US2017183362A1PendingUtilityA1
Inhibitors of arginase and their therapeutic applications
Est. expiryApr 22, 2030(~3.7 yrs left)· nominal 20-yr term from priority
Inventors:Michael Van ZandtAdam GolebiowskiMin Koo JiDarren WhitehouseTodd RyderRaymond Paul Beckett
A61P 37/02A61P 7/06A61P 9/10A61P 37/06A61P 9/00A61P 9/12A61P 37/00A61P 3/10A61P 43/00A61P 7/00A61P 33/02A61P 29/00A61P 25/00A61P 31/04A61P 31/00A61P 35/00A61P 31/10A61P 25/08A61P 25/28A61P 31/18A61P 31/20A61P 15/10A61P 13/02A61P 21/00A61P 11/06A61P 1/16A61P 1/04A61P 17/02A61P 1/02A61P 19/08A61P 17/06A61P 11/00A61P 15/00A61P 13/12A61P 19/02A61P 1/14A61P 21/04A61P 1/00A61P 17/00C07F 5/025A61K 31/69A61K 49/00A61K 31/155C07F 5/02
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Claims
Abstract
Compounds according to Formula I and Formula II are potent inhibitors of Arginase I and II activity: where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , D, M, X, and Y are defined as set forth in the specification. The invention also provides pharmaceutical compositions of the compounds and methods of their use for treating or preventing a disease or a condition associated with arginase activity.
Claims
exact text as granted — not AI-modified1 - 53 . (canceled)
54 . A compound according to Formula I,
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein:
R 1 is selected from —OH, OR a , and NR b R c ;
R a is selected from hydrogen, straight or branched chain (C 1 -C 6 )alkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-;
R b and R c are each independently selected from H, —OH, straight or branched (C 1 -C 6 )alkyl, —S(O) 2 —(C 1 -C 6 )alkyl, (C 3 -C 14 )aryl-S(O) 2 —, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, and (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-;
R 3 and R 4 are each independently selected from hydrogen, straight or branched (C 1 -C 6 )alkyl, and C(O)—R′,
or R 3 and R 4 together with the boron atom to which they are bound form a 5- or 6-membered ring that is fully or partially saturated, and that optionally contains 1-3 additional heteroatom ring members selected from O, S, and N;
D is selected from straight or branched (C 1 -C 6 )alkylene, straight or branched (C 2 -C 8 )alkenylene, straight or branched (C 2 -C 8 )alkynylene, (C 3 -C 14 )arylene, and (C 3 -C 14 )cycloalkylene;
wherein one or more —CH 2 — groups in D are optionally and independently replaced with a moiety Q that is selected from O, NR′, S, SO, SO 2 , and CR′R″; or
wherein any two adjacent —CH 2 — groups optionally are replaced by two members of a (C 3 -C 14 )-cycloalkylenyl group;
provided that D does not contain two adjacent Q moieties selected from O, NR′, S, SO, and SO 2 ;
R′ and R″ are each independently selected from the group consisting of H, (C 1 -C 8 )alkyl, and (C 3 -C 6 )aryl; and
wherein either:
(A) R 2 is selected from straight or branched (C 1 -C 6 )alkyl, straight or branched (C 2 -C 6 )alkenyl, straight or branched (C 2 -C 6 )alkynyl, (C 3 -C 14 )aryl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 3 -C 6 )heterocycloalkylene-, (C 3 -C 14 )aryl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )-aryl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, and —(CH 2 ) m —(X) u —(CH 2 ) n —(Y) v —R f ;
u and v are each independently 0 or 1, and u+v≧1;
m and n are each independently 0, 1, 2, 3, 4, 5, or 6, wherein m+n≧1;
X and Y are independently selected from —NH, —O— and —S—;
R f is selected from H, hydroxyl, straight or branched (C 1 -C 6 )alkyl and (C 3 -C 14 )aryl; and
R 5 is selected from straight or branched (C 1 -C 6 ) alkyl and (C 1 -C 6 )alkyl-C(O)—; or
(B) R 2 is (C 3 -C 14 )heterocycloalkyl-(C 1 -C 2 )alkylene-; and
R 5 is selected from the group consisting of H, straight or branched (C 1 -C 6 ) alkyl, and (C 1 -C 6 )alkyl-C(O)—;
wherein any alkyl, alkylene, alkenyl, alkenylene, alkynyl, or alkynylene is optionally substituted with one or more members selected from halogen, oxo, —COOH, —CN, —NO 2 , —OH, —NR d R e , —NR g S(O) 2 R h , (C 1 -C 6 )alkoxy, and (C 3 -C 14 )aryloxy;
R d , R e , R g , and R h are each independently selected from H, straight or branched (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 14 )aryl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )aminoalkyl, H 2 N(C 1 -C 6 )alkylene-, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 14 )heterocycloalkyl, optionally substituted (C 3 -C 14 )heteroaryl, optionally substituted (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene-, NR′R″C(O)—, and (C 3 -C 6 )aryl-(C 3 -C 14 )-cycloalkylene-, and
wherein any aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more members selected from halogen, —OH, oxo, —COOH, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, —CN, —NO 2 , —NH 2 , (C 1 -C 6 )alkyl-S—, (C 3 -C 14 )cycloalkyl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heteroaryl, —C(O)NH—(C 1 -C 6 )alkyl, —NHC(O)—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )hydroxyalkyl.
55 . The compound of claim 54 , wherein D is straight or branched (C 1 -C 6 )alkylene.
56 . The compound of claim 55 , wherein D is butylene.
57 . The compound of claim 55 , wherein R 1 is —OH.
58 . The compound of claim 57 , wherein
(A) R 2 is selected from straight or branched (C 1 -C 6 )alkyl, straight or branched (C 2 -C 6 )alkenyl, straight or branched (C 2 -C 6 )alkynyl, (C 3 -C 14 )aryl, (C 3 -C 14 )-cycloalkyl, (C 3 -C 14 )aryl(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 3 -C 6 )heterocycloalkylene-, (C 3 -C 14 )aryl-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )-aryl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-(C 3 -C 14 )heterocycloalkylene-, and —(CH 2 ) m —(X) u —(CH 2 ) n —(Y) v —R f ; and each of R 3 and R 4 is hydrogen; or (B) R 2 is (C 3 -C 14 )heterocycloalkyl-(C 1 -C 2 )alkylene-; and each of R 3 , and R 4 and R 5 is hydrogen.
59 . The compound of claim 58 , wherein:
R 2 is selected from (C 1 -C 6 )alkyl, (C 3 -C 14 )aryl, (C 3 -C 14 )heteroaryl, (C 3 -C 14 )heterocycloalkyl, (C 3 -C 14 )heterocycloalkyl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-, (C 3 -C 14 )aryl-(C 1 -C 6 )alkylene- and —(CH 2 ) n —(X) u —(CH 2 ) m —(Y) v —R f , and R 5 is selected from straight or branched (C 1 -C 6 ) alkyl and (C 1 -C 6 )alkyl-C(O)—.
60 . The compound of claim 59 , wherein R 2 is (C 3 -C 6 )heterocycloalkyl-(C 1 -C 2 )alkylene optionally substituted with one or more members selected from —(C 1 -C 6 )alkoxy, —(C 1 -C 6 )alkyl, and —OH.
61 . The compound of claim 59 , wherein R 2 is (C 3 -C 14 )heteroaryl-(C 1 -C 6 )alkylene-.
62 . The compound of claim 54 , selected from the following table:
or a pharmaceutically acceptable salt or stereoisomer thereof.
63 . A compound according to claim 62 , selected from:
or a pharmaceutically acceptable salt or stereoisomer thereof.
64 . A pharmaceutical composition comprising at least one compound of claim 54 , or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; and a pharmaceutically acceptable carrier.
65 . A method for the treatment or prevention of a disease or condition associated with expression or activity of arginase I, arginase II, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of at least one compound according to claim 54 .
66 . The method of claim 65 , wherein the disease or condition is selected from cardiovascular disorders, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, pulmonary disorders, and hemolytic disorders.
67 . The method of claim 66 , wherein the disease or condition is a cardiovascular disorder selected from systemic hypertension, pulmonary arterial hypertension (PAH), pulmonary arterial hypertension in high altitude, ischemia reperfusion (IR) injury, myocardial infarction, atherosclerosis, Peyronie's Disease, erectile dysfunction, reduced hepatic blood flow disorders, and cerebral vasospasm.
68 . The method of claim 66 , wherein the disease or condition is a pulmonary disorder selected from chemically-induced lung fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.
69 . The method of claim 66 , wherein the disease or condition is an autoimmune disorder selected from encephalomyelitis, multiple sclerosis, anti-phospholipid syndrome 1, autoimmune hemolytic anaemia, chronic inflammatory demyelinating polyradiculoneuropathy, dermatitis herpetiformis, dermatomyositis, myasthenia gravis, pemphigus, rheumatoid arthritis, stiff-person syndrome, type 1 diabetes, ankylosing spondylitis, paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria, severe idiopathic autoimmune hemolytic anemia, and Goodpasture's syndrome.
70 . The method of claim 66 , wherein the disease or condition is an immune disorder selected from myeloid-derived suppressor cell (MDSC) mediated T-cell dysfunction, human immunodeficiency virus (HIV), autoimmune encephalomyelitis, and ABO mismatch transfusion reaction.
71 . The method of claim 66 , wherein the disease or condition is a hemolytic disorder selected from sickle-cell disease, thalassemias, hereditary spherocytosis, stomatocytosis, microangiopathic hemolytic anemias, pyruvate kinase deficiency, infection-induced anemia, cardiopulmonary bypass and mechanical heart valve-induced anemia, and chemical induced anemia.
72 . The method of claim 66 , wherein the disease or condition is a gastrointestinal disorder selected from gastrointestinal motility disorders, gastric cancers, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and gastric ulcers.
73 . The method of claim 66 , wherein the disease or condition is selected from renal disease, inflammation, psoriasis, leishmaniasis, neurodegenerative diseases, wound healing, hepatitis B virus (HBV), H. pylori infections, fibrotic diseases, arthritis, candidiasis, periodontal disease, keloids, adenotonsillar disease, African sleeping sickness, and Chagas' disease.
74 . The method of claim 65 , wherein the disease or condition is cancer.
75 . The method of claim 74 , wherein the cancer is renal cell carcinoma, prostate cancer, colorectal cancer, breast cancer, skin cancer, lung cancer, ovarian cancer, or gastric cancer.Join the waitlist — get patent alerts
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