(JP2019505568) PAD4 Bicyclic inhibitor 机翻标题: 暂无翻译,请尝试点击翻译按钮。

(JP2019505568) PAD4 Bicyclic inhibitor
JP2019505568 / 2019-02-28
JP2018549402 / 2016-12-09
Rajesh DebrageGunanasan Bandam KumarabelMichael F. ParkerLaura GleevePhilip KellyAdrian CotyThomas KrallChristina LetchMirko MeniconiHeather Thailand;
A61K-008/49 A61K-031/4184 A61K-031/437 A61K-031/4375 A61K-031/438 A61K-031/439 A61K-031/4545 A61K-031/46 A61K-031/519 A61K-031/5383 A61K-045/00 A61P-001/02 A61P-001/04 A61P-001/14 A61P-001/16 A61P-001/18 A61P-003/00 A61P-003/02 A61P-003/04 A61P-003/06 A61P-003/10 A61P-005/14 A61P-005/38 A61P-007/00 A61P-007/04 A61P-007/06 A61P-007/10 A61P-009/00 A61P-009/10 A61P-009/12 A61P-009/14 A61P-011/00 A61P-011/02 A61P-011/04 A61P-011/06 A61P-011/14 A61P-011/16 A61P-013/12 A61P-015/00 A61P-017/00 A61P-017/02 A61P-017/04 A61P-017/06 A61P-017/08 A61P-017/10 A61P-017/14 A61P-019/02 A61P-019/04 A61P-019/08 A61P-021/00 A61P-021/04 A61P-025/00 A61P-025/02 A61P-025/04 A61P-025/14 A61P-025/20 A61P-025/28 A61P-027/02 A61P-027/06 A61P-027/12 A61P-027/14 A61P-027/16 A61P-029/00 A61P-029/02 A61P-031/04 A61P-031/06 A61P-031/18 A61P-031/22 A61P-033/02 A61P-035/00 A61P-035/02 A61P-037/06 A61P-037/08 A61P-039/02 A61P-043/00 A61Q-017/04 A61Q-019/00 C07D-403/14 C07D-453/06 C07D-471/04 C07D-487/04 C07D-519/00 C12N-009/78 C12N-009/99
(JP2019505568) The present invention relates to, PAD4 compounds useful as inhibitors of, and compositions therefor PAD4 provides methods for treating inflammation-related diseases.
(JP2019505568) Norihito Yamao Reg. Nb: 100145403 Shinagawa Erikoshi Reg. Nb: 100126778 Wu Ying Reg. Nb: 100162684 Shuhei Kabeiri Reg. Nb: 100162695 Masahiro Suwara Reg. Nb: 100156155
(JP2019505568) 1. Of the formula I ': [shown in the formula, the ring is A, or, A is a ring, a fluorine, - CN, - OR or C1-6 aliphatic group is preferably (1-3 optionally substituted with one fluorine atom and may also be) one group selected from 1-4 and may be optionally substituted; B is ring, and; R1 is, hydrogen, - CN, - OR, or C1-6 aliphatic group (fluorine, - CN or - OR is selected from 1-4 optionally substituted with one group that may be) and the; R2 is, or is hydrogen, fluorine, - CN or - OR is selected from 1-5 optionally substituted with one group that may be C1-10 aliphatic group; X1 and X2 are each, independently, C N or (R4) is selected from the group; R3 is, halogen, - CN, - R, or - OR and; each R4 is, independently, halogen, - CN, - R, and; R5 is, hydrogen or halogen; 0-4 and n is; R and each is, independently, hydrogen or, or a 1-3 optionally substituted with one fluorine atom and may be aliphatic group C1-6] of the compound or a pharmaceutically acceptable salt thereof.  2. A is a ring,  in, a compound according to claim 1.  3. A is a ring,  in, a compound according to claim 1. 4. R1 Is, methyl, ethyl or propyl, wherein the compound of any one of claims 1-3. 5. R2 Is, 1-5 optionally substituted with one fluorine atom and may be aliphatic group C1-10, of a compound according to any one of claims 1-4. 6. R2 Is, methyl, ethyl or cyclopropyl - CH2-, the compound according to claim 5. 7. R2 Is, one fluorine atom is substituted by a 1-5 C1-10 is an aliphatic group, a compound according to claim 5. 8. R2 Is, - CH2CF3 in, a compound of according to claim 7. 9. X1 Is X2 and both N, the compound of any one of claims 1-8. 10. X1 Is N and, when X2 is CH, wherein the compound of any one of claims 1-8. 11. X1 Is CH and, when X2 is N, compound of any one of claims 1-8. 12. X1 Is CH X2 and both, wherein the compound of any one of claims 1-8. 13. R4 Is, in the aliphatic group or an - OR C1-6, of a compound according to any one of claims 1-12. 14. R4 Is, in which the ethyl or - OCH3, of a compound according to claim 13. 15. Wherein the compound of any one of claims 1-14, and a pharmaceutically acceptable carrier, adjuvant or vehicle, a pharmaceutically acceptable composition. 16. In combination with another therapeutic agent, a composition according to claim 15. 17. PAD4 The, compound of any one of claims 1-14 contacting and, in a biological sample of the subject or inhibiting PAD4. 18. PAD4-mediated disease, disorder or condition the treatment method comprising, administering to said subject a composition according to claim 15 characterized by the, method. 19. Wherein the subject is a human subject, the method according to claim 18. 20. PAD4-mediated disease, disorder or condition is, acid-induced lung injury, acne (PAPA), acute lymphocytic leukemia, acute respiratory distress syndrome, Addison's disease, adrenal hyperplasia, adrenal cortical function, aging, AIDS, alcoholic hepatitis, alcoholic hepatitis, alcoholic liver disease, allergic asthma, allergic bronchopulmonary aspergillosis, allergic conjunctivitis, alopecia, Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis and weight loss, angina, angioedema, noteasily non-ectodermal imperfecta (AHED-ID), ankylosing spondylitis, inflammatory eye, anti phospholipid syndrome, aphthous stomatitis, appendicitis, arthritis, asthma, arteriosclerosis is atherosclerosis, atopic dermatitis, auto-immune diseases, auto-immune hepatitis, Suma sting-induced inflammation, Behcet's disease, Behcet's Syndrome, Bell's palsy, beryllium Trombiculiasis intoxication, blaeu Syndrome, bone pain, bronchiolitis, burns, gouty arthritis, cancer, cardiac hypertrophy, carpal tunnel syndrome, catabolic disorders, cataracts, cerebral aneurysm, chemical irritant-induced inflammation, chorioidea retinitis, chronic heart disease, chronic lung disease of prematurity, chronic lymphocytic leukemia, or chronic obstructive pulmonary disease, colitis, complex regional pain syndrome, collagen, corneal ulcers, or Crohn's disease, cryopyrin-associated periodic syndrome heat, Cryptococcus Trombiculiasis, cystic fibrosis, interleukin-1-receptor antagonist (DIRA) deficiency, dermatitis, endotoxemia dermatitis, dermatomyositis, brain stem glioma unit FEVI, endometriosis, endotoxemia, epicondylitis, erythroblasts thrombocytopenia, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean Fever, fetal growth retardation, glaucoma, glomerular disease, glomerulonephritis, gout, gouty arthritis, graft versus host disease, gastrointestinal disease, head trauma, migraine, hearing loss, a heart disease, hemolytic anemia, Henoch, shea line purpura, hepatitis, inflammatory syndromes of hereditary self, herpes simplex and herpes zoster, HIV-1, Hodgkin's disease, Huntington's disease, hyaline membrane disease, hyperammonemia, hypercalcemia, hypercholesterolemia, high heat cycle with blood immunoglobulin (HIDS) D syndrome, aplastic anemia and other anemia, aplastic anemia, idiopathic thrombocytopenic purpura, Kanko dystonia, NNIS mononuclear infectious, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory pain, inflammation of insect bites, iris prostatistis, irritant-induced inflammation, ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidney disease, renal dysfunction caused by a parasite infection, parasite infection causing the renal dysfunction, kidney transplant rejection prevention, Leptospirosis, leukemia, leffler syndrome, lung injury, lung injury, lupus erythematosus, lupus erythematosus, lupus nephritis, lymphoma, meningitis, mesothelioma, a mixed collagen, (urticaria deafness amyloidosis) muckle wells syndrome, multiple sclerosis, muscle fatigue, muscular dystrophy, myasthenia gravis, myocarditis, breath dehaving aspapillomatosis Wagatsuma-, breath-Wagatsuma epithelieal, myelodysplastic syndrome, myositis, nasal sinusitis, necrotic enteritis total, neonatal onset (NOMID) inflammatory diseases of multi-organ failure, nephrotic syndrome, neuritis, neuropathological diseases, non-allergic asthma induced, obesity, ocular allergies, optic neuritis, organ implanted, osteoarthritis, otitis media, Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigoid, pericarditis, the thermal cycle, periodontatitis, peritoneal endometriosis, cough, sore throat (PFAPA syndrome) prostatistis or lymph nodes, plant STIMULATION inflammation, pneumonia, lung prostatistis (pneumonitis), pneumocystic pneumonia, ivy induced inflammatory oil/heptadecyicatechol, tuberosity pericardiacophrenic polyneuropathy, cartilage herpesvisrus, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress disease, pulmonary disease, pulmonary hypertension, lung fibrosis, psoriasis pus-gangrene, suppurative arthritis, kidney disease, retinal disease, rheumatic arthritis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, demonstrtaes, severe pain, sickle cell disease, sickle cell anemia, and silica-induced disease, Sjogren's syndrome, skin disorders, sleep apnea, solid tumors, spinal cord injury, stevens, Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn, temporalis arteritis, paratendinitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, implant, traumatic brain injury, tuberculosis, diabetes I, diabetes type II, ulcerative colitis, uveitis gradate urticaria, wegener and uveitis is selected from the group consisting of granulomatous disease, the method according to claim 18. 21. PAD4-mediated disease, disorder or condition, arthritis such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis selected from the, method according to claim 18.