Methods of treatment using phenyl indole allosteric inhibitors of P97 ATPase
The present invention is directed to methods of inhibiting p97 and compounds and compositions useful in such methods. Diseases and conditions the can be treated with the compounds and compositions of the invention include, but are not limited to, cancer and neurodegenerative disorders susceptible to treatment by inhibition of p97.
1 . A method of treating a neurodegenerative disease susceptible to treatment by p97 inhibition in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a compound of formula II, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula II and at least one pharmaceutically acceptable excipient:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR 5 R 6 , —C(O)OR 5 , —N═N + ═N − , an optionally substituted C 1 -C 3 alkyl, an optionally substituted C 1 -C 3 alkoxy, S(O) 2 NR 5 R 6 , an optionally substituted 6-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, —S(O) 2 R 5 , —OCZ 3 , —OCHZ 2 , —OCH 2 Z, —SZ 3 , —SCZ 3 , or S(Z) 5 ;
each of R 5 or R 6 is independently H, D, an optionally substituted C 1 -C 5 alkyl, an optionally substituted C 1 -C 3 alkoxy, or R 5 and R 6 , together with the intervening atoms to which they are attached, can form a 5-6 membered ring;
Z is a halo;
ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl;
R 2 is H, D, halo, cyano, or an optionally substituted C 1 -C 3 alkyl;
m is 0, 1, 2, 3, or 4;
R 3 is H, D, or an optionally substituted C 1 -C 3 alkyl; or R 2 and R 3 , together with the intervening atoms to which they are attached, can form a 5-6 membered ring
L 1 is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR 5 C(O)NR 6 —; —NR 6 C(O)O—; —C(O)NR 6 —; —S(O)—; or —S(O) 2 —;
X is CH or N;
Y is a bond, CH, CH 2 , CH 3 , N, NH, NH 2 , O, or S;
L 2 is a bond, an optionally substituted C 1 -C 5 alkyl, or an optionally substituted 3-10 membered cycloalkyl;
A is —NR 10 R 10 , —C(O)OR 10 , an optionally substituted C 1 -C 5 alkyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl;
each R 10 independently is H, an optionally substituted C 1 -C 3 alkyl, an optionally substituted 5-7 membered heteroaryl, or an optionally substituted 6-10 membered aryl;
p is 0, 1, 2, 3, or 4; and
denotes a single or double bond.
2 . The method of claim 1 , wherein the neurodegenerative disease susceptible to treatment is selected from the group consisting of inclusion body myopathy (IBM), Paget's disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
3 . The method of claim 2 , wherein the neurodegenerative disease is IBM.
4 . The method of claim 2 , wherein the neurodegenerative disease is PDB.
5 . The method of claim 2 , wherein the neurodegenerative disease is FTD.
6 . The method of claim 2 , wherein the neurodegenerative disease is ALS.
7 . The method of claim 1 , wherein the neurodegenerative disease is a multisystem degenerative disorder characterized by one or more of four main phenotypes, which are inclusion body myopathy (IBM), Paget's disease of the bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).
8 . The method of claim 1 , wherein the neurodegenerative disease is characterized by one or more symptoms selected from the group consisting of Parkinsonism, ataxia, cataracts, dilated cardiomyopathy, hepatic fibrosis, and hearing loss.
9 . The method of claim 1 , wherein the neurodegenerative disease is a multisystem proteinopathy.
10 . The method of claim 9 , wherein the multisystem proteinopathy is characterized by penetrance of muscle, bone and CNS degenerative phenotypes along with the accumulation of ubiquitin and TDP-43-positive inclusions.
11 . The method of claim 1 , wherein the neurodegenerative disease is caused by proteostatic malfunction.
12 . The method of claim 1 , wherein the compound of formula II is administered in an amount sufficient to cure, or at least partially arrest, the symptoms of the disease, including its complications and intermediate pathological phenotypes in development of the disease.
13 . The method of claim 1 , wherein X is N.
14 . The method of claim 1 , wherein Y is NH.
15 . The method of claim 1 , wherein A is a 5-10 membered heterocyclyl.
16 . The method of claim 1 , wherein at least one ring heteroatom of A is N.
17 . The method of claim 1 , wherein A has the structure:
wherein each R 3 is independently CH or N and Mis an optionally substituted C 1 -C 6 alkyl.
18 . The method of claim 17 , wherein A has the structure:
19 . The method of claim 18 , wherein Mis a C 1 -C 3 alkyl.
20 . The method of claim 1 , wherein R 1 is H, D, halo, cyano, hydroxyl, nitro, or —N═N + ═N − .
21 . The method of claim 1 , wherein R 1 is halo, cyano, N(O) 2 , hydroxyl, or —C(O)NR 5 R 6 .
22 . The method of claim 17 , wherein both R 3 are N.
23 . The method of claim 1 , wherein L 2 is an optionally substituted C 1 -C 3 alkyl.
24 . The method of claim 1 , wherein L 2 is a C 2 alkyl.
25 . The method of claim 1 , wherein p=0.
26 . The method of claim 1 , wherein the compound of formula (II) is selected from the group consisting of: