1 is independently selected from C 1 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different;
  • R 11 and R 12 are each independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl can optionally be Substituted by one or more R 121 , said R 121 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, said substituents are the same or different;
  • R 2 is independently selected from C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl; said C 1 -C 6 alkyl and 4-8 membered heterocycloalkyl may optionally be replaced by one or more R 21 is substituted, and each R 21 is independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
  • R 1 is independently selected from C 2 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered Heteroaryl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl can be optionally substituted by one or more R 13 ,
  • the R 13 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
  • R 1 is independently selected from -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
  • the compound as shown in formula I is:
  • R has the definition described above.
  • the compound as shown in formula I is:
  • R 1 has the definition described in the present invention
  • R 2a and R 2b form a 4-8 membered heterocycloalkyl group together with the N to which they are attached
  • the 4-8 membered heterocycloalkyl group can be optionally replaced by one or Substituted by multiple R 21
  • each R 21 is independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, when there are multiple R 21 , the R 21 are the same or different .
  • the number of said heteroatoms or heteroatom groups is 1, 2 or 3.
  • R 1 when R 1 is substituted by one or more R 13 , said R 13 is substituted by 1, 2 or 3.
  • R 1 when R 1 is substituted by one or more R 13 , said R 13 is substituted by one or two.
  • halogen when R13 is halogen, said halogen is F or Cl.
  • halogen when R13 is halogen, said halogen is F.
  • R 1 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • R 1 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is methyl
  • R 1 is C 3 -C 6 cycloalkyl
  • said C 3 -C 6 cycloalkyl is cyclopropyl
  • R 1 is -NR 11 R 12
  • said -NR 11 R 12 is -NHCH 3 , -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) or —N(CH 2 CH 3 ) 2 .
  • R 1 is -NR 11 R 12
  • said -NR 11 R 12 is -N(CH 3 ) 2 .
  • R 1 is a 6-10-membered aryl group
  • the 6-10-membered aryl group is phenyl
  • R when R is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazole , thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.
  • R 1 when R 1 is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyridyl.
  • R 2 when R 2 is substituted by one or more R 21 , said R 21 is substituted by 1, 2 or 3.
  • R 2 when R 2 is substituted by one or more R 21 , said R 21 is substituted by 1 or 2.
  • halogen when R21 is halogen, said halogen is F or Cl.
  • halogen when R21 is halogen, said halogen is F.
  • R21 is hydroxyl
  • R21 is F, Cl or hydroxyl.
  • R 2 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • R 2 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is isopropyl
  • R 2 is a 4-8 membered heterocycloalkyl group
  • the 4-8 membered cycloalkyl group is azetidinyl, azetidinyl, oxetidine , pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  • R 2 is a 4-8 membered heterocycloalkyl group
  • the 4-8 membered cycloalkyl group is azetidinyl or morpholinyl.
  • R 3 when R 3 is substituted by one or more R 31 , said R 31 is substituted by 1, 2 or 3.
  • R 3 when R 3 is substituted by one or more R 31 , the number of R 31 substitutions is 3.
  • R 31 when R 31 is halogen, said halogen is F, Cl, Br or I.
  • halogen when R31 is halogen, said halogen is F.
  • R 3 when R 3 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
  • R 3 is C 1 -C 6 alkyl
  • said C 1 -C 6 alkyl is methyl
  • R 1 is selected from -CH 3 , -CHF 2 ,
  • R is selected from
  • R3 is -CF3 .
  • the compound shown in formula I is selected from any of the following compounds:
  • the present invention proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically An acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations, which are suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
  • the formulation can be administered by any route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous (eg oral mucosa or rectum, etc.). Administration can be systemic or local.
  • formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations can be prepared by methods known in the art, and contain carriers, diluents or excipients commonly used in the field of pharmaceutical formulations.
  • the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in medicines for treating or preventing diseases related to IRAK4.
  • the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used in the preparation of the treatment and prevention of IRAK4 Use in disease medicaments for the treatment of autoimmune diseases as well as cancer.
  • autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema;
  • these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin
  • the present invention proposes the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition for the treatment of Or prevent diseases associated with IRAK4.
  • the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used for treating or preventing autoimmunity disease or cancer.
  • autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema;
  • these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin
  • the present invention provides a method for treating or preventing diseases related to IRAK4.
  • the method includes administering to the patient an effective amount of the above compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above drug combination.
  • the IRAK4-related diseases include autoimmune diseases or cancer.
  • autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema;
  • these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacant
  • sarcoma
  • the present invention proposes the following intermediates, which are selected from any of the following compounds or stereoisomers, tautomers or pharmaceutically acceptable salts of any of the following compounds.
  • the intermediates according to the embodiments of the present invention can be used for the synthesis of the compounds of the present invention:
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • composition means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid.
  • Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
  • HPLC high performance liquid chromatography
  • SFC supercritical fluid chromatography
  • any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Keto substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or
  • C 3 -C 6 cycloalkyl is understood to mean saturated monocyclic or bicyclic hydrocarbon rings having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • 4-8 membered heterocyclyl or “4-8 membered heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms selected from N, O and S, which may be attached through carbon or nitrogen unless otherwise stated, wherein the -CH2- group is optionally replaced by a -C(O)- and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or an S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally is substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens.
  • heterocyclyl when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other.
  • the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic.
  • heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
  • 6-10 membered aryl should be understood as an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-10 carbon atoms, especially a ring having 6 carbon atoms ("C 6 aryl”), such as phenyl; when the 6-10 membered aryl is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution site, for example, it may be an ortho, para or meta substitution.
  • 5-8 membered heteroaryl is understood to mean a monocyclic ring having 5-8 ring atoms, especially 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S , bicyclic or tricyclic aromatic ring groups.
  • Monocyclic, bicyclic or tricyclic aromatic ring groups of 1 to 3 heteroatoms independently selected from N, O and S are preferred, and may additionally be benzofused in each case.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • the present invention has at least one of the following technical effects:
  • the present invention provides an IRAK4 inhibitor with novel structure, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat or prevent IRAK4-related diseases and diseases.
  • the ratio of the free drug in the human and mouse plasma of the compound of the present invention is high, and the druggability is good.
  • the compound of the present invention has no inhibitory effect on CYP2C9, CYP2D6, and CYP3A4 enzymes at 10 ⁇ M, and potential drug-drug interactions The risk is low, and the compound of the present invention also exhibits relatively good stability in liver metabolism.
  • the compounds of the present invention exhibit better pharmacokinetic properties in mouse and rat species.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
  • T3P ⁇ DMF 1-propyl phosphoric anhydride 50% N,N-dimethylformamide solution
  • IC 50 half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • Embodiment 1 the preparation of target compound I-1
  • the first step Synthesis of 3-fluoro-N,N-bis(4-methoxybenzyl)-5-nitropyridin-2-amine (I-1b)
  • Step 3 Synthesis of (6-(two(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)carbamate tert-butyl ester (I-1d)
  • Step 4 Synthesis of (6-(two(4-methoxybenzyl)amino)-5-fluoro-4-iodopyridin-3-yl)carbamate tert-butyl ester (I-1e)
  • Step 5 Synthesis of (4-acetyl-6-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)carbamate tert-butyl ester (I-1f)
  • the sixth step the synthesis of 1-(5-amino-2-(two(4-methoxybenzyl)amino)-3-fluoropyridin-4-yl)ethanone (1-1g)
  • the seventh step N-(4-acetyl-5-fluoro-6-((4-methoxybenzyl)amino)pyridin-3-yl)-6-(trifluoromethyl)picolinamide (I Synthesis of -1h)
  • Step 8 Synthesis of N-(4-acetyl-6-amino-5-fluoropyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1j)
  • N-(4-acetyl-5-fluoro-6-((4-methoxybenzyl)amino)pyridin-3-yl)-6-(trifluoromethyl)picolinamide ( I-1h) (5.00g, 10.8mmol) was added to trifluoroacetic acid (20.0mL), and the mixture was stirred at 50°C for 1 hour.
  • N-(4-acetyl-6-amino-5-fluoropyridin-3-yl)-6-(trifluoromethyl)picolinamide (2.60 g, 7.60 mmol) was added to tetrahydrofuran (52.0 mL) , then, at 0°C, methylmagnesium bromide (3.00M, 12.7mL) was added dropwise to it, after the dropwise addition was completed, the reaction solution was stirred at 25°C for 12 hours, after the reaction was completed, saturated ammonium chloride ( 100 mL), then extracted with ethyl acetate (100 mL ⁇ 3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product.
  • Step 12 N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyridine-6 Synthesis of -yl)-6-(trifluoromethyl)picolinamide (I-1)
  • the crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min) to separate N-(8- Fluoro-7-(2-hydroxypropan-2-yl)-2-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl base) picolinamide (I-1) (77.01 mg, yield 18.7%).
  • reverse phase chromatographic column: Phenomenex Synergi C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min
  • Embodiment 2 the preparation of target compound 1-2
  • the first step the synthesis of 3-(cyclopropylthio) methyl propionate (I-2b)
  • Methyl 3-mercaptopropionate (I-2a) (5 g, 41.6 mmol), bromocyclopropane (5.03 g, 41.6 mmol) and potassium tert-butoxide (4.67 g, 41.6 mmol) were dissolved in dimethylsulfoxide ( 50 mL) in a hydrogenation bottle, the reaction was a closed reaction, and the reaction solution was heated to 120° C. for 12 hours.
  • the second step the synthesis of 3-(cyclopropylthio)propionic acid (I-2c)
  • the third step the synthesis of 3-(cyclopropylthio) propionyl chloride (I-2d)
  • the fourth step the synthesis of 1-chloro-4-(cyclopropylthio)butan-2-one (I-2e)
  • Embodiment 3 the preparation of target compound 1-3
  • the first step the synthesis of ethyl 3-((4-fluorophenyl)thio)propionate (I-3c)
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure
  • the third step the synthesis of 1-chloro-4-((4-fluorophenyl)sulfonyl)butan-2-one (I-3e)
  • Embodiment 4 the preparation of target compound 1-6
  • the first step 3-(nitrogen, nitrogen-dimethylsulfonyl)propionic acid (I-6b)
  • the second step 3-(nitrogen, nitrogen-dimethylsulfonyl)propionyl chloride
  • the third step 4-chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (I-6e)
  • the fourth step nitrogen-(2-(2-(nitrogen, nitrogen-dimethylsulfonyl) ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl) imidazo[1,2 -a] pyridin-6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-6)
  • the crude product was purified by reverse-phase column HPLC (chromatographic column: Phenomenex Synergi C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min) to obtain nitrogen -(2-(2-(nitrogen, nitrogen-dimethylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridine- 6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-6) (10 mg, 100% purity)
  • Embodiment 5 the preparation of target compound 1-8
  • the synthetic route of target compound 1-8 is as follows:
  • reaction solution was washed with water (20 mL) and ethyl acetate (20 mL*2), the organic phases were combined, washed twice with brine, then dried over sodium sulfate, filtered and spin-dried to obtain a crude product.
  • the third step nitrogen-(5-fluoro-6-((4-methoxybenzyl) amino)-4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridineamide (I -8c)
  • reaction solution was extracted with water and ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • the fourth step Nitrogen-(6-amino-5-fluoro-4-morpholinylpyridin-3-yl)-6-(trifluoromethyl)pyridineamide (I-8d)
  • Nitrogen-(5-fluoro-6-((4-methoxybenzyl)amino)-4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8c) (100mg, 1eq) was dissolved in dichloromethane (3mL), then trifluoroacetic acid (1mL) was added, and the reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with sodium bicarbonate, and the aqueous phase was extracted three times with dichloromethane (5mL*3).
  • Step 5 Nitrogen-(8-fluoro-2-(2-(methylsulfonyl)ethyl)-7-morpholinoimidazo[1,2-a]pyridin-6-yl)-6-(tri Fluoromethyl) pyridinamide (target compound I-8)
  • Nitrogen-(6-amino-5-fluoro-4-morpholinylpyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8d) (100mg, 0.260mmol) and 1-chloro- 4-(Methylsulfonyl)butan-2-one (1A) (144 mg, 0.779 mmol) was dissolved in a closed tube of ethanol (1 mL), and the reaction solution was reacted at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated and spin-dried to obtain a crude product.
  • Test Example 1 Mobility Shift Assay to detect the inhibition of IRAK4 kinase activity by compounds
  • test results show that the compounds of this patent exhibit better inhibitory activity on IRAK4 kinase, especially the inhibitory activity of compound I-1 is significantly better.
  • Test Example 2 Inhibitory activity of compound on R848 stimulating PBMC to produce TNF- ⁇
  • cryopreserved PBMC cells were revived, centrifuged at 200 rpm for 5 min to obtain the supernatant, resuspended with 1640+10% FBS+1% P/S complete medium and counted. According to the density of 8 ⁇ 10 4 /well, 100 ⁇ l/well cells were seeded into 96-well plate and grown overnight.
  • the prepared R848 was added to the cells at 50 ⁇ l/well, and control wells without R848 were set at the same time.
  • the supernatants were collected after the cells were further incubated for 24 hours, and 50% of the supernatants were collected for detection with a Human TNF- ⁇ kit (Invitrogen, LOT: 189974010).
  • the inhibition rate of the compound was calculated according to the control well, and the IC50 value of the compound was calculated by fitting the curve with GraphPad software.
  • Table 2 Inhibitory activity of test compounds on R848-stimulated PBMC to produce TNF- ⁇
  • test compound IC50(nM) Control compound 1 172 I-1 26.7
  • test results show that, compared with the reference compound 1, the compound of this patent has a stronger inhibitory ability to TNF- ⁇ production at the cellular level, especially the inhibitory activity of the compound I-1 is significantly better than that of the reference compound 1.
  • % binding rate 100 ⁇ ([supply side concentration] 6h ⁇ [receiving side concentration] 6h )/[supply side concentration] 6h .
  • Ratio (%) of free drug in plasma 100-% binding rate
  • the stability test of human liver microsomes was detected by incubating the compound with human liver microsomes in vitro. Firstly, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Use PBS to dilute human liver microsomes (Corning) into a microsome/buffer solution, and use this solution to dilute 0.5 mM compound to become a working solution. The concentration of the compound in the working solution is 1.5 ⁇ M, and the concentration of human liver microsomes is 0.75 mg/mL .
  • cytochrome P450 subtype CYP3A4 two substrates midazolam and testosterone
  • CYP450 cytochrome P450 subtype CYP3A4
  • the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent
  • the CYP3A4 inhibitor ketoconazole was prepared as a 2.5 mM stock solution in DMSO solvent.
  • the compound to be tested and ketoconazole were diluted to 400-fold final concentration with acetonitrile (compound: 10 ⁇ M, ketoconazole: 2.5 ⁇ M).
  • the reaction was terminated by adding 120 ⁇ L of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS 2/4) for 10 minutes (600 rpm/min), and then centrifuged for 15 minutes. Take the supernatant after centrifugation, add purified water at 1:1 and perform LC-MS/MS detection to obtain the peak area ratio of the compound to the internal standard peak area, compare the peak area ratio of the compound with the peak area ratio of the control inhibitor, and calculate the inhibition Rate.
  • mice For the mouse pharmacokinetic test, use male ICR mice, 20-25g, fasted overnight. Take 3 mice, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. The blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model
  • Rat pharmacokinetic test using male SD rats, 180-240g, fasted overnight. Take 3 rats, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C to collect plasma and stored at -20°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.

Abstract

Disclosed are an IRAK4 inhibitor and a use thereof. Specifically, provided are an imidazopyridine compound shown by formula (II), a preparation method therefor, and a use in the preparation of a drug for treating IRAK4-related diseases.

Description

IRAK4抑制剂及其用途IRAK4 inhibitors and uses thereof 技术领域technical field
本发明属于医药化学领域，具体的，本发明涉及IRAK4抑制剂，更具体的，本发明涉及一种可抑制IRAK4激酶的咪唑并吡啶化合物及其制备方法，以及其在制备药物中的用途。The invention belongs to the field of medicinal chemistry. Specifically, the invention relates to an IRAK4 inhibitor. More specifically, the invention relates to an imidazopyridine compound capable of inhibiting IRAK4 kinase, a preparation method thereof, and an application thereof in preparing medicine.
背景技术Background technique
IRAK4，白细胞介素-1受体相关激酶4，属于IRAK家族。家族成员还包括IRAK1、IRAK2、IRAKM(I-RAK3)等。人类的IRAK-4基因位于x染色体p11.12区，编码52KDa蛋白质。IRAK4蛋白与其他家族成员一样，都含有丝氨酸-苏氨酸激酶结构域(KD)和位于N端保守的死亡结构域(DD)，是Toll样受体(Toll like receptor，TLRs)、白细胞介素1受体(inteleukin-1，IL-1Rs)信号通路中的关键分子，参与调控细胞内信号级联及炎症反应。TLRs是跨膜模式识别受体家族，在先天性免疫信号传递中发挥核心功能。IL-1Rs家族可在多种IL-1细胞因子刺激下启动免疫反应。IRAK4, interleukin-1 receptor-associated kinase 4, belongs to the IRAK family. Family members also include IRAK1, IRAK2, IRAKM (I-RAK3) and so on. The human IRAK-4 gene is located in the p11.12 region of the x chromosome and encodes a 52KDa protein. IRAK4 protein, like other family members, contains a serine-threonine kinase domain (KD) and a conserved death domain (DD) at the N-terminus. It is a Toll-like receptor (Toll like receptor, TLRs), interleukin 1 receptor (intelukin-1, IL-1Rs) signaling pathway key molecules involved in the regulation of intracellular signaling cascade and inflammatory response. TLRs are a family of transmembrane pattern recognition receptors that play a central role in innate immune signaling. The IL-1Rs family can initiate immune responses under the stimulation of various IL-1 cytokines.
在IL-1R、IL-18R和大多数TLR受到刺激后，髓系分化因子88(MyD88)作为接头蛋白与这些受体结合，随后IRAK4蛋白被招募到TLRs/IL-1R复合物。IRAK4可与MyD88及IRAK2通过共有的死亡结构域相互结合，形成蛋白质复合体Myddosome，活化IRAK4的激酶活性，导致下游IRAK1和/或IRAK2的磷酸化。IRAK1磷酸化引起了自身构象改变，促使其与肿瘤坏死因子受体相关因子6(TRAF6)结合，从而活化丝氨酸-苏氨酸激酶TAK1，激活下游NF-κB，启动IL-1、IL-8以及IL-33等促炎性因子的转录和表达，引起炎症反应。此外，JNK信号通路也被TRAF6激活，调控炎症、细胞凋亡及细胞增殖相关基因的转录。敲除IRAK4的小鼠模型中，IL-1、IL-18和大多数TLR配体的信号转导和细胞应答均严重受损，验证了IRAK4在IL-1R、IL-18R和多数TLR信号通路中的重要作用(Suzuki N,et al.Nature 2002,416,750-756.)。After stimulation of IL-1R, IL-18R, and most TLRs, myeloid differentiation factor 88 (MyD88) acts as an adapter protein to bind to these receptors, and the IRAK4 protein is subsequently recruited to the TLRs/IL-1R complex. IRAK4 can combine with MyD88 and IRAK2 through the shared death domain to form a protein complex Myddosome, activate the kinase activity of IRAK4, and lead to the phosphorylation of downstream IRAK1 and/or IRAK2. Phosphorylation of IRAK1 causes a change in its own conformation, prompting it to bind to tumor necrosis factor receptor-associated factor 6 (TRAF6), thereby activating serine-threonine kinase TAK1, activating downstream NF-κB, and activating IL-1, IL-8 and Transcription and expression of pro-inflammatory factors such as IL-33, causing inflammatory response. In addition, the JNK signaling pathway is also activated by TRAF6 to regulate the transcription of genes related to inflammation, apoptosis and cell proliferation. In the IRAK4 knockout mouse model, the signal transduction and cellular responses of IL-1, IL-18 and most TLR ligands were severely impaired, verifying the role of IRAK4 in IL-1R, IL-18R and most TLR signaling pathways important role in (Suzuki N, et al. Nature 2002, 416, 750-756.).
由于IRAK4在细胞因子信号网络中的关键角色，IRAK4的异常高表达或沉默都会诱使机体的免疫***异常。其中，IRAK4异常高表达会导致TRL/IL-1R通路过度激活，使体内长期分泌高水平的促炎性因子，引起持续性的炎症反应，最终诱发自身免疫疾病，包括类风湿性关节炎、银屑病、***性红斑狼疮、多发性硬化症等。有研究者发现类风湿性关节炎患者的关节滑液中存在的IL-1明显高于健康者(Nouri AM,et al.Clin Exp Immunol 1984；55(2):295–302.)，而进一步研究证明拮抗TLR4可降低IL-1的分泌，并在小鼠模型上有预防关节炎症的作用(Abdollahi-Roodsaz S,et al.2007；56(9):2957–67.)TLR7和TLR9的激活可 刺激pDC细胞中IFNα的产生，这也被认为是***性红斑狼疮的潜在诱因(Chiang EY,et al.J Immunol 2011；186(2):1279–88.)。许多其他自身免疫性疾病，包括炎性肠病(Coccia M,et al.J Exp Med 2012；209(9):1595–609.)、干燥综合征(Low HZ,et al.Arthritis Res Ther 2011；13(3):1–7.)等都与TLR信号增强有关，进一步提示了抑制IRAK4对自身免疫疾病的潜在药效。Due to the key role of IRAK4 in the cytokine signaling network, abnormally high expression or silencing of IRAK4 will induce abnormalities in the body's immune system. Among them, the abnormally high expression of IRAK4 will lead to excessive activation of the TRL/IL-1R pathway, which will cause the long-term secretion of high levels of pro-inflammatory factors in the body, cause persistent inflammatory responses, and eventually induce autoimmune diseases, including rheumatoid arthritis, silver Psoriasis, systemic lupus erythematosus, multiple sclerosis, etc. Some researchers found that the IL-1 in the synovial fluid of patients with rheumatoid arthritis was significantly higher than that of healthy people (Nouri AM, et al. Clin Exp Immunol 1984; 55(2):295-302.), and further Studies have shown that antagonizing TLR4 can reduce the secretion of IL-1 and prevent joint inflammation in mouse models (Abdollahi-Roodsaz S, et al.2007; 56(9):2957-67.) Activation of TLR7 and TLR9 It can stimulate the production of IFNα in pDC cells, which is also considered as a potential cause of systemic lupus erythematosus (Chiang EY, et al. J Immunol 2011; 186(2):1279–88.). Many other autoimmune diseases, including inflammatory bowel disease (Coccia M, et al. J Exp Med 2012; 209(9): 1595–609.), Sjogren's syndrome (Low HZ, et al. Arthritis Res Ther 2011; 13(3):1–7.), etc. are all related to the enhancement of TLR signaling, further suggesting the potential efficacy of inhibiting IRAK4 on autoimmune diseases.
IRAK4也被报道在多种恶性肿瘤的发生发展中起着关键作用，包括黑色素瘤、Waldenstrom巨球蛋白血症(WM)、慢性淋巴细胞白血病(CLL)、急性淋巴细胞白血病(T-ALL)、ABC性弥漫大B细胞淋巴瘤(ABC-DLCBL)等。MyD88-L256P的功能增强型突变造成的myddosome复合体上调，导致NF-κB的激活引起一系列肿瘤细胞系的存活及增殖。黑色素瘤活检的免疫组化结果显示磷酸化的IRAK4在病变组织中高度表达(Srivastava R,et al.Cancer Res 2012；72(23):6209–16.)。在T-ALL细胞中也观察到了IRAK1和IRAK4的mRNA表达水平的增加，以及IRAK1和IRAK4的磷酸化水平的升高(Li Z,et al.J Clin Invest 2015；125(3):1081–97.)。用shRNA沉默IRAK4或小分子抑制其酶活性会削弱来自T-ALL患者的样本中的细胞增殖，表明介由IRAK4的信号转导是疾病进展中的关键因素。还有报道称，IRAK4抑制剂与Ibrutinib(一种BTK抑制剂)联合应用，可协同抑制MyD88-L256P突变的ABC-DLBCL细胞系的增殖。(Kelly PN,et al.J ExpMed 2015；212(13):2189–201.)。以上研究结果均证实了IRAK4靶点在肿瘤治疗领域的潜在价值。IRAK4 has also been reported to play a key role in the occurrence and development of a variety of malignant tumors, including melanoma, Waldenstrom's macroglobulinemia (WM), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (T-ALL), ABC diffuse large B-cell lymphoma (ABC-DLCBL) and so on. An enhance-of-function mutation of MyD88-L256P results in upregulation of the myddosome complex, leading to activation of NF-κB that leads to the survival and proliferation of a range of tumor cell lines. Immunohistochemical results of melanoma biopsies show that phosphorylated IRAK4 is highly expressed in diseased tissues (Srivastava R, et al. Cancer Res 2012;72(23):6209–16.). Increased mRNA expression levels of IRAK1 and IRAK4, as well as increased phosphorylation levels of IRAK1 and IRAK4 were also observed in T-ALL cells (Li Z, et al. J Clin Invest 2015; 125(3): 1081–97 .). Silencing IRAK4 with shRNA or inhibiting its enzymatic activity with small molecules impairs cell proliferation in samples from T-ALL patients, suggesting that signaling through IRAK4 is a key factor in disease progression. It has also been reported that the combination of an IRAK4 inhibitor and Ibrutinib, a BTK inhibitor, synergistically inhibits the proliferation of an ABC-DLBCL cell line with a MyD88-L256P mutation. (Kelly PN, et al. J ExpMed 2015; 212(13):2189–201.). The above research results all confirmed the potential value of the IRAK4 target in the field of tumor therapy.
此外，Fms样酪氨酸激酶(FLT3)的激活突变会导致其自身磷酸化和细胞内信号通路的启动，从而促进白血病细胞的存活和增殖，是AML产生对FLT3抑制剂适应性耐药的因素之一。有研究者已经证实，FLT3抑制剂引起FLT3-ITD突变耐药的机制，与IRAK1/4代偿性激活有关。IRAK1/4信号引起TLR通路的激活导致了自身免疫应激活化，敲低IRAK4或抑制IRAK4活性的试验证实了IRAK1/4在FLT3-ITD突变体产生适应性抵抗过程中的必需性(Melgar K,et al.Sci Transl Med 2019；508(11))，提示了同时抑制FLT3信号转导和IRAK1/4代偿性激活有治疗FLT3突变AML患者的潜力。In addition, activating mutations in Fms-like tyrosine kinase (FLT3) lead to its autophosphorylation and initiation of intracellular signaling pathways, thereby promoting the survival and proliferation of leukemia cells, which is a factor in the development of adaptive resistance to FLT3 inhibitors in AML one. Some researchers have confirmed that the mechanism by which FLT3 inhibitors cause FLT3-ITD mutation resistance is related to the compensatory activation of IRAK1/4. IRAK1/4 signal-induced activation of the TLR pathway leads to autoimmune response activation, and experiments to knock down IRAK4 or inhibit IRAK4 activity have confirmed the necessity of IRAK1/4 in the process of adaptive resistance in FLT3-ITD mutants (Melgar K, et al.Sci Transl Med 2019; 508(11)), suggesting that simultaneous inhibition of FLT3 signal transduction and IRAK1/4 compensatory activation has the potential to treat patients with FLT3-mutant AML.
发明内容Contents of the invention
本发明旨在提出一种新的IRAK4抑制剂，可用于制备***相关疾病的药物。The invention aims to propose a new IRAK4 inhibitor, which can be used to prepare medicines for treating tumor-related diseases.
本发明的第一方面，本发明提出了一种化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The first aspect of the present invention, the present invention proposes a kind of compound, it is the stereoisomer of the compound shown in formula (II) or the compound shown in formula (II), tautomer, nitrogen oxide, solvent compounds, metabolites, pharmaceutically acceptable salts or prodrugs,
Figure PCTCN2022136130-appb-000001
Figure PCTCN2022136130-appb-000001
其中，R 1独立地选自C 1-C 6烷基、-NR 11R 12、C 3-C 6环烷基、6-10元芳基或5-8元杂芳基，所述C 1-C 6烷基、C 3-C 6环烷基、6-10元芳基和5-8元杂芳基可以任选地被一个或多个R 13取代，所述R 13各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基；当R 13为多个时，所述的R 13相同或不同； Wherein, R 1 is independently selected from C 1 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 13s , the R 13s are the same or different;
R 11和R 12各自独立地选自C 1-C 6烷基、C 3-C 6环烷基或R 11和R 12连同其所连接的N形成3～6元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基以及3～6元杂环基可以任选地被一个或多个R 121取代，所述R 121各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基；当R 121为多个时，所述的R 121相同或不同； R 11 and R 12 are each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or R 11 and R 12 together with the N they are connected to form a 3-6 membered heterocyclic group, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclic groups may be optionally substituted by one or more R 121 , each of which R 121 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 121 , said R 121 are the same or different;
R 2独立地选自C 1-C 6烷基或4-8元杂环烷基，所述C 1-C 6烷基和4-8元杂环烷基可以任选地被一个或多个R 21取代，所述R 21各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 21为多个时，所述的R 21相同或不同； R 2 is independently selected from C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl, and the C 1 -C 6 alkyl and 4-8 membered heterocycloalkyl can optionally be replaced by one or more R 21 is substituted, and the R 21 are each independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, and when there are multiple R 21 , the R 21 are the same or different;
R 3独立地选自C 1-C 6烷基，所述C 1-C 6烷基可以任选地被一个或多个R 31取代，所述R 31各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 31为多个时，所述的R 31相同或不同； R 3 is independently selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl may be optionally substituted by one or more R 31 , each of said R 31 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano, when there are multiple R 31 , said R 31 are the same or different;
m为1，2，3或4；m is 1, 2, 3 or 4;
n为1，2，3，4，5或6；n is 1, 2, 3, 4, 5 or 6;
所述“5-8元杂芳基”、“3-6元杂环基”和“4-8元杂环烷基”的“杂”为杂原子或杂原子团；所述杂原子或杂原子团的个数为1个或多个，分别独立地为N、-O-、-NH-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2-；当所述杂原子或杂原子团的个数为多个时，所述杂原子或杂原子团相同或不同。 The "hetero" of the "5-8 membered heteroaryl", "3-6 membered heterocyclic group" and "4-8 membered heterocycloalkyl" is a heteroatom or a heteroatom group; the heteroatom or heteroatom group The number of is 1 or more, which are independently N, -O-, -NH-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O) 2 -; when there are multiple heteroatoms or heteroatom groups, the heteroatoms or heteroatom groups are the same or different.
在本发明的第二方面，本发明提出了一种化合物，其为式I所示化合物，In the second aspect of the present invention, the present invention proposes a compound, which is a compound represented by formula I,
Figure PCTCN2022136130-appb-000002
Figure PCTCN2022136130-appb-000002
其中，in,
R 1独立地选自C 1-C 6烷基、-NR 11R 12、C 3-C 6环烷基、6-10元芳基或5-8元杂芳基，所述C 1-C 6烷基、C 3-C 6环烷基、6-10元芳基和5-8元杂芳基可以任选地被一个或多个R 13取代，所述R 13各自独立地选自C 1-C 6烷基、卤素、羟基或氰基；当取代基为多个时，所述的取代基相同或不同； R 1 is independently selected from C 1 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different;
R 11和R 12各自独立地选自C 1-C 6烷基或C 3-C 6环烷基，所述C 1-C 6烷基和C 3-C 6环烷基可以任选地被一个或多个R 121取代，所述R 121各自独立地选自C 1-C 6烷基、卤素、羟基或氰基；当取代基为多个时，所述的取代基相同或不同； R 11 and R 12 are each independently selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, and the C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl can optionally be Substituted by one or more R 121 , said R 121 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, said substituents are the same or different;
R 2独立地选自C 1-C 6烷基或4-8元杂环烷基；所述C 1-C 6烷基和4-8元杂环烷基可以任选地被一个或多个R 21取代，所述R 21各自独立地选自C 1-C 6烷基、卤素、羟基或氰基；当取代基为多个时，所述的取代基相同或不同。 R 2 is independently selected from C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl; said C 1 -C 6 alkyl and 4-8 membered heterocycloalkyl may optionally be replaced by one or more R 21 is substituted, and each R 21 is independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，R 1独立地选自C 2-C 6烷基、-NR 11R 12、C 3-C 6环烷基、6-10元芳基或5-8元杂芳基，所述C 1-C 6烷基、C 3-C 6环烷基、6-10元芳基和5-8元杂芳基可以任选地被一个或多个R 13取代，所述R 13各自独立地选自C 1-C 6烷基、卤素、羟基或氰基；当取代基为多个时，所述的取代基相同或不同。 In an optional embodiment of the present invention, R 1 is independently selected from C 2 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered Heteroaryl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl can be optionally substituted by one or more R 13 , The R 13 are each independently selected from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，R 1独立地选自-NR 11R 12、C 3-C 6环烷基、6-10元芳基或5-8元杂芳基，所述C 1-C 6烷基、C 3-C 6环烷基、6-10元芳基和5-8元杂芳基可以任选地被一个或多个R 13取代，所述R 13各自独立地选自C 1-C 6烷基、卤素、羟基或氰基；当取代基为多个时，所述的取代基相同或不同。 In an optional embodiment of the present invention, R 1 is independently selected from -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from from C 1 -C 6 alkyl, halogen, hydroxyl or cyano; when there are multiple substituents, the substituents are the same or different.
在本发明一任选实施方案中，如式I所示的化合物为：In an optional embodiment of the present invention, the compound as shown in formula I is:
Figure PCTCN2022136130-appb-000003
Figure PCTCN2022136130-appb-000003
其中，R 1具有前文所述的定义。 Wherein, R has the definition described above.
在本发明一任选实施方案中，如式I所示的化合物为：In an optional embodiment of the present invention, the compound as shown in formula I is:
Figure PCTCN2022136130-appb-000004
Figure PCTCN2022136130-appb-000004
其中，R 1具有本发明所述的定义，R 2a和R 2b连同其所连接的N形成4-8元杂环烷基，所述4-8元杂环烷基可以任选地被一个或多个R 21取代，所述R 21各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 21为多个时，所述的R 21相同或不同。在本发明一任选实施方案中，所述杂原子或杂原子团的个数为1个、2个或3个。 Wherein, R 1 has the definition described in the present invention, R 2a and R 2b form a 4-8 membered heterocycloalkyl group together with the N to which they are attached, and the 4-8 membered heterocycloalkyl group can be optionally replaced by one or Substituted by multiple R 21 , each R 21 is independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, when there are multiple R 21 , the R 21 are the same or different . In an optional embodiment of the present invention, the number of said heteroatoms or heteroatom groups is 1, 2 or 3.
在本发明一任选实施方案中，当R 1被一个或多个R 13取代时，所述R 13取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 1 is substituted by one or more R 13 , said R 13 is substituted by 1, 2 or 3.
在本发明一任选实施方案中，当R 1被一个或多个R 13取代时，所述R 13取代为1个或2个。 In an optional embodiment of the present invention, when R 1 is substituted by one or more R 13 , said R 13 is substituted by one or two.
在本发明一任选实施方案中，当R 13为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R13 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，当R 13为卤素时，所述卤素为F。 In an optional embodiment of the present invention, when R13 is halogen, said halogen is F.
在本发明一任选实施方案中，当R 1为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In an optional embodiment of the present invention, when R 1 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在本发明一任选实施方案中，当R 1为C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R 1 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl.
在本发明一任选实施方案中，当R 1为C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基。 In an optional embodiment of the present invention, when R 1 is C 3 -C 6 cycloalkyl, said C 3 -C 6 cycloalkyl is cyclopropyl.
在本发明一任选实施方案中，当R 1为-NR 11R 12时，所述-NR 11R 12为-NHCH 3、-N(CH 3) 2、-N(CH 3)(CH 2CH 3)或-N(CH 2CH 3) 2。 In an optional embodiment of the present invention, when R 1 is -NR 11 R 12 , said -NR 11 R 12 is -NHCH 3 , -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) or —N(CH 2 CH 3 ) 2 .
在本发明一任选实施方案中，当R 1为-NR 11R 12时，所述-NR 11R 12为-N(CH 3) 2。 In an optional embodiment of the present invention, when R 1 is -NR 11 R 12 , said -NR 11 R 12 is -N(CH 3 ) 2 .
在本发明一任选实施方案中，当R 1为6-10元芳基时，所述6-10元芳基为苯基。 In an optional embodiment of the present invention, when R 1 is a 6-10-membered aryl group, the 6-10-membered aryl group is phenyl.
在本发明一任选实施方案中，当R 1为5-8元杂芳基时，所述5-8元杂芳基为吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、噻二唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基或三嗪基。 In an optional embodiment of the present invention, when R is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazole , thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.
在本发明一任选实施方案中，当R 1为5-8元杂芳基时，所述5-8元杂芳基为吡啶基。 In an optional embodiment of the present invention, when R 1 is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyridyl.
在本发明一任选实施方案中，当R 2被一个或多个R 21取代时，所述R 21取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 2 is substituted by one or more R 21 , said R 21 is substituted by 1, 2 or 3.
在本发明一任选实施方案中，当R 2被一个或多个R 21取代时，所述R 21取代为1个或2个。 In an optional embodiment of the present invention, when R 2 is substituted by one or more R 21 , said R 21 is substituted by 1 or 2.
在本发明一任选实施方案中，当R 21为卤素时，所述卤素为F或Cl。 In an optional embodiment of the present invention, when R21 is halogen, said halogen is F or Cl.
在本发明一任选实施方案中，当R 21为卤素时，所述卤素为F。 In an optional embodiment of the present invention, when R21 is halogen, said halogen is F.
在本发明一任选实施方案中，R 21为羟基。 In an optional embodiment of the invention, R21 is hydroxyl.
在本发明一任选实施方案中，R 21为F、Cl或羟基。 In an optional embodiment of the invention, R21 is F, Cl or hydroxyl.
在本发明一任选实施方案中，当R 2为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In an optional embodiment of the present invention, when R 2 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在本发明一任选实施方案中，当R 2为C 1-C 6烷基时，所述C 1-C 6烷基为异丙基。 In an optional embodiment of the present invention, when R 2 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is isopropyl.
在本发明一任选实施方案中，当R 2为4-8元杂环烷基时，所述4-8元环烷基为氮杂环丁基、氮杂环戊基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基。 In an optional embodiment of the present invention, when R 2 is a 4-8 membered heterocycloalkyl group, the 4-8 membered cycloalkyl group is azetidinyl, azetidinyl, oxetidine , pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
在本发明一任选实施方案中，当R 2为4-8元杂环烷基时，所述4-8元环烷基为氮杂环丁基或吗啉基。 In an optional embodiment of the present invention, when R 2 is a 4-8 membered heterocycloalkyl group, the 4-8 membered cycloalkyl group is azetidinyl or morpholinyl.
在本发明一任选实施方案中，当R 3被一个或多个R 31取代时，所述R 31取代为1个、2个或3个。 In an optional embodiment of the present invention, when R 3 is substituted by one or more R 31 , said R 31 is substituted by 1, 2 or 3.
在本发明一任选实施方案中，当R 3被一个或多个R 31取代时，所述R 31取代为3个。 In an optional embodiment of the present invention, when R 3 is substituted by one or more R 31 , the number of R 31 substitutions is 3.
在本发明一任选实施方案中，当R 31为卤素时，所述卤素为F、Cl、Br或I。 In an optional embodiment of the present invention, when R 31 is halogen, said halogen is F, Cl, Br or I.
在本发明一任选实施方案中，当R 31为卤素时，所述卤素为F。 In an optional embodiment of the invention, when R31 is halogen, said halogen is F.
在本发明一任选实施方案中，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In an optional embodiment of the present invention, when R 3 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl or tert-butyl.
在本发明一任选实施方案中，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为甲基。 In an optional embodiment of the present invention, when R 3 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl.
在本发明一任选实施方案中，R 1选自-CH 3、-CHF 2、
Figure PCTCN2022136130-appb-000005
In an optional embodiment of the present invention, R 1 is selected from -CH 3 , -CHF 2 ,
Figure PCTCN2022136130-appb-000005
在本发明一任选实施方案中，R 2选自
Figure PCTCN2022136130-appb-000006
In an optional embodiment of the present invention, R is selected from
Figure PCTCN2022136130-appb-000006
在本发明一任选实施方案中，R 3为-CF 3。 In an optional embodiment of the invention, R3 is -CF3 .
在本发明一任选实施方案中，如式I所示的化合物选自下列任一化合物：In an optional embodiment of the present invention, the compound shown in formula I is selected from any of the following compounds:
Figure PCTCN2022136130-appb-000007
Figure PCTCN2022136130-appb-000007
本发明的第三方面，本发明提出了一种药物组合物，所述药物组合物包括治疗有效剂量的上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂。In the third aspect of the present invention, the present invention proposes a pharmaceutical composition, which includes a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically An acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent or excipient.
根据本发明的具体实施例，可以将本发明的所述药物组合物包括治疗有效剂量的上述化合物，其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体、稀释剂或赋形剂。According to specific embodiments of the present invention, the pharmaceutical composition of the present invention may include a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt Or prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations, which are suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes. The formulation can be administered by any route, for example, by infusion or bolus injection, by absorption through the epithelium or mucocutaneous (eg oral mucosa or rectum, etc.). Administration can be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations can be prepared by methods known in the art, and contain carriers, diluents or excipients commonly used in the field of pharmaceutical formulations.
本发明的第四方面，本发明提出了上述化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于治疗或预防与IRAK4相关疾病药物中的用途。In the fourth aspect of the present invention, the present invention proposes the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of Use in medicines for treating or preventing diseases related to IRAK4.
根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备治疗与预防IRAK4相关疾病药物中的用途，所述药物可用于治疗自身免疫性疾病以及癌症。这些自身免疫性疾病包括例如多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹；这些癌症包括例如脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。According to a specific embodiment of the present invention, the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used in the preparation of the treatment and prevention of IRAK4 Use in disease medicaments for the treatment of autoimmune diseases as well as cancer. These autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema; these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, Seminoma, melanoma; acute myelogenous leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, Hematological malignancies of splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.
在本发明的第五方面，本发明提出了上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物用于治疗或预防与IRAK4相关疾病。In the fifth aspect of the present invention, the present invention proposes the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition for the treatment of Or prevent diseases associated with IRAK4.
根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、水合物、溶剂化 物、药学上可接受的盐或前药或上述药物组合物用于治疗或预防自身免疫性疾病或癌症。这些自身免疫性疾病包括例如多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹；这些癌症包括例如脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。According to a specific embodiment of the present invention, the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition is used for treating or preventing autoimmunity disease or cancer. These autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema; these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, Seminoma, melanoma; acute myelogenous leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, Hematological malignancies of splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.
在本发明的第六方面，本发明提出了一种治疗或预防与IRAK4相关疾病的方法。根据本发明的实施例，所述方法包括给与患者有效量的上述化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物。In the sixth aspect of the present invention, the present invention provides a method for treating or preventing diseases related to IRAK4. According to an embodiment of the present invention, the method includes administering to the patient an effective amount of the above compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above drug combination.
根据本发明的具体实施例，所述IRAK4相关疾病包括自身免疫性疾病或癌症。这些自身免疫性疾病包括例如多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹；这些癌症包括例如脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。According to a specific embodiment of the present invention, the IRAK4-related diseases include autoimmune diseases or cancer. These autoimmune diseases include, for example, multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis Crohn's disease, ulcerative colitis, atopic dermatitis and atopic eczema; these cancers include, for example, brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumors, breast cancer, bladder colon cancer cancer, prostate, pancreas, lung, cervix, testis, skin, bone, or thyroid; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal, neck and Head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, Seminoma, melanoma; acute myelogenous leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, Hematological malignancies of splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.
最后，本发明提出了下述中间体，其为选自下列任一化合物或下列任一化合物的立体异构体、互变异构体或药学上可接受的盐。根据本发明实施例的中间体，可用于本发明化合物的合成：Finally, the present invention proposes the following intermediates, which are selected from any of the following compounds or stereoisomers, tautomers or pharmaceutically acceptable salts of any of the following compounds. The intermediates according to the embodiments of the present invention can be used for the synthesis of the compounds of the present invention:
Figure PCTCN2022136130-appb-000008
Figure PCTCN2022136130-appb-000008
术语和定义Terms and Definitions
除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise stated, the terms and definitions used in the present application, including the description and claims of the present application, are as follows.
本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，
Figure PCTCN2022136130-appb-000009
用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。 Those skilled in the art can understand that, according to the convention used in this field, in the structural formula of the present application,
Figure PCTCN2022136130-appb-000009
Used to depict a chemical bond, which is the point at which a moiety or substituent is attached to a core or backbone structure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。The term "pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of categories of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis. The prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound. Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。The term "stereoisomer" refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的 形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and processes, the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process Spin body. Many geometric isomers of olefins, C=N double bonds, etc. may also exist in the compounds described herein, and all such stable isomers are contemplated in the present invention. When compounds described herein contain olefinic double bonds, unless otherwise stated, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may be in cis or trans (cis- or trans-) configuration.
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。When the bond with the chiral carbon in the formula of the present invention is described as a straight line, it should be understood that the (R) and (S) two configurations of the chiral carbon and the resulting enantiomerically pure compounds and Mixtures of both are included within the scope of the general formula. Graphical representations of racemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise stated, the absolute configuration of a stereocenter is indicated by wedge-shaped bonds and dashed-line bonds.
旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的色谱柱上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Resolution of racemic mixtures of compounds can be performed by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as β- D and L forms of camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine in stereomerically pure form (e.g., S and R forms or in diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Selection of specific methods, elution conditions, and selection of chromatographic columns can be selected by those skilled in the art according to the structure of the compound and test results. Furthermore, any enantiomer or diastereomer of the compounds described in the present invention can also be obtained by stereoorganic synthesis using optically pure starting materials or reagents of known configuration.
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种 类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。 The term "C 1 -C 6 alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, said groups have 1, 2 or 3 carbon atoms (“C 1 -C 3 alkyl”), for example methyl, ethyl, n-propyl or isopropyl.
术语“C 3-C 6环烷基”应理解为表示饱和的单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环***。如环丙基、环丁基、环戊基、环己基。 The term "C 3 -C 6 cycloalkyl" is understood to mean saturated monocyclic or bicyclic hydrocarbon rings having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
术语“4-8元杂环基”或“4-8元杂环烷基”应理解为表示具有4至8个原子的饱和、不饱和或部分饱和的单环、二环或三环，其中1、2、3、4或5个环原子选自N、O和S，除非另有说明，其可通过碳或氮连接，其中-CH 2-基团任选被-C(O)-代替；及其中除非另有相反说 明，环氮原子或环硫原子任选被氧化以形成N-氧化物或S-氧化物或环氮原子任选被季铵化；其中环中的-NH任选被乙酰基、甲酰基、甲基或甲磺酰基取代；及环任选被一个或多个卤素取代。应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。若所述杂环基为二环或三环，则至少一个环可任选为杂芳族环或芳族环，条件是至少一个环是非杂芳族的。若所述杂环基为单环，则其一定不是芳族的。杂环基的实例包括但不限于哌啶基、N-乙酰基哌啶基、N-甲基哌啶基、N-甲酰基哌嗪基、N-甲磺酰基哌嗪基、高哌嗪基、哌嗪基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、四氢异喹啉基、四氢喹啉基、二氢吲哚基、四氢吡喃基、二氢-2H-吡喃基、四氢呋喃基、四氢噻喃基、四氢噻喃-1-氧化物、四氢噻喃-1,1-二氧化物、1H-吡啶-2-酮和2,5-二氧代咪唑烷基。 The term "4-8 membered heterocyclyl" or "4-8 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms selected from N, O and S, which may be attached through carbon or nitrogen unless otherwise stated, wherein the -CH2- group is optionally replaced by a -C(O)- and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or an S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally is substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic or aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is monocyclic, it must not be aromatic. Examples of heterocyclic groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydroindolyl, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuryl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 - dioxoimidazolidinyl.
术语“6-10元芳基”应理解为具有6-10个碳原子的芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；当所述6-10元芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为邻位、对位或间位取代。 The term "6-10 membered aryl" should be understood as an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-10 carbon atoms, especially a ring having 6 carbon atoms ("C 6 aryl"), such as phenyl; when the 6-10 membered aryl is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution site, for example, it may be an ortho, para or meta substitution.
术语“5-8元杂芳基”应理解为具有5-8个环原子，特别是5或6个碳原子，且包含1-5个独立选自N、O和S的杂原子的单环、双环或三环芳族环基团。优选1-3个且独立选自N、O和S的杂原子的单环、双环或三环芳族环基团，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。The term "5-8 membered heteroaryl" is understood to mean a monocyclic ring having 5-8 ring atoms, especially 5 or 6 carbon atoms, and containing 1-5 heteroatoms independently selected from N, O and S , bicyclic or tricyclic aromatic ring groups. Monocyclic, bicyclic or tricyclic aromatic ring groups of 1 to 3 heteroatoms independently selected from N, O and S are preferred, and may additionally be benzofused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, Diazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridyl, pteridine carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.
术语“卤代基”或“卤素”为氟、氯、溴和碘。The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
术语“任选”或“任选地”意思是随后所述的事件或情形可发生或可不发生，且所述描述包括其中所述事件或情形发生的情况以及其中所述事件或情形不发生的情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not Condition.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless otherwise clearly stated, the description method "...independently" used in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independent are the same or different specific groups. In more detail, the description "...independently" can mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the same symbol The specific options expressed between them do not affect each other.
有益效果Beneficial effect
根据本发明的实施例，本发明至少具有如下技术效果至少之一：According to the embodiments of the present invention, the present invention has at least one of the following technical effects:
(1)本发明提供了结构新颖、药代动力学性质优良、药效或成药性好的IRAK4抑制剂，可以用于有效治疗或预防IRAK4相关的疾病、病症。(1) The present invention provides an IRAK4 inhibitor with novel structure, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat or prevent IRAK4-related diseases and diseases.
(2)本专利化合物表现出更为优良的对IRAK4激酶抑制活性，而且化合物I-1的抑制活性显著更优；另一方面与对照化合物1相比，本专利化合物在细胞水平表现出对TNF-α产生具有更强的抑制能力，尤其是化合物I-1的抑制活性显著优于对照化合物1。(2) The patent compound shows more excellent inhibitory activity to IRAK4 kinase, and the inhibitory activity of compound I-1 is significantly better; on the other hand, compared with the reference compound 1, the patent compound shows TNF inhibitory activity at the cellular level. -α production has a stronger inhibitory ability, especially the inhibitory activity of compound I-1 is significantly better than that of control compound 1.
(3)本发明化合物在人和小鼠血浆中游离药物的比率均较高，成药性好，本发明中的化合物在10μM时对CYP2C9、CYP2D6、CYP3A4酶没有抑制作用，潜在的药物药物相互作用风险低，本发明中的化合物还表现出较为优良的肝代谢稳定性。(3) The ratio of the free drug in the human and mouse plasma of the compound of the present invention is high, and the druggability is good. The compound of the present invention has no inhibitory effect on CYP2C9, CYP2D6, and CYP3A4 enzymes at 10 μM, and potential drug-drug interactions The risk is low, and the compound of the present invention also exhibits relatively good stability in liver metabolism.
(4)本发明化合物在小鼠、大鼠物种中表现出更为优良的药代动力学性质。(4) The compounds of the present invention exhibit better pharmacokinetic properties in mouse and rat species.
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
具体实施方式Detailed ways
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The solutions of the present invention will be explained below in conjunction with examples. Those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。 Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents determined by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
本发明的缩写定义如下：The abbreviations of the present invention are defined as follows:
M：摩尔浓度，如1M盐酸表示1mol/L盐酸溶液M: molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: Equivalent concentration, for example, 2N hydrochloric acid means 2mol/L hydrochloric acid solution
T3P·DMF：1-丙基磷酸酐50％N,N-二甲基甲酰胺溶液T3P·DMF: 1-propyl phosphoric anhydride 50% N,N-dimethylformamide solution
Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
PMB：对甲氧基苄基PMB: p-methoxybenzyl
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
LC-MS：液质联用色谱LC-MS: liquid chromatography-mass chromatography
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度。 IC 50 : half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
对照1：对照化合物1的制备Control 1: Preparation of Control Compound 1
Figure PCTCN2022136130-appb-000010
Figure PCTCN2022136130-appb-000010
参考WO2016083433A1合成。Refer to WO2016083433A1 for synthesis.
实施例1：目标化合物I-1的制备Embodiment 1: the preparation of target compound I-1
N-(8-氟-7-(2-羟基丙烷-2-基)-2-(2-(甲磺酰)乙基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)甲基吡啶酰胺N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyridin-6-yl)-6 -(trifluoromethyl)picolinamide
Figure PCTCN2022136130-appb-000011
Figure PCTCN2022136130-appb-000011
目标化合物I-1合成路线如下所示：The synthetic route of target compound I-1 is as follows:
Figure PCTCN2022136130-appb-000012
Figure PCTCN2022136130-appb-000012
第一步：3-氟-N,N-二(4-甲氧苄基)-5-硝基吡啶-2-胺(I-1b)的合成The first step: Synthesis of 3-fluoro-N,N-bis(4-methoxybenzyl)-5-nitropyridin-2-amine (I-1b)
Figure PCTCN2022136130-appb-000013
Figure PCTCN2022136130-appb-000013
将2-氯-3-氟-5-硝基-吡啶(I-1a)(29g,164mmol)溶于N,N-二甲基甲酰胺(400mL)中，再加入N,N-二异丙基乙胺(42.5g,329mmol)和1-(4-甲氧苯基)-N-[(4-甲氧苯基)甲基]甲胺(46.5g,180mmol)，反应液在25℃下搅拌16小时，反应完成后加水(500mL)稀释，之后用乙酸乙酯(300mL×3)萃取，有机相用饱和食盐水(300mL)洗涤和无水硫酸钠干燥后过滤，滤饼用乙酸乙酯洗涤，将滤液浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到5:1)纯化得到黄色固体化合物3-氟-N,N-二(4-甲氧苄基)-5-硝基吡啶-2-胺(I-1b)(59.0g，收率90.4％)。2-Chloro-3-fluoro-5-nitro-pyridine (I-1a) (29g, 164mmol) was dissolved in N,N-dimethylformamide (400mL), and N,N-diisopropyl Ethylamine (42.5g, 329mmol) and 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (46.5g, 180mmol), the reaction solution was heated at 25°C Stir for 16 hours. After the reaction is completed, add water (500mL) to dilute, and then extract with ethyl acetate (300mL×3). The organic phase is washed with saturated brine (300mL) and dried over anhydrous sodium sulfate. After washing, the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain yellow solid compound 3-fluoro-N,N-di(4-methoxybenzyl)-5-nitro Pyridin-2-amine (I-1b) (59.0 g, yield 90.4%).
LC-MS,M/Z(ESI):398.2[M+H] + LC-MS, M/Z(ESI):398.2[M+H] +
第二步：3-氟-N 2,N 2-二(4-甲氧苄基)吡啶-2,5-二胺(I-1c)的合成 The second step: Synthesis of 3-fluoro-N 2 ,N 2 -bis(4-methoxybenzyl)pyridine-2,5-diamine (I-1c)
Figure PCTCN2022136130-appb-000014
Figure PCTCN2022136130-appb-000014
将3-氟-N,N-二(4-甲氧苄基)-5-硝基吡啶-2-胺(I-1b)(59.0g,149mmol)加入到甲醇(600mL)中，然后在氮气保护下，向其加入铂钒碳(6.00g)，然后反应液在氢气(15psi)氛围下,在25℃下搅拌三个小时，反应完成后，过滤，滤饼用甲醇(100mL)洗涤，滤液浓缩得到红色固体化合物即3-氟-N 2,N 2-二(4-甲氧苄基)吡啶-2,5-二胺(I-1c)(53.0g，收率97.16％)。 3-Fluoro-N,N-bis(4-methoxybenzyl)-5-nitropyridin-2-amine (I-1b) (59.0 g, 149 mmol) was added to methanol (600 mL), and then Under protection, platinum vanadium carbon (6.00g) was added thereto, and then the reaction solution was stirred at 25°C for three hours under a hydrogen (15psi) atmosphere. After the reaction was completed, it was filtered, and the filter cake was washed with methanol (100mL). Concentration gave a red solid compound, namely 3-fluoro-N 2 ,N 2 -bis(4-methoxybenzyl)pyridine-2,5-diamine (I-1c) (53.0 g, yield 97.16%).
LC-MS,M/Z(ESI):368.1[M+H] + LC-MS, M/Z(ESI):368.1[M+H] +
第三步：(6-(二(4-甲氧苄基)氨基)-5-氟吡啶-3-基)氨基甲酸叔丁酯(I-1d)的合成Step 3: Synthesis of (6-(two(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)carbamate tert-butyl ester (I-1d)
Figure PCTCN2022136130-appb-000015
Figure PCTCN2022136130-appb-000015
将3-氟-N,N-二[(4-甲氧苯基)甲基]吡啶-2,5-二胺(I-1c)(49.0g,133mmol),三乙胺(14.8g,147mmol)和碳酸二叔丁酯(32.0g,147mmol)加入到N,N-二甲基甲酰胺(250mL)中，反应液在90℃下搅拌12小时，反应完成后，向反应液中加入水(300mL)，之后用乙酸乙酯(200mL×3)萃取，有机相用饱和食盐水(300mL)洗涤和无水硫酸钠干燥后过滤，滤饼用乙酸乙酯洗涤，将滤液浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到5:1)纯化得到黄色油状化合物(6-(二(4-甲氧苄基)氨基)-5-氟吡啶-3-基)氨基甲酸叔丁酯(I-1d)(48.0g，收率76.9％)。3-fluoro-N, N-bis[(4-methoxyphenyl)methyl]pyridine-2,5-diamine (I-1c) (49.0g, 133mmol), triethylamine (14.8g, 147mmol ) and di-tert-butyl carbonate (32.0g, 147mmol) were added to N,N-dimethylformamide (250mL), and the reaction solution was stirred at 90°C for 12 hours. After the reaction was completed, water was added to the reaction solution ( 300 mL), then extracted with ethyl acetate (200 mL×3), the organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate, then filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain yellow oily compound (6-(di(4-methoxybenzyl)amino)-5-fluoropyridine-3 -yl) tert-butyl carbamate (I-1d) (48.0 g, yield 76.9%).
LC-MS,M/Z(ESI):468.3[M+H] + LC-MS, M/Z(ESI):468.3[M+H] +
第四步：(6-(二(4-甲氧苄基)氨基)-5-氟-4-碘吡啶-3-基)氨基甲酸叔丁酯(I-1e)的合成Step 4: Synthesis of (6-(two(4-methoxybenzyl)amino)-5-fluoro-4-iodopyridin-3-yl)carbamate tert-butyl ester (I-1e)
Figure PCTCN2022136130-appb-000016
Figure PCTCN2022136130-appb-000016
在-65℃和氮气保护下，向N-[6-[二[(4-甲氧苯基)甲基]氨基]-5-氟-3-吡啶基]氨基甲酸叔丁酯(I-1d)(30.0g,64.2mmol)和四甲基乙二胺(29.8g,257mmol)的四氢呋喃(450mL)溶液中，滴加正丁基锂(2.50M,103mL)的四氢呋喃溶液,滴加完成后，反应液在-65℃下，搅拌1.5 小时。然后在-65℃下，向反应液中滴加碘(26.1g,103mmol)的四氢呋喃(150mL)溶液，滴加完成后，反应液在-65℃下，搅拌1.5小时。反应完成后，向反应液中加入饱和氯化铵溶液(500mL)，之后用乙酸乙酯(300mL×3)萃取，有机相用饱和食盐水(300mL)洗涤和无水硫酸钠干燥后，然后过滤，滤饼用乙酸乙酯洗涤，将滤液浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到5:1)纯化得到化合物(6-(二(4-甲氧苄基)氨基)-5-氟-4-碘吡啶-3-基)氨基甲酸叔丁酯(I-1e)(20.0g，收率52.5％)。Under nitrogen protection at -65°C, N-[6-[bis[(4-methoxyphenyl)methyl]amino]-5-fluoro-3-pyridyl]carbamate tert-butyl ester (I-1d ) (30.0g, 64.2mmol) and tetramethylethylenediamine (29.8g, 257mmol) in tetrahydrofuran (450mL) solution, dropwise add n-butyllithium (2.50M, 103mL) in tetrahydrofuran solution, after the dropwise addition was completed, The reaction solution was stirred at -65°C for 1.5 hours. Then, at -65°C, a solution of iodine (26.1 g, 103 mmol) in tetrahydrofuran (150 mL) was added dropwise to the reaction solution. After the dropwise addition, the reaction solution was stirred at -65°C for 1.5 hours. After the reaction was completed, saturated ammonium chloride solution (500mL) was added to the reaction solution, followed by extraction with ethyl acetate (300mL×3), the organic phase was washed with saturated brine (300mL) and dried over anhydrous sodium sulfate, and then filtered , the filter cake was washed with ethyl acetate, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the compound (6-(di(4-methoxybenzyl)amino)-5-fluoro-4-iodopyridine -3-yl) tert-butyl carbamate (I-1e) (20.0 g, yield 52.5%).
LC-MS,M/Z(ESI):594.1[M+H] + LC-MS, M/Z(ESI):594.1[M+H] +
第五步：(4-乙酰基-6-(二(4-甲氧苄基)氨基)-5-氟吡啶-3-基)氨基甲酸叔丁酯(I-1f)的合成Step 5: Synthesis of (4-acetyl-6-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)carbamate tert-butyl ester (I-1f)
Figure PCTCN2022136130-appb-000017
Figure PCTCN2022136130-appb-000017
将N-[6-[二[(4-甲氧苯基)甲基]氨基]-5-氟-4-碘-3-吡啶基]氨基甲酸叔丁酯(I-1e)(5.00g,8.43mmol)和三丁基(1-乙氧基乙烯基)锡烷(6.69g,18.5mmol)溶于二氧六环(70.0mL)中，然后在氮气保护下加入二氯双(三苯基膦)钯(II)(591mg,843μmol)中，反应液物在60℃下搅拌12小时，反应完成后，向反应液中加入盐酸(4M，41.85mL)，反应液在室温下搅拌12小时，反应完成后，向反应液中加入饱和的氟化钾溶液(100mL)并在室温下搅拌2个小时，之后用乙酸乙酯(100mL)萃取，有机相用饱和碳酸氢钠溶液(100mL)和饱和食盐水(100mL)洗涤后，再用无水硫酸钠干燥后过滤，浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到5:1)纯化得到红色油状化合物(4-乙酰基-6-(二(4-甲氧苄基)氨基)-5-氟吡啶-3-基)氨基甲酸叔丁酯((I-1f))(17.1g，粗品，四批次投料合并)。N-[6-[bis[(4-methoxyphenyl)methyl]amino]-5-fluoro-4-iodo-3-pyridyl]carbamate tert-butyl ester (I-1e) (5.00g, 8.43mmol) and tributyl(1-ethoxyvinyl)stannane (6.69g, 18.5mmol) were dissolved in dioxane (70.0mL), then dichlorobis(triphenyl Phosphine) palladium (II) (591 mg, 843 μmol), the reaction liquid was stirred at 60 ° C for 12 hours, after the reaction was completed, hydrochloric acid (4M, 41.85 mL) was added to the reaction liquid, and the reaction liquid was stirred at room temperature for 12 hours, After the reaction was completed, a saturated potassium fluoride solution (100 mL) was added to the reaction solution and stirred at room temperature for 2 hours, then extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium bicarbonate solution (100 mL) and saturated After washing with brine (100 mL), drying over anhydrous sodium sulfate, filtration, and concentration to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain red oily compound (4-acetyl-6-(bis(4-methoxybenzyl)amino)-5 -Fluoropyridin-3-yl) tert-butyl carbamate ((I-1f)) (17.1 g, crude product, four batches were combined).
LC-MS,M/Z(ESI):510.3[M+H] + LC-MS, M/Z(ESI):510.3[M+H] +
第六步：1-(5-氨基-2-(二(4-甲氧苄基)氨基)-3-氟吡啶-4-基)乙酮(I-1g)的合成The sixth step: the synthesis of 1-(5-amino-2-(two(4-methoxybenzyl)amino)-3-fluoropyridin-4-yl)ethanone (1-1g)
Figure PCTCN2022136130-appb-000018
Figure PCTCN2022136130-appb-000018
将(4-乙酰基-6-(二(4-甲氧苄基)氨基)-5-氟吡啶-3-基)氨基甲酸叔丁酯(I-1f)(17.1g,33.4mmol)溶于乙酸乙酯(80.0mL)溶液中，再加入盐酸乙酸乙酯(4M,80.0mL)溶液，反应液在25℃下搅拌4小时，反应完成后过滤，滤饼用石油醚(100mL)洗涤，之后将滤饼干燥得到黄色固 体化合物1-(5-氨基-2-(二(4-甲氧苄基)氨基)-3-氟吡啶-4-基)乙酮((I-1g))(8.20g，收率75.2％)。Dissolve tert-butyl (4-acetyl-6-(bis(4-methoxybenzyl)amino)-5-fluoropyridin-3-yl)carbamate (I-1f) (17.1 g, 33.4 mmol) in In the ethyl acetate (80.0mL) solution, add ethyl acetate hydrochloride (4M, 80.0mL) solution, the reaction solution was stirred at 25°C for 4 hours, filtered after the reaction was completed, the filter cake was washed with petroleum ether (100mL), and then The filter cake was dried to give yellow solid compound 1-(5-amino-2-(bis(4-methoxybenzyl)amino)-3-fluoropyridin-4-yl)ethanone ((1-1g)) (8.20 g, yield 75.2%).
LC-MS,M/Z(ESI):290.0[M+H] + LC-MS, M/Z(ESI):290.0[M+H] +
第七步：N-(4-乙酰基-5-氟-6-((4-甲氧苄基)氨基)吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1h)的合成The seventh step: N-(4-acetyl-5-fluoro-6-((4-methoxybenzyl)amino)pyridin-3-yl)-6-(trifluoromethyl)picolinamide (I Synthesis of -1h)
Figure PCTCN2022136130-appb-000019
Figure PCTCN2022136130-appb-000019
将1-[5-氨基-3-氟-2-[(4-甲氧苯基)甲基氨基]-4-吡啶基]乙酮(I-1g)(8.20g,28.4mmol)，6-(三氟甲基)吡啶-2-羧酸(6.50g,34.0mmol)溶于N,N-二甲基甲酰胺(100mL)中，再加入2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(13.0g,34.0mmol)和N,N-二异丙基乙胺(11.0g,85.3mmol)，反应液液在25℃下搅拌3小时，反应完成后，用水(200mL)稀释，之后用乙酸乙酯(200mL×3)萃取，有机相用饱和食盐水(200mL)洗涤和无水硫酸钠干燥后过滤，浓缩得粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝5:1到1:1)纯化得到黄色有油状化合物N-(4-乙酰基-5-氟-6-((4-甲氧苄基)氨基)吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1h)(5.00g，得到率38.2％)。1-[5-amino-3-fluoro-2-[(4-methoxyphenyl)methylamino]-4-pyridyl]ethanone (I-1g) (8.20g, 28.4mmol), 6- (Trifluoromethyl)pyridine-2-carboxylic acid (6.50g, 34.0mmol) was dissolved in N,N-dimethylformamide (100mL), and 2-(7-azobenzotriazole) was added -N,N,N,N-tetramethyluronium hexafluorophosphate (13.0g, 34.0mmol) and N,N-diisopropylethylamine (11.0g, 85.3mmol), the reaction solution was at 25°C Stir for 3 hours. After the reaction is complete, dilute with water (200 mL), and then extract with ethyl acetate (200 mL×3). The organic phase is washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain the yellow oily compound N-(4-acetyl-5-fluoro-6-((4-methoxybenzyl yl)amino)pyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1h) (5.00 g, yield 38.2%).
LC-MS,M/Z(ESI):463.1[M+H] + LC-MS, M/Z(ESI):463.1[M+H] +
第八步：N-(4-乙酰基-6-氨基-5-氟吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1j)的合成Step 8: Synthesis of N-(4-acetyl-6-amino-5-fluoropyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1j)
Figure PCTCN2022136130-appb-000020
Figure PCTCN2022136130-appb-000020
在室温下，将N-(4-乙酰基-5-氟-6-((4-甲氧苄基)氨基)吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1h)(5.00g,10.8mmol)加入到三氟乙酸(20.0mL)中，混合液在50℃下搅拌1小时，反应完成后，用水(100mL)稀释，加入饱和碳酸钠溶液调节pH至8～9，之用乙酸乙酯(100mL×3)萃取，有机相用饱和食盐水(100mL)洗涤和无水硫酸钠干燥后过滤，浓缩得到化合物N-(4-乙酰基-6-氨基-5-氟吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1j)(3.50g，收率94.6％)。At room temperature, N-(4-acetyl-5-fluoro-6-((4-methoxybenzyl)amino)pyridin-3-yl)-6-(trifluoromethyl)picolinamide ( I-1h) (5.00g, 10.8mmol) was added to trifluoroacetic acid (20.0mL), and the mixture was stirred at 50°C for 1 hour. After the reaction was complete, it was diluted with water (100mL), and saturated sodium carbonate solution was added to adjust the pH to 8-9, extracted with ethyl acetate (100mL×3), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound N-(4-acetyl-6-amino- 5-fluoropyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1j) (3.50 g, yield 94.6%).
LC-MS,M/Z(ESI):343.0[M+H] + LC-MS, M/Z(ESI):343.0[M+H] +
第九步：N-(6-氨基-5-氟-4-(2-羟基丙烷-2-基)吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1k)的合成Ninth step: N-(6-amino-5-fluoro-4-(2-hydroxypropan-2-yl)pyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1k )Synthesis
Figure PCTCN2022136130-appb-000021
Figure PCTCN2022136130-appb-000021
将N-(4-乙酰基-6-氨基-5-氟吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(2.60g,7.60mmol)加入到四氢呋喃(52.0mL)中，然后，在0℃时，向其滴加甲基溴化镁(3.00M,12.7mL)，滴加完成后，反应液在25℃下搅拌12小时，反应完成后，加入饱和氯化铵(100mL)淬灭，之后用乙酸乙酯(100mL×3)萃取，有机相用饱和食盐水(100mL)洗涤和无水硫酸钠干燥后过滤，浓缩得到粗品。粗品通过柱层析(二氧化硅，石油醚：乙酸乙酯＝5:1到2:1)制备得到化合物N-(6-氨基-5-氟-4-(2-羟基丙烷-2-基)吡啶-3-基)-6-(三氟甲基)甲基吡啶酰胺(I-1k)(1.00g，收率36.8％)。N-(4-acetyl-6-amino-5-fluoropyridin-3-yl)-6-(trifluoromethyl)picolinamide (2.60 g, 7.60 mmol) was added to tetrahydrofuran (52.0 mL) , then, at 0°C, methylmagnesium bromide (3.00M, 12.7mL) was added dropwise to it, after the dropwise addition was completed, the reaction solution was stirred at 25°C for 12 hours, after the reaction was completed, saturated ammonium chloride ( 100 mL), then extracted with ethyl acetate (100 mL×3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was prepared by column chromatography (silica, petroleum ether: ethyl acetate = 5:1 to 2:1) to obtain the compound N-(6-amino-5-fluoro-4-(2-hydroxypropan-2-yl )pyridin-3-yl)-6-(trifluoromethyl)picolinamide (I-1k) (1.00 g, yield 36.8%).
LC-MS,M/Z(ESI):359.1[M+H] + LC-MS, M/Z(ESI):359.1[M+H] +
第十步：1-氯-4-(甲硫基)丁烷-2-酮的合成Step 10: Synthesis of 1-chloro-4-(methylthio)butan-2-one
Figure PCTCN2022136130-appb-000022
Figure PCTCN2022136130-appb-000022
将3-甲硫基丙酸甲酯(5.00g,37.3mmol)和氯碘代甲烷(26.3g,149mmol)加入到四氢呋喃(300mL)中，然后，在-65℃下，向其滴加二异丙基胺基锂(2.00M,93.2mL)，滴加完成后，反应液在-65℃下搅拌0.5小时，反应完成后，加入饱和氯化铵溶液(100mL)淬灭，然后用乙酸乙酯(200mL×3)萃取，有机相用饱和食盐水(100mL)洗涤和无水硫酸钠干燥后过滤，浓缩得到粗品。粗品通过柱层析(二氧化硅，石油醚：乙酸乙酯＝20:1到10:1)制备得到棕色油状化合物1-氯-4-(甲硫基)丁烷-2-酮(3.00g，收率52.8％)。Methyl 3-methylthiopropionate (5.00 g, 37.3 mmol) and chloroiodomethane (26.3 g, 149 mmol) were added to tetrahydrofuran (300 mL), and then, at -65° C., diiso Lithium propylamide (2.00M, 93.2mL), after the dropwise addition was completed, the reaction solution was stirred at -65°C for 0.5 hours. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution (100mL), and then washed with ethyl acetate (200mL×3) extraction, the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was prepared by column chromatography (silica, petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain brown oily compound 1-chloro-4-(methylthio)butan-2-one (3.00g , yield 52.8%).
第十一步：1-氯-4-(甲磺酰)丁烷-2-酮(1A)的合成The eleventh step: the synthesis of 1-chloro-4-(methylsulfonyl)butan-2-one (1A)
Figure PCTCN2022136130-appb-000023
Figure PCTCN2022136130-appb-000023
将1-氯-4-(甲硫基)丁烷-2-酮(3.00g,19.7mmol)加入到二氯甲烷(60.0mL)中，然后，在0℃下，向其分批加入间氯过氧化苯甲酸(7.46g,43.2mmol)，然后反应液在25℃下搅拌2小时，反应完成后，向其加入饱和硫代硫酸钠溶液(100mL)淬灭，然后用二氯甲烷(100mL×3)萃取， 有机相用饱和食盐水(100mL)洗涤和无水硫酸钠干燥后，然后过滤，浓缩粗品。粗品通过柱层析(二氧化硅，石油醚：乙酸乙酯＝10:1到5:1)制备得到类白色固体化合物1-氯-4-(甲磺酰)丁烷-2-酮(1A)(1.00g，收率27.6％)。1-Chloro-4-(methylthio)butan-2-one (3.00 g, 19.7 mmol) was added into dichloromethane (60.0 mL), and then, m-chloro was added thereto in portions at 0° C. Benzoic acid peroxide (7.46g, 43.2mmol), then the reaction solution was stirred at 25°C for 2 hours, after the reaction was completed, it was quenched by adding saturated sodium thiosulfate solution (100mL), and then dichloromethane (100mL× 3) Extraction, the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, then filtered, and the crude product was concentrated. The crude product was prepared by column chromatography (silica, petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain off-white solid compound 1-chloro-4-(methylsulfonyl)butan-2-one (1A ) (1.00 g, yield 27.6%).
第十二步：N-(8-氟-7-(2-羟基丙烷-2-基)-2-(2-(甲磺酰)乙基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)甲基吡啶酰胺(I-1)的合成Step 12: N-(8-fluoro-7-(2-hydroxypropan-2-yl)-2-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyridine-6 Synthesis of -yl)-6-(trifluoromethyl)picolinamide (I-1)
Figure PCTCN2022136130-appb-000024
Figure PCTCN2022136130-appb-000024
将N-[6-氨基-5-氟-4-(1-羟基-1-甲基-乙基)-3-吡啶基]-6-(三氟甲基)吡啶-2-甲酰胺(300mg,837μmol)和1-氯-4-甲磺酰-丁烷-2-酮(534mg,2.89mmol)加入到乙醇(9.00mL)中，反应液100℃下搅拌12小时，反应完成后，向反应液中加入水(20.0mL)，之后用乙酸乙酯(20.0mL×3)萃取，有机相用饱和食盐水(10.0mL)洗涤和无水硫酸钠干燥后过滤，浓缩得到粗品。粗品经反相制备(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.1％氨水)-乙腈]；B％:18％-52％,12min)分离得到N-(8-氟-7-(2-羟基丙烷-2-基)-2-(2-(甲磺酰)乙基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)甲基吡啶酰胺(I-1)(77.01mg，收率18.7％)。N-[6-amino-5-fluoro-4-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]-6-(trifluoromethyl)pyridine-2-carboxamide (300mg ,837μmol) and 1-chloro-4-methanesulfonyl-butane-2-one (534mg, 2.89mmol) were added to ethanol (9.00mL), and the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the Water (20.0 mL) was added to the solution, followed by extraction with ethyl acetate (20.0 mL×3), the organic phase was washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was prepared by reverse phase (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min) to separate N-(8- Fluoro-7-(2-hydroxypropan-2-yl)-2-(2-(methylsulfonyl)ethyl)imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl base) picolinamide (I-1) (77.01 mg, yield 18.7%).
1H NMR(400MHz，DMSO)δ＝12.65(s,1H),9.51(s,1H),8.4-8.5(m,1H),8.4-8.4(m,1H),8.20(d,1H),8.01(d,1H),6.59(br s,1H),3.5-3.5(m,2H),3.1-3.2(m,2H),3.03(s,3H),1.70(br d,6H)。 1 H NMR (400MHz, DMSO) δ=12.65(s,1H),9.51(s,1H),8.4-8.5(m,1H),8.4-8.4(m,1H),8.20(d,1H),8.01 (d, 1H), 6.59 (br s, 1H), 3.5-3.5 (m, 2H), 3.1-3.2 (m, 2H), 3.03 (s, 3H), 1.70 (br d, 6H).
LC-MS,M/Z(ESI):488.9[M+H] + LC-MS, M/Z(ESI):488.9[M+H] +
实施例2：目标化合物I-2的制备Embodiment 2: the preparation of target compound 1-2
氮-(2-(2-(环丙磺酰基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-2)。Nitrogen-(2-(2-(cyclopropylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-6-yl) -6-(trifluoromethyl)pyridine amide (target compound I-2).
Figure PCTCN2022136130-appb-000025
Figure PCTCN2022136130-appb-000025
目标化合物I-2的合成路线如下所示：The synthetic route of target compound 1-2 is as follows:
Figure PCTCN2022136130-appb-000026
Figure PCTCN2022136130-appb-000026
第一步：3-(环丙硫基)丙酸甲酯(I-2b)的合成The first step: the synthesis of 3-(cyclopropylthio) methyl propionate (I-2b)
Figure PCTCN2022136130-appb-000027
Figure PCTCN2022136130-appb-000027
将3-巯基丙酸甲酯(I-2a)(5g，41.6mmol)、溴环丙烷(5.03g，41.6mmol)和叔丁醇钾(4.67g，41.6mmol)溶于二甲基亚砜(50mL)的氢化瓶中，反应为密闭反应，将反应液加热至120℃反应12小时。反应完成后，将反应液用水(30mL)洗涤，然后用乙酸乙酯(30mL*3)萃取三次，合并有机相，用无水硫酸钠干燥，然后低温浓缩旋干得到粗产品3-(环丙硫基)丙酸甲酯(I-2b)(3.8g)。Methyl 3-mercaptopropionate (I-2a) (5 g, 41.6 mmol), bromocyclopropane (5.03 g, 41.6 mmol) and potassium tert-butoxide (4.67 g, 41.6 mmol) were dissolved in dimethylsulfoxide ( 50 mL) in a hydrogenation bottle, the reaction was a closed reaction, and the reaction solution was heated to 120° C. for 12 hours. After the reaction was completed, the reaction solution was washed with water (30mL), then extracted three times with ethyl acetate (30mL*3), the organic phases were combined, dried with anhydrous sodium sulfate, then concentrated at low temperature and spin-dried to obtain the crude product 3-(cyclopropane Thio)propanoic acid methyl ester (I-2b) (3.8 g).
第二步：3-(环丙硫基)丙酸(I-2c)的合成The second step: the synthesis of 3-(cyclopropylthio)propionic acid (I-2c)
Figure PCTCN2022136130-appb-000028
Figure PCTCN2022136130-appb-000028
将3-(环丙硫基)丙酸甲酯(I-2b)(3.4g，21.22mmol)溶于四氢呋喃：水：甲醇＝18:12:2的混合溶液中，然后加入氢氧化锂(2.54g，106mmol)，反应液室温反应过夜。反应完成后，将反应液浓缩，除掉甲醇，然后将浓缩物用乙酸乙酯(10mL*2)萃取2遍，将水相用1N的盐酸溶液调至pH＝3，然后再用乙酸乙酯(10mL*5)萃取，合并有机相，用无水硫酸钠干燥，过滤后浓缩得到产物3-(环丙硫基)丙酸(I-2c)(2.4g，产率77％)。Methyl 3-(cyclopropylthio)propionate (I-2b) (3.4g, 21.22mmol) was dissolved in a mixed solution of tetrahydrofuran:water:methanol=18:12:2, and lithium hydroxide (2.54 g, 106 mmol), and the reaction solution was reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to remove methanol, then the concentrate was extracted twice with ethyl acetate (10mL*2), the aqueous phase was adjusted to pH=3 with 1N hydrochloric acid solution, and then ethyl acetate was used to (10mL*5) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 3-(cyclopropylthio)propionic acid (I-2c) (2.4g, yield 77%).
第三步：3-(环丙硫基)丙酰氯(I-2d)的合成The third step: the synthesis of 3-(cyclopropylthio) propionyl chloride (I-2d)
Figure PCTCN2022136130-appb-000029
Figure PCTCN2022136130-appb-000029
将3-(环丙硫基)丙酸(I-2c)(3.4g，23.25mmol)溶于二氯甲烷(5mL)中，加入 草酰氯(8.85g，69.8mmol)，然后在反应液中滴加一滴DMF，反应液在室温下反应2小时。反应完成后，将反应液低温下浓缩得到粗产物3-(环丙硫基)丙酰氯(I-2d)(2.4g)Dissolve 3-(cyclopropylthio)propionic acid (I-2c) (3.4g, 23.25mmol) in dichloromethane (5mL), add oxalyl chloride (8.85g, 69.8mmol), and drop in the reaction solution A drop of DMF was added, and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated at low temperature to obtain the crude product 3-(cyclopropylthio)propionyl chloride (I-2d) (2.4g)
第四步：1-氯-4-(环丙硫基)丁-2-酮(I-2e)的合成The fourth step: the synthesis of 1-chloro-4-(cyclopropylthio)butan-2-one (I-2e)
Figure PCTCN2022136130-appb-000030
Figure PCTCN2022136130-appb-000030
将3-(环丙硫基)丙酰氯(I-2d)(2.4g，14.58mmol)溶于乙腈(20mL)中，用氮气置换三次，将反应液降至0℃，在0℃下加入叠氮基三甲基硅烷(17.49mL，350mmol)，将反应缓慢升温至室温，反应2小时。然后将反应液再次降至0℃，缓慢加入盐酸/二氧六环溶液(5mL)，反应1小时。反应完成后，加入三乙胺使反应液pH为中性，然后浓缩反应液，在浓缩物中加入水(10mL)和乙酸乙酯(30mL*2)萃取，合并有机相，再用盐水洗涤，将有机相用无水硫酸钠干燥，过滤浓缩得到产物1-氯-4-(环丙硫基)丁-2-酮(I-2e)(1.4g，粗品)。Dissolve 3-(cyclopropylthio)propionyl chloride (I-2d) (2.4g, 14.58mmol) in acetonitrile (20mL), replace it with nitrogen three times, lower the reaction solution to 0°C, and add Nitrotrimethylsilane (17.49 mL, 350 mmol), the reaction was slowly warmed up to room temperature, and reacted for 2 hours. Then the reaction solution was lowered to 0°C again, hydrochloric acid/dioxane solution (5 mL) was slowly added, and reacted for 1 hour. After the reaction was completed, triethylamine was added to make the pH of the reaction solution neutral, then the reaction solution was concentrated, water (10 mL) and ethyl acetate (30 mL*2) were added to the concentrate for extraction, the organic phases were combined, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the product 1-chloro-4-(cyclopropylthio)butan-2-one (I-2e) (1.4 g, crude).
第五步：1-氯-4-(环丙基磺酰基)丁-2-酮(I-2f)的合成Step 5: Synthesis of 1-chloro-4-(cyclopropylsulfonyl)butan-2-one (I-2f)
Figure PCTCN2022136130-appb-000031
Figure PCTCN2022136130-appb-000031
将1-氯-4-(环丙硫基)丁-2-酮(I-2e)(1.4g，7.84mmol)和钨酸钠二水合物(0.258g，0.784mmol)溶在甲醇(12mL)中，然后0℃下加入30％的双氧水(1.761mL，17.24mmol)，将反应液在室温下反应16小时。反应完成后，将反应液浓缩，然后加入水(10mL)和乙酸乙酯(15mL*3)萃取，合并有机相，用无水硫酸钠干燥后，过滤浓缩得到产物1-氯-4-(环丙基磺酰基)丁-2-酮(I-2f)(1.4g)，产物无需纯化，直接进行下一步。1-Chloro-4-(cyclopropylthio)butan-2-one (I-2e) (1.4 g, 7.84 mmol) and sodium tungstate dihydrate (0.258 g, 0.784 mmol) were dissolved in methanol (12 mL) , then 30% hydrogen peroxide (1.761 mL, 17.24 mmol) was added at 0° C., and the reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated, then added water (10mL) and ethyl acetate (15mL*3) for extraction, the organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated to obtain the product 1-chloro-4-(cyclo Propylsulfonyl)butan-2-one (I-2f) (1.4g), the product was directly carried on to the next step without purification.
第六步：Step six:
氮-(2-(2-(环丙磺酰基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-2)。Nitrogen-(2-(2-(cyclopropylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-6-yl) -6-(trifluoromethyl)pyridine amide (target compound I-2).
Figure PCTCN2022136130-appb-000032
Figure PCTCN2022136130-appb-000032
将1-氯-4-(环丙基磺酰基)丁-2-酮(I-2f)(470mg，2.233mmol)和N-(6-氨基-5-氟-4-(2-羟基丙基-2-基)吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-1k)(160mg，0.447mmol)和溶于乙醇(4mL)的密封管中，将反应液在100℃下搅拌16小时。反应完成后，将反应液浓缩得到粗品。将粗品经反相柱HPLC(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.1％氨水)-乙腈]；B％:18％-52％,12min)纯化后，得到类N-(2-(2-(环丙磺酰基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-2)(7mg，99.45％纯度)1-Chloro-4-(cyclopropylsulfonyl)butan-2-one (I-2f) (470mg, 2.233mmol) and N-(6-amino-5-fluoro-4-(2-hydroxypropyl -2-yl)pyridin-3-yl)-6-(trifluoromethyl)pyridineamide (I-1k) (160mg, 0.447mmol) and in a sealed tube dissolved in ethanol (4mL), the reaction solution was dissolved at 100 Stir at °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product. After the crude product was purified by reverse-phase column HPLC (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min), the obtained N-(2-(2-(cyclopropylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-6-yl) -6-(trifluoromethyl)pyridine amide (target compound I-2) (7 mg, 99.45% purity)
LC-MS,M/Z(ESI):514.5[M+1] + LC-MS, M/Z(ESI):514.5[M+1] +
1H NMR(400MHz,CDCl 3)δ12.63(s,1H),9.52(d,J＝0.8Hz,1H),8.46(d,J＝7.6Hz,1H),8.14(t,J＝7.6Hz,1H),7.87(dd,J＝7.8,0.8Hz,1H),7.51(t,J＝4.0Hz,1H),5.44–5.25(m,1H),3.62–3.54(m,2H),3.36(dd,J＝9.6,6.4Hz,2H),2.02(dd,J＝12.8,9.2Hz,1H),1.30–1.23(m,6H),1.06–0.99(m,2H),0.91–0.73(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ12.63(s, 1H), 9.52(d, J=0.8Hz, 1H), 8.46(d, J=7.6Hz, 1H), 8.14(t, J=7.6Hz ,1H),7.87(dd,J=7.8,0.8Hz,1H),7.51(t,J=4.0Hz,1H),5.44–5.25(m,1H),3.62–3.54(m,2H),3.36( dd,J＝9.6,6.4Hz,2H),2.02(dd,J＝12.8,9.2Hz,1H),1.30–1.23(m,6H),1.06–0.99(m,2H),0.91–0.73(m, 2H).
实施例3：目标化合物I-3的制备Embodiment 3: the preparation of target compound 1-3
N-(8-氟-2-(2-(4-氟苯基)磺酰基)乙基)-7-(2-羟基丙-2-基)咪唑并[1，2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-3)N-(8-fluoro-2-(2-(4-fluorophenyl)sulfonyl)ethyl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridine-6 -yl)-6-(trifluoromethyl)pyridinamide (target compound I-3)
Figure PCTCN2022136130-appb-000033
Figure PCTCN2022136130-appb-000033
化合物I-3的合成路线如下所示：The synthetic route of compound 1-3 is as follows:
Figure PCTCN2022136130-appb-000034
Figure PCTCN2022136130-appb-000034
第一步：3-((4-氟苯基)硫代)丙酸乙酯(I-3c)的合成The first step: the synthesis of ethyl 3-((4-fluorophenyl)thio)propionate (I-3c)
Figure PCTCN2022136130-appb-000035
Figure PCTCN2022136130-appb-000035
室温下，分别称取化合物I-3b(4.30g，42.9mmol)，无水乙酸钠(0.48g，5.85mmol)于无水四氢呋喃(25mL)和水(25mL)的混合溶液中，然后加入化合物I-3a(5.0g，39.0mmol)。加完后，反应液在25℃下反应18小时。TLC(PE:EtOAc(V/V)＝10:1)监测反应完全。反应液用饱和碳酸氢钠水溶液(30mL)淬灭，用乙酸乙酯(50mL*2)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压浓缩旋干得到粗品，粗产品用硅胶柱层析梯度洗脱(硅胶；PE:EtOAc(V/V)＝1:0-1:1)分离得到黄色液体3-((4-氟苯基)硫代)丙酸乙酯(I-3c)(8.60g，产率97％)。At room temperature, weigh compound I-3b (4.30g, 42.9mmol), anhydrous sodium acetate (0.48g, 5.85mmol) in a mixed solution of anhydrous tetrahydrofuran (25mL) and water (25mL), and then add compound I - 3a (5.0 g, 39.0 mmol). After the addition, the reaction solution was reacted at 25°C for 18 hours. TLC (PE:EtOAc(V/V)=10:1) monitored the completion of the reaction. The reaction solution was quenched with saturated aqueous sodium bicarbonate (30 mL), extracted with ethyl acetate (50 mL*2), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated and spin-dried to obtain a crude product, the crude product was eluted with a silica gel column chromatography gradient (silica gel; PE:EtOAc(V/V)=1:0-1:1) to separate and obtain a yellow liquid 3-((4-fluorophenyl) Ethylthio)propionate (I-3c) (8.60 g, 97% yield).
第二步：1-氯-4-((4-氟苯基)硫代)丁-2-酮(I-3d)的合成The second step: the synthesis of 1-chloro-4-((4-fluorophenyl)thio)butan-2-one (I-3d)
Figure PCTCN2022136130-appb-000036
Figure PCTCN2022136130-appb-000036
氮气保护，-78℃条件下，将化合物I-3c(2.0g，8.76mmol)和氯碘甲烷(4.64g，26.3mmol)溶于无水四氢呋喃(20mL)中，然后滴加二异丙基胺基锂的正己烷溶液(13.14mL，26.3mmol,2M)，滴加过程中维持温度不超过-65℃。加完后，反应液在-78℃下反应1.5小时。TLC(PE:EtOAc＝10:1)监测反应完全。反应液用饱和氯化铵水溶液(20mL)淬灭，乙酸乙酯(20mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压浓缩旋干得到粗品，粗产品用硅胶柱层析梯度洗脱(硅胶；PE:EtOAc(V/V)＝1:0-10:1)分离得到1-氯-4-((4-氟苯基)硫代)丁-2-酮(I-3d)(0.55g，产率：27.0％)。Under nitrogen protection, at -78°C, compound I-3c (2.0g, 8.76mmol) and chloroiodomethane (4.64g, 26.3mmol) were dissolved in anhydrous tetrahydrofuran (20mL), then diisopropylamine was added dropwise Lithium in n-hexane solution (13.14mL, 26.3mmol, 2M), keep the temperature not exceeding -65°C during the dropwise addition. After the addition, the reaction solution was reacted at -78°C for 1.5 hours. TLC (PE:EtOAc=10:1) monitored the completion of the reaction. The reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL×3), combined the organic phases, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The crude product was spin-dried to obtain the crude product, and the crude product was eluted by gradient elution of silica gel column chromatography (silica gel; PE:EtOAc(V/V)=1:0-10:1) to obtain 1-chloro-4-((4-fluorophenyl )thio)butan-2-one (I-3d) (0.55 g, yield: 27.0%).
第三步：1-氯-4-((4-氟苯基)磺酰基)丁-2-酮(I-3e)的合成The third step: the synthesis of 1-chloro-4-((4-fluorophenyl)sulfonyl)butan-2-one (I-3e)
Figure PCTCN2022136130-appb-000037
Figure PCTCN2022136130-appb-000037
冰浴条件下，把化合物I-3d(0.48g，2.06mmol)和二水合钨酸钠(0.07g，0.21mmol)溶于无水甲醇(5mL)中，然后缓慢加入双氧水(0.52g，4.54mmol,30％)。加完后，反应液缓慢升至25℃，并在该条件下反应10小时。该反应液用饱和亚硫酸钠水溶液(5mL)淬灭，乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液通过减压浓缩旋干得到粗品，粗产品用硅胶柱层析梯度洗脱(硅胶；PE:EtOAc(V/V)＝1:0-10:1)分离得到1-氯-4-((4-氟苯基)磺酰基)丁-2-酮(I-3e)(130mg，产率：23.81％)。Under ice-bath conditions, compound I-3d (0.48g, 2.06mmol) and sodium tungstate dihydrate (0.07g, 0.21mmol) were dissolved in anhydrous methanol (5mL), then slowly added hydrogen peroxide (0.52g, 4.54mmol ,30%). After the addition, the reaction solution was slowly raised to 25° C., and reacted under this condition for 10 hours. The reaction solution was quenched with saturated aqueous sodium sulfite (5 mL), extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was filtered through Concentrated under pressure and spin-dried to obtain the crude product, the crude product was eluted with silica gel column chromatography gradient (silica gel; PE:EtOAc(V/V)=1:0-10:1) to obtain 1-chloro-4-((4-fluoro Phenyl)sulfonyl)butan-2-one (I-3e) (130 mg, yield: 23.81%).
第四步：N-(8-氟-2-(2-(4-氟苯基)磺酰基)乙基)-7-(2-羟基丙-2-基)咪唑并[1，2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-3)的合成The fourth step: N-(8-fluoro-2-(2-(4-fluorophenyl)sulfonyl)ethyl)-7-(2-hydroxypropan-2-yl)imidazo[1,2-a Synthesis of ]pyridin-6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-3)
Figure PCTCN2022136130-appb-000038
Figure PCTCN2022136130-appb-000038
室温下，分别称取化合物I-3e(0.070g，0.20mmol)和化合物I-1k(155.17mg，0.60mmol)于10毫升聚四氟乙烯试管中，然后加入无水乙醇(2mL)。加完后，在100℃下，密闭的试管中反应12小时。LCMS监测反应完全，将反应液减压浓缩旋干，粗产品用高压液相制备色 谱分离((色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.1％氨水)-乙腈]；B％:18％-52％,12min))得到N-(8-氟-2-(2-(4-氟苯基)磺酰基)乙基)-7-(2-羟基丙-2-基)咪唑并[1，2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(I-3)。At room temperature, weigh compound I-3e (0.070 g, 0.20 mmol) and compound I-1k (155.17 mg, 0.60 mmol) into 10 ml polytetrafluoroethylene test tubes, and then add absolute ethanol (2 mL). After the addition, react in a closed test tube at 100°C for 12 hours. LCMS monitors that the reaction is complete, the reaction solution is concentrated under reduced pressure and spin-dried, and the crude product is separated by high-pressure liquid chromatography ((chromatographic column: Phenomenex Synergi C18 150 × 25mm × 10 μm; mobile phase: [water (0.1% ammonia water)-acetonitrile] ; B%: 18%-52%, 12min)) to obtain N-(8-fluoro-2-(2-(4-fluorophenyl)sulfonyl)ethyl)-7-(2-hydroxypropane-2- base) imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)pyridineamide (I-3).
1H NMR(400MHz,CD 3OD)δ9.75(s,1H),8.48(d,1H,J＝8.0Hz),8.31(t,1H,J＝8.0Hz),8.06(d,1H,J＝8.0Hz),7.98-7.95(m,3H),7.32(t,2H,J＝8.0Hz),3.77-3.73(m,2H),3.31-3.26(m,2H),1.82(s,6H)。 1 H NMR (400MHz, CD 3 OD) δ9.75(s, 1H), 8.48(d, 1H, J=8.0Hz), 8.31(t, 1H, J=8.0Hz), 8.06(d, 1H, J =8.0Hz),7.98-7.95(m,3H),7.32(t,2H,J=8.0Hz),3.77-3.73(m,2H),3.31-3.26(m,2H),1.82(s,6H) .
LC-MS,M/Z(ESI):568.9[M+H] + LC-MS, M/Z(ESI):568.9[M+H] +
实施例4：目标化合物I-6的制备Embodiment 4: the preparation of target compound 1-6
氮-(2-(2-(氮，氮-二甲基磺胺基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-6)Nitrogen-(2-(2-(nitrogen, nitrogen-dimethylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridine -6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-6)
Figure PCTCN2022136130-appb-000039
Figure PCTCN2022136130-appb-000039
目标化合物I-6的合成路线如下所示：The synthetic route of target compound 1-6 is as follows:
Figure PCTCN2022136130-appb-000040
Figure PCTCN2022136130-appb-000040
第一步：3-(氮，氮-二甲基磺胺基)丙酸(I-6b)The first step: 3-(nitrogen, nitrogen-dimethylsulfonyl)propionic acid (I-6b)
Figure PCTCN2022136130-appb-000041
Figure PCTCN2022136130-appb-000041
将3-(氮，氮-二甲基磺胺基)丙酸甲酯(700mg，3.59mmol)溶于四氢呋喃：水：甲醇＝4.5:3:0.5的混合溶液中，然后加入氢氧化锂(429mg，17.93mmol)，反应液室温反应过夜。反应完成后，将反应液浓缩，除掉甲醇，然后将浓缩物用乙酸乙酯(10mL*2)萃取，将水相用1N的盐酸溶液调至pH＝3，然后再用乙酸乙酯(10mL*5)萃取，合并有机相，用无水硫酸钠干燥，过滤后浓缩得到产物3-(氮，氮-二甲基磺胺基)丙酸(I-6b)(600mg)。Dissolve methyl 3-(nitrogen, nitrogen-dimethylsulfonyl)propionate (700mg, 3.59mmol) in a mixed solution of tetrahydrofuran:water:methanol=4.5:3:0.5, and then add lithium hydroxide (429mg, 17.93mmol), the reaction solution was reacted overnight at room temperature. After the reaction was completed, the reaction solution was concentrated to remove methanol, then the concentrate was extracted with ethyl acetate (10mL*2), the aqueous phase was adjusted to pH=3 with 1N hydrochloric acid solution, and then ethyl acetate (10mL *5) extraction, combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the product 3-(nitrogen, nitrogen-dimethylsulfonylamino)propionic acid (I-6b) (600 mg).
第二步：3-(氮，氮-二甲基磺胺基)丙酰氯The second step: 3-(nitrogen, nitrogen-dimethylsulfonyl)propionyl chloride
Figure PCTCN2022136130-appb-000042
Figure PCTCN2022136130-appb-000042
将3-(氮，氮-二甲基磺胺基)丙酸(I-6b)(500mg，2.76mmol)溶于二氯甲烷(5mL)中，加入草酰氯(1.05g，8.28mmol)，然后在反应液中滴加一滴DMF，反应液在室温下反应2小时。反应完成后，将反应液低温下浓缩得到粗产物3-(N，N-二甲基磺胺基)丙酰氯(I-6c)(550mg)。Dissolve 3-(nitrogen, nitrogen-dimethylsulfamoyl)propionic acid (I-6b) (500mg, 2.76mmol) in dichloromethane (5mL), add oxalyl chloride (1.05g, 8.28mmol), and then A drop of DMF was added dropwise to the reaction solution, and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated at low temperature to obtain the crude product 3-(N,N-dimethylsulfonyl)propionyl chloride (I-6c) (550 mg).
第三步：4-氯-氮，氮-二甲基-3-氧代丁烷-1-磺酰胺(I-6e)The third step: 4-chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (I-6e)
Figure PCTCN2022136130-appb-000043
Figure PCTCN2022136130-appb-000043
将3-(氮，氮-二甲基磺胺基)丙酰氯(200mg，1.002mmol)溶于乙腈(2mL)中，用氮气置换三次，将反应液降至0℃，在0度下加入叠氮基三甲基硅烷(1.2mL，24.04mmol)，将反应缓慢升温至室温，反应2小时。然后将所得含4-二氮-N，N-二甲基-3-氧代丁烷-1-磺酰胺(I-6d)的反应液再次降至0℃，缓慢加入盐酸/二氧六环溶液(1mL)，反应1小时。反应完成后，加入三乙胺使反应液pH为中性，然后浓缩反应液，在浓缩物中加入水(5mL)和乙酸乙酯(10mL*2)萃取，合并有机相，再用盐水洗涤，将有机相用无水硫酸钠干燥，过滤浓缩得到产物4-氯-氮，氮-二甲基-3-氧代丁烷-1-磺酰胺(I-6e)(200mg)。Dissolve 3-(nitrogen, nitrogen-dimethylsulfonyl)propionyl chloride (200mg, 1.002mmol) in acetonitrile (2mL), replace with nitrogen three times, lower the reaction solution to 0°C, and add azide at 0°C Trimethylsilane (1.2 mL, 24.04 mmol), the reaction was slowly warmed to room temperature, and reacted for 2 hours. Then the resulting reaction solution containing 4-diazo-N,N-dimethyl-3-oxobutane-1-sulfonamide (I-6d) was lowered to 0°C again, and hydrochloric acid/dioxane was slowly added solution (1 mL), reacted for 1 hour. After the reaction was completed, triethylamine was added to make the pH of the reaction solution neutral, then the reaction solution was concentrated, water (5 mL) and ethyl acetate (10 mL*2) were added to the concentrate for extraction, the organic phases were combined, and then washed with brine. The organic phase was dried over anhydrous sodium sulfate, concentrated by filtration to give the product 4-chloro-nitrogen,nitrogen-dimethyl-3-oxobutane-1-sulfonamide (I-6e) (200mg).
第四步：氮-(2-(2-(氮，氮-二甲基磺胺基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-6)The fourth step: nitrogen-(2-(2-(nitrogen, nitrogen-dimethylsulfonyl) ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl) imidazo[1,2 -a] pyridin-6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-6)
Figure PCTCN2022136130-appb-000044
Figure PCTCN2022136130-appb-000044
将4-氯-氮，氮-二甲基-3-氧代丁烷-1-磺酰胺(119mg，0.558mmol)和N-(6-氨基-5-氟-4-(2-羟基丙基-2-基)吡啶-3-基)-6-(三氟甲基)吡啶酰胺(40mg，0.112mmol)和溶于乙醇(1mL)的密封管中，将反应液在100℃下搅拌16小时。反应完成后，将反应液浓缩得到粗品。将粗品经反相柱HPLC(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.1％氨水)-乙腈]；B％:18％-52％,12min)纯化后，得到氮-(2-(2-(氮，氮-二甲基磺胺基)乙基)-8-氟-7-(2-羟基丙基-2-基)咪唑并[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-6)(10mg，100％纯度)4-Chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (119 mg, 0.558 mmol) and N-(6-amino-5-fluoro-4-(2-hydroxypropyl -2-yl)pyridin-3-yl)-6-(trifluoromethyl)pyridineamide (40mg, 0.112mmol) and dissolved in ethanol (1mL) in a sealed tube, the reaction was stirred at 100°C for 16 hours . After the reaction was completed, the reaction solution was concentrated to obtain a crude product. The crude product was purified by reverse-phase column HPLC (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min) to obtain nitrogen -(2-(2-(nitrogen, nitrogen-dimethylsulfonyl)ethyl)-8-fluoro-7-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridine- 6-yl)-6-(trifluoromethyl)pyridinamide (target compound I-6) (10 mg, 100% purity)
LC-MS,M/Z(ESI):517.5[M+1] + LC-MS, M/Z(ESI):517.5[M+1] +
1H NMR(400MHz,CDCl 3)δ12.63(s,1H),9.51(s,1H),8.44(d,J＝7.6Hz,1H),8.13(t,J＝7.6Hz,1H),7.86(d,J＝7.6Hz,1H),7.48(d,J＝3.2Hz,1H),5.32(d,J＝17.2Hz,1H),3.42(dd,J＝10.0,5.7Hz,2H),3.28(dd,J＝10.0,5.9Hz,2H),2.89(s,6H),1.88(d,J＝3.6Hz,6H). 1 H NMR (400MHz, CDCl 3 )δ12.63(s,1H),9.51(s,1H),8.44(d,J=7.6Hz,1H),8.13(t,J=7.6Hz,1H),7.86 (d,J=7.6Hz,1H),7.48(d,J=3.2Hz,1H),5.32(d,J=17.2Hz,1H),3.42(dd,J=10.0,5.7Hz,2H),3.28 (dd,J=10.0,5.9Hz,2H),2.89(s,6H),1.88(d,J=3.6Hz,6H).
实施例5：目标化合物I-8的制备Embodiment 5: the preparation of target compound 1-8
氮-(8-氟-2-(2-(甲基磺酰基)乙基)-7-吗啉并咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-8)Nitrogen-(8-fluoro-2-(2-(methylsulfonyl)ethyl)-7-morpholinoimidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl) Pyridinamide (target compound I-8)
Figure PCTCN2022136130-appb-000045
Figure PCTCN2022136130-appb-000045
目标化合物I-8的合成路线如下所示：The synthetic route of target compound 1-8 is as follows:
Figure PCTCN2022136130-appb-000046
Figure PCTCN2022136130-appb-000046
第一步：(6-(双(4-甲氧基苄基)氨基)-5-氟-4-吗啉基吡啶-3-基)氨基甲酸叔丁酯(I-8a)The first step: tert-butyl (6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-morpholinylpyridin-3-yl)carbamate (I-8a)
Figure PCTCN2022136130-appb-000047
Figure PCTCN2022136130-appb-000047
将(6-(双(4-甲氧基苄基)氨基)-5-氟-4-碘吡啶-3-基)氨基甲酸叔丁酯(I-1e)(2g，6.74mmol)和吗啉(0.587g，6.74mmol)溶于1,4-二氧六环(20mL)中，依次加入碳酸铯(2.196g，6.74mmol)，三(二亚苄基丙酮)二钯(0.309g，0.337mmol)和Xantphos(0.390g，0.674mmol)，将反应液氮气置换三次，然后升温至90℃反应2小时。反应完成后，将反应液用水(20mL)和乙酸乙酯(20mL*2)洗涤，合并有机相，用盐水洗涤两次，然后用硫酸钠干燥，过滤旋干得到粗品。将粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到3:1)，纯化后得到黄色油状化合物(6-(双(4-甲氧基苄基)氨基)-5-氟-4-吗啉基吡啶-3-基)氨基甲酸叔丁酯(I-8a)(400mg，产率21.48％)。(6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-iodopyridin-3-yl)carbamate (I-1e) (2 g, 6.74 mmol) and morpholine (0.587g, 6.74mmol) was dissolved in 1,4-dioxane (20mL), cesium carbonate (2.196g, 6.74mmol), tris(dibenzylideneacetone)dipalladium (0.309g, 0.337mmol) were added successively ) and Xantphos (0.390g, 0.674mmol), the reaction liquid nitrogen was replaced three times, and then the temperature was raised to 90°C for 2 hours. After the reaction was complete, the reaction solution was washed with water (20 mL) and ethyl acetate (20 mL*2), the organic phases were combined, washed twice with brine, then dried over sodium sulfate, filtered and spin-dried to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain yellow oily compound (6-(bis(4-methoxybenzyl)amino)-5- tert-butylfluoro-4-morpholinopyridin-3-yl)carbamate (I-8a) (400 mg, yield 21.48%).
LC-MS,M/Z(ESI):553.4[M+1] + LC-MS, M/Z(ESI):553.4[M+1] +
1H NMR(400MHz,CDCl 3)δ7.20(d,J＝8.6Hz,4H),7.09(s,1H),6.83(d,J＝8.6Hz,4H),4.46(s,4H),3.85–3.81(m,4H),3.80(s,6H),3.08(s,4H),1.54(d,J＝4.4Hz,10H). 1 H NMR (400MHz, CDCl 3 ) δ7.20(d, J=8.6Hz, 4H), 7.09(s, 1H), 6.83(d, J=8.6Hz, 4H), 4.46(s, 4H), 3.85 –3.81(m,4H),3.80(s,6H),3.08(s,4H),1.54(d,J=4.4Hz,10H).
第二步：3-氟-N2-(4-甲氧基苄基)-4-吗啉基吡啶-2,5-二胺(I-8b)The second step: 3-fluoro-N2-(4-methoxybenzyl)-4-morpholinylpyridine-2,5-diamine (I-8b)
Figure PCTCN2022136130-appb-000048
Figure PCTCN2022136130-appb-000048
将(6-(双(4-甲氧基苄基)氨基)-5-氟-4-吗啉基吡啶-3-基)氨基甲酸叔丁酯(I-8a)(400mg，0.742mmol)溶在二氯甲烷(5mL)中，然后加入盐酸/二氧六环(0.5mL)，反应液在室温下反应1小时。反应完成后，将反应液浓缩旋干得到粗品3-氟-N 2-(4-甲氧基苄基)-4-吗啉基吡啶-2,5-二胺(I-8b)(200mg，产率83％)，直接用于下一步。 Tert-butyl (6-(bis(4-methoxybenzyl)amino)-5-fluoro-4-morpholinylpyridin-3-yl)carbamate (I-8a) (400 mg, 0.742 mmol) was dissolved in In dichloromethane (5 mL), hydrochloric acid/dioxane (0.5 mL) was then added, and the reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated and spin-dried to obtain the crude product 3-fluoro-N 2 -(4-methoxybenzyl)-4-morpholinopyridine-2,5-diamine (I-8b) (200 mg, Yield 83%), used directly in the next step.
第三步：氮-(5-氟-6-((4-甲氧基苄基)氨基)-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8c)The third step: nitrogen-(5-fluoro-6-((4-methoxybenzyl) amino)-4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridineamide (I -8c)
Figure PCTCN2022136130-appb-000049
Figure PCTCN2022136130-appb-000049
将3-氟-N2-(4-甲氧基苄基)-4-吗啉基吡啶-2,5-二胺(I-8b)(200mg，0.442mmol)和6-(三氟甲基)吡啶甲酸(101mg，0.530mmol)溶在DMF(4mL)中，依次加入DIEA(114mg，0.884mmol)和T 3P·DMF(35.4mg，0.884mmol)，将反应液在50℃下反应16小时。反应完成后，将反应液用水和乙酸乙酯萃取，合并有机层，用饱和食盐水洗涤有机相，无水硫酸钠干燥，浓缩得到粗品。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10:1到3:1)，纯化后得到产物氮-(5-氟-6-((4-甲氧基苄基)氨基)-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8c)(100mg)。 Mix 3-fluoro-N2-(4-methoxybenzyl)-4-morpholinylpyridine-2,5-diamine (I-8b) (200mg, 0.442mmol) and 6-(trifluoromethyl) Picolinic acid (101mg, 0.530mmol) was dissolved in DMF (4mL), DIEA (114mg, 0.884mmol) and T 3 P·DMF (35.4mg, 0.884mmol) were added sequentially, and the reaction solution was reacted at 50°C for 16 hours. After the reaction was completed, the reaction solution was extracted with water and ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to 3:1), and the product nitrogen-(5-fluoro-6-((4-methoxybenzyl)amino)- 4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8c) (100 mg).
LC-MS,M/Z(ESI):506.1[M+1] + LC-MS, M/Z(ESI):506.1[M+1] +
1H NMR(400MHz,CDCl 3)δ10.66(s,1H),9.21(s,1H),8.52(d,J＝8.0Hz,1H),8.14(t,J＝8.0Hz,1H),7.89(d,J＝7.6Hz,1H),7.33(t,J＝10.4Hz,2H),6.90(d,J＝8.8Hz,2H),4.62(d,J＝5.6Hz,2H),3.99–3.88(m,4H),3.82(s,3H),3.21–3.03(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ10.66(s, 1H), 9.21(s, 1H), 8.52(d, J=8.0Hz, 1H), 8.14(t, J=8.0Hz, 1H), 7.89 (d, J=7.6Hz, 1H), 7.33(t, J=10.4Hz, 2H), 6.90(d, J=8.8Hz, 2H), 4.62(d, J=5.6Hz, 2H), 3.99–3.88 (m,4H),3.82(s,3H),3.21–3.03(m,4H).
第四步：氮-(6-氨基-5-氟-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8d)The fourth step: Nitrogen-(6-amino-5-fluoro-4-morpholinylpyridin-3-yl)-6-(trifluoromethyl)pyridineamide (I-8d)
Figure PCTCN2022136130-appb-000050
Figure PCTCN2022136130-appb-000050
将氮-(5-氟-6-((4-甲氧基苄基)氨基)-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8c)(100mg，1eq)溶在二氯甲烷(3mL)中，然后加入三氟乙酸(1mL)，将反应液在室温下反应16小时。反应完成后，将反应液用碳酸氢钠洗涤，水相再用二氯甲烷萃取三次(5mL*3)，合并有机层，用硫酸钠干燥，减压浓缩得到产物氮-(6-氨基-5-氟-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8d)(50mg)。Nitrogen-(5-fluoro-6-((4-methoxybenzyl)amino)-4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8c) (100mg, 1eq) was dissolved in dichloromethane (3mL), then trifluoroacetic acid (1mL) was added, and the reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with sodium bicarbonate, and the aqueous phase was extracted three times with dichloromethane (5mL*3). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the product nitrogen-(6-amino-5 -Fluoro-4-morpholinopyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8d) (50 mg).
LC-MS,M/Z(ESI):386.5[M+1] + LC-MS, M/Z(ESI):386.5[M+1] +
第五步：氮-(8-氟-2-(2-(甲基磺酰基)乙基)-7-吗啉并咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-8)Step 5: Nitrogen-(8-fluoro-2-(2-(methylsulfonyl)ethyl)-7-morpholinoimidazo[1,2-a]pyridin-6-yl)-6-(tri Fluoromethyl) pyridinamide (target compound I-8)
Figure PCTCN2022136130-appb-000051
Figure PCTCN2022136130-appb-000051
将氮-(6-氨基-5-氟-4-吗啉基吡啶-3-基)-6-(三氟甲基)吡啶酰胺(I-8d)(100mg，0.260mmol)和1-氯-4-(甲磺酰基)丁-2-酮(1A)(144mg，0.779mmol)溶在乙醇(1mL)的封闭管中，将反应液在100℃下反应12小时。反应完成后，将反应液浓缩旋干得到粗品。将粗品经反相柱HPLC(色谱柱:Phenomenex Synergi C18 150×25mm×10μm；流动相:[水(0.1％氨水)-乙腈]；B％:18％-52％,12min)纯化后，得到类氮-(8-氟-2-(2-(甲基磺酰基)乙基)-7-吗啉并咪唑[1,2-a]吡啶-6-基)-6-(三氟甲基)吡啶酰胺(目标化合物I-8)(5mg，100％纯度)。Nitrogen-(6-amino-5-fluoro-4-morpholinylpyridin-3-yl)-6-(trifluoromethyl)pyridinamide (I-8d) (100mg, 0.260mmol) and 1-chloro- 4-(Methylsulfonyl)butan-2-one (1A) (144 mg, 0.779 mmol) was dissolved in a closed tube of ethanol (1 mL), and the reaction solution was reacted at 100° C. for 12 hours. After the reaction was completed, the reaction solution was concentrated and spin-dried to obtain a crude product. After the crude product was purified by reverse-phase column HPLC (chromatographic column: Phenomenex Synergi C18 150×25mm×10 μm; mobile phase: [water (0.1% ammonia water)-acetonitrile]; B%: 18%-52%, 12min), the obtained Nitrogen-(8-fluoro-2-(2-(methylsulfonyl)ethyl)-7-morpholinoimidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl) Pyridinamide (target compound I-8) (5 mg, 100% purity).
LC-MS,M/Z(ESI):516.10[M+1] + LC-MS, M/Z(ESI):516.10[M+1] +
1H NMR(400MHz,CDCl 3)δ11.15(s,1H),9.42(s,1H),8.52(d,J＝7.6Hz,1H),8.19(t,J＝7.6Hz,1H),7.95(d,J＝7.6Hz,1H),7.53(d,J＝2.8Hz,1H),4.00(s,3H),3.82(dd,J＝21.6,7.2Hz,1H),3.67–3.44(m,4H),3.40–3.29(m,2H),2.94–2.88(m,3H),2.28–2.17(m,1H),2.03(s,1H). 1 H NMR (400MHz, CDCl 3 ) δ11.15(s, 1H), 9.42(s, 1H), 8.52(d, J=7.6Hz, 1H), 8.19(t, J=7.6Hz, 1H), 7.95 (d,J=7.6Hz,1H),7.53(d,J=2.8Hz,1H),4.00(s,3H),3.82(dd,J=21.6,7.2Hz,1H),3.67–3.44(m, 4H), 3.40–3.29(m,2H), 2.94–2.88(m,3H), 2.28–2.17(m,1H), 2.03(s,1H).
参考WO2016083433A1合成得到下述表格中各化合物：Refer to WO2016083433A1 to synthesize the compounds in the following tables:
Figure PCTCN2022136130-appb-000052
Figure PCTCN2022136130-appb-000052
测试例1：迁移率改变法(Mobility Shift Assay)检测化合物对IRAK4激酶活性的抑制Test Example 1: Mobility Shift Assay to detect the inhibition of IRAK4 kinase activity by compounds
首先，将前面所合成的待测化合物溶解于DMSO并配制成10mM的母液，随后配制1×激酶base缓冲液(50mM HEPES,pH 7.5；0.0015％Brij-35)及终止缓冲液(100mM HEPES,pH7.5；0.015％Brij-35，0.2％Coating Reagent#3，50mM EDTA)备用。First, dissolve the previously synthesized compound to be tested in DMSO and prepare a 10mM stock solution, then prepare 1× kinase base buffer (50mM HEPES, pH 7.5; 0.0015% Brij-35) and stop buffer (100mM HEPES, pH7 .5; 0.015% Brij-35, 0.2% Coating Reagent#3, 50mM EDTA) for standby.
接着，用DMSO将化合物母液稀释至浓度梯度最高点的50倍，转移100μL此稀释液至96孔板中，随后连续稀释4倍直至达到10个浓度梯度。加100μL DMSO至同一96孔板的2个空孔中，设为无化合物对照以及无酶对照。转移梯度稀释的10μL化合物及对照溶液至一块新的96孔板，在每孔中加入90μL的1×激酶缓冲液，放置于摇床10min以混合均匀。每孔分别吸取5μL，转移至384孔板的两个复孔。Next, dilute the compound mother solution with DMSO to 50 times the highest point of the concentration gradient, transfer 100 μL of this dilution to a 96-well plate, and then serially dilute 4 times until reaching 10 concentration gradients. Add 100 μL DMSO to two empty wells of the same 96-well plate, and set it as no compound control and no enzyme control. Transfer 10 μL of gradient diluted compound and control solutions to a new 96-well plate, add 90 μL of 1× kinase buffer to each well, and place on a shaker for 10 min to mix evenly. Pipette 5 μL from each well and transfer to two duplicate wells of a 384-well plate.
在1×激酶base缓冲液中加入IRAK4激酶(Carna)配制成2.5×酶溶液，在1×激酶base缓冲液中加入FAM标记的多肽和ATP配制成2.5×多肽溶液。吸取2.5×酶溶液加入已含有5μL化合物的384孔板中，每孔10μL，室温孵育10min。吸取2.5×多肽溶液加入之前的384孔板中，每孔10μL，于28℃孵育1h。孵育结束后，每孔加入30μL终止缓冲液以停止反应，随后转移至Caliper仪器采集每孔的数据，根据对照孔计算抑制率，用GraphPad软件拟合曲线 计算化合物的IC 50值。 Add IRAK4 kinase (Carna) to 1× kinase base buffer to prepare 2.5× enzyme solution, and add FAM-labeled polypeptide and ATP to 1× kinase base buffer to prepare 2.5× polypeptide solution. Pipette 2.5× enzyme solution into the 384-well plate containing 5 μL of the compound, 10 μL per well, and incubate at room temperature for 10 min. Pipette 2.5×peptide solution into the previous 384-well plate, 10 μL per well, and incubate at 28°C for 1 hour. After the incubation, 30 μL of stop buffer was added to each well to stop the reaction, and then transferred to a Caliper instrument to collect the data of each well, the inhibition rate was calculated according to the control well, and the IC 50 value of the compound was calculated by using GraphPad software to fit the curve.
表1：测试化合物对IRAK4激酶的抑制活性Table 1: Inhibitory activity of test compounds against IRAK4 kinase
Figure PCTCN2022136130-appb-000053
Figure PCTCN2022136130-appb-000053
试验结果表明，本专利化合物表现出更为优良的对IRAK4激酶抑制活性，尤其化合物I-1的抑制活性显著更优。The test results show that the compounds of this patent exhibit better inhibitory activity on IRAK4 kinase, especially the inhibitory activity of compound I-1 is significantly better.
测试例2：化合物对R848刺激PBMC产生TNF-α的抑制活性Test Example 2: Inhibitory activity of compound on R848 stimulating PBMC to produce TNF-α
首先，复苏冻存的PBMC细胞，200rpm，5min离心取上清，用1640+10％FBS+1％P/S完全培养基重悬后计数。按照8×10 4/孔的密度，100μl/孔接种细胞至96孔板生长过夜。 First, cryopreserved PBMC cells were revived, centrifuged at 200 rpm for 5 min to obtain the supernatant, resuspended with 1640+10% FBS+1% P/S complete medium and counted. According to the density of 8×10 4 /well, 100 μl/well cells were seeded into 96-well plate and grown overnight.
接着，配制10mM前面所合成的化合物母液并用DMSO依次3倍稀释，然后用1640+10％FBS+1％P/S完全培养基将一系列浓度稀释500倍，达到4倍终浓度(20μM)。将配制的化合物，按照50μl/孔加入到细胞中，同时设定不加化合物的对照孔，预孵育30min。孵育的同时，配制浓度为10mg/mL的R848母液，用1640+10％FBS+1％P/S培养基先稀释100倍再稀释31.25倍，达到4倍终浓度(3.2μg/mL)。将配制好的R848按照50μl/孔加入到细胞中，同时设定不加R848的对照孔。细胞继续孵育24h后收集上清，分别取50％上清，用Human TNF-α试剂盒(Invitrogen，LOT:189974010)进行检测。根据对照孔计算化合物的抑制率，用GraphPad软件拟合曲线计算化合物的IC 50值。 Next, prepare 10 mM stock solution of the previously synthesized compound and dilute it sequentially 3 times with DMSO, and then use 1640+10% FBS+1% P/S complete medium to dilute a series of concentrations 500 times to reach 4 times the final concentration (20 μM). The prepared compound was added to the cells at 50 μl/well, and a control well without compound was set at the same time, and pre-incubated for 30 min. While incubating, prepare the R848 stock solution with a concentration of 10 mg/mL, and dilute it 100 times and then 31.25 times with 1640+10% FBS+1% P/S medium to reach a final concentration of 4 times (3.2 μg/mL). The prepared R848 was added to the cells at 50 μl/well, and control wells without R848 were set at the same time. The supernatants were collected after the cells were further incubated for 24 hours, and 50% of the supernatants were collected for detection with a Human TNF-α kit (Invitrogen, LOT: 189974010). The inhibition rate of the compound was calculated according to the control well, and the IC50 value of the compound was calculated by fitting the curve with GraphPad software.
表2：测试化合物对R848刺激PBMC产生TNF-α的抑制活性Table 2: Inhibitory activity of test compounds on R848-stimulated PBMC to produce TNF-α
测试化合物test compound IC50(nM)IC50(nM)
对照化合物1Control compound 1 172172
I-1I-1 26.726.7
试验结果表明，与对照化合物1相比，本专利化合物在细胞水平表现出对TNF-α产生具有更强的抑制能力，尤其是化合物I-1的抑制活性显著优于对照化合物1。The test results show that, compared with the reference compound 1, the compound of this patent has a stronger inhibitory ability to TNF-α production at the cellular level, especially the inhibitory activity of the compound I-1 is significantly better than that of the reference compound 1.
测试例3：平衡透析法测血浆蛋白结合率Test Example 3: Measurement of Plasma Protein Binding Rate by Equilibrium Dialysis
用DMSO将化合物配制为储备液，再用甲醇:乙腈:水＝1:1:2(v/v/v)稀释至浓度为100μM。 采用平衡透析法测定化合物与不同种属血浆的结合程度。使用96孔透析装置(HTDialysis，美国)，分别取6μL供试液与594μL血浆混合，所得血浆中化合物浓度为1μM，有机溶剂量不大于1％。The compound was prepared as a stock solution with DMSO, and then diluted with methanol:acetonitrile:water=1:1:2 (v/v/v) to a concentration of 100 μM. Equilibrium dialysis was used to determine the degree of compound binding to plasma of different species. Using a 96-well dialysis device (HTDialysis, USA), 6 μL of the test solution was mixed with 594 μL of plasma. The concentration of the compound in the obtained plasma was 1 μM, and the amount of organic solvent was not more than 1%.
分别转移150μL血浆样品和150μL磷酸盐缓冲液(含0.002％吐温80)至透析膜两侧供试室及接收室(平行2份)。封板膜封板，37℃往复震荡水浴锅中孵育6小时，震荡速度80次/分钟。分别转移10μL供试室样品，加入90μL磷酸盐缓冲液(含0.002％吐温80，pH 7.4)，混匀，加入沉淀剂(含内标)。分别转移90μL接收室样品，加入10μL相应种属空白血浆，混匀，加入沉淀剂(含内标)。Transfer 150 μL of plasma sample and 150 μL of phosphate buffer (containing 0.002% Tween 80) to the testing chamber and receiving chamber on both sides of the dialysis membrane (parallel 2 copies). Seal the plate with film and incubate in a reciprocating shaking water bath at 37°C for 6 hours at a shaking speed of 80 times/min. Transfer 10 μL of samples from the test chamber, add 90 μL of phosphate buffer (containing 0.002% Tween 80, pH 7.4), mix well, and add precipitant (including internal standard). Transfer 90 μL samples from the receiving chamber, add 10 μL blank plasma of the corresponding species, mix well, and add precipitant (including internal standard).
以上所有样品经蛋白沉淀后，离心取上清液加水1:1(v/v)稀释后进样分析，最后根据稀释倍数折算原浓度。After protein precipitation, all the above samples were centrifuged to take the supernatant and diluted with water 1:1 (v/v) before injection for analysis, and finally the original concentration was converted according to the dilution factor.
使用以下公式对血浆蛋白结合率及游离药物的比率进行计算：％结合率＝100×([供给侧浓度] 6h-[接收侧浓度] 6h)/[供给侧浓度] 6h。血浆中游离药物的比率(％)＝100-％结合率 The ratio of plasma protein binding rate and free drug was calculated using the following formula: % binding rate=100×([supply side concentration] 6h− [receiving side concentration] 6h )/[supply side concentration] 6h . Ratio (%) of free drug in plasma = 100-% binding rate
实验结果表明，本发明化合物在人和小鼠血浆中游离药物的比率均较高，成药性好。Experimental results show that the compound of the present invention has high ratios of free drugs in human and mouse plasma and good druggability.
测试例4：人肝微粒体稳定性试验Test Example 4: Stability Test of Human Liver Microsomes
人肝微粒体稳定性试验采用化合物与人肝微粒体体外共孵育进行检测。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，随后使用乙腈将化合物稀释至0.5mM。使用PBS稀释人肝微粒体(Corning)成微粒体/缓冲液溶液，并使用该溶液稀释0.5mM的化合物成为工作溶液，工作溶液中化合物浓度为1.5μM，人肝微粒体浓度为0.75mg/mL。取深孔板，每孔加入30μL工作溶液，然后加入15μL预热好的6mM NADPH溶液启动反应，37℃孵育。在孵育的0、5、15、30、45分钟时，加入135μL乙腈至相应的孔中终止反应。在最后45分钟时间点用乙腈终止反应后，深孔板涡旋振动10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得每个时间点化合物峰面积与内标峰面积比值，将5、15、30、45分钟时化合物的峰面积比值与0分钟时的峰面积比值进行比较，计算每个时间点化合物的剩余百分比，使用Graphpad 5软件计算T 1/2。 The stability test of human liver microsomes was detected by incubating the compound with human liver microsomes in vitro. Firstly, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and then the compound was diluted to 0.5 mM with acetonitrile. Use PBS to dilute human liver microsomes (Corning) into a microsome/buffer solution, and use this solution to dilute 0.5 mM compound to become a working solution. The concentration of the compound in the working solution is 1.5 μM, and the concentration of human liver microsomes is 0.75 mg/mL . Take a deep-well plate, add 30 μL of working solution to each well, then add 15 μL of preheated 6 mM NADPH solution to start the reaction, and incubate at 37 °C. At 0, 5, 15, 30, and 45 minutes of incubation, 135 μL of acetonitrile was added to the corresponding wells to terminate the reaction. After stopping the reaction with acetonitrile at the final 45 minute time point, the deep well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. After centrifugation, take the supernatant, add purified water at 1:1 and perform LC-MS/MS detection, obtain the ratio of the peak area of the compound to the peak area of the internal standard at each time point, and calculate the peak area of the compound at 5, 15, 30, and 45 minutes The ratios were compared with the peak area ratios at 0 minutes, the remaining percentage of the compound was calculated at each time point, and T 1/2 was calculated using Graphpad 5 software.
实验结果表明，本发明中的化合物表现出较为优良的肝代谢稳定性。The experimental results show that the compound of the present invention exhibits relatively good stability in liver metabolism.
测试例5：化合物对细胞色素P450的抑制试验Test Example 5: Inhibition Test of Compounds on Cytochrome P450
检测化合物对细胞色素P450(CYP450)亚型CYP3A4(2种底物咪达***和睾酮)的抑制潜力。首先将待测化合物在DMSO溶剂中配制成10mM的储备液，CYP3A4抑制剂酮康唑在DMSO溶剂中配制成2.5mM的储备液。用乙腈将待测化合物和酮康唑稀释至400倍终浓度(化 合物：10μM，酮康唑：2.5μM)。The inhibitory potential of compounds on cytochrome P450 (CYP450) subtype CYP3A4 (two substrates midazolam and testosterone) was tested. First, the compound to be tested was prepared as a 10 mM stock solution in DMSO solvent, and the CYP3A4 inhibitor ketoconazole was prepared as a 2.5 mM stock solution in DMSO solvent. The compound to be tested and ketoconazole were diluted to 400-fold final concentration with acetonitrile (compound: 10 µM, ketoconazole: 2.5 µM).
用磷酸钾缓冲液(0.1M，pH 7.4)配制4倍终浓度的NADPH辅因子(10mL磷酸钾缓冲液中加入66.7mg NADPH)和底物，咪达***4倍终浓度为20μM，睾酮4倍终浓度为320μM。Prepare 4-fold final concentration of NADPH cofactor (66.7 mg NADPH in 10 mL potassium phosphate buffer) and substrate with potassium phosphate buffer (0.1M, pH 7.4), midazolam 4-fold final concentration is 20 μM, testosterone 4 The final concentration was 320 μM.
在冰上用磷酸钾缓冲液配制人肝微粒体溶液，浓度为0.2mg/mL。在冰上用人肝微粒体溶液配制2倍终浓度的待测化合物。向测试孔中分别加入30μL的待测化合物，并加入15μL底物，进行复孔操作。在37℃下预孵育96孔测定板和NADPH溶液5分钟，将15μL预热的8mM NADPH溶液添加到测定板中以启动反应。37℃下孵育5分钟。加入120μL乙腈终止反应，淬灭后，在振动器(IKA，MTS 2/4)上摇动平板10分钟(600rpm/min)，然后离心15分钟。离心后取上清，1:1加入纯化水后进行LC-MS/MS检测，获得化合物峰面积与内标峰面积比值，化合物的峰面积比值与对照抑制剂的峰面积比值进行比较，计算抑制率。Prepare a solution of human liver microsomes with potassium phosphate buffer on ice at a concentration of 0.2 mg/mL. The compounds to be tested were prepared at 2-fold final concentration with human liver microsome solution on ice. Add 30 μL of the compound to be tested and 15 μL of the substrate to the test wells to perform a duplicate well operation. Pre-incubate the 96-well assay plate and NADPH solution at 37 °C for 5 min, and add 15 μL of pre-warmed 8 mM NADPH solution to the assay plate to initiate the reaction. Incubate at 37°C for 5 minutes. The reaction was terminated by adding 120 μL of acetonitrile, and after quenching, the plate was shaken on a shaker (IKA, MTS 2/4) for 10 minutes (600 rpm/min), and then centrifuged for 15 minutes. Take the supernatant after centrifugation, add purified water at 1:1 and perform LC-MS/MS detection to obtain the peak area ratio of the compound to the internal standard peak area, compare the peak area ratio of the compound with the peak area ratio of the control inhibitor, and calculate the inhibition Rate.
实验结果表明，本发明中的化合物在10μM时对CYP2C9、CYP2D6、CYP3A4酶没有抑制作用，潜在的药物药物相互作用风险低。Experimental results show that the compound of the present invention has no inhibitory effect on CYP2C9, CYP2D6, and CYP3A4 enzymes at 10 μM, and the potential drug-drug interaction risk is low.
测试例6：药代动力学试验Test Example 6: Pharmacokinetic Test
小鼠药代动力学试验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析For the mouse pharmacokinetic test, use male ICR mice, 20-25g, fasted overnight. Take 3 mice, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. The blood sample was 6800g, centrifuged at 2-8°C for 6 minutes, the plasma was collected and stored at -80°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model
大鼠药代动力学试验，采用雄性SD大鼠，180-240g，禁食过夜。取3只大鼠，口服灌胃给药10mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品于4℃以8000转/分钟离心6分钟，收集血浆，于-20℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Rat pharmacokinetic test, using male SD rats, 180-240g, fasted overnight. Take 3 rats, orally administer 10 mg/kg by gavage. Blood was collected before dosing and at 15, 30 minutes and 1, 2, 4, 8, 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C to collect plasma and stored at -20°C. Take the plasma at each time point, add 3-5 times the amount of acetonitrile solution containing the internal standard and mix, vortex for 1 minute, centrifuge at 13000 rpm at 4°C for 10 minutes, take the supernatant and add 3 times the amount of water to mix, and take an appropriate amount of the mixture LC-MS/MS analysis was performed. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software non-compartmental model.
表3：小鼠药代动力学试验结果Table 3: Pharmacokinetic test results in mice
Figure PCTCN2022136130-appb-000054
Figure PCTCN2022136130-appb-000054
Figure PCTCN2022136130-appb-000055
Figure PCTCN2022136130-appb-000055
表4：大鼠药代动力学试验结果Table 4: Pharmacokinetic test results in rats
Figure PCTCN2022136130-appb-000056
Figure PCTCN2022136130-appb-000056
实验结果表明，本发明化合物在小鼠、大鼠物种中表现出更为优良的药代动力学性质。Experimental results show that the compound of the present invention exhibits better pharmacokinetic properties in mouse and rat species.

Claims (24)

  1. 一种化合物，其为式(II)所示的化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，A compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of the compound represented by formula (II) or prodrugs,
    Figure PCTCN2022136130-appb-100001
    Figure PCTCN2022136130-appb-100001
    其中，R 1独立地选自C 1-C 6烷基、-NR 11R 12、C 3-C 6环烷基、6-10元芳基或5-8元杂芳基，所述C 1-C 6烷基、C 3-C 6环烷基、6-10元芳基和5-8元杂芳基可以任选地被一个或多个R 13取代，所述R 13各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基；当R 13为多个时，所述的R 13相同或不同； Wherein, R 1 is independently selected from C 1 -C 6 alkyl, -NR 11 R 12 , C 3 -C 6 cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted by one or more R 13 , each of which R 13 is independently selected from from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 13s , the R 13s are the same or different;
    R 11和R 12各自独立地选自C 1-C 6烷基、C 3-C 6环烷基或R 11和R 12连同其所连接的N形成3-6元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基以及3-6元杂环基可以任选地被一个或多个R 121取代，所述R 121各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基；当R 121为多个时，所述的R 121相同或不同； R 11 and R 12 are each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or R 11 and R 12 form a 3-6 membered heterocyclic group together with the N to which they are attached, and the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 3-6 membered heterocyclyl can be optionally substituted by one or more R 121 , each of which R 121 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano; when there are multiple R 121 , said R 121 are the same or different;
    R 2独立地选自C 1-C 6烷基或4-8元杂环烷基，所述C 1-C 6烷基和4-8元杂环烷基可以任选地被一个或多个R 21取代，所述R 21各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 21为多个时，所述的R 21相同或不同； R 2 is independently selected from C 1 -C 6 alkyl or 4-8 membered heterocycloalkyl, and the C 1 -C 6 alkyl and 4-8 membered heterocycloalkyl can optionally be replaced by one or more R 21 is substituted, and the R 21 are each independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, and when there are multiple R 21 , the R 21 are the same or different;
    R 3独立地选自C 1-C 6烷基，所述C 1-C 6烷基可以任选地被一个或多个R 31取代，所述R 31各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 31为多个时，所述的R 31相同或不同； R 3 is independently selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl may be optionally substituted by one or more R 31 , each of said R 31 is independently selected from C 1 -C 6 Alkyl, halogen, -NH 2 , hydroxyl or cyano, when there are multiple R 31 , said R 31 are the same or different;
    m为1，2，3或4；m is 1, 2, 3 or 4;
    n为1，2，3，4，5或6；n is 1, 2, 3, 4, 5 or 6;
    所述“5-8元杂芳基”、“3-6元杂环基”和“4-8元杂环烷基”的“杂”为杂原子或杂原子团；所述杂原子或杂原子团的个数为1个或多个，分别独立地为N、-O-、-NH-、-P(O)-、-P(O)O-、-S-、-S(O)-、-S(O) 2-；当所述杂原子或杂原子团的个数为多个时，所述杂原子或杂原子团相同或不同。 The "hetero" of the "5-8 membered heteroaryl", "3-6 membered heterocyclic group" and "4-8 membered heterocycloalkyl" is a heteroatom or a heteroatom group; the heteroatom or heteroatom group The number of is 1 or more, which are independently N, -O-, -NH-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O) 2 -; when there are multiple heteroatoms or heteroatom groups, the heteroatoms or heteroatom groups are the same or different.
  2. 根据权利要求1所述的化合物，其特征在于，其为式(I)所示的化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1, characterized in that it is a compound represented by formula (I) or a stereoisomer, a tautomer, an nitrogen oxide, a solvate, or a compound represented by formula (I). Metabolites, pharmaceutically acceptable salts or prodrugs,
    Figure PCTCN2022136130-appb-100002
    Figure PCTCN2022136130-appb-100002
  3. 根据权利要求1所述的化合物，其特征在于，其为式(I-a)所示的化合物或式(I-a)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1, characterized in that it is a compound shown in formula (I-a) or a stereoisomer, tautomer, nitrogen oxide, solvate, or compound shown in formula (I-a). Metabolites, pharmaceutically acceptable salts or prodrugs,
    Figure PCTCN2022136130-appb-100003
    Figure PCTCN2022136130-appb-100003
  4. 根据权利要求1所述的化合物，其特征在于，其为式(I-b)所示的化合物或式(I-b)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1, characterized in that it is a compound shown in formula (I-b) or a stereoisomer, tautomer, nitrogen oxide, solvate, or compound shown in formula (I-b). Metabolites, pharmaceutically acceptable salts or prodrugs,
    Figure PCTCN2022136130-appb-100004
    Figure PCTCN2022136130-appb-100004
    其中，R 2a和R 2b连同其所连接的N形成4-8元杂环烷基，所述4-8元杂环烷基可以任选地被一个或多个R 21取代，所述R 21各自独立地选自C 1-C 6烷基、卤素、-NH 2、羟基或氰基，当R 21为多个时，所述的R 21相同或不同。 Wherein, R 2a and R 2b form a 4-8 membered heterocycloalkyl group together with the N to which they are attached, and the 4-8 membered heterocycloalkyl group may be optionally substituted by one or more R 21 , and the R 21 Each is independently selected from C 1 -C 6 alkyl, halogen, -NH 2 , hydroxyl or cyano, and when there are multiple R 21 , the R 21 are the same or different.
  5. 根据权利要求1所述的化合物，其特征在于，其特征在于，The compound according to claim 1, characterized in that,
    当R 1被一个或多个R 13取代时，所述R 13取代为1个、2个或3个； When R 1 is substituted by one or more R 13 , said R 13 is substituted by 1, 2 or 3;
    和/或，当R 13为卤素时，所述卤素为F或Cl； And/or, when R 13 is halogen, said halogen is F or Cl;
    和/或，当R 1为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 1 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl;
    和/或，当R 1为C 3-C 6环烷基时，所述C 3-C 6环烷基为环丙基； And/or, when R 1 is C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl;
    和/或，当R 1为-NR 11R 12时，所述-NR 11R 12为-NHCH 3、-N(CH 3) 2、-N(CH 3)(CH 2CH 3)或-N(CH 2CH 3) 2； And/or, when R 1 is -NR 11 R 12 , said -NR 11 R 12 is -NHCH 3 , -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) or -N ( CH2CH3 ) 2 ;
    和/或，当R 1为6-10元芳基时，所述6-10元芳基为苯基； And/or, when R 1 is a 6-10 membered aryl group, the 6-10 membered aryl group is a phenyl group;
    和/或，当R 1为5-8元杂芳基时，所述5-8元杂芳基为吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、噻二唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基或三嗪基。 And/or, when R is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl , pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.
  6. 根据权利要求1所述的化合物，其特征在于，The compound according to claim 1, characterized in that,
    当R 2被一个或多个R 21取代时，所述R 21取代为1个、2个或3个； When R 2 is substituted by one or more R 21 , said R 21 is substituted by 1, 2 or 3;
    和/或，当R 21为卤素时，所述卤素为F或Cl； And/or, when R 21 is halogen, said halogen is F or Cl;
    和/或，R 21为羟基； And/or, R 21 is hydroxyl;
    和/或，R 21为F、Cl或羟基； And/or, R 21 is F, Cl or hydroxyl;
    和/或，当R 2为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 2 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl;
    和/或，当R 2为4-8元杂环烷基时，所述4-8元环烷基为氮杂环丁基、氮杂环戊基、氧杂环丁基、吡咯烷基、四氢呋喃基、吡唑烷基、咪唑烷基、噁唑烷基、吗啉基、吡咯烷基、吗啉基或哌嗪基。 And/or, when R 2 is a 4-8 membered heterocycloalkyl group, the 4-8 membered cycloalkyl group is azetidinyl, azacyclopentyl, oxetanyl, pyrrolidinyl, Tetrahydrofuryl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  7. 根据权利要求1所述的化合物，其特征在于，当R 3被一个或多个R 31取代时，所述R 31取代为1个、2个或3个； The compound according to claim 1, wherein when R 3 is substituted by one or more R 31 , the R 31 is substituted by 1, 2 or 3;
    和/或，当R 31为卤素时，所述卤素为F、Cl、Br或I； And/or, when R 31 is halogen, said halogen is F, Cl, Br or I;
    和/或，当R 3为C 1-C 6烷基时，所述C 1-C 6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, when R 3 is C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec Butyl or tert-butyl;
    和/或，R 3为-CF 3。 And/or, R 3 is -CF 3 .
  8. 根据权利要求1所述的化合物，其特征在于，The compound according to claim 1, characterized in that,
    R 1选自-CH 3、-CHF 2、
    Figure PCTCN2022136130-appb-100005
    R 1 is selected from -CH 3 , -CHF 2 ,
    Figure PCTCN2022136130-appb-100005
  9. 根据权利要求1所述的化合物，其特征在于，The compound according to claim 1, characterized in that,
    R 2选自
    Figure PCTCN2022136130-appb-100006
     R2 is selected from
    Figure PCTCN2022136130-appb-100006
  10. 根据权利要求1所述的化合物，其特征在于，其为选自下列任一化合物或下列任一化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，
    Figure PCTCN2022136130-appb-100007
    The compound according to claim 1, characterized in that it is selected from any of the following compounds or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
    Figure PCTCN2022136130-appb-100007
    Figure PCTCN2022136130-appb-100008
    Figure PCTCN2022136130-appb-100008
  11. 一种中间体，其特征在于，其为选自下列任一化合物或下列任一化合物的立体异构体、互变异构体或药学上可接受的盐，An intermediate, characterized in that it is selected from any of the following compounds or stereoisomers, tautomers or pharmaceutically acceptable salts of any of the following compounds,
    Figure PCTCN2022136130-appb-100009
    Figure PCTCN2022136130-appb-100009
  12. 一种药物组合物，其特征在于，其包含如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药和任选的药学上可接受的药用载体、稀释剂或赋形剂。A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and optionally a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.
  13. 如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物在制备用于治疗或预防与IRAK4相关疾病的药物中的用途。The compound as described in any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or as described in claim 12 Use of the pharmaceutical composition in the preparation of medicines for treating or preventing diseases related to IRAK4.
  14. 如权利要求13所述的用途，其特征在于，所述IRAK4相关疾病为自身免疫性疾病或癌症。The use according to claim 13, wherein the IRAK4-related disease is an autoimmune disease or cancer.
  15. 如权利要求14所述的用途，其特征在于，所述自身免疫性疾病为多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹。The use according to claim 14, wherein the autoimmune disease is multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis , reactive arthritis, systemic juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, and atopic eczema.
  16. 如权利要求14所述的用途，其特征在于，所述癌症为脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢 性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。The use according to claim 14, wherein the cancer is brain cancer, kidney cancer, liver cancer, gastric cancer, vaginal cancer, ovarian cancer, gastric tumor, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer , cervical cancer, testicular cancer, skin cancer, bone cancer, or thyroid cancer; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma , keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma, melanoma; Acute myelogenous leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, intravascular Hematologic malignancies of B-cell lymphoma, plasmacytoma, and multiple myeloma.
  17. 如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物，用于治疗或预防与IRAK4相关疾病。The compound as described in any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or as described in claim 12 The pharmaceutical composition is used for treating or preventing diseases related to IRAK4.
  18. 如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物，用于治疗或预防自身免疫性疾病或癌症。The compound as described in any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or as described in claim 12 A pharmaceutical composition for treating or preventing an autoimmune disease or cancer.
  19. 如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物，用于治疗或预防多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹。The compound as described in any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or as described in claim 12 Pharmaceutical composition for treating or preventing multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, reactive arthritis, systemic juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, and atopic eczema.
  20. 如权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物，用于治疗或预防脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。The compound as described in any one of claims 1-10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or as described in claim 12 Pharmaceutical composition for treating or preventing brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, stomach tumor, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer, cervical cancer, testicular cancer, skin cancer Carcinoma, bone or thyroid cancer; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma, keratoacanthoma, epidermoid Carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma, melanoma; acute myelogenous leukemia, chronic myeloid Leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/ Leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma Hematologic malignancies and multiple myeloma.
  21. 一种治疗或预防与IRAK4相关疾病的方法，其特征在于，给与患者有效量的权利要求1-10中任一项所述的化合物或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或如权利要求12所述的药物组合物。A method for treating or preventing diseases related to IRAK4, characterized in that the compound or its tautomers, stereoisomers, and hydrates thereof according to any one of claims 1-10 are given to patients in an effective dose , solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition as claimed in claim 12.
  22. 根据权利要求21所述的方法，其特征在于，所述IRAK4相关疾病为自身免疫性疾病或癌症。The method according to claim 21, wherein the IRAK4-related disease is an autoimmune disease or cancer.
  23. 根据权利要求22所述的方法，其特征在于，所述自身免疫性疾病为多发性硬化、***性红斑狼疮、银屑病、银屑病性关节炎、强直性脊柱炎、类风湿性关节炎、反应性关节炎、全身型幼年特发性关节炎、克罗恩氏病、溃疡性结肠炎、特应性皮炎和过敏性湿疹。The method according to claim 22, wherein the autoimmune disease is multiple sclerosis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis , reactive arthritis, systemic juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, and atopic eczema.
  24. 如权利要求22所述的方法，其特征在于，所述癌症为脑癌、肾癌、肝癌、胃癌、***癌、卵巢癌、胃肿瘤、乳腺癌、膀胱结肠癌、***癌、胰腺癌、肺癌、***、睾丸癌、皮肤癌、骨癌或甲状腺癌；肉瘤、成胶质细胞瘤、成神经细胞瘤、多发性骨髓瘤、胃肠癌、颈部和头部肿瘤、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、霍奇金和非霍奇金淋巴瘤、***癌、滤泡癌、***状癌、***瘤、黑素瘤；急性骨髓性白血病、慢性骨髓性白血病、弥漫性大B细胞淋巴瘤、活化B细胞样弥漫性大B细胞淋巴瘤、慢性淋巴细胞性白血病、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症、脾边缘区淋巴瘤、血管内大B细胞淋巴瘤、浆细胞瘤和多发性骨髓瘤的血液恶性肿瘤。The method according to claim 22, wherein the cancer is brain cancer, kidney cancer, liver cancer, gastric cancer, vaginal cancer, ovarian cancer, gastric tumor, breast cancer, bladder and colon cancer, prostate cancer, pancreatic cancer, lung cancer , cervical cancer, testicular cancer, skin cancer, bone cancer, or thyroid cancer; sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck and head tumors, adenoma, adenocarcinoma , keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, Hodgkin and non-Hodgkin lymphoma, breast cancer, follicular carcinoma, papillary carcinoma, seminoma, melanoma; Acute myelogenous leukemia, chronic myelogenous leukemia, diffuse large B-cell lymphoma, activated B-cell-like diffuse large B-cell lymphoma, chronic lymphocytic leukemia, chronic lymphocytic lymphoma, primary exudative lymphoma Burkitt lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, intravascular Hematologic malignancies of B-cell lymphoma, plasmacytoma, and multiple myeloma.
PCT/CN2022/136130 2021-12-03 2022-12-02 Irak4 inhibitor and use thereof WO2023098857A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111467839 2021-12-03
CN202111467839.2 2021-12-03

Publications (1)

Publication Number Publication Date
WO2023098857A1 true WO2023098857A1 (en) 2023-06-08

Family

ID=86611562

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/136130 WO2023098857A1 (en) 2021-12-03 2022-12-02 Irak4 inhibitor and use thereof

Country Status (1)

Country Link
WO (1) WO2023098857A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016083433A1 (en) * 2014-11-26 2016-06-02 Bayer Pharma Aktiengesellschaft New substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs
WO2020035020A1 (en) * 2018-08-17 2020-02-20 浙江海正药业股份有限公司 Imidazopyridine derivative, preparation method therefor, and application thereof in medicine
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
WO2020259626A1 (en) * 2019-06-26 2020-12-30 南京明德新药研发有限公司 Imidazopyridine compound as irak4 inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016083433A1 (en) * 2014-11-26 2016-06-02 Bayer Pharma Aktiengesellschaft New substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs
WO2020035020A1 (en) * 2018-08-17 2020-02-20 浙江海正药业股份有限公司 Imidazopyridine derivative, preparation method therefor, and application thereof in medicine
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
WO2020259626A1 (en) * 2019-06-26 2020-12-30 南京明德新药研发有限公司 Imidazopyridine compound as irak4 inhibitor

Similar Documents

Publication Publication Date Title
USRE47739E1 (en) 2-(pyridin-2-ylamino)-pyrido[2,3-D]pyrimidin-7-ones
US7781583B2 (en) Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d] pryimidin-7-ones
CN110114357B (en) Hetero-bicyclic compounds useful as modulators of IL-12, IL-23, and/or IFN alpha response
CN111171049B (en) Tyrosine kinase inhibitors and uses thereof
AU2019375825B2 (en) Macrocyclic tyrosine kinase inhibitor and uses thereof
KR20230004612A (en) Substituted pyridines for the treatment of inflammatory diseases
WO2022135432A1 (en) Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof
JP7420403B2 (en) Compounds used as kinase inhibitors and their applications
WO2018214866A1 (en) Azaaryl derivative, preparation method therefor, and application thereof for use in pharmacy
WO2022213980A1 (en) Tyk2 inhibitor and use thereof
CN115260187A (en) Pyridone compounds and uses thereof
JP2022517723A (en) Macrocycle compound as a CDK inhibitor, its production method and its application in pharmaceutical products
WO2021237121A1 (en) Substituted pyridines
WO2023098857A1 (en) Irak4 inhibitor and use thereof
WO2022156788A1 (en) Benzimidazole compound and use thereof
WO2022253311A1 (en) Hpk1 inhibitor and use thereof
CN117624185A (en) LRRK2 inhibitor compound, pharmaceutical composition, preparation method and application thereof
TW202312995A (en) Azaaryl compound, and preparation method therefor and use thereof
EP4337648A1 (en) Substituted heterocyclic compounds
WO2024083024A1 (en) Preparation and use of ret inhibitor
EP4337656A1 (en) Substituted heterocyclic compounds
WO2022206730A1 (en) Pyrimidopyrazine compound and use thereof
TW202227447A (en) Pyrimidinone compounds and uses thereof
CN116535424A (en) Tri-fused ring compounds as MALT1 inhibitors, pharmaceutical compositions and uses thereof

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: 22900661

Country of ref document: EP

Kind code of ref document: A1