P62-ZZ CHEMICAL INHIBITOR
A method for treating a p62-mediated disease (e.g., multiple myeloma) in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one p62-ZZ inhibitor compound.
1 . A method for treating a p62-mediated disease in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one p62-ZZ inhibitor compound of structural Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein
Ar is an arylene or heteroarylene;
R 1 has a structure of:
wherein W is an alkanediyl, alkenediyl, a carbonyl, or a combination thereof;
X is —NR 5 —, wherein R 5 is H or an alkyl, or —O—; and
Y is a hydroxyalkyl, an aminoalkyl, or a carboxylalkyl;
each R 2 is the same or different and has a structure of:
wherein Z is —NR 6 —, wherein R 6 is H or an alkyl, —O—, —S—, or —CH 2 —;
Z 1 is (—CH 2 —) m wherein m is 0 to 5, or an alkenediyl having 2 to 6 carbon atoms;
Cy is a 3-8-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and
each R 4 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and
each R 3 is the same or different and is selected from hydrogen, hydroxy, halogen, —CN, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a nitro, wherein a is 0 to 5, and b is 0 to 3.
2 . The method of claim 1 , wherein b is 0.
3 . The method of claim 2 , wherein W is —CH 2 .
4 . The method of claim 2 , wherein:
X is —NR 5 ; and
R 5 is H.
5 . The method of claim 2 , wherein Cy is phenyl.
6 . The method of claim 2 , wherein a is 1 or 2.
7 . The method of claim 2 , wherein:
R 4 is alkyl or halogen; and
c is 1 or 2.
8 . The method of claim 7 , wherein R 4 is methyl.
9 . The method of claim 7 , wherein R 4 is fluorine.
10 . The method of claim 2 , wherein R 2 is
11 . The method of claim 2 , wherein Z is —O—.
12 . The method of claim 2 , wherein:
Z 1 is (—CH 2 —) m ; and
m is 1.
13 . The method of claim 2 , wherein Ar is a benzenetriyl.
14 . The method of claim 2 , wherein Y is hydroxyalkyl.
15 . The method of claim 2 , wherein Y is aminoalkyl.
16 . The method of claim 15 , wherein the compound is selected from the group consisting of
17 . The method of claim 2 , wherein Y is carboxylalkyl.
18 . The method of claim 17 , wherein the compound is
19 . The method of claim 2 , wherein:
Y is R 1 ;
R 1 is —CH 2 —X—(CH 2 ) 2 —R 11 ;
X is NH or O; and
R 11 is hydroxy, carboxyl, substituted carboxyl or amino.
20 . The method of claim 19 , wherein X is NH and R 11 is amino.
21 . The method of claim 20 , wherein the compound is selected from the group consisting of:
22 . The method of claim 19 , wherein X is NH and R 11 is hydroxyl.
23 . The method of claim 22 , wherein the compound is selected from the group consisting of
24 . The method of claim 1 , wherein the p62-mediated disease is multiple myeloma.
25 . The method of claim 1 , further comprising inhibiting osteoclastogenesis and/or reducing osteoclast activation.
26 . The method of claim 1 , wherein the p62-mediated disease is drug-resistant multiple myeloma.
27 . The method of claim 1 , further comprising co-administering the compound with at least one anti-cancer agent.
28 . A method of modulating p62 activity in stromal cells, comprising contacting stromal cells with a compound of structural Formula I or a pharmaceutically acceptable salt or ester thereof.
29 . A method of inhibiting multiple myeloma cell growth, comprising contacting multiple myeloma cells with at least one p62-ZZ inhibitor compound of structural Formula I or a pharmaceutically acceptable salt or ester thereof.
30 . A compound of structural Formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein:
Ar is an arylene or heteroarylene;
R 1 has a structure of:
wherein W is an alkanediyl, alkenediyl, a carbonyl, or a combination thereof;
X is —NR 5 —, wherein R 5 is H or an alkyl, or —O—; and
Y is a hydroxyalkyl, an aminoalkyl, or a carboxylalkyl;
each R 2 is the same or different and has a structure of:
wherein Z is —NR 6 —, wherein R 6 is H or an alkyl, —O—, —S—, or —CH 2 —;
Z 1 is (—CH 2 —) m wherein m is 0 to 5, or an alkenediyl having 2 to 6 carbon atoms;
Cy is a 3-8-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and
each R 4 is the same or different and is selected from hydroxy, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, or amino; and c is 0 to 5; and
each R 3 is the same or different and is selected from hydrogen, hydroxy, halogen, —CN, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, amino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a nitro, wherein a is 0 to 5, and b is 0 to 3, provided that the compound is not:
31 . The compound of claim 30 , wherein b is 0.
32 . The compound of claim 31 , wherein W is —CH 2 .
33 . The compound of claim 31 , wherein:
X is —NR 5 ; and
R 5 is H.
34 . The compound of claim 31 , wherein Cy is phenyl.
35 . The compound of claim 31 , wherein a is 1 or 2.
36 . The compound of claim 31 , wherein:
R 4 is alkyl or halogen; and
c is 1 or 2.
37 . The compound of claim 36 , wherein R 4 is methyl.
38 . The compound of claim 36 , wherein R 4 is fluorine.
39 . The compound of claim 31 , wherein R 2 is
40 . The compound of claim 31 , wherein Z is —O—.
41 . The compound of claim 31 , wherein:
Z 1 is (—CH 2 —) m ; and
m is 1.
42 . The compound of claim 31 , wherein Ar is a benzenetriyl.
43 . The compound of claim 31 , wherein Y is hydroxyalkyl.
44 . The compound of claim 31 , wherein Y is aminoalkyl.
45 . The compound of claim 44 , wherein the compound is selected from the group consisting of
46 . The compound of claim 31 , wherein Y is carboxylalkyl.
47 . The compound of claim 46 , wherein the compound is
48 . The compound of claim 31 , wherein:
Y is R 1 ;
R 1 is —CH 2 —X—(CH 2 ) 2 —R 11 ;
X is NH or O; and
R 11 is hydroxy, carboxyl, substituted carboxyl or amino.
49 . The compound of claim 48 , wherein X is NH and R 11 is amino.
50 . The compound of claim 49 , wherein the compound is selected from the group consisting of:
51 . The compound of claim 48 , wherein X is NH and R 11 is hydroxyl.
52 . The compound of claim 51 , wherein the compound is selected from the group consisting of
53 . A pharmaceutical composition comprising at least one pharmaceutically acceptable additive, and compound, or a pharmaceutically acceptable salt or ester thereof, of structural Formula I.