US2017196874A1PendingUtilityA1
Biaryl compositions and methods for modulating a kinase cascade
Est. expiryDec 28, 2024(expired)· nominal 20-yr term from priority
Inventors:David G. Hangauer, Jr.
A61P 9/10A61P 35/04A61P 37/02A61P 37/00A61P 9/00A61P 3/10A61P 25/00A61P 27/02A61P 31/20A61P 27/16A61P 31/12A61P 3/04A61P 35/00A61K 31/495A61P 19/10C07D 403/04A61K 31/5377C07C 233/13C07D 213/74C07D 213/56A61P 17/06A61K 9/0053C07D 239/26C07D 401/12C07D 213/89C07D 239/34C07D 213/64C07C 233/22
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Claims
Abstract
The invention relates to compounds and methods for modulating one or more components of a kinase cascade.
Claims
exact text as granted — not AI-modified1 .- 3 . (canceled)
4 . A method of inhibiting or relieving a disease or disorder selected from hearing loss, osteoporosis, type II diabetes, obesity, transplant rejection, stroke, atherosclerosis, chronic neuropathic pain, hepatitis B, a cardiovascular disorder, an immune system dysfunction, and an ophthalmic disorder in a subject, comprising administering to the subject a compound having Formula I:
or a salt, solvate, hydrate, or prodrug thereof, wherein:
T is a bond, CR 12 R 13 , C(O), O, S, S(O), S(O) 2 , NR 14 , C(R 15 R 16 )C(R 17 R 18 ), CH 2 O, or OCH 2 ;
X y is CZ, CY, N, or N—O;
X z is CZ, CY, N, or N—O;
at least one of X y and X z is CZ;
Y is H, hydroxyl, halogen, lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, or O-benzyl;
X a is CR a N, or N—O;
X b is CR b , N, or N—O;
X c is CR, N, or N—O;
X d is CR d N, or N—O;
X e is Me, N, or N—O;
R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 are independently H, hydroxyl, halogen, P, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, COOH, COO-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 6 , or C 6 alkyl-aryl;
P is SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 20 R 21 ,
tetrazole, O-lower (C 1 , C 2 , C 3 , C 4 , CS, or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , CS, or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19, R 20 , and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —;
R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
Z is (CHR 1 ) n —C(O)—NR 2 (CHR 3 ) m —Ar, wherein Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group;
R 2 , and R 3 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; and
n and m are independently 0, 1, or 2.
5 . The method of claim 4 , wherein T is a bond.
6 . The method of claim 4 , wherein at least one of X a , X b , X c , X d , X e , X y , and X z is N.
7 . The method of claim 4 , wherein X y is CY, N, or N—O and X z is CZ.
8 . The method of claim 7 , wherein X y is N.
9 . The method of claim 7 , wherein X y is CY.
10 . The method of claim 7 , wherein Z is
wherein:
R 7 , R 8 , R 9 , R 10 , and R 11 are independently H, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH. C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O—C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl,
W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl; and
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —.
11 . The method of claim 10 , wherein at least one of R 7 , R 8 , R 9 , R 10 and R 11 is halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or O-benzyl.
12 . The method of claim 10 , wherein m and n are each 1 and R 2 and R 3 are each H.
13 . The method of claim 4 , wherein X b is CR b ; X c is CR c ; and X d is CR d .
14 . The method of claim 4 , wherein the compound is selected from:
15 . The method of claim 4 , wherein the compound is selected from:
16 . The method of claim 4 , wherein the disease or disorder is selected from hearing loss, osteoporosis, type II diabetes, obesity, transplant rejection, stroke, atherosclerosis, chronic neuropathic pain, and hepatitis B.
17 . The method of claim 4 , wherein the compound is administered orally.
18 . The method of claim 4 , wherein the compound is administered with a pharmaceutically acceptable carrier.Cited by (0)
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