(US20190358216) 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
(US20190358216) Heteroaryl inhibitors of pad4
公开号/公开日
US20190358216 / 2019-11-28
申请号/申请日
US16/331,622 / 2017-09-11
发明人
DEVRAJ RAJESHKUMARAVEL GNANASAMBANDAMLECCI CRISTINALOKE PUI LENGMENICONI MIRCOMONCK NATHANIEL JULIUS THOMASNORTH CARL LESLIERIDGILL MARK PETERTYE HEATHER;
申请人
PADLOCK THERAPEUTICS;
主分类号
IPC分类号
A61K-031/4412 A61K-031/47 A61K-031/4709 A61K-031/5377 C07D-213/647 C07D-215/227 C07D-401/14 C07D-413/06
摘要
(US20190358216) 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
代理机构
;
优先权号
2016US-62393209 2017WO-US50886 US201716331622
主权利要求
(US20190358216) 1. A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound of formula I or formula II:  or a pharmaceutically acceptable salt thereof, wherein:   R1 is hydrogen or an optionally substituted group selected from aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R2 is hydrogen or optionally substituted C1-6-aliphatic;   L is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of L are optionally and independently replaced by —C(O)—, —C(O)NH—, —NHC(O)—, or —S(O)2—;   R3 is hydrogen or Ring A;   Ring A is an optionally substituted ring selected from a 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R4 is R or —C(O)OR;   each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;   R5 is hydrogen or CN, or:    R5 and R4 are taken together with their intervening atoms to form a triazole ring; or    R5 and R3 are taken together with their intervening atoms to form a triazole ring; and   Rx and Ry are each independently selected from hydrogen, halogen, optionally substituted C1-6 aliphatic, or:    Rx and Ry are taken together with their intervening atoms to form a optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 2. A method of treating a PAD4-mediated disease, disorder, or condition in a subject in need thereof comprising the step of administering to said subject a compound formula I or formula II:  or a pharmaceutically acceptable salt thereof, wherein:   R1 is hydrogen or an optionally substituted group selected from aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R2 is hydrogen or optionally substituted C1-6-aliphatic;   L is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of L are optionally and independently replaced by —C(O)—, —C(O)NH—, —NHC(O)—, or —S(O)2—;   R3 is hydrogen or Ring A;   Ring A is an optionally substituted ring selected from a 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R4 is R or —C(O)OR;   each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;   R5 is hydrogen or CN, or:    R5 and R4 are taken together with their intervening atoms to form a triazole ring; or    R5 and R3 are taken together with their intervening atoms to form a triazole ring; and   Rx and Ry are each independently selected from hydrogen, halogen, optionally substituted C1-6 aliphatic, or:    Rx and Ry are taken together with their intervening atoms to form a optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 3. The method according to claim 2, selected from any one of formula I-i, I-ii, II-i, or II-ii: or a pharmaceutically acceptable salt thereof. 4. The method according to claim 3, wherein R1 is —S(CH3), 5. The method according to claim 3, wherein R2 is H, methyl, ethyl, 6. The method according to claim 3, wherein L is 7. The method according to claim 2, wherein R3 is selected from H, 8. The method according to claim 2, wherein R4 is H, CH3 or —C(O)OR. 9. The method according to claim 2, wherein R5 is hydrogen or CN, or: R5 and R4 are taken together with their intervening atoms to form a triazole ring; or R5 and R3 are taken together with their intervening atoms to form a triazole ring. 10. The method according to claim 2, wherein Rx and Ry are each independently selected from hydrogen, halogen, or optionally substituted C1-6 aliphatic. 11. The method according to claim 2, wherein Rx and Ry are taken together with their intervening atoms to form a optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 12. The method according to claim 3, wherein said compound is selected from those set forth in Table 1, or a pharmaceutically acceptable salt thereof. 13. The method according to claim 2, wherein said subject is a human subject. 14. The method according to claim 2, wherein said subject is a veterinary subject. 15. The method according to claim 13, 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, Bell's 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, cryptococcosis, 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. 16. The method according to claim 15, 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. 17. A compound of formula I or formula II:  or a pharmaceutically acceptable salt thereof, wherein:   R1 is hydrogen or an optionally substituted group selected from aliphatic, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R2 is hydrogen or optionally substituted C1-6-aliphatic;   L is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of L are optionally and independently replaced by —C(O)—, —C(O)NH—, —NHC(O)—, or —S(O)2—;   R3 is hydrogen or Ring A;   Ring A is an optionally substituted ring selected from a 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring, phenyl, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered monocyclic saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   R4 is R or —C(O)OR;   each R is independently hydrogen or C1-6 aliphatic optionally substituted with 1-3 fluorine atoms;   R5 is hydrogen or CN, or:    R5 and R4 are taken together with their intervening atoms to form a triazole ring; or    R5 and R3 are taken together with their intervening atoms to form a triazole ring; and   Rx and Ry are each independently selected from hydrogen, halogen, optionally substituted C1-6 aliphatic, or:    Rx and Ry are taken together with their intervening atoms to form a optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;   provided that said compound of formula I is other than a compound selected from I-69, I-76 or I-114 and those depicted in Table 2. 18. The compound according to claim 17, wherein said compound is selected from any one of formula I-i, I-ii, II-i, or II-ii:  or a pharmaceutically acceptable salt thereof. 19. The compound according to claim 17, wherein R1 is —S(CH3), 20. The compound according to claim 17, wherein R2 is H, methyl, ethyl, 21. The compound according to claim 17, wherein L is 22. The compound according to claim 17, wherein R3 is selected from H, 23. The compound according to claim 17, wherein R4 is H, CH3 or —C(O)OR. 24. The compound according to claim 17, wherein R5 is hydrogen or CN, or: R5 and R4 are taken together with their intervening atoms to form a triazole ring; or   R5 and R3 are taken together with their intervening atoms to form a triazole ring. 25. The compound according to claim 17, wherein Rx and Ry are each independently selected from hydrogen, halogen, or optionally substituted C1-6 aliphatic. 26. The compound according to claim 17, wherein Rx and Ry are taken together with their intervening atoms to form a optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 27. The compound according to claim 17, wherein said compound is selected from those set forth in Table 1, or a pharmaceutically acceptable salt thereof. 28. A pharmaceutically acceptable composition comprising the compound according to claim 17, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 29. The composition according to claim 28, in combination with an additional therapeutic agent.
法律状态
PENDING
专利类型码
A1
国别省市代码
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