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US-12624019-B2 - Indazole derivative, and preparation method therefor and use thereof

US12624019B2US 12624019 B2US12624019 B2US 12624019B2US-12624019-B2

Abstract

A class of indazole derivatives targeting an IRAK4 kinase protein for degradation, and a preparation method therefor and the use thereof are provided. In particular, the compound of formula I, a preparation method therefor, and a pharmaceutical composition thereof and the use thereof are presented. The compound can significantly degrade the IRAK4 kinase protein in cells and can be used as a drug for the treatment and/or prevention of related diseases or conditions mediated by the IRAK4, such as cancers, immune diseases, and inflammatory diseases.

Inventors

  • Yan Feng
  • Shiqiang Li

Assignees

  • LEADINGTAC PHARMACEUTICAL (SHAOXING) CO., LTD.

Dates

Publication Date
20260512
Application Date
20210204
Priority Date
20201026

Claims (18)

  1. 1 . A compound of formula I, or a stereoisomer, an enantiomer, a diastereomer, a deuterate, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein: R a is hydrogen; ring A is 5-10 membered heteroaryl; R d is each independently halogen, or C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more halogen; n is 1; R e is hydrogen or C1-C6 alkyl; R c is —O—(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the alkyl groups are optionally substituted by one or more hydroxyl; R b is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; ring B is 3-12 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; ring C is 3-12 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S; X is bond; W is C(O); L is —(CH 2 ) j —, and one or more CH 2 in the —(CH 2 ) j — are optionally replaced by a group selected from CR 1′ R 2′ ; R 1′ and R 2′ are each independently C1-C4 alkyl, and j is 1, 2, 3, 4, 5 or 6.
  2. 2 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein, ring B is 3-8-membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms.
  3. 3 . The compound of formula I according to claim 2 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein ring B is piperidinyl or piperazinyl.
  4. 4 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein, ring C is 3-8-membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms, or 7-12-membered spiro heterocycloalkyl containing 1-2 N heteroatoms.
  5. 5 . The compound of formula I according to claim 4 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein ring C is, piperidinyl, piperazinyl,
  6. 6 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.
  7. 7 . The compound of formula I according to claim 6 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein, R d is each independently halogen or C1-C6 alkyl optionally substituted by one or more F.
  8. 8 . The compound of formula I according to claim 7 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein R d is hydrogen, F, methyl, difluoromethyl, trifluoromethyl or 2-hydroxypropyl.
  9. 9 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein, R c is C1-C6 alkyl optionally substituted by one or more hydroxyl, or R c is —O(C1-C6 alkyl) optionally substituted by one or more hydroxyl.
  10. 10 . The compound of formula I according to claim 9 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein, R c is 2-hydroxypropyl, methoxy, ethoxy or isopropoxy.
  11. 11 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein R b is hydrogen or methyl.
  12. 12 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein L is —(CH 2 ) j —, and one or more CH 2 in the —(CH 2 ) j — are optionally replaced by a group selected from —CR 1′ R 2′ ; wherein R 1′ and R 2′ are each independently C1-C4 alkyl, j is 1, 2 or 3.
  13. 13 . The compound of formula I according to claim 12 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, wherein L is
  14. 14 . The compound of formula I according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, the or the pharmaceutically acceptable salt thereof, wherein the compound is the following specific compounds
  15. 15 . A pharmaceutical composition comprising the compound according to claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  16. 16 . A method for the treatment or prevention of IRAK4-mediated diseases or conditions, or TLR (other than TLR3R) or IL-1β receptor family mediated diseases or conditions comprising the step of administrating the compound of claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, the and/or the pharmaceutically acceptable salt thereof to a subject in need thereof.
  17. 17 . A method for the treatment or prevention of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplantation-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases or CNS diseases comprising the step of administrating the compound of claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof to a subject in need thereof.
  18. 18 . A method for the treatment or prevention of brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary cancer, esophageal cancer, Laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck or head tumor, epidermal hyperhyperplasia, psoriasis, prostate hyperplasia, Adenoma, adenocarcinoma, keratoacanthoma, epidermoid cancer, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular cancer, undifferentiated tumor, papillary tumor, seminoma, melanoma, ABC DLBCL, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, chronic lymphocytic leukemia, smoldering indolent multiple myeloma, leukemia, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, pre-B cell lymphocytic leukemia, lymphoplasmic lymphoma, Waldenstroms's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, or plasmacytoma or intravascular large B-cell lymphoma, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, neurodegenerative diseases caused by organ transplantation or graft-versus-host disease, eye disease, such as eye allergy, conjunctivitis, dry eye or spring conjunctivitis, diseases affecting the nose, including allergic rhinitis; autoimmune hematological diseases, such as hemolytic anemia, aplastic anemia, pure red blood cell anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stephen-Johnson syndrome, idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease, bowel syndrome, celiac disease, root periostitis, lung hyaline membrane disease, nephropathy, glomerular disease, Alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, Sarcomatosis, dry eye, spring conjunctival keratitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, Glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolismobesity, slow fetal growth, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidromic ectodermal dysplasia, Behcet's disease, pigment incontinence, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reaction, systemic allergic reaction, sinusitis, eye allergy, silica-induced diseases, COPD, lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, Cataract, muscle inflammation combined with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, Endometritis, enteritis, enterocolitis, upper ankle inflammation, epididymitis, fasciitis, fibrous tissue inflammation, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, suppurative sweat Inflammation, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, liver fibrosis, renal fibrosis, alcoholic fatty liver, non-alcoholic fatty liver, heart fibrosis, psoriasis, Crohn's disease, inflammatory bowel disease, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, local pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, articular inflammation, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, sclerosis, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, deciduous pemphigus, paraneoplastic pemphigus, acquired bullous epidermal laxity, acute and chronic gout, chronic gouty arthritis, bovine skin moss, bovine skin arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome or osteoarthritis diseases comprising the step of administrating the compound of claim 1 , or the stereoisomer, the enantiomer, the diastereomer, the deuterate, the hydrate, the solvate, or the pharmaceutically acceptable salt thereof into a subject in need thereof.

Description

FIELD OF THE INVENTION The present invention belongs to the field of pharmaceuticals. In particular, the present invention relates to indazole derivatives targeting IRAK4 protein for degradation, preparation methods therefor and their use in the preparation of medicaments for the treatment and/or prevention of related diseases or conditions mediated by IRAK4, such as cancer, immune diseases and inflammatory diseases. BACKGROUND Interleukin-1 receptor kinase 4 (IRAK4) is a serine/threonine-specific protein kinase with biologically important kinase activity and plays an important role in activating the immune system. Studies have shown that IRAK4 is a key factor downstream of IL-1β family receptors (including IL-1R, IL-18R, IL-33R, IL-36R) and Toll-like receptor (TLR) signaling pathways. Both IRAK4-deficient mice and IRAK4-deficient patients do not respond to TLR (except TLR3) and IL-1β family stimulation (Suzuki, Suzuki et al., Nature, 2002; Davidson, Currie et al., The Journal of Immunology, 2006; Ku, von Bernuth et al., JEM, 2007; Kim, Staschke et al., JEM, 2007). According to the presence or absence of MyD88, TLR/IL-1β mediated signaling pathways can be divided into MyD88-dependent signaling pathways and MyD88-independent pathways, in which IL-1R and TLR2, TLR4, TLR7/8, TLR9 mediated signal transduction pathways rely on MyD88 as a regulator to activate downstream inflammatory signaling pathways. After TLR/IL-1β binds to the ligand, MyD88 molecules are recruited. MyD88 further recruits IRAK4 into TLR/IL-1β complex through its N-terminal death domain, and interacts with IRAK1 or IRAK2 and activates them (Kollewe, Mackensen et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009), thus transmitting signals to E3 ubiquitin ligase TNF receptor related factor (TRAF6) downstream, activating serine/threonine kinase TAK1, and then activating NF-κB and MAPK signal pathways (Wang, Deng et al., Nature, 2001), which causes the release of a variety of inflammatory cytokines and anti-apoptotic molecules. IRAK4-dependent TLR/IL-1β signaling pathway has been shown to be associated with a variety of diseases, such as multiple sclerosis, atherosclerosis, myocardial infarction, myocarditis (Valaperti, Nishii et al., Circulation, 2013), Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus (SLE), obesity (Ahmad, R., P. Shihab et al., Diabetology & Metabolic Syndrome, 2015), type 1 diabetes, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, chronic inflammatory intestinal diseases and viral diseases, such as HIV (human immunodeficiency virus), hepatitis virus (Staschke et al., The Journal of Immunology, 2009; Marquez et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza et al., International Journal of Inflammation, 2014; Wang et al., Experimental and Therapeutic Medicine, 2015; Ciccia et al., Rheumatology, 2015); skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acneinversa and acne vulgaris; other inflammatory diseases such as allergy, Behcet's disease, gout, adult-onset Still's disease, pericarditis and chronic inflammatory intestinal diseases such as ulcerative colitis and Crohn's disease, transplant rejection reactions and graft-versus-host reactions; Gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia and endometriosis, in particular, endometriosis-related pain and other endometriosis-related symptoms such as dysmenorrhea, dyspareunia, dysuria and dyschezia (Akoum, Lawson et al., Human Reproduction, 2007; Allhorn, Boing et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima et al, Journal of Obstetrics and Gynaecology Research, 2013; Santulli, Borghese et al., Human Reproduction, 2013); eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis sicca, keratoconjunctivitis sicca, macular degeneration and uveitis (Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor et al, J Leukoc Biol, 2011; Chang, McCluskey et al., Clinical & Experimental Ophthalmology, 2012; Guo, Gao et al., Immunol Cell Biol, 2012; Lee, Hattori et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao et al., Investigative Ophthalmology & Visual Science, 2014); fibrosis diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao et al., Scand J Gastroenterol, 2011; Benias, Gopal et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu et al., Biochim Biophys Acta., 2015); chronic liver diseases, such