(EP3490989) Covalent inhibitors of pad4 机翻标题: 暂无翻译,请尝试点击翻译按钮。

(EP3490989) Covalent inhibitors of pad4
EP3490989EP3490989 / 2020-09-092019-06-05
EP17749074 / 2017-07-27
A61K-031/4184 A61K-031/437 A61K-031/4545 A61P-003/00 A61P-009/00 A61P-017/00 A61P-029/00 A61P-031/18 A61P-035/00 A61P-035/02 A61P-037/00 C07D-401/14 C07D-471/04
(EP3490989) The present invention provides compounds of formula I useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.
(EP3490989) Kling, Edouard ; Swords Laboratories, Ireland ([CH]) Reg. Nb: 101577342
2016US-62367389 2017WO-US44194
(EP3490989) 1. A compound of formula Ior a pharmaceutically acceptable salt thereof, wherein:   G isor   each R4 is independently selected from   R1 is hydrogen or C1-6 aliphatic;   R2 is hydrogen or C1-10 aliphatic;   X is selected from N or CH;   R3 is -R, or -OR; and   each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms. 2. The compound according to claim 1, wherein G is 3. The compound according to claim 1, wherein G isor 4. The compound according to claim 1, wherein G is selected from 5. The compound according to any one of claims 1 through 4, wherein R1 is methyl. 6. The compound according to any one of claims 1 through 5, wherein R2 is C1-10 aliphatic. 7. The compound according to claim 6, wherein R2 is -CH2-cyclopropyl. 8. The compound according to any one of claims 1 through 7, wherein X is N. 9. The compound according to any one of claims 1 through 7, wherein X is CH. 10. The compound according to claim 1, wherein said compound is selected from:andor a pharmaceutically acceptable salt thereof. 11. A pharmaceutically acceptable composition comprising the compound according to any of claims 1 through 10, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 12. The composition according to claim 11, in combination with an additional therapeutic agent. 13. A compound according to anyone of claims 1 to 10 or a pharmaceutically acceptable salt thereof or composition according to claim 11 to 12 for use in therapy. 14. A compound according to anyone of claims 1 to 10 or a pharmaceutically acceptable salt thereof or composition according to claim 11 to 12 for use in treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof, wherein the PAD4-mediated disease, disorder, or condition is selected from the group consisting of acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute, respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergen induced asthma, allergic bronchopulmonary, aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotropic lateral sclerosis, and weight loss, angina pectoris, angioedema, anhidrotic ecodermal dysplasia-ID, ankylosing spondylitis, anterior segment, inflammation, antiphospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmune hepatitis, bee sting-induced inflammation, behcet's disease, Behcet's syndrome, Bells Palsey, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns, bursitis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioretinitis, chronic heart failure, chronic lung disease of prematurity, chronic lymphocytic leukemia, chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, connective tissue disease, corneal ulcer, crohn's disease, cryopyrin-associated periodic syndromes, cyrptococcosis, cystic fibrosis, deficiency of the interleukin-1-receptor antagonist (DIRA), dermatitis, dermatitis endotoxemia, dermatomyositis, diffuse intrinsic pontine glioma, endometriosis, endotoxemia, epicondylitis, erythroblastopenia, familial amyloidotic polyneuropathy, familial cold urticarial, familial mediterranean fever, fetal growth retardation, glaucoma, glomerular disease, glomerular nephritis, gout, gouty arthritis, graft-versus-host disease, gut diseases, head injury, headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholein purpura, hepatitis, hereditary periodic fever syndrome, herpes zoster and simplex, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, hyperimmunoglobulinemia D with recurrent fever (HIDS), hypoplastic and other anemias, hypoplastic anemia, idiopathic thrombocytopenic purpura, incontinentia pigmenti, infectious mononucleosis, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, insect bite-induced inflammation, iritis, irritant-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, kidney injury caused by parasitic infections, kidney injury caused by parasitic infections, kidney transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler's syndrome, lung injury, lung injury, lupus, lupus, lupus nephritis, lymphoma, meningitis, mesothelioma, mixed connective tissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis), multiple sclerosis, muscle wasting, muscular dystrophy, myasthenia gravis, myocarditis, mycosis fungiodes, mycosis fungoides, myelodysplastic syndrome, myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onset multisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis, neuropathological diseases, non-allergen induced asthma, obesity, ocular allergy, optic neuritis, organ transplant, osterarthritis, otitis media, paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus, pericarditis, periodic fever, periodontitis, peritoneal endometriosis, pertussis, pharyngitis and adenitis (PFAPA syndrome), plant irritant-induced inflammation, pneumonia, pneumonitis, pneumosysts infection, poison ivy/ urushiol oil-induced inflammation, polyarteritis nodosa, polychondritis, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress diseases, pulmonary disease, pulmonary hypertension, pulmonayr fibrosis, pyoderma gangrenosum, pyogenic sterile arthritis, renal disease, retinal disease, rheumatic carditis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, severe pain, sickle cell, sickle cell anemia, silica-induced disease, Sjogren's syndrome, skin diseases, sleep apnea, solid tumors, spinal cord injury, Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporal arteritis, tenosynovitis, thrombocytopenia, thyroiditis, tissue transplant, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, transplant, traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, urticarial, uveitis, and Wegener's granulomatosis. 15. The compound or pharmaceutically acceptable salt thereof or composition for use according to claim 14, wherein the PAD4-mediated disease, disorder, or condition is selected from rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.