INHIBITORS OF MICROBIALLY INDUCED AMYLOID
The present disclosure provides compounds useful for the prevention of amyloid formation and the treatment of amyloid related disorders, including synucleopathies such as Parkinson's Disease.
1 . A compound for Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A 1 is —C(R 7 )(R 8 ), or —CO—; or A 1 is —N(R 7 )— when X is —SO 2 —, CO or —C(R 9 )(R 10 );
A 2 is absent, or —C(R 5 )(R 6 );
L 1 is a bond, (—CH 2 -) m , —CF 2 —, —(C═O)—, or —C(R 9 )(R 10 )-;
L 2 is a bond, (—CH 2 -) m , —CF 2 —, —(C═O)—, or —C(R 9 )(R 10 )-;
X is —N(R 11 )—, —N(R 14 )—, —O—, —CO—, —S—, —S(═O)—, —SO 2 —, —CF 2 —, —C(R 9 )(R 10 )—;
Y is O or S;
Z is ═C(R 13 )—, ═N—, or —N(R 11 )—;
R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl;
R 2 is substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, or substituted or unsubstituted heterocyclyl;
R 3 and R 4 are independently absent, as permitted by valence, or are selected from —H, substituted or unsubstituted C 1 -C 10 alkyl, acyl, —CO 2 R 7 , —CON(R 7 )(R 8 ), —P═O(OH) 2 or —SO 2 (OH);
R 5 and R 6 are independently absent, as permitted by valence, or are selected from —H, and C 1 -C 10 alkyl, or together form a spirocarbocyclic or spiro(hetero)carbocyclic ring;
R 7 and R 8 are independently absent as permitted by valence, or are selected from —H, substituted or unsubstituted C 1 -C 10 alkyl, —(CH 2 ) m -aryl, —(CH 2 ) m -heteroaryl, —(CH 2 ) m -substituted or unsubstituted cycloalkyl, —R 14 ; or together form a spiropentanyl ring;
R 9 and R 10 are independently, for each occurrence, —H, —Cl, —Br, —F, —CF 3 , C 1 -C 10 alkyl;
R 11 and R 12 are independently, for each occurrence, —H, acyl, sulfonyl, substituted or unsubstituted C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, C 3-6 heterocyclyl, substituted or unsubstituted benzyl, —(CH 2 ) o -(substituted or unsubstituted aryl),or —(CH 2 ) o -(substituted or unsubstituted heteroaryl);
R 13 is selected from —H, —OH, —OR 11 , —Cl, —Br, —F, —CN, —CF 3 , —CH 2 F, —CHF 2 , substituted or unsubstituted C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 heterocyclyl, acyl, —CO 2 R 7 , —(CH 2 ) m CO 2 N(R 11 )(R 12 ), —CON(R 7 )(R 8 ), —(CH 2 ) m OH, —(CH 2 ) m CO 2 H, —(CH 2 ) m NH 2 , —(CH 2 ) m N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —NR 11 (C═O)(CH 2 ) m CH 3 , —NR 11 (C═O)R 12 , and NR 12 (SO 2 )(CH 2 ) m CH 3 ;
R 14 is —H, C 1 -C 10 alkyl, C 1 -C 10 alkenyl, C 1 -C 10 (mono or poly)hydroxylated alkyl, —(CH 2 ) o —R 15 , —(CH 2 CH 2 O) o —R 15 , —(CH 2 ) m —CO 2 H, —(CH 2 ) m —NH 2 , —(CH 2 ) m —(CO)NR 16 R 17 , or a protecting group;
R 15 is —CON(R 11 )(R 12 ), —N(R 11 )(R 12 ), acyl, —CO 2 R 7 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl;
R 16 and R 17 independently are —H or —CH 3 ;
m is, independently for each occurrence, 0-10;
n is, independently for each occurrence, 1-5;
o is independently, for each occurrence, 1-20; and
represents a single bond or a double bond;
provided that the compound of Formula (I) is not:
2 . The compound of claim 1 , wherein X is —SO 2 — or —N(R 14 )—.
3 . (canceled)
4 . The compound of claim 1 , wherein A 1 is —C(R 7 )(R 8 )_.
5 . The compound of claim 1 , wherein A 2 is —C(R 5 )(R 6 )—.
6 . (canceled)
7 . The compound of claim 1 , wherein L 1 is a bond.
8 . The compound of claim 1 , wherein L 2 is —C(R 9 )(R 10 )-.
9 - 10 . (canceled)
11 . The compound of claim 1 , wherein Z is ═C(R 13 )—.
12 - 13 . (canceled)
14 . The compound of claim 1 , wherein R 1 is trifluoromethylphenyl.
15 . The compound of claim 1 , wherein R 2 is unsubstituted naphthyl.
16 . The compound of claim 1 , wherein R 3 is —H and R 4 is —CO 2 R 7 .
17 . The compound of claim 1 , having the structure of Formula (II) or (III):
18 . The compound of claim 17 , having the structure of Formula (IIa), Formula (IIb) or Formula (IIc):
wherein:
L 1 is a bond, (—CH 2 -) m , —CF 2 —, or —(C═O)—;
L 2 is a bond, (—CH 2 -) m , —CF 2 —, or —(C═O)—;
m is, independently for each occurrence, 0-10;
R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl;
R 2 is substituted or unsubstituted naphthyl, or substituted or unsubstituted heterocyclyl;
R 3 is —CO 2 H,
R 5 and R 6 are each H;
R 7 is substituted or unsubstituted C 1 -C 10 alkyl, or substituted or unsubstituted cycloalkyl; and
R 13 is selected from —H, —Cl, —Br, —F, —CN, —CF 3 , —CH 2 F, —CHF 2 , substituted or unsubstituted C 1 -C 10 alkyl, —NH 2 , —CONH 2 , —(CH 2 )—N(CH 3 ) 2 , —NH(cyclopentyl), —NH(benzyl), —NH(tetrahydropyran), —NH—(CH 2 )(cyclopentyl), and —O—(CH 2 ) 2 -phenyl.
19 . The compound of claim 17 , selected from compounds:
and pharmaceutically acceptable salts thereof.
20 . (canceled)
21 . The compound of claim 1 , having the structure of formula (IV), (V), (VI), (VII), (VIII), (IX), or (X):
22 . The compound of claim 21 , having the structure of Formula (IXa), Formula (IXb), or Formula (IXc):
wherein:
L 1 is a bond, (—CH 2 -) m , —CF 2 —, or —(C═O)—;
L 2 is a bond, (—CH 2 -) m , —CF 2 —, or —(C═O)—;
m is, independently for each occurrence, 0-10;
o is, independently for each occurrence, 1-20;
R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl;
R 2 is substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted phenyl, or substituted or unsubstituted heterocyclyl;
R 3 is —CO 2 H,
R 13 is selected from —H, —Cl, —Br, —F, —CN, —CF 3 , —CH 2 F, —CHF 2 , —(CH 2 ) m —NMe 2 , —CONH 2 , —CO 2 H, and substituted or unsubstituted C 1 -C 10 alkyl; and
R 14 is C 1 -C 10 alkyl, —(CH 2 ) o -(unsubstituted cycloalkyl), —(CH 2 ) o -(substituted or unsubstituted phenyl), —(CH 2 ) o -naphthyl, or —(CH 2 ) o -biaryl.
23 . The compound of claim 21 , selected from compounds:
and pharmaceutically acceptable salts thereof.
24 . (canceled)
25 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
26 - 28 . (canceled)
29 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is formulated for enteric delivery.
30 - 37 . (canceled)
38 . A method for inhibiting amyloid formation in a subject in need thereof, or preventing or treating an amyloid disorder in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
39 - 72 . (canceled)
73 . A method for preventing or treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
74 - 75 . (canceled)