(EP3419969) Heteroaryl inhibitors of pad4 机翻标题: 暂无翻译,请尝试点击翻译按钮。

源语言标题
(EP3419969) Heteroaryl inhibitors of pad4
公开号/公开日
EP3419969 EP3419969 / 2019-12-18 2019-01-02
申请号/申请日
EP17708142 / 2017-02-22
发明人
DEVRAJ RAJESHKUMARAVEL GNANASAMBANDAMATTON HOLLYBEAUMONT EDWARDGADOULEAU ELISEGLEAVE LAURAKERRY PHILLIP STEPHENLECCI CRISTINAMENICONI MIRCOMONCK NATPALFREY JORDANPAPADOPOULOS KOSTASTYE HEATHERWOODS PHILIP A;
申请人
PADLOCK THERAPEUTICS;
主分类号
IPC分类号
A61K-031/4184 A61P-035/00 C07D-401/14 C07D-417/14 C07D-471/04
摘要
(EP3419969) The present invention provides compounds useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders.
机翻摘要
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地址
代理人
(EP3419969) Kling, Edouard ; Swords Laboratories, Ireland ([CH]) Reg. Nb: 101577342
代理机构
;
优先权号
2016US-62298726 2017WO-US18790
主权利要求
(EP3419969) 1. A compound of formula I':or a pharmaceutically acceptable salt thereof, wherein:   Ring A iswherein Ring A is optionally substituted with 1-4 groups selected from fluorine, -CN, -OR, or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;   Ring B is a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R1 is hydrogen, -Cy, or C1-6 aliphatic optionally substituted with -Cy and optionally further substituted with 1-4 groups selected from fluorine, -CN, or -OR;   each -Cy is independently a 6-membered aryl ring containing 0-2 nitrogen atoms, or a 4-7 membered saturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulphur, wherein -Cy is optionally substituted with 1-4 groups selected from fluorine, -CN, or -OR;   R2 is hydrogen, -CN, -OR, -Cy, or C1-10 aliphatic optionally substituted with -Cy and optionally further substituted with 1-5 groups selected from fluorine, -CN, or -OR; or: two R2 groups on the same carbon are optionally taken together to form =O;   n is 1, 2, or 3;   X1 is N or C(R3);   R3 is -R, halogen, or -OR;   each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;   L is selected from a covalent bond or a C1-6 membered straight or branched, saturated or unsaturated hydrocarbon chain wherein one methylene unit of L is optionally replaced by-S(O)2- or -C(O)N(Ry)-, wherein Ry is R or -CH2phenyl; and   R4 is halogen, R, phenyl, or a 5-6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulphur, wherein R4 is optionally substituted with 1-4 groups independently selected from halogen, -CN, -OR, -C(O)OH, or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms. 2. The compound according to claim 1, wherein said compound is of formula I'-a:or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, wherein said compound is of formula I'-b:or a pharmaceutically acceptable salt thereof. 4. The compound according to any of claims 1 through 3, wherein Ring A is 5. The compound according to claim 4, wherein Ring A is 6. The compound according to any of claims 1 through 5, wherein Ring B is a 6-membered heteroaryl ring having 1-2 nitrogens. 7. The compound according to any of claims 1 through 5, wherein Ring B is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 8. The compound according to claim 6, wherein Ring B is pyridyl. 9. The compound according to claim 7, wherein Ring B is imidazolyl, pyrazolyl, pyrrolyl, or thiazolyl. 10. The compound according to claim 9, wherein Ring B is pyrrolyl. 11. The compound according to any of claims 1 through 10, wherein R4 is phenyl or pyridyl. 12. The compound according to claim 1, which is selected from: 13. A pharmaceutically acceptable composition comprising the compound according to any of claims 1 through 12, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 14. The composition according to claim 13, in combination with an additional therapeutic agent. 15. A compound according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof for use in therapy. 16. A compound according to any of claims 1 to 12 or a pharmaceutically acceptable salt thereof or composition according to claim 15 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 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 syndrome, Bells Palsy, 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, 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 transplant rejection prophylaxis, leptospiriosis, leukemia, Loeffler's syndrome, lung injury, lung injury, 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, 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, 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. 17. The compound or pharmaceutically acceptable salt thereof or composition for use according to claim 16, 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. 18. The compound or pharmaceutically acceptable salt thereof or composition for use according to claims 16 or 17, wherein said subject is a human subject.
法律状态
GRANTED
专利类型码
B1 A1
国别省市代码
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