Interleukin-17 inhibitors

Abstract

The present invention relates to novel pyridine-N-oxide substituted 2-formamido (N-phenyl and N-pyridyl) acetamide compounds that are interleukin-17 (IL-17) inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in diseases and disorders mediated by IL-17.

Claims

1. Formula (IB): 【Chemistry 1】 (In the formula, R ７ is selected from Cl, methyl and trifluoromethyl; R ２ is selected from H and F; R ５ teeth, 【Chemistry 2】 (In the formula, R ５ａ is selected from methyl and ethyl; and R ５ｂ is selected from methyl and ethyl Selected from: R ９ teeth, 【Chemistry 3】 (selected from or a pharma- ceutically acceptable salt thereof.

2. 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide; 4-chloro-3-(4-((S)-2-cyclohexyl-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)-2-fluorophenyl)-2-methylpyridine 1-oxide; 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-methylcyclohexyl)acetamido)phenyl)pyridine 1-oxide; 4-chloro-3-(4-((S)-2-(3-ethylisoxazole-4-carboxamido)-2-((1r,4S)-4-(trifluoromethyl)cyclohexyl)acetamido)phenyl)-2-methylpyridine 1-oxide; (S)-3-(4-(2-cyclopentyl-2-(3-ethylisoxazole-4-carboxamido)acetamido)phenyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide; 4-chloro-3-(4-((S)-2-((S)-3,3-difluorocyclohexyl)-2-(3-ethylisoxazole-4-carboxamido)acetamido)phenyl)-2-methylpyridine 1-oxide; 3-(4-((S)-2-(1-ethyl-1H-pyrazole-5-carboxamido)-2-((1r,4S)-4-(trifluoromethyl)cyclohexyl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide; 3-(4-((S)-2-(3-ethylisoxazole-4-carboxamido)-2-((1r,4S)-4-(trifluoromethyl)cyclohexyl)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide; 3-(4-((S)-2-((S)-3,3-difluorocyclohexyl)-2-(3-methylisoxazole-4-carboxamido)acetamido)phenyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide; 3-(4-((S)-2-((S)-3,3-difluorocyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide; (S)-3-(4-(2-(4,4-difluorocyclohexyl)-2-(1-ethyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-2-methyl-4-(trifluoromethyl)pyridine 1-oxide; 3-(4-((2S)-2-(4-fluorocyclohex-3-en-1-yl)-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide; 3-(4-((S)-2-((R)-4-fluorocyclohex-3-en-1-yl)-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide; or 3-(4-((S)-2-((S)-4-fluorocyclohex-3-en-1-yl)-2-(1-methyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-2,4-dimethylpyridine 1-oxide 2. The compound of claim 1, selected from:

3. The compound 2,4-dimethyl-3-(4-((S)-2-(1-methyl-1H-pyrazole-5-carboxamido)-2-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamido)phenyl)pyridine 1-oxide or a pharma- ceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

5. A combination comprising a compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof and one or more therapeutically active agents.

6. A compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof for use as a medicament.

7. A compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of autoimmune diseases and inflammatory conditions, the autoimmune diseases and inflammatory conditions being selected from the group consisting of arthritis, rheumatic diseases, rheumatic diseases with bone loss, inflammatory pain, spondyloarthropathies, Reiter's syndrome, reactive arthritis, psoriatic arthritis, enteropathic arthritis, osteoarthritis, tendinopathy, hypersensitivity, allergy, asthma, autoimmune blood diseases, systemic lupus erythematosus, inflammatory myopathies, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine eye disorders, Graves' syndrome, and the like. and / or a pharmacologic agent that is capable of treating or preventing the onset of atopic dermatitis, sarcoidosis, primary biliary cirrhosis, juvenile onset diabetes mellitus (type I diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, Behcet's disease, lichen planus pilaris, lichen planus, hidradenitis suppurativa, acne, recurrent aphthous stomatitis and periodontal disease, pyoderma gangrenosum and other neutrophilic dermatoses, pityriasis rubra pilaris, bullous pemphigoid, ichthyosis, endometriosis, nonalcoholic steatohepatitis, interstitial pulmonary fibrosis, glomerulonephritis (with or without nephrotic syndrome), tumors, multiple sclerosis, autism, depressor DNA, Alzheimer's disease, inflammatory diseases of the skin and cornea, myositis, bone implant relaxation, and metabolic diseases.

8. 4. A compound according to any one of claims 1 to 3 or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis.

9. The pharmaceutical composition according to claim 4 for use in the treatment or prevention of autoimmune diseases and inflammatory conditions, wherein the autoimmune diseases and inflammatory conditions are selected from the group consisting of arthritis, rheumatic diseases, rheumatic diseases with bone loss, inflammatory pain, spondyloarthropathies, Reiter's syndrome, reactive arthritis, psoriatic arthritis, enteropathic arthritis, osteoarthritis, tendinopathy, hypersensitivity, allergy, asthma, autoimmune blood diseases, systemic lupus erythematosus, inflammatory myopathies, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, endocrine eye disorders, Graves' disease, sarcoidosis, and osteoporosis. idosis, primary biliary cirrhosis, juvenile diabetes mellitus (type I diabetes), uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, Behcet's disease, lichen planus pilaris, lichen planus, hidradenitis suppurativa, acne, recurrent aphthous stomatitis and periodontal disease, pyoderma gangrenosum and other neutrophilic dermatoses, pityriasis rubra pilaris, bullous pemphigoid, ichthyosis, endometriosis, non-alcoholic steatohepatitis, interstitial pulmonary fibrosis, glomerulonephritis (with or without nephrotic syndrome), tumors, multiple sclerosis, autism, depressor DNA, Alzheimer's disease, inflammatory diseases of the skin and cornea, myositis, loosening of bone implants, and metabolic diseases.

10. A pharmaceutical composition as described in claim 4 for use in the treatment or prevention of psoriasis, psoriatic arthritis, ankylosing spondylitis and axial spondyloarthritis not fulfilling radiographic criteria.

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