(JP2019505597) PAD4 Heteroaryl inhibitors 机翻标题: 暂无翻译,请尝试点击翻译按钮。

(JP2019505597) PAD4 Heteroaryl inhibitors
JP2019505597 / 2019-02-28
JP2018563393 / 2017-02-22
Rajesh DebrageGunanasan Bandam KumarabelLaura GleeveChristina LetchMirko MeniconiHeather Thailand;
A61K-031/4184 A61K-031/437 A61K-031/4439 A61K-031/454 A61K-031/4545 A61K-031/506 A61K-031/5377 A61K-045/00 A61P-001/00 A61P-001/02 A61P-001/04 A61P-001/16 A61P-001/18 A61P-003/04 A61P-003/06 A61P-003/10 A61P-003/14 A61P-005/14 A61P-005/38 A61P-007/00 A61P-007/02 A61P-007/04 A61P-007/06 A61P-007/10 A61P-009/00 A61P-009/10 A61P-009/12 A61P-011/00 A61P-011/02 A61P-011/06 A61P-011/14 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-019/06 A61P-019/08 A61P-021/00 A61P-021/02 A61P-021/04 A61P-025/00 A61P-025/02 A61P-025/04 A61P-025/14 A61P-025/16 A61P-025/18 A61P-025/22 A61P-025/28 A61P-027/02 A61P-027/06 A61P-027/12 A61P-027/16 A61P-029/00 A61P-029/02 A61P-031/04 A61P-031/06 A61P-031/10 A61P-031/18 A61P-031/22 A61P-033/02 A61P-035/00 A61P-035/02 A61P-037/02 A61P-037/06 A61P-037/08 A61P-039/02 A61P-043/00 C07D-401/14 C07D-403/14 C07D-405/14 C07D-417/14 C07D-471/04
(JP2019505597) The present invention provides, PAD4 compounds useful as inhibitors and compositions thereof, as well as PAD4 provides methods for treating inflammation-related diseases.
(JP2019505597) 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
(JP2019505597) 1. Of the formula I ': [shown in the formula, the ring is A, FPAs, A is ring or, fluorine, - CN, - OR or aliphatic C1-6 (1-3 one fluorine atom and optionally substituted with one or) one group selected from 1-4 and may be optionally substituted; B is a ring, the nitrogen, oxygen or sulfur 1-3 are independently selected from a 5-6 membered heteroaryl having one heteroatom in the ring; R1 is, hydrogen, or an aliphatic - Cy C1-6 (- Cy is an optionally substituted group which may be, and fluorine, - CN or - OR is selected from a 1-4 one of the two radicals optionally may be further substituted) and; - Cy is each, independently, 0-2 6 membered containing one nitrogen atom in the aryl ring, or nitrogen, are independently selected from nitrogen oxygen or sulfur heteroatoms 0-2 membered saturated monocyclic ring having 4-7 and, in this case is - Cy, fluorine, - CN or - OR is selected from 1-4 optionally substituted with one group that may or may not be; R2 is, hydrogen, - CN, - OR, or - Cy C1-10 aliphatic (- Cy is an optionally substituted group which may be, and fluorine, - CN or - OR is selected from a 1-5 one of the two radicals optionally may be further optionally substituted) and; 2 on the same carbon or two R2 groups, together if desired, may be=O form; n is, 1, 2 or 3 and; X1 is, (R3) and N C or; R3 is, - R, halogen or - OR and; R are each, independently, hydrogen or, or a 1-3 optionally substituted with one fluorine atom and may be aliphatic C1-6; L is, or is selected from a covalent bond, or straight-chain or branched C1-6-membered saturated or unsaturated chain and a saturated hydrocarbon chain, wherein one methylene unit of the 1 L, -S (O) 2-or (Ry) - C N (O) -by may be optionally substituted, where Ry is, or a R, or - CH2 phenyl; R4 is, halogen, R, phenyl or 5-6 membered heteroaryl ring (nitrogen, oxygen or sulfur independently selected heteroatoms having 1-3) and, in this case is R4, halogen, - CN, - OR, OH or (O) - C aliphatic C1-6 (1-3 one fluorine atom and optionally substituted with one or) 1-4 are independently selected from the groups is optionally substituted with one group that may be] compound, or a pharmaceutically acceptable salt thereof.  2. Of the formula I ' - a:  in, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.  3. Of the formula I ' - b:  in, a compound according to claim 1 or a pharmaceutically acceptable salt thereof.  4. A is a ring,  in, wherein the compound of any one of claims 1-3.  5. A is a ring,  in, a compound according to claim 4. 6. B is a ring, 1-2 membered heteroaryl ring having one nitrogen in the 6, of a compound of any one of claims 1-5. 7. B is a ring, the nitrogen, oxygen or sulfur and independently selected from a 5 membered heteroaryl having 1-3 heteroatoms in the ring, comprising a compound of any one of claims 1-5. 8. B is a ring, pyridyl, of a compound according to claim 6. 9. B is a ring, imidazolyl, pyrazolyl, pyrrolyl or thiazolyl, of a compound according to claim 7. 10. B ring is a pyrrolyl, a compound according to claim 9. 11. R4 Is, phenyl or pyridyl, any one of claims 1-10 compound. 12. Wherein said compound is, selected from the compounds described in Table 1 that is, a compound according to claim 1. 13. Wherein the compound of any one of claims 1-12, and a pharmaceutically acceptable carrier, adjuvant or vehicle, a pharmaceutically acceptable composition. 14. In combination with another therapeutic agent, a composition according to claim 13. 15. PAD4 The, compound of any one of claims 1-12 contacting and, in a biological sample of the subject or inhibiting PAD4. 16. PAD4-mediated disease, disorder or condition in a method of treating, according to claim 13 composition to said subject and wherein the step of administering, the method. 17. Wherein the subject is a human subject, the method according to claim 16. 18. Wherein the subject is a livestock subject, the method according to claim 16. 19. PAD4-mediated disease, disorder or condition, of 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 part children, 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, hereditary periodic fever syndrome, herpes simplex and herpes zoster, HIV-1, Hodgkin's disease, Huntington's disease, idiopathic neonatal respiratory disorder aspapillomatosis (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, infectious mononuclear disease, 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, renal disorders caused by a parasite infection, kidney transplantation 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-Wagatsuma Trombiculiasis dehaving, breath-Wagatsuma epithelieal, myelodysplastic syndrome, myositis, sinusitis, necrotizing enterocolitis and enteritis, neonatal onset (NOMID) multiple organ system disease, 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, pertussis, pharyngitis or lymph nodes prostatistis (PFAPA syndrome), inflammation INVERSE plant, (pneumonia) pneumonia, lung prostatistis (pneumonitis), pneumocystic pneumonia, ivy induced inflammatory oil/heptadecyicatechol, polyarteritis, cartilage Malehorn, polycystic kidney disease, polymyositis, psoriasis, psoriasis, psoriasis, psoriasis, psychosocial stress disease, pulmonary disease, pulmonary hypertension, lung fibrosis, psoriasis pus-gangrene, suppurative Mutagen arthritis, kidney disease, retinal disease, rheumatic arthritis, rheumatic disease, rheumatoid arthritis, sarcoidosis, seborrhea, sepsis, 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, temporal arteritis, paratendinitis, thrombocytopenia, thyroiditis, tissue transplantation, TNF receptor associated periodic syndrome (TRAPS), toxoplasmosis, implant, traumatic brain injury, tuberculosis, I diabetes mellitus, type II diabetes, ulcerative colitis, uveitis gradate urticaria, wegener and uveitis is selected from the group consisting of granulomatous disease, the method according to claim 16. 20. PAD4-mediated disease, disorder or condition, rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, lupus erythematosus and psoriasis is selected from a skin, a method according to claim 16.