IP Library › Patent Application 17151835

Patent Application

App. No. 17/151,835

BIARYL COMPOSITIONS AND METHODS FOR MODULATING A KINASE CASCADE

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App. No.: 17/151,835

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Abstract

The invention relates to compounds and methods for modulating one or more components of a kinase cascade.

Claims (75)

1 . A compound according to Formula IA

or a salt, solvate, hydrate, or prodrug thereof, wherein: T is absent, 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 selected from hydrogen, 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, and O-benzyl;

X a is CR a or N, or N—O;

X b is CR b , N, or N—O;

X c is CR c or N, or N—O;

X d is CR d or N, or N—O;

X e is CR e , N, or N—O;

R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 are, independently, hydrogen, 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,

wherein W is H, or 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 alkyl-aryl;

P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 2 OR 21 ,

tetrazole, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , 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 , C 5 , 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 —, —O—CH 2 —, —OCH 2 CH 2 — or —OCH 2 CH 2 CH 2 —;

R 12 , R 13 , R 14 , R 15 , R 16 , Rn, and R 18 , are, independently, H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl; and

Z is (CHR 1 ) n —C(O)—NR 2 (CHR 3 ) m —Ar, where Ar is a substituted or unsubstituted aryl or nitrogen-containing heteroaryl group, R 1 , 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;

provided that at least one of R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 is P.

2 . A method of protecting against or treating hearing loss or osteoporosis in a subject comprising administering a compound having the Formula I:

or a salt, solvate, hydrate, or prodrug thereof, wherein:

T is absent, 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;

X a is CR a or N, or N—O;

X b is CR b , N, or N—O;

X c is CR c or N, or N—O;

X d is CR d or N, or N—O;

X e is CR e , N, or N—O;

where W is H, or 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 alkyl-aryl;

P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NHR 2 OR 21 ,

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 29 glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or

R 19 , R 20 and R 21 are 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 —, —O—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; and

n and m are independently 0, 1, or 2.

3 . A method of preventing or treating a cell proliferation disorder comprising administering to a subject in need thereof a compound having the formula IA: