CN118302425A

CN118302425A - IRAK4 inhibitors and uses thereof

Info

Publication number: CN118302425A
Application number: CN202280077366.1A
Authority: CN
Inventors: 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: Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2021-12-03
Filing date: 2022-12-02
Publication date: 2024-07-05
Also published as: WO2023098857A1

Abstract

Discloses IRAK4 inhibitor and application thereof, in particular discloses an imidazopyridine compound shown in a formula (II), a preparation method thereof and application thereof in preparing medicaments for treating IRAK4 related diseases.

Description

IRAK4 inhibitors and uses thereof

Technical Field

The invention belongs to the field of medicinal chemistry, in particular relates to an IRAK4 inhibitor, and more particularly relates to an imidazopyridine compound capable of inhibiting IRAK4 kinase, a preparation method thereof and application thereof in preparation of medicines.

Background

IRAK4, interleukin-1 receptor associated kinase 4, belongs to the IRAK family. Family members also include IRAK1, IRAK2, IRAKM (I-RAK 3), and the like. The human IRAK-4 gene is located in the p11.12 region of the x chromosome and codes for 52kDa protein. IRAK4 protein, like other family members, contains serine-threonine Kinase Domain (KD) and N-terminal conserved Death Domain (DD), and is a key molecule in Toll-like receptor (Toll like receptor, TLRs) and interleukin 1 receptor (inteleukin-1, IL-1 Rs) signaling pathway, and is involved in regulating 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 initiates immune responses upon stimulation by a variety of IL-1 cytokines.

After IL-1R, IL-18R and most TLRs are stimulated, myeloid differentiation factor 88 (MyD 88) binds to these receptors as a linker protein, followed by recruitment of IRAK4 protein to the TLRs/IL-1R complex. IRAK4 may bind to MyD88 and IRAK2 via a common death domain to form a protein complex Myddosome, activating the kinase activity of IRAK4, resulting in phosphorylation of downstream IRAK1 and/or IRAK 2. IRAK1 phosphorylation causes a conformational change itself, which promotes binding to tumor necrosis factor receptor-associated factor 6 (TRAF 6), thereby activating serine-threonine kinase TAK1, downstream NF- κB, and initiating transcription and expression of pro-inflammatory factors such as IL-1, IL-8, and IL-33, leading to an inflammatory response. In addition, JNK signaling pathway is also activated by TRAF6, regulating transcription of genes related to inflammation, apoptosis and cell proliferation. In a mouse model with IRAK4 knockdown, signaling and cellular responses of IL-1, IL-18 and most of the TLR ligands are severely impaired, verifying the important role of IRAK4 in IL-1R, IL-18R and most of the TLR signaling pathways (Suzuki N, et al Nature 2002,416,750-756.).

Due to the critical role of IRAK4 in cytokine signaling networks, abnormally high expression or silencing of IRAK4 can induce an abnormality in the immune system of the body. Wherein, the abnormal high expression of IRAK4 can cause the excessive activation of TRL/IL-1R channel, so that high-level pro-inflammatory factors are secreted in the body for a long time, and persistent inflammatory reaction is caused, and finally autoimmune diseases including rheumatoid arthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis and the like are induced. IL-1 was found to be significantly higher in joint synovial fluid in rheumatoid arthritis patients than in healthy subjects (Nouri AM, et al Clin Exp Immunol 1984;55 (2): 295-302.), while further studies demonstrated that antagonism of TLR4 reduced IL-1 secretion and had a prophylactic effect on joint inflammation in the mouse model (Abdollahi-Roodsaz S, et al 2007;56 (9): 2957-67.) activation of TLR7 and TLR9 stimulated IFNα production in pDC cells, which was also considered 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 associated with enhanced TLR signaling, further suggesting a potential for inhibiting IRAK4 against autoimmune disease.

IRAK4 has also been reported to play a key role in the development and progression of a variety of malignancies, including melanoma, waldenstrom Macroglobulinemia (WM), chronic Lymphocytic Leukemia (CLL), acute lymphoblastic leukemia (T-ALL), ABC-type diffuse large B-cell lymphoma (ABC-DLCBL), and the like. Up-regulation of myddosome complex by the function-enhancing mutation of MyD88-L256P results in activation of NF- κb leading to survival and proliferation of a range of tumor cell lines. Immunohistochemical results of melanoma biopsies showed that phosphorylated IRAK4 was highly expressed in diseased tissue (SRIVASTAVA R, et al cancer Res 2012;72 (23): 6209-16.). An increase in the mRNA expression levels of IRAK1 and IRAK4, and an increase in the phosphorylation levels of IRAK1 and IRAK4, were also observed in T-ALL cells (Li Z, et al J CLIN INVEST; 125 (3): 1081-97.). Silencing IRAK4 or small molecules with shRNA inhibiting their enzymatic activity impairs cell proliferation in samples from T-ALL patients, suggesting that signal transduction via IRAK4 is a critical factor in disease progression. It has also been reported that IRAK4 inhibitors, when used in combination with Ibrutinib (a BTK inhibitor), synergistically inhibit proliferation of the ABC-DLBCL cell line mutated in MyD 88-L256P. (Kelly PN, et al J ex pMed 2015;212 (13): 2189-201.). The research results prove the potential value of the IRAK4 target in the tumor treatment field.

In addition, activating mutations in Fms-like tyrosine kinase (FLT 3) lead to its own phosphorylation and initiation of intracellular signaling pathways, thereby promoting survival and proliferation of leukemic cells, one of the factors that AML produces adaptive resistance to FLT3 inhibitors. There are researchers that the mechanism by which FLT3 inhibitors cause FLT3-ITD mutation resistance is associated with IRAK1/4 compensatory activation. The activation of the TLR pathway by IRAK1/4 signaling results in autoimmune stress activation, and assays to knock down IRAK4 or inhibit IRAK4 activity confirm the necessity of IRAK1/4 in the development of adaptive resistance by FLT3-ITD mutants (Melgar K, et al Sci TRANSL MED 2019;508 (11)), suggesting the potential for simultaneous inhibition of FLT3 signaling and IRAK1/4 compensatory activation for the treatment of FLT3 mutant AML patients.

Disclosure of Invention

The invention aims at providing a novel IRAK4 inhibitor which can be used for preparing medicines for treating tumor-related diseases.

In a first aspect, the present invention provides a compound which is a compound of formula (II) or a stereoisomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (II),

Wherein R ¹ is independently selected from C ₁-C ₆ alkyl, -NR ¹¹R ¹²、C ₃-C ₆ cycloalkyl, 6-10 membered aryl, or 5-8 membered heteroaryl, which C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 6-10 membered aryl, and 5-8 membered heteroaryl may be optionally substituted with one or more R ¹³, each R ¹³ is independently selected from C ₁-C ₆ alkyl, halogen, -NH ₂, hydroxy, or cyano; when R ¹³ is plural, R ¹³ 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 to which they are attached form a 3-to 6-membered heterocyclyl, which C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl and 3-to 6-membered heterocyclyl may be optionally substituted with one or more R ¹²¹, which R ¹²¹ is each independently selected from C ₁-C ₆ alkyl, halogen, -NH ₂, hydroxy or cyano; when R ¹²¹ is plural, R ¹²¹ are the same or different;

R ² is independently selected from C ₁-C ₆ alkyl or 4-8 membered heterocycloalkyl, which C ₁-C ₆ alkyl and 4-8 membered heterocycloalkyl may be optionally substituted with one or more R ²¹, each R ²¹ is independently selected from C ₁-C ₆ alkyl, halogen, -NH ₂, hydroxy or cyano, when R ²¹ is plural, said R ²¹ are the same or different;

R ³ is independently selected from C ₁-C ₆ alkyl, which C ₁-C ₆ alkyl may be optionally substituted with one or more R ³¹, each of said R ³¹ is independently selected from C ₁-C ₆ alkyl, halogen, -NH ₂, hydroxy or cyano, when R ³¹ is plural, said R ³¹ are the same or different;

m is 1,2,3 or 4;

n is 1,2,3,4,5 or 6;

The "hetero" of the "5-8 membered heteroaryl", "3-6 membered heterocyclyl" and "4-8 membered heterocycloalkyl" are heteroatoms or heteroatomic groups; the number of the hetero atoms or the hetero atom groups is 1 or more, and the hetero atoms or the hetero atom groups are respectively and independently N, -O-, -NH-, -P (O) O-, -S (O) ₂ -; when the number of the hetero atoms or hetero atom groups is plural, the hetero atoms or hetero atom groups may be the same or different.

In a second aspect of the invention, the invention provides a compound of formula I,

Wherein,

R ¹ is independently selected from C ₁-C ₆ alkyl, -NR ¹¹R ¹²、C ₃-C ₆ cycloalkyl, 6-10 membered aryl, or 5-8 membered heteroaryl, which C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 6-10 membered aryl, and 5-8 membered heteroaryl may be optionally substituted with one or more R ¹³, each R ¹³ is independently selected from C ₁-C ₆ alkyl, halogen, hydroxy, or cyano; when there are a plurality of substituents, the substituents may be 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, which C ₁-C ₆ alkyl and C ₃-C ₆ cycloalkyl may be optionally substituted with one or more R ¹²¹, and each R ¹²¹ is independently selected from C ₁-C ₆ alkyl, halogen, hydroxy or cyano; when there are a plurality of substituents, the substituents may be the same or different;

R ² is independently selected from C ₁-C ₆ alkyl or 4-8 membered heterocycloalkyl; the C ₁-C ₆ alkyl and 4-8 membered heterocycloalkyl may be optionally substituted with one or more R ²¹, each R ²¹ is independently selected from C ₁-C ₆ alkyl, halogen, hydroxy or cyano; when there are plural substituents, the substituents may be the same or different.

In an optional embodiment of the invention, R ¹ is independently selected from C ₂-C ₆ alkyl, -NR ¹¹R ¹²、C ₃-C ₆ cycloalkyl, 6-10 membered aryl, or 5-8 membered heteroaryl, which C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 6-10 membered aryl, and 5-8 membered heteroaryl may be optionally substituted with one or more R ¹³, each R ¹³ is independently selected from C ₁-C ₆ alkyl, halogen, hydroxy, or cyano; when there are plural substituents, the substituents may be the same or different.

In an optional embodiment of the invention, R ¹ is independently selected from-NR ¹¹R ¹²、C ₃-C ₆ cycloalkyl, 6-10 membered aryl or 5-8 membered heteroaryl, which C ₁-C ₆ alkyl, C ₃-C ₆ cycloalkyl, 6-10 membered aryl and 5-8 membered heteroaryl may be optionally substituted with one or more R ¹³, each R ¹³ is independently selected from C ₁-C ₆ alkyl, halogen, hydroxy or cyano; when there are plural substituents, the substituents may be the same or different.

In an alternative embodiment of the invention, the compound of formula I is:

Wherein R ¹ has the definition as described above.

In an alternative embodiment of the invention, the compound of formula I is:

Wherein R ¹ has the definition set forth herein, R ^2a and R ^2b together with the N to which they are attached form a 4-8 membered heterocycloalkyl, which 4-8 membered heterocycloalkyl may be optionally substituted with one or more R ²¹, each of said R ²¹ is independently selected from C ₁-C ₆ alkyl, halogen, -NH ₂, hydroxy or cyano, and when R ²¹ is plural, said R ²¹ is the same or different. In an alternative embodiment of the invention, the number of heteroatoms or groups of heteroatoms is 1,2 or 3.

In an alternative embodiment of the invention, when R ¹ is substituted with one or more R ¹³, the R ¹³ is substituted with 1,2, or 3.

In an alternative embodiment of the invention, when R ¹ is substituted with one or more R ¹³, the R ¹³ substitution is 1 or 2.

In an optional embodiment of the invention, when R ¹³ is halogen, the halogen is F or Cl.

In an optional embodiment of the invention, when R ¹³ is halogen, the halogen is F.

In an optional embodiment of the invention, when R ¹ is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In an alternative embodiment of the invention, when R ¹ is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is methyl.

In an alternative embodiment of the invention, when R ¹ is C ₃-C ₆ cycloalkyl, the C ₃-C ₆ cycloalkyl is cyclopropyl.

In an alternative embodiment of the invention, when R ¹ is-NR ¹¹R ¹², the-NR ¹¹R ¹² is-NHCH ₃、-N(CH ₃) ₂、-N(CH ₃)(CH ₂CH ₃) or-N (CH ₂CH ₃) ₂.

In an alternative embodiment of the invention, when R ¹ is-NR ¹¹R ¹², the-NR ¹¹R ¹² is-N (CH ₃) ₂.

In an optional embodiment of the invention, when R ¹ is a 6-10 membered aryl, the 6-10 membered aryl is phenyl.

In an optional embodiment of the invention, when R ¹ is a 5-8 membered heteroaryl, the 5-8 membered heteroaryl is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.

In an optional embodiment of the invention, when R ¹ is a 5-8 membered heteroaryl, the 5-8 membered heteroaryl is pyridinyl.

In an alternative embodiment of the invention, when R ² is substituted with one or more R ²¹, the R ²¹ is substituted with 1,2, or 3.

In an alternative embodiment of the invention, when R ² is substituted with one or more R ²¹, the R ²¹ substitution is 1 or 2.

In an optional embodiment of the invention, when R ²¹ is halogen, the halogen is F or Cl.

In an optional embodiment of the invention, when R ²¹ is halogen, the halogen is F.

In an optional embodiment of the invention, R ²¹ is hydroxy.

In an optional embodiment of the invention, R ²¹ is F, cl or hydroxy.

In an optional embodiment of the invention, when R ² is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In an alternative embodiment of the invention, when R ² is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is isopropyl.

In an alternative embodiment of the invention, when R ² is 4-8 membered heterocycloalkyl, the 4-8 membered cycloalkyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl, or piperazinyl.

In an alternative embodiment of the invention, when R ² is 4-8 membered heterocycloalkyl, the 4-8 membered cycloalkyl is azetidinyl or morpholinyl.

In an alternative embodiment of the invention, when R ³ is substituted with one or more R ³¹, the R ³¹ is substituted with 1,2, or 3.

In an alternative embodiment of the invention, when R ³ is substituted with one or more R ³¹, the R ³¹ is substituted with 3.

In an alternative embodiment of the invention, when R ³¹ is halogen, the halogen is F, cl, br or I.

In an optional embodiment of the invention, when R ³¹ is halogen, the halogen is F.

In an optional embodiment of the invention, when R ³ is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In an alternative embodiment of the invention, when R ³ is C ₁-C ₆ alkyl, the C ₁-C ₆ alkyl is methyl.

In an alternative embodiment of the invention, R ¹ is selected from the group consisting of-CH ₃、-CHF ₂,

In an optional embodiment of the invention, R ² is selected from

In an alternative embodiment of the invention, R ³ is-CF ₃.

In an alternative embodiment of the present invention, the compound of formula I is selected from any one of the following compounds:

In a third aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound as described above, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

According to a specific embodiment of the present invention, the pharmaceutical composition of the present invention may comprise a therapeutically effective dose of the above-mentioned compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, diluents or excipients, in admixture for the manufacture of pharmaceutical preparations 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 may be administered by any route, for example by infusion or bolus injection, by absorption through the epithelial or skin mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of formulations for oral administration include solid or liquid dosage forms, specifically including tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.

In a fourth aspect, the present invention provides the use of a compound as defined above, a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as defined above, in the manufacture of a medicament for the treatment or prophylaxis of a disease associated with IRAK 4.

According to a specific embodiment of the present invention, the use of the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof or the above-mentioned pharmaceutical compositions for the preparation of a medicament for the treatment and prevention of IRAK4 related diseases, said medicament being useful 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 allergic eczema; such cancers include, for example, brain, kidney, liver, stomach, vagina, ovary, stomach, breast, bladder colon, prostate, pancreas, lung, cervical, testis, skin, bone, or thyroid; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, neck and head tumors, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, hodgkin and non-hodgkin lymphomas, breast carcinoma, follicular carcinoma, papillary carcinoma, seminomas, 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's lymphoma/leukemia, acute lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and hematological malignancies of multiple myeloma.

In a fifth aspect of the invention, the invention provides a compound as described above, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described above, for use in the treatment or prevention of a disease associated with IRAK 4.

According to a specific embodiment of the present invention, the above-mentioned compound or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof or the above-mentioned pharmaceutical composition is used for the treatment or prevention of autoimmune diseases or cancers. 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 allergic eczema; such cancers include, for example, brain, kidney, liver, stomach, vagina, ovary, stomach, breast, bladder colon, prostate, pancreas, lung, cervical, testis, skin, bone, or thyroid; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, neck and head tumors, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, hodgkin and non-hodgkin lymphomas, breast carcinoma, follicular carcinoma, papillary carcinoma, seminomas, 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's lymphoma/leukemia, acute lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and hematological malignancies of multiple myeloma.

In a sixth aspect of the invention, the invention provides a method of treating or preventing a disease associated with IRAK 4. According to an embodiment of the invention, the method comprises administering to the patient an effective amount of a compound as described above or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition as described above.

According to a specific embodiment of the invention, the IRAK4 related disease comprises an autoimmune 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 allergic eczema; such cancers include, for example, brain, kidney, liver, stomach, vagina, ovary, stomach, breast, bladder colon, prostate, pancreas, lung, cervical, testis, skin, bone, or thyroid; sarcomas, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancers, neck and head tumors, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, hodgkin and non-hodgkin lymphomas, breast carcinoma, follicular carcinoma, papillary carcinoma, seminomas, 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's lymphoma/leukemia, acute lymphocytic leukemia, B-cell pre-lymphocytic leukemia, lymphoplasmacytic lymphoma, waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and hematological malignancies of multiple myeloma.

Finally, the present invention provides intermediates which are stereoisomers, tautomers or pharmaceutically acceptable salts selected from any one of the following compounds or any one of the following compounds. The intermediates according to embodiments of the present invention are useful in the synthesis of the compounds of the present invention:

Terminology and definitions

Unless otherwise indicated, terms and definitions used in the present application, including the description of the present application and the claims, are as follows.

As will be appreciated by those skilled in the art, in accordance with the conventions used in the art, in the structural formulae of the present application,For depicting chemical bonds, which are points where a moiety or substituent is attached to a core structure or a backbone structure.

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

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.

In addition to pharmaceutically acceptable salts, other salts are contemplated by the present invention. They may serve as intermediates in the purification of the compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the invention.

The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression.

The term "prodrug" refers to a compound of the invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo to give the parent compound. Prodrugs include compounds wherein a hydroxyl group or amino group of a compound of the invention is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl group, free amino group, respectively.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.

Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes D and L or (+) and (-) are symbols for designating the rotation of plane polarized light by a compound, where (-) or L represents that the compound is left-handed. The compound prefixed with (+) or D is 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 generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. Many geometric isomers of olefins, c=n double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When the compounds described herein contain olefinic double bonds, such double bonds include E and Z geometric isomers unless specified otherwise. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in cis or trans (cis-or trans-) configuration.

When the bonds to chiral carbons in the formulae of the present invention are depicted in straight lines, it is understood that both the (R) and (S) configurations of the chiral carbons and the enantiomerically pure compounds and mixtures thereof resulting therefrom are included within the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key.

Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. The compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of the racemic mixture of the compounds may be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active salified organic acid. Suitable resolving agents for use in the fractional recrystallisation process are, for example, D and L forms of optically active acids such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulphonic acids such as β -camphorsulphonic acid. Other resolving agents suitable for the fractional crystallization process include stereoisomerically pure forms of α -methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methyl ephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of the racemic mixture may also be carried out by eluting on a chromatographic column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High Performance Liquid Chromatography (HPLC) or Supercritical Fluid Chromatography (SFC) may be used. The choice of the particular method and elution conditions, choice of chromatographic column can be selected by one skilled in the art based on the structure of the compound and the results of the assay. Further, any enantiomer or diastereomer of a compound described herein may also be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (² H), tritium (³ H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

The term "C ₁-C ₆ alkyl" is understood to mean a straight 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-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. In particular, the groups have 1,2 or 3 carbon atoms ("C ₁-C ₃ alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

The term "C ₃-C ₆ cycloalkyl" is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "4-8 membered heterocyclyl" or "4-8 membered heterocycloalkyl" is understood to mean a saturated, unsaturated or partially saturated mono-, bi-or tricyclic ring having 4 to 8 atoms, wherein 1,2, 3, 4 or 5 ring atoms are selected from N, O and S, which may be linked through carbon or nitrogen unless otherwise indicated, and wherein the-CH _2- group is optionally replaced by-C (O) -; and wherein, unless otherwise specified to the contrary, the ring nitrogen atom or the ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized; wherein the-NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens. It will be appreciated that when the total number of S and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to one another. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be heteroaromatic or aromatic, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is a single ring, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1, 1-dioxide, 1H-pyridin-2-one, and 2, 5-dioxoimidazolidinyl.

The term "6-10 membered aryl" is understood to mean an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms ("C ₆ aryl"), for example phenyl; when the 6-10 membered aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.

The term "5-8 membered heteroaryl" is understood to mean a monocyclic, bicyclic or tricyclic aromatic ring radical having 5 to 8 ring atoms, in particular 5 or 6 carbon atoms, and comprising 1 to 5 heteroatoms independently selected from N, O and S. Preferably 1 to 3, and independently selected from the group consisting of N, O and S heteroatoms, and may additionally be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.

The term "halo" or "halogen" is fluoro, chloro, bromo and iodo.

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 the event or circumstance occurs and instances where it does not.

In addition, unless explicitly indicated otherwise, the description "… …" as used in the present invention is to be understood in a broad sense as meaning that the individual entities described are independent of each other and may independently be the same or different specific groups. In more detail, the expression "… …" independently "may mean that the specific options expressed between the same coincidence in different groups do not affect each other, or that the specific options expressed between the same symbols in the same groups do not affect each other.

Advantageous effects

According to an embodiment of the present invention, the present invention has at least one of the following technical effects:

(1) The IRAK4 inhibitor provided by the invention has the advantages of novel structure, excellent pharmacokinetic property and good drug effect or patentability, and can be used for effectively treating or preventing IRAK4 related diseases and symptoms.

(2) The compound of the patent shows better IRAK4 kinase inhibition activity, and the inhibition activity of the compound I-1 is obviously better; on the other hand, compared with the control compound 1, the compound of the patent shows stronger inhibition capability on TNF-alpha production at the cellular level, and particularly, the inhibition activity of the compound I-1 is obviously superior to that of the control compound 1.

(3) The compound has higher ratio of free drugs in human and mouse plasma, good patentability, no inhibition effect on CYP2C9, CYP2D6 and CYP3A4 enzymes at 10 mu M, low risk of potential drug-drug interaction, and excellent liver metabolism stability.

(4) The compounds of the invention exhibit more excellent pharmacokinetic properties in mouse and rat species.

Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

Unless otherwise indicated, the compounds of the present invention are structurally defined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift was 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS).

Abbreviations for the present invention are defined as follows:

M: molar concentration, e.g. 1M hydrochloric acid means 1mol/L hydrochloric acid solution

N: equivalent concentration, e.g. 2N hydrochloric acid means 2mol/L hydrochloric acid solution

T3P DMF: 1-propylphosphoric anhydride 50% N, N-dimethylformamide solution

Xantphos:4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene

PMB: p-methoxybenzyl group

DMSO: dimethyl sulfoxide

LC-MS: liquid chromatography-mass spectrometry

IC ₅₀: half inhibition concentration refers to the concentration at which half of the maximum inhibition effect is achieved.

Control 1: preparation of control Compound 1

Reference is made to WO2016083433A 1.

Example 1: preparation of target Compound I-1

N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (2- (methylsulfonyl) ethyl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) picolinamide

The synthetic route of the target compound I-1 is shown as follows:

the first step: synthesis of 3-fluoro-N, N-bis (4-methoxybenzyl) -5-nitropyridin-2-amine (I-1 b)

2-Chloro-3-fluoro-5-nitro-pyridine (I-1 a) (29 g,164 mmol) was dissolved in N, N-dimethylformamide (400 mL), N-diisopropylethylamine (42.5 g,329 mmol) and 1- (4-methoxyphenyl) -N- [ (4-methoxyphenyl) methyl ] methylamine (46.5 g,180 mmol) were added, the reaction mixture was stirred at 25℃for 16 hours, water (500 mL) was added to dilute the mixture after completion of the reaction, followed by extraction with ethyl acetate (300 mL. Times.3), the organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate, and then filtered, and the cake was washed with ethyl acetate, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 5:1) to give 3-fluoro-N, N-bis (4-methoxybenzyl) -5-nitropyridin-2-amine (I-1 b) as a yellow solid (59.0 g, yield 90.4%).

LC-MS,M/Z(ESI):398.2[M+H] ⁺

And a second step of: synthesis of 3-fluoro-N ²,N ² -bis (4-methoxybenzyl) pyridine-2, 5-diamine (I-1 c)

3-Fluoro-N, N-bis (4-methoxybenzyl) -5-nitropyridin-2-amine (I-1 b) (59.0 g,149 mmol) was added to methanol (600 mL), then platinum vanadium carbon (6.00 g) was added thereto under nitrogen protection, then the reaction solution was stirred under hydrogen (15 psi) atmosphere at 25℃for three hours, after completion of the reaction, filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated to give a red solid compound, 3-fluoro-N ²,N ² -bis (4-methoxybenzyl) pyridine-2, 5-diamine (I-1 c) (53.0 g, yield 97.16%).

LC-MS,M/Z(ESI):368.1[M+H] ⁺

And a third step of: synthesis of tert-butyl (6- (di (4-methoxybenzyl) amino) -5-fluoropyridin-3-yl) carbamate (I-1 d)

3-Fluoro-N, N-bis [ (4-methoxyphenyl) methyl ] pyridine-2, 5-diamine (I-1 c) (49.0 g,133 mmol), triethylamine (14.8 g,147 mmol) and di-tert-butyl carbonate (32.0 g,147 mmol) were added to N, N-dimethylformamide (250 mL), the reaction solution was stirred at 90℃for 12 hours, after completion of the reaction, water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (200 mL. Times.3), the organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate, filtered, and the cake was washed with ethyl acetate, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 5:1) to give tert-butyl (I-1 d) carbamate (48.0 g, yield 76.9%) as a yellow oily compound (6- (bis (4-methoxybenzyl) amino) -5-fluoropyridin-3-yl).

LC-MS,M/Z(ESI):468.3[M+H] ⁺

Fourth step: synthesis of tert-butyl (6- (di (4-methoxybenzyl) amino) -5-fluoro-4-iodopyridin-3-yl) carbamate (I-1 e)

To a solution of tert-butyl N- [6- [ bis [ (4-methoxyphenyl) methyl ] amino ] -5-fluoro-3-pyridyl ] carbamate (I-1 d) (30.0 g,64.2 mmol) and tetramethyl ethylenediamine (29.8 g, 255 mmol) in tetrahydrofuran (450 mL) at-65℃under nitrogen protection was added dropwise a solution of N-butyllithium (2.50M, 103 mL) in tetrahydrofuran, and after the completion of the addition, the reaction solution was stirred at-65℃for 1.5 hours. Then, a solution of iodine (26.1 g,103 mmol) in tetrahydrofuran (150 mL) was added dropwise to the reaction solution at-65℃and, after completion of the addition, the reaction solution was stirred at-65℃for 1.5 hours. After completion of the reaction, a saturated ammonium chloride solution (500 mL) was added to the reaction solution, followed by extraction with ethyl acetate (300 ml×3), and the organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate, then filtered, and the filter cake was washed with ethyl acetate, and the filtrate was concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 5:1) to give the compound (tert-butyl 6- (di (4-methoxybenzyl) amino) -5-fluoro-4-iodopyridin-3-yl) carbamate (I-1 e) (20.0 g, yield 52.5%).

LC-MS,M/Z(ESI):594.1[M+H] ⁺

Fifth step: synthesis of tert-butyl (4-acetyl-6- (di (4-methoxybenzyl) amino) -5-fluoropyridin-3-yl) carbamate (I-1 f)

Tert-butyl N- [6- [ bis [ (4-methoxyphenyl) methyl ] amino ] -5-fluoro-4-iodo-3-pyridinyl ] carbamate (I-1 e) (5.00 g,8.43 mmol) and tributyl (1-ethoxyvinyl) stannane (6.69 g,18.5 mmol) were dissolved in dioxane (70.0 mL), then bis (triphenylphosphine) palladium (II) (591 mg, 843. Mu. Mol) was added under nitrogen protection, the reaction mixture was stirred at 60℃for 12 hours, hydrochloric acid (4M, 41.85 mL) was added to the reaction mixture after completion of the reaction, the reaction mixture was stirred at room temperature for 12 hours, a saturated potassium fluoride solution (100 mL) was added to the reaction mixture and stirred at room temperature for 2 hours, then ethyl acetate (100 mL) was used for extraction, the organic phase was washed with saturated sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), then filtered again after filtration and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 5:1) to give (4-acetyl-6- (bis (4-methoxybenzyl) amino) -5-fluoropyridin-3-yl) carbamic acid tert-butyl ester ((I-1 f)) (17.1 g, crude product, four batch feeds combined) as a red oil.

LC-MS,M/Z(ESI):510.3[M+H] ⁺

Sixth step: synthesis of 1- (5-amino-2- (bis (4-methoxybenzyl) amino) -3-fluoropyridin-4-yl) ethanone (I-1 g)

Tert-butyl (4-acetyl-6- (bis (4-methoxybenzyl) amino) -5-fluoropyridin-3-yl) carbamate (I-1 f) (17.1 g,33.4 mmol) was dissolved in ethyl acetate (80.0 mL), ethyl acetate hydrochloride (4M, 80.0 mL) was further added, the reaction mixture was stirred at 25℃for 4 hours, after completion of the reaction, the mixture was filtered, and the cake was washed with petroleum ether (100 mL), after which the cake was dried to give the yellow solid compound 1- (5-amino-2- (bis (4-methoxybenzyl) amino) -3-fluoropyridin-4-yl) ethanone ((I-1 g)) (8.20 g, yield 75.2%).

LC-MS,M/Z(ESI):290.0[M+H] ⁺

Seventh step: synthesis of N- (4-acetyl-5-fluoro-6- ((4-methoxybenzyl) amino) pyridin-3-yl) -6- (trifluoromethyl) picolinamide (I-1 h)

1- [ 5-Amino-3-fluoro-2- [ (4-methoxyphenyl) methylamino ] -4-pyridyl ] ethanone (I-1 g) (8.20 g,28.4 mmol), 6- (trifluoromethyl) pyridine-2-carboxylic acid (6.50 g,34.0 mmol) were dissolved in N, N-dimethylformamide (100 mL), 2- (7-azobenzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (13.0 g,34.0 mmol) and N, N-diisopropylethylamine (11.0 g,85.3 mmol) were added thereto, the reaction mixture was stirred at 25℃for 3 hours, after completion of the reaction, diluted with water (200 mL), extracted with ethyl acetate (200 mL. Times.3), and the organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=5:1 to 1:1) to give the yellow oily compound N- (4-acetyl-5-fluoro-6- ((4-methoxybenzyl) amino) pyridin-3-yl) -6- (trifluoromethyl) picolinamide (I-1 h) (5.00 g, yield 38.2%).

LC-MS,M/Z(ESI):463.1[M+H] ⁺

Eighth step: synthesis of N- (4-acetyl-6-amino-5-fluoropyridin-3-yl) -6- (trifluoromethyl) picolinamide (I-1 j)

N- (4-acetyl-5-fluoro-6- ((4-methoxybenzyl) amino) pyridin-3-yl) -6- (trifluoromethyl) methylpyridine amide (I-1 h) (5.00 g,10.8 mmol) was added to trifluoroacetic acid (20.0 mL) at room temperature, the mixture was stirred at 50℃for 1 hour, after completion of the reaction, diluted with water (100 mL), saturated sodium carbonate solution was added to adjust the pH to 8-9, which was extracted with ethyl acetate (100 mL. Times.3), the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give the compound N- (4-acetyl-6-amino-5-fluoropyridin-3-yl) -6- (trifluoromethyl) methylpyridine amide (I-1 j) (3.50 g, yield 94.6%).

LC-MS,M/Z(ESI):343.0[M+H] ⁺

Ninth step: synthesis of N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethyl) picolinamide (I-1 k)

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 methyl magnesium bromide (3.00M, 12.7 mL) was added dropwise thereto at 0℃and after completion of the dropwise addition, the reaction solution was stirred at 25℃for 12 hours, after completion of the reaction, saturated ammonium chloride (100 mL) was added to quench, followed by extraction with ethyl acetate (100 mL. Times.3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was prepared by column chromatography (silica, petroleum ether: ethyl acetate=5:1 to 2:1) to give the compound N- (6-amino-5-fluoro-4- (2-hydroxypropan-2-yl) pyridin-3-yl) -6- (trifluoromethyl) picolinamide (I-1 k) (1.00 g, yield 36.8%).

LC-MS,M/Z(ESI):359.1[M+H] ⁺

Tenth step: synthesis of 1-chloro-4- (methylthio) butan-2-one

Methyl 3-methylthiopropionate (5.00 g,37.3 mmol) and chloroiodomethane (26.3 g,149 mmol) were added to tetrahydrofuran (300 mL), then lithium diisopropylamide (2.00M, 93.2 mL) was added dropwise thereto at-65℃and after the completion of the addition, the reaction solution was stirred at-65℃for 0.5 hour, after the completion of the reaction, saturated ammonium chloride solution (100 mL) was added for quenching, followed by extraction with ethyl acetate (200 mL. Times.3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was prepared by column chromatography (silica, petroleum ether: ethyl acetate=20:1 to 10:1) to give the compound 1-chloro-4- (methylthio) butan-2-one (3.00 g, yield 52.8%) as a brown oil.

Eleventh step: synthesis of 1-chloro-4- (methylsulfonyl) butan-2-one (1A)

1-Chloro-4- (methylthio) butan-2-one (3.00 g,19.7 mmol) was added to methylene chloride (60.0 mL), then m-chloroperoxybenzoic acid (7.46 g,43.2 mmol) was added thereto in portions at 0℃and then the reaction mixture was stirred at 25℃for 2 hours, after completion of the reaction, a saturated sodium thiosulfate solution (100 mL) was added thereto for quenching, followed by extraction with methylene chloride (100 mL. Times.3), and 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 give the compound 1-chloro-4- (methylsulfonyl) butan-2-one (1A) (1.00 g, yield 27.6%) as an off-white solid.

Twelfth step: synthesis of N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (2- (methylsulfonyl) ethyl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) picolinamide (I-1)

N- [ 6-amino-5-fluoro-4- (1-hydroxy-1-methyl-ethyl) -3-pyridinyl ] -6- (trifluoromethyl) pyridine-2-carboxamide (300 mg, 837. Mu. Mol) and 1-chloro-4-methanesulfonyl-butan-2-one (534 mg,2.89 mmol) were added to ethanol (9.00 mL), the reaction mixture was stirred at 100℃for 12 hours, after completion of the reaction, water (20.0 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20.0 mL. Times.3), and the organic phase was washed with saturated brine (10.0 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was isolated by reverse phase preparation (column: phenomenex Synergi C, 150X 25mm X10 μm; mobile phase: [ water (0.1% ammonia) -acetonitrile ]; B%:18% -52%,12 min) to give N- (8-fluoro-7- (2-hydroxypropan-2-yl) -2- (2- (methylsulfonyl) ethyl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) 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).

LC-MS,M/Z(ESI):488.9[M+H] ⁺

Example 2: preparation of target Compound I-2

Nitrogen- (2- (2- (cyclopropanesulfonyl) ethyl) -8-fluoro-7- (2-hydroxypropyl-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (compound I-2 of interest).

The synthetic route for the target compound I-2 is shown below:

The first step: synthesis of methyl 3- (cyclopropylthio) propionate (I-2 b)

Methyl 3-mercaptopropionate (I-2 a) (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 a hydrogenation bottle of dimethyl sulfoxide (50 mL), the reaction was closed, and the reaction solution was heated to 120℃for 12 hours. After the reaction was completed, the reaction solution was washed with water (30 mL), then extracted three times with ethyl acetate (30 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated at low temperature to spin dry to give the crude methyl 3- (cyclopropylsulfanyl) propionate (I-2 b) (3.8 g).

And a second step of: synthesis of 3- (cyclopropylthio) propionic acid (I-2 c)

Methyl 3- (cyclopropylthio) propionate (I-2 b) (3.4 g,21.22 mmol) was dissolved in tetrahydrofuran: water: to the mixed solution of methanol=18:12:2, lithium hydroxide (2.54 g,106 mmol) was then added, 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 with ethyl acetate (10 ml x 2) for 2 times, the aqueous phase was adjusted to ph=3 with 1N hydrochloric acid solution, then extracted with ethyl acetate (10 ml x 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the product 3- (cyclopropylthio) propionic acid (I-2 c) (2.4 g, yield 77%).

And a third step of: synthesis of 3- (cyclopropylthio) propionyl chloride (I-2 d)

3- (Cyclopropylthio) propionic acid (I-2 c) (3.4 g,23.25 mmol) was dissolved in methylene chloride (5 mL), oxalyl chloride (8.85 g,69.8 mmol) was added, 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 completion of the reaction, the reaction mixture was concentrated at low temperature to give 3- (cyclopropylthio) propionyl chloride (I-2 d) (2.4 g) as a crude product

Fourth step: synthesis of 1-chloro-4- (cyclopropylthio) butan-2-one (I-2 e)

3- (Cyclopropylthio) propionyl chloride (I-2 d) (2.4 g,14.58 mmol) was dissolved in acetonitrile (20 mL), replaced with nitrogen three times, the reaction solution was cooled to 0℃and azido trimethylsilane (17.49 mL,350 mmol) was added at 0℃and the reaction was slowly warmed to room temperature and allowed to react for 2 hours. Then, the reaction mixture was cooled to 0℃again, and a hydrochloric acid/dioxane solution (5 mL) was slowly added thereto, followed by reaction for 1 hour. After completion of the reaction, triethylamine was added to make the reaction solution pH neutral, then the reaction solution was concentrated, water (10 mL) and ethyl acetate (30 ml×2) were added to the concentrate to extract, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered and concentrated to give 1-chloro-4- (cyclopropylthio) butan-2-one (I-2 e) (1.4 g, crude product).

Fifth step: synthesis of 1-chloro-4- (cyclopropylsulfonyl) butan-2-one (I-2 f)

1-Chloro-4- (cyclopropylthio) butan-2-one (I-2 e) (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 0deg.C, and the reaction solution was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated, then extracted with water (10 mL) and ethyl acetate (15 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration to give the product 1-chloro-4- (cyclopropylsulfonyl) butan-2-one (I-2 f) (1.4 g), which was directly carried on to the next step without purification.

Sixth step:

1-Chloro-4- (cyclopropylsulfonyl) butan-2-one (I-2 f) (470 mg,2.233 mmol) and N- (6-amino-5-fluoro-4- (2-hydroxypropyl-2-yl) pyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-1 k) (160 mg,0.447 mmol) were placed in a sealed tube dissolved in ethanol (4 mL), and the reaction solution was stirred at 100℃for 16 hours. After the reaction is completed, the reaction solution is concentrated to obtain a crude product. Purification of the crude product by reverse phase column HPLC (column: phenomenex Synergi C18:150X25 mm. Times.10 μm; mobile phase: [ water (0.1% ammonia) -acetonitrile ]; B%:18% -52%,12 min) gave, after purification, N- (2- (2- (cyclopropanesulfonyl) 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] ⁺

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).

Example 3: preparation of target Compound I-3

N- (8-fluoro-2- (2- (4-fluorophenyl) sulfonyl) ethyl) -7- (2-hydroxypropan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-3)

The synthetic route for compound I-3 is shown below:

The first step: synthesis of ethyl 3- ((4-fluorophenyl) thio) propionate (I-3 c)

Compound I-3b (4.30 g,42.9 mmol) was weighed out separately at room temperature, anhydrous sodium acetate (0.48 g,5.85 mmol) was added to a mixed solution of anhydrous tetrahydrofuran (25 mL) and water (25 mL), followed by the addition of compound I-3a (5.0 g,39.0 mmol). After the addition was completed, the reaction mixture was reacted at 25℃for 18 hours. TLC (PE: etOAc (V/V) =10:1) monitored reaction complete. The reaction was quenched with saturated aqueous sodium bicarbonate (30 mL), extracted with ethyl acetate (50 mL x 2), the organic phases combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum to give the crude product which was isolated as a yellow liquid from ethyl 3- ((4-fluorophenyl) thio) propionate (I-3 c) (8.60 g, 97% yield) by column chromatography over silica gel gradient elution (PE: etOAc (V/V) =1:0-1:1).

And a second step of: synthesis of 1-chloro-4- ((4-fluorophenyl) thio) butan-2-one (I-3 d)

Compound I-3c (2.0 g,8.76 mmol) and chloroiodomethane (4.64 g,26.3 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL) under nitrogen protection at-78deg.C, then lithium diisopropylamide in n-hexane (13.14 mL,26.3mmol, 2M) was added dropwise, maintaining the temperature no more than-65deg.C during the addition. After the addition was completed, the reaction mixture was reacted at-78℃for 1.5 hours. TLC (PE: etoac=10:1) monitored reaction complete. The reaction solution was quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by vacuum to give the crude product which was separated by column chromatography over silica gel gradient (silica gel; PE: etOAc (V/V) =1:0-10:1) to give 1-chloro-4- ((4-fluorophenyl) thio) butan-2-one (I-3 d) (0.55 g, yield: 27.0%).

And a third step of: synthesis of 1-chloro-4- ((4-fluorophenyl) sulfonyl) butan-2-one (I-3 e)

Compound I-3d (0.48 g,2.06 mmol) and sodium tungstate dihydrate (0.07 g,0.21 mmol) were dissolved in anhydrous methanol (5 mL) under ice-bath conditions, followed by slow addition of hydrogen peroxide (0.52 g,4.54mmol, 30%). After the addition was completed, the reaction solution was slowly raised to 25℃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), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by reduced pressure to give a crude product which was eluted with a silica gel column chromatography gradient (silica gel; PE: etOAc (V/V) =1:0-10:1) to separate 1-chloro-4- ((4-fluorophenyl) sulfonyl) butan-2-one (I-3 e) (130 mg, yield: 23.81%).

Fourth step: synthesis of N- (8-fluoro-2- (2- (4-fluorophenyl) sulfonyl) ethyl) -7- (2-hydroxy-propan-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-3)

Compound I-3e (0.070 g,0.20 mmol) and compound I-1k (155.17 mg,0.60 mmol) were weighed into a 10mL polytetrafluoroethylene tube at room temperature, and then absolute ethanol (2 mL) was added. After the addition, the reaction was carried out in a closed tube at 100℃for 12 hours. LCMS monitors completion of the reaction, concentrating the reaction mixture under reduced pressure and spin-drying, and separating the crude product by high pressure liquid phase chromatography ((column: phenomenex Synergi C, 150X 25mm X10 μm; mobile phase: [ water (0.1% ammonia) -acetonitrile ]; B%:18% -52%,12 min)) to give N- (8-fluoro-2- (2- (4-fluorophenyl) sulfonyl) ethyl) -7- (2-hydroxypropyl-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (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).

LC-MS,M/Z(ESI):568.9[M+H] ⁺

Example 4: preparation of target Compound I-6

Nitrogen- (2- (2- (nitrogen, nitrogen-dimethyl-sulphonylamino) ethyl) -8-fluoro-7- (2-hydroxypropyl-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-6)

The synthetic route for the target compound I-6 is shown below:

The first step: 3- (Nitrogen, nitrogen-dimethyl-sulfonamide) propionic acid (I-6 b)

Methyl 3- (nitrogen, nitrogen-dimethyl-sulphonylamino) propionate (700 mg,3.59 mmol) was dissolved in tetrahydrofuran: water: to the mixed solution of methanol=4.5:3:0.5, lithium hydroxide (429 mg,17.93 mmol) was then added, 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 with ethyl acetate (10 ml x 2), the aqueous phase was adjusted to ph=3 with 1N hydrochloric acid solution, then extracted with ethyl acetate (10 ml x 5), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the product 3- (nitrogen, nitrogen-dimethyl-sulfonamide) propionic acid (I-6 b) (600 mg).

And a second step of: 3- (N, N-dimethyl-sulfoamino) propionyl chloride

3- (Nitrogen, N-dimethyl-sulfonamide) propionic acid (I-6 b) (500 mg,2.76 mmol) was dissolved in methylene chloride (5 mL), oxalyl chloride (1.05 g,8.28 mmol) was added, 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 completion of the reaction, the reaction mixture was concentrated at low temperature to give 3- (N, N-dimethyl-sulfamide) propionyl chloride (I-6 c) (550 mg) as a crude product.

And a third step of: 4-chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (I-6 e)

3- (Nitrogen, N-dimethyl-sulfonamide) propionyl chloride (200 mg,1.002 mmol) was dissolved in acetonitrile (2 mL), replaced three times with nitrogen, the reaction solution was cooled to 0℃and azido trimethylsilane (1.2 mL,24.04 mmol) was added at 0℃and the reaction was slowly warmed to room temperature and allowed to react for 2 hours. Then, the obtained reaction solution containing 4-diaza-N, N-dimethyl-3-oxobutane-1-sulfonamide (I-6 d) was again cooled to 0℃and a hydrochloric acid/dioxane solution (1 mL) was slowly added to react for 1 hour. After completion of the reaction, triethylamine was added to make the reaction solution pH neutral, then the reaction solution was concentrated, water (5 mL) and ethyl acetate (10 ml×2) were added to the concentrate to extract, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and filtered and concentrated to give the product 4-chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (I-6 e) (200 mg).

Fourth step: nitrogen- (2- (2- (nitrogen, nitrogen-dimethyl-sulphonylamino) ethyl) -8-fluoro-7- (2-hydroxypropyl-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-6)

4-Chloro-nitrogen, nitrogen-dimethyl-3-oxobutane-1-sulfonamide (119 mg, 0.578 mmol) and N- (6-amino-5-fluoro-4- (2-hydroxypropyl-2-yl) pyridin-3-yl) -6- (trifluoromethyl) pyridine amide (40 mg,0.112 mmol) were placed in a sealed tube and the reaction was stirred at 100℃for 16 hours. After the reaction is completed, the reaction solution is concentrated to obtain a crude product. Purification of the crude product by reverse phase column HPLC (column: phenomenex Synergi C18:150X125 mm. Times.10 μm; mobile phase: [ water (0.1% ammonia) -acetonitrile ]; B%:18% -52%,12 min) afforded nitrogen- (2- (nitrogen, nitrogen-dimethylsulfoxide) ethyl) -8-fluoro-7- (2-hydroxypropyl-2-yl) imidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-6) (10 mg,100% purity)

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).

Example 5: preparation of target Compound I-8

Nitrogen- (8-fluoro-2- (2- (methylsulfonyl) ethyl) -7-morpholinoimidazole [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-8)

The synthetic route for the target compound I-8 is shown below:

The first step: (6- (bis (4-methoxybenzyl) amino) -5-fluoro-4-morpholinylpyridin-3-yl) carbamic acid tert-butyl ester (I-8 a)

Tert-butyl (6- (bis (4-methoxybenzyl) amino) -5-fluoro-4-iodopyridin-3-yl) carbamate (I-1 e) (2 g,6.74 mmol) and morpholine (0.587 g,6.74 mmol) were dissolved in 1, 4-dioxane (20 mL), cesium carbonate (2.196 g,6.74 mmol), tris (dibenzylideneacetone) dipalladium (0.309 g,0.337 mmol) and Xantphos (0.390 g, 0.6754 mmol) were added sequentially, the reaction solution was replaced with nitrogen three times and then warmed to 90℃for reaction for 2 hours. After the reaction was completed, the reaction solution was washed with water (20 mL) and ethyl acetate (20 mL x 2), the organic phases were combined, washed twice with brine, then dried over sodium sulfate, filtered and spun dry to give the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 3:1) to give, after purification, tert-butyl (I-8 a) carbamate (400 mg, yield 21.48%) as a yellow oily compound (6- (bis (4-methoxybenzyl) amino) -5-fluoro-4-morpholinopyridin-3-yl).

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).

And a second step of: 3-fluoro-N2- (4-methoxybenzyl) -4-morpholinylpyridine-2, 5-diamine (I-8 b)

Tert-butyl (6- (bis (4-methoxybenzyl) amino) -5-fluoro-4-morpholinopyridin-3-yl) carbamate (I-8 a) (400 mg,0.742 mmol) was dissolved in dichloromethane (5 mL), then hydrochloric acid/dioxane (0.5 mL) was added and the reaction solution was reacted at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated and dried to give crude 3-fluoro-N ₂ - (4-methoxybenzyl) -4-morpholinylpyridine-2, 5-diamine (I-8 b) (200 mg, yield 83%) which was used directly in the next step.

And a third step of: nitrogen- (5-fluoro-6- ((4-methoxybenzyl) amino) -4-morpholinylpyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 c)

3-Fluoro-N2- (4-methoxybenzyl) -4-morpholinopyridine-2, 5-diamine (I-8 b) (200 mg,0.442 mmol) and 6- (trifluoromethyl) picolinic acid (101 mg,0.530 mmol) were dissolved in DMF (4 mL), DIEA (114 mg,0.884 mmol) and T ₃ P. DMF (35.4 mg,0.884 mmol) were added in this order, and the reaction was reacted at 50℃for 16 hours. After the completion of the reaction, the reaction mixture was extracted with water and ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate=10:1 to 3:1) to give the product nitrogen- (5-fluoro-6- ((4-methoxybenzyl) amino) -4-morpholinylpyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 c) (100 mg).

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).

Fourth step: nitrogen- (6-amino-5-fluoro-4-morpholinylpyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 d)

Nitrogen- (5-fluoro-6- ((4-methoxybenzyl) amino) -4-morpholinylpyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 c) (100 mg,1 eq) was dissolved in methylene chloride (3 mL), then trifluoroacetic acid (1 mL) was added, and the reaction solution was reacted at room temperature for 16 hours. After completion of the reaction, the reaction mixture was washed with sodium bicarbonate, the aqueous phase was extracted three times with dichloromethane (5 ml x 3), the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to give the product nitrogen- (6-amino-5-fluoro-4-morpholinopyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 d) (50 mg).

LC-MS,M/Z(ESI):386.5[M+1] ⁺

Fifth step: nitrogen- (8-fluoro-2- (2- (methylsulfonyl) ethyl) -7-morpholinoimidazole [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-8)

Nitrogen- (6-amino-5-fluoro-4-morpholinopyridin-3-yl) -6- (trifluoromethyl) pyridine amide (I-8 d) (100 mg,0.260 mmol) and 1-chloro-4- (methylsulfonyl) butan-2-one (1A) (144 mg,0.779 mmol) were dissolved in a closed tube of ethanol (1 mL), and the reaction solution was reacted at 100℃for 12 hours. After the reaction is completed, the reaction solution is concentrated and dried by spin to obtain a crude product. The crude product was purified by reverse phase column HPLC (column: phenomenex Synergi C18:150×25mm×10 μm; mobile phase: [ water (0.1% ammonia) -acetonitrile ]; B%:18% -52%,12 min) to give nitrogen-like- (8-fluoro-2- (2- (methylsulfonyl) ethyl) -7-morpholinoimidazo [1,2-a ] pyridin-6-yl) -6- (trifluoromethyl) pyridine amide (target compound I-8) (5 mg,100% purity).

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).

Reference WO2016083433A1 was referenced to synthesize each compound in the following table:

Test example 1: detection of inhibition of IRAK4 kinase Activity by Compounds by Mobility Change method (Mobility SHIFT ASSAY)

First, the test compound synthesized above was dissolved in DMSO and prepared as a 10mM stock solution, followed by preparation of 1 Xkinase 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 use.

Next, the compound stock solution was diluted 50 times to the highest point of the concentration gradient with DMSO, 100 μl of this dilution was transferred into a 96-well plate, followed by serial dilution 4 times until 10 concentration gradients were reached. 100 μl DMSO was added to 2 wells of the same 96-well plate, and the compound-free control and enzyme-free control were set. Transfer 10 μl of compound and control solution in gradient dilutions to a new 96-well plate, add 90 μl of 1 Xkinase buffer to each well, and place on shaker for 10min for mixing well. mu.L of each well was pipetted separately into two replicate wells of a 384 well plate.

IRAK4 kinase (Cana) was added to the 1 Xkinase base buffer to prepare a 2.5 Xenzyme solution, and FAM-labeled polypeptide and ATP were added to the 1 Xkinase base buffer to prepare a 2.5 Xpolypeptide solution. The 2.5 Xenzyme solution was pipetted into 384 well plates already containing 5. Mu.L of compound, 10. Mu.L per well and incubated at room temperature for 10min. The 2.5 Xpolypeptide solution was pipetted into 384 well plates 10. Mu.L per well and incubated for 1h at 28 ℃. After incubation, 30 μl of stop buffer was added per well to stop the reaction, and then transferred to a Caliper instrument to collect data per well, calculate inhibition rate from control wells, and calculate IC ₅₀ values for compounds using GraphPad software to fit a curve.

Table 1: test Compounds for IRAK4 kinase inhibitory Activity

The test result shows that the compound of the patent shows better IRAK4 kinase inhibition activity, and especially the inhibition activity of the compound I-1 is obviously better.

Test example 2: inhibition of R848-stimulated PBMC production of TNF-alpha by Compounds

First, cryopreserved PBMC cells were recovered, centrifuged at 200rpm for 5min, and the supernatant was resuspended in 1640+10% FBS+1% P/S complete medium and counted. Cells were seeded at a density of 8X 10 ⁴/well and 100. Mu.l/well into 96-well plates for overnight growth.

Next, 10mM of the previously synthesized compound stock solution was prepared and diluted 3-fold sequentially with DMSO, and then a series of concentrations were diluted 500-fold with 1640+10% FBS+1% P/S complete medium to reach 4-fold final concentration (20. Mu.M). The formulated compound was added to the cells at 50 μl/well, while control wells without compound were set, pre-incubated for 30min. At the same time of incubation, an R848 mother liquor was prepared at a concentration of 10mg/mL, diluted 100-fold and then 31.25-fold with 1640+10% FBS+1% P/S medium to a final concentration of 4-fold (3.2. Mu.g/mL). The formulated R848 was added to the cells at 50. Mu.l/well, while control wells without R848 were set. After 24h of incubation, the supernatants were collected and 50% of the supernatants were assayed using the Human TNF-. Alpha.kit (Invitrogen, LOT: 189974010). The inhibition of the compounds was calculated from control wells and IC ₅₀ values for the compounds were calculated using GraphPad software fitting curves.

Table 2: test Compounds for inhibition of R848-stimulated PBMC production of TNF-alpha

Test compounds	IC50(nM)
Control Compound 1	172
I-1	26.7

The test result shows that compared with the control compound 1, the compound has stronger inhibition capability on TNF-alpha production at the cellular level, and particularly, the inhibition activity of the compound I-1 is obviously superior to that of the control compound 1.

Test example 3: measurement of plasma protein binding Rate by equilibrium dialysis

The compound was formulated as stock solution with DMSO and diluted to a concentration of 100 μm with methanol: acetonitrile: water=1:1:2 (v/v/v). The extent of binding of the compounds to plasma of different species was determined by equilibrium dialysis. Using a 96 Kong Touxi unit (HTDIALYSIS, U.S.) 6. Mu.L of the test solution was mixed with 594. Mu.L of plasma, and the concentration of the compound in the resulting plasma was 1. Mu.M, and the amount of the organic solvent was not more than 1%.

Transfer 150 μl of plasma sample and 150 μl of phosphate buffer (containing 0.002% tween 80) to the test and receiving chambers on both sides of the dialysis membrane (parallel 2). And (3) sealing the membrane sealing plates, and incubating in a 37 ℃ reciprocating oscillating water bath kettle for 6 hours, wherein the oscillating speed is 80 times/min. Transfer 10. Mu.L of the test chamber samples, add 90. Mu.L of phosphate buffer (containing 0.002% Tween 80, pH 7.4), mix well, add precipitant (containing internal standard). Transfer 90 μl of each receiving chamber sample, add 10 μl of corresponding species blank plasma, mix well, add precipitant (containing internal standard).

And (3) after protein precipitation of all the samples, centrifuging, taking supernatant, diluting with water at a ratio of 1:1 (v/v), and carrying out sample injection analysis, and finally converting the original concentration according to dilution times.

The ratio of plasma protein binding to free drug was calculated using the following formula: % binding ratio = 100× ([ supply side concentration ] _6h - [ receiver side concentration ] _6h)/[ supply side concentration ] _6h. Ratio of free drug in plasma (%) =100-% binding rate

Experimental results show that the compound has higher free drug ratio in human and mouse plasma and good patentability.

Test example 4: human liver microsome stability test

The stability test of the human liver microsome is carried out by adopting the co-incubation of the compound and the human liver microsome in vitro. Test compounds were first formulated as a 10mM stock solution in DMSO solvent, followed by dilution of the compounds to 0.5mM using acetonitrile. Human liver microsomes (Corning) were diluted with PBS to a microsome/buffer solution, and 0.5mM of the compound was diluted with the solution to a working solution having a compound concentration of 1.5. Mu.M and a human liver microsome concentration of 0.75mg/mL. The reaction was started by taking a deep well plate, adding 30. Mu.L of working solution per well, then adding 15. Mu.L of pre-warmed 6mM NADPH solution, and incubating at 37 ℃. At 0, 5, 15, 30, 45 minutes of incubation, the reaction was terminated by adding 135 μl acetonitrile to the corresponding wells. After the reaction was terminated with acetonitrile at the last 45 min time point, the deep-well plate was vortexed for 10 minutes (600 rpm/min) and then centrifuged for 15 minutes. Taking the supernatant after centrifugation, adding purified water in a ratio of 1:1, performing LC-MS/MS detection to obtain the ratio of the peak area of the compound to the internal standard peak area at each time point, comparing the ratio of the peak area of the compound at 5, 15, 30 and 45 minutes with the ratio of the peak area at 0 minute, calculating the residual percentage of the compound at each time point, and calculating T _1/2 by using Graphpad 5 software.

Experimental results show that the compound of the invention has better liver metabolism stability.

Test example 5: test for inhibition of cytochrome P450 by Compounds

The inhibitory potential of the compounds against cytochrome P450 (CYP 450) subtype CYP3A4 (2 substrates midazolam and testosterone) was examined. Firstly, preparing a compound to be tested into a 10mM stock solution in a DMSO solvent, and preparing a CYP3A4 inhibitor ketoconazole into a 2.5mM stock solution in the DMSO solvent. The test compound and ketoconazole were diluted to 400-fold final concentration (compound: 10. Mu.M, ketoconazole: 2.5. Mu.M) with acetonitrile.

NADPH cofactor (66.7 mg NADPH in 10mL potassium phosphate buffer) and substrate were formulated at 4-fold final concentration with potassium phosphate buffer (0.1M, pH 7.4), midazolam at 20. Mu.M, testosterone at 320. Mu.M.

Human liver microsome solution was prepared with potassium phosphate buffer at a concentration of 0.2mg/mL on ice. The test compound was formulated in 2-fold final concentration with human liver microsome solution on ice. To the test wells, 30. Mu.L of the test compound was added, and 15. Mu.L of the substrate was added, respectively, to perform the multiplex well operation. The 96-well assay plate and NADPH solution were pre-incubated at 37 ℃ for 5 minutes, and 15 μl of pre-warmed 8mM NADPH solution was added to the assay plate to initiate the reaction. Incubate for 5 minutes at 37 ℃. The reaction was quenched by the addition of 120. Mu.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. And taking the supernatant after centrifugation, adding purified water in a ratio of 1:1, performing LC-MS/MS detection to obtain the ratio of the peak area of the compound to the peak area of the internal standard, comparing the ratio of the peak area of the compound to the ratio of the peak area of the control inhibitor, and calculating the inhibition rate.

Experimental results show that the compound has no inhibition effect on CYP2C9, CYP2D6 and CYP3A4 enzymes at the temperature of 10 mu M, and the potential drug-drug interaction risk is low.

Test example 6: pharmacokinetic test

Mouse pharmacokinetic experiments Male ICR mice, 20-25g, were used, fasted overnight. 3 mice were taken and orally administered with 10mg/kg by intragastric administration. Blood was collected 15, 30 minutes and 1,2,4, 8, 24 hours before and after dosing. Blood samples 6800g were centrifuged at 2-8deg.C for 6 minutes, and plasma was collected and stored at-80deg.C. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. Principal pharmacokinetic parameters were analyzed using WinNonlin 7.0 software non-compartmental model

Rat pharmacokinetic experiments Male SD rats, 180-240g, were used, fasted overnight. 3 rats were taken and given 10mg/kg orally by gavage. Blood was collected 15, 30 minutes and 1, 2,4, 8, 24 hours before and after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4℃and plasma was collected and stored at-20 ℃. Plasma at each time point is taken, 3-5 times of acetonitrile solution containing an internal standard is added for mixing, vortex mixing is carried out for 1 minute, 13000 r/min and 4 ℃ are centrifugated for 10 minutes, 3 times of water is added for mixing the supernatant, and a proper amount of mixed solution is taken for LC-MS/MS analysis. The principal pharmacokinetic parameters were analyzed using the WinNonlin 7.0 software non-compartmental model.

Table 3: results of the pharmacokinetic test in mice

Table 4: results of rat pharmacokinetic experiments

Experimental results show that the compound of the invention shows more excellent pharmacokinetic properties in mouse and rat species.

Claims

A compound, which is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II),

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, and the 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 , and the R ¹³ is independently selected from C ₁ -C ₆ alkyl, halogen, -NH ₂ , hydroxyl or cyano; when there are multiple R ¹³ , the R ¹³ 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 to which they are attached form a 3-6 membered heterocyclic group, and the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl and 3-6 membered heterocyclic group may be optionally substituted by one or more R ¹²¹ , and the R ¹²¹ is each independently selected from C ₁ -C ₆ alkyl, halogen, -NH ₂ , hydroxyl or cyano; when there are multiple R ¹²¹ , the 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 may be optionally substituted by one or more R ²¹ , and the 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;

R ³ is independently selected from C ₁ -C ₆ alkyl, the C ₁ -C ₆ alkyl may be optionally substituted by one or more R ³¹ , the R ³¹ is independently selected from C ₁ -C ₆ alkyl, halogen, -NH ₂ , hydroxyl or cyano, when there are multiple R ³¹ , the R ³¹ are the same or different;

m is 1, 2, 3 or 4;

n is 1, 2, 3, 4, 5 or 6;

The "hetero" of the "5-8 membered heteroaryl", "3-6 membered heterocyclyl" and "4-8 membered heterocycloalkyl" is a heteroatom or a heteroatom group; the number of the heteroatom or heteroatom group is 1 or more, and are independently N, -O-, -NH-, -P(O)-, -P(O)O-, -S-, -S(O)-, -S(O) _2- ; when the number of the heteroatom or heteroatom group is more than one, the heteroatom or heteroatom group may be the same or different.

The compound according to claim 1, characterized in that it is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

The compound according to claim 1, characterized in that it is a compound represented by formula (I-a) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-a),

The compound according to claim 1, characterized in that it is a compound represented by formula (I-b) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-b),

Wherein, R ^2a and R ^2b together with the N to which they are connected form a 4-8 membered heterocycloalkyl group, and the 4-8 membered heterocycloalkyl group may be optionally substituted by one or more R ²¹ , and the R ²¹ is independently selected from C ₁ -C ₆ alkyl, halogen, -NH ₂ , hydroxyl or cyano. When there are multiple R ^21s , the R ^21s are the same or different.

The compound according to claim 1, characterized in that

When R ¹ is substituted by one or more R ¹³ , the R ¹³ is substituted by 1, 2 or 3;

and/or, when R ¹³ is halogen, the halogen is F or Cl;

and/or, when R ¹ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group;

and/or, when R ¹ is a C ₃ -C ₆ cycloalkyl group, the C ₃ -C ₆ cycloalkyl group is a cyclopropyl group;

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(CH ₂ CH ₃ ) ₂ ;

and/or, when ^R1 is a 6-10 membered aryl group, the 6-10 membered aryl group is a phenyl group;

and/or, when R ¹ is a 5-8 membered heteroaryl group, the 5-8 membered heteroaryl group is pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl or triazinyl.

The compound according to claim 1, characterized in that

When R ² is substituted by one or more R ²¹ , the R ²¹ is substituted by 1, 2 or 3;

and/or, when R ²¹ is halogen, the halogen is F or Cl;

and/or, R ²¹ is hydroxyl;

and/or, R ²¹ is F, Cl or hydroxyl;

and/or, when R ² is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group;

and/or, when ^R2 is a 4-8 membered heterocycloalkyl group, the 4-8 membered cycloalkyl group is azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, morpholinyl, pyrrolidinyl, morpholinyl or piperazinyl.

The compound according to claim 1, characterized in that when R ³ is substituted by one or more R ³¹ , the R ³¹ is substituted by 1, 2 or 3;

and/or, when R ³¹ is halogen, the halogen is F, Cl, Br or I;

and/or, when R ³ is a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group;

and/or, R ³ is -CF ₃ .

The compound according to claim 1, characterized in that

R ¹ is selected from -CH ₃ , -CHF ₂ ,

The compound according to claim 1, characterized in that

R ² is selected from

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 of any of the following compounds,

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,

A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and an optional pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

Use of the compound according to any one of claims 1 to 10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing a disease associated with IRAK4.

The use according to claim 13, characterized in that the IRAK4-related disease is an autoimmune disease or cancer.

The use according to claim 14, characterized in that 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 allergic eczema.

The use according to claim 14, characterized in that the cancer is brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumor, breast cancer, bladder 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 myeloid leukemia, chronic myeloid leukemia, Hematological malignancies include 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 lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

The compound according to any one of claims 1 to 10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 12, for treating or preventing a disease associated with IRAK4.

A compound according to any one of claims 1 to 10 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 12, for use in treating or preventing an autoimmune disease or cancer.

A compound according to any one of claims 1 to 10 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 12, for use in 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 allergic eczema.

A compound according to any one of claims 1 to 10 or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 12, for treating or preventing brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumor, breast cancer, bladder 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; hematological malignancies of acute myeloid 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 lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.

A method for treating or preventing a disease associated with IRAK4, characterized by administering to a patient an effective amount of the compound according to any one of claims 1 to 10 or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the pharmaceutical composition according to claim 12.

The method according to claim 21, characterized in that the IRAK4-related disease is an autoimmune disease or cancer.

The method according to claim 22, characterized in that 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 allergic eczema.

The method of claim 22, wherein the cancer is brain cancer, kidney cancer, liver cancer, stomach cancer, vaginal cancer, ovarian cancer, gastric tumor, breast cancer, bladder 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, spermatocystoma Hematologic malignancies including acute myeloid 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's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, plasmacytoma, and multiple myeloma.