US2021154184A1PendingUtilityA1
Compounds for tau protein degradation
Assignee: DANA FARBER CANCER INST INCPriority: Jul 12, 2017Filed: Jul 12, 2018Published: May 27, 2021
Est. expiryJul 12, 2037(~11 yrs left)· nominal 20-yr term from priority
Inventors:Nathanael S. GrayStephen J. HaggartyQuan CaiTinghu ZhangMaria Catarina Telo Baptista Lima Da SilvaFleur M. Ferguson
G01N 33/6896G01N 33/534A61K 47/55A61P 25/28A61K 38/05C07D 471/04A61K 31/437A61K 38/1709C07K 5/06034C07K 14/4711A61K 31/4545C12N 9/93A61K 51/0455
58
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are bifunctional compounds that bind tau protein and/or promote targeted ubiquitination for the degradation of tau protein. In particular, provided are compounds that can bind tau protein, a protein whose aggregation is implicated in a variety of neurodegenerative disease (e.g., tauopathies), and can promote its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon), which can ubiquitinate tau protein, marking it for proteasomal degradation. Also provided are radiolabeled forms of the bifunctional compounds, pharmaceutical compositions comprising the bifunctional compounds, methods of detecting and/or diagnosing neurological disorders, methods of detecting and/or diagnosing pathological aggregation of tau protein (e.g., in the central nervous system), methods of treating and/or preventing neurological disorders, and methods of promoting the degradation of tau protein by E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
T-L-E I
or a pharmaceutically acceptable salt thereof, wherein:
T is a tau protein binding moiety;
E is an E3 ubiquitin ligase binding moiety;
L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, —O—, —N(R A )—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NR A —, —NR A C(═O)—, —NR A C(═O)R A —, —C(═O)R A —, —NR A C(═O)O—, —NR A C(═O)N(R A )—, —OC(═O)—, —OC(═O)O—, —OC(═O)N(R A )—, —S(O) 2 NR A —, —NR A S(O) 2 —, or a combination thereof; and
each occurrence of R A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group when attached to a nitrogen atom, or two R A groups are joined to form a substituted or unsubstituted heterocyclic ring.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of formula T-I:
wherein:
L is N or CR 5 ;
M is N or CR 6 ;
P is N or CR 7 ;
Q is N or CR 8 ;
X is a bond or substituted or unsubstituted C 1-12 alkylene, wherein one or more carbon is optionally replaced with C(O), O, S, SO 2 , NH, or NC 1-6 alkyl optionally substituted with halogen, OH, or C 1-6 alkyl;
R 9 is hydrogen, —N 3 , alkynyl, OH, halogen, NH 2 , N(C 1-6 alkyl) 2 , aryl, heteroaryl, or a protecting group, wherein the aryl and heteroaryl are optionally substituted with halogen, SO 2 , NH 2 , or C 1-6 alkyl optionally substituted with halogen or C 3-8 cycloalkyl;
R 3 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, —(CH 2 ) n —(C═O)NR A —, -A-(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n -A—(C═O)NR A —, -A-NR A —(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —S(O) 2 NR A —, or —(CH 2 ) n -A-S(O) 2 NR A —;
A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
each of R 1 , R 2 , and R 4 -R 8 are independently hydrogen, OH, halogen, NH 2 , CH 3 , SO 2 , NO 2 , a leaving group, a protecting group, aryl, heteroaryl, NHR 12 , N(R 12 ) 2 C 3-8 cycloalkyl, N(R 12 ) 2 heterocyclyl, or —(CH 2 ) n —R 12 ;
R 12 is hydrogen, —CH 3 , aryl, or heteroaryl; and
n is 0-12;
wherein one or more carbon of R 1-8 is optionally replaced with C(O), O, S, SO 2 , NH, NH-C 1-6 alkyl, NC 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein T is of formula T-I-a:
4 . The compound of claim 2 or 3 , or a pharmaceutically acceptable salt thereof, wherein T is of formula T-I-b:
5 . The compound of any of claims 2 - 4 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is —(CH 2 ) n —NR A —, —(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, or -A-O—(CH 2 ) n —(C═O)NR A —.
6 . The compound of any of claims 2 - 5 , or a pharmaceutically acceptable salt thereof, wherein:
R 3 is —(CH 2 ) n —(C═O)NR A —, -A-(CH 2 ) n —NR A —, or -A-O—(CH 2 ) n —(C═O)NR A —; and A is unsubstituted heteroarylene.
7 . The compound of any of claims 1 - 6 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
8 . The compound of any of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
9 . The compound of any of claims 1 - 8 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
10 . The compound of any of claims 1 - 8 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-II:
wherein:
X 1 is CH, N, NH, O, or S;
X 2 is CH, C, or N;
X 3 is CR 15 or N;
X 4 is CR 15 or N;
X 5 is CR 15 or N;
each occurrence of R 13 and R 15 is independently hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino, aminoaryl, alkoxy, —NR A (C═O)Oalkyl, —NR A (C═O)Oaryl, —NR A (C═O)alkyl, —NR A (C═O)aryl, —(C═O)Oalkyl, —(C═O)Oaryl, —(C═O)alkyl, —(C═O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
R 14 is —(CH 2 ) n —O—, -A-(CH 2 ) n —O—, —(CH 2 ) n -A-O—, -A-O—(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —S—, -A-(CH 2 ) n —S—, —(CH 2 ) n -A-S—, -A-S—(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —NR A —, -A-(CH 2 ) n —NR A —, —(CH 2 ) n -A-NR A —, -A-NR A —(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n —(C═O)NR A —, -A-(CH 2 ) n —(C═O)NR A —, —(CH 2 ) n -A—(C═O)NR A —, —(CH 2 ) n —S(O) 2 NR A —, -A-(CH 2 ) n —S(O) 2 NR A —, or —(CH 2 ) n -A-S(O) 2 NR A —;
A is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and
n is 0-12;
wherein one or more carbon of R 13 , R 14 , and R 15 is optionally replaced with C(O), O, S, SO 2 , NH, NC 1-6 alkyl, NH-C 1-6 alkyl, NH 2 , or N(C 1-6 alkyl) 2 .
12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-II-a:
13 . The compound of claim 11 or 12 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-II-b:
14 . The compound of any of claims 11 - 13 , or a pharmaceutically acceptable salt thereof, wherein:
R 14 is -A-(CH 2 ) n —NR A —, -A-(CH 2 ) n —(C═O)NR A —, or -A-(CH 2 ) n —S(O) 2 NR A —; and A is unsubstituted heterocyclylene.
15 . The compound of any of claim 1 or 11 - 14 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-III or T-IV:
wherein:
R 20 and R 21 are independently halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
G is substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R 22 (CH 2 ) n —O—, —(CH 2 ) n —S—, —(CH 2 ) n —NR A —, —(CH 2 ) n —(C═O)NR A —, or —(CH 2 ) n —S(O) 2 NR A —;
R 23 is halogen, —OH, —COOH, —SO 3 H, —NO 2 , —SH, —NR x R y , substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy;
R 24 is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups;
R x and R y are independently hydrogen, or substituted or unsubstituted alkyl;
n is 0-12;
t is 0, 1, 2, 3, or 4; and
r is 0, 1, or 2.
17 . The compound of claim 1 or 16 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-III:
18 . The compound of any of claim 1 , 16 , or 17 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-III-a:
19 . The compound of any of claims 16 - 18 , or a pharmaceutically acceptable salt thereof, wherein:
R 20 is unsubstituted alkyl, alkyl substituted with one or more halogen or hydroxy groups, unsubstituted alkoxy, or alkoxy substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 22 (CH 2 ) n —NR A — or —(CH 2 ) n —(C═O)NR A —.
20 . The compound of any of claim 1 or 16 - 19 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
21 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-IV:
22 . The compound of claim 16 or 21 , or a pharmaceutically acceptable salt thereof, wherein T is of Formula T-IV-a:
23 . The compound of any of claim 16 , 21 , or 22 , or a pharmaceutically acceptable salt thereof, wherein:
R 24 is unsubstituted alkylene, alkylene substituted with one or more halogen or hydroxy groups, unsubstituted alkoxylene, or alkoxylene substituted with one or more halogen or hydroxy groups; G is unsubstituted arylene or unsubstituted heteroarylene; and R 23 is NR x R y .
24 . The compound of any of claim 1 , 16 , or 21 - 23 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
25 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
27 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is of the formula:
28 . The compound of any of claims 1 - 27 , or a pharmaceutically acceptable salt thereof, wherein L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted heteroalkylene.
29 . The compound of any of claims 1 - 28 , or a pharmaceutically acceptable salt thereof, wherein:
L is
q is 1-12;
u is 1-12;
p is 1-10; and
s is 1-10.
30 . The compound of any one of claims 1 - 29 , or a pharmaceutically acceptable salt thereof, wherein:
L is
q is 1-5;
p is 2-5; and
s is 1-5.
31 . The compound of any of claims 1 - 28 , or a pharmaceutically acceptable salt thereof, wherein:
L is an unsubstituted C 3 -C 12 alkylene or
wherein q is 1-12.
32 . The compound of any of claims 1 - 31 , or a pharmaceutically acceptable salt thereof, wherein E is a cereblon E3 ubiquitin ligase binding moiety or a VHL E3 ubiquitin ligase binding moiety.
33 . The compound of any of claims 1 - 32 , or a pharmaceutically acceptable salt thereof, wherein E is of Formula E-II or E-III:
wherein:
Y is —(CH 2 ) k —, —(CH 2 ) k —O—, —O(CH 2 ) k —, —NR B (CH 2 ) k —, —(CH 2 ) k —NR B —, —(CH 2 ) k —(C═O)NR B —, —(CH 2 ) k —(C═O)NR B —, —O(CH 2 ) k —NR B (C═O)—, —NR B (C═O)—(CH 2 ) k —O—, —NR B (CH 2 ) k —NR B (C═O)—, or —(CH 2 ) k —NR B (C═O)—;
X A is C(O) or C(R 3A ) 2 ;
X 1 -X 2 is C(R 3A )=N or C(R 3A ) 2 -C(R 3A ) 2 ;
each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
each R 3A is, independently, H or C 1 -C 3 alkyl;
each R 3 ′ is, independently, C 1 -C 3 alkyl;
each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5A is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
k is 0, 1, 2, 3, 4, 5, or 6;
m is 0, 1, 2 or 3; and
n is 1 or 2.
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein E is of Formula E-II-a:
35 . The compound of any of claims 1 - 32 , or a pharmaceutically acceptable salt thereof, wherein E is of the formula:
36 . The compound of any of claims 1 - 34 , or a pharmaceutically acceptable salt thereof, wherein E is of the formula:
37 . The compound of any of claims 1 - 32 , or a pharmaceutically acceptable salt thereof, wherein E is of the formula:
38 . The compound of any of claims 1 - 32 , or a pharmaceutically acceptable salt thereof, wherein E is of the formula:
39 . The compound of any of claims 1 - 37 , or a pharmaceutically acceptable salt thereof, wherein E is of the formula:
40 . The compound of any of claim 2 , 3 , 5 , 6 , or 28 - 39 , wherein the compound is of Formula I-a:
or a pharmaceutically acceptable salt thereof, wherein q is 1-6.
41 . The compound of any of claim 2 - 6 or 28 - 40 , wherein the compound is of Formula I-b:
or a pharmaceutically acceptable salt thereof, wherein q is 1-6.
42 . The compound of any of claim 11 , 12 , 14 , or 28 - 39 , wherein the compound is of Formula I-c:
or a pharmaceutically acceptable salt thereof, wherein q is 1-6.
43 . The compound of any of claim 11 - 14 , 28 - 39 , or 42 , wherein the compound is of Formula I-d:
or a pharmaceutically acceptable salt thereof, wherein q is 1-6.
44 . The compound of any of claim 16 - 19 , or 28 - 39 , wherein the compound is of Formula I-e:
or a pharmaceutically acceptable salt thereof, wherein q is 1-5.
45 . The compound of any of claim 16 , 21 - 23 , or 28 - 39 , wherein the compound is of Formula I-f:
or a pharmaceutically acceptable salt thereof, wherein q is 1-5.
46 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-g:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-6.
47 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-h:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-6.
48 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-i:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-6.
49 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-j:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-4.
50 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-k:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and
q is 1-4.
51 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-1:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-4.
52 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-m:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-6.
53 . The compound of any of claims 1 - 32 , wherein the compound is of Formula I-n:
or a pharmaceutically acceptable salt thereof, wherein T is a tau protein binding moiety; and q is 1-4.
54 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
55 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
56 . A radiolabeled compound comprising the compound of any of claims 1 - 55 , or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.
57 . A pharmaceutical composition comprising a compound of any one of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
58 . A method of treating a neurological disorder in a subject in need thereof, the method comprising administering a compound of any one of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 to the subject.
59 . The method of claim 58 , wherein the neurological disorder is a neurodegenerative disease.
60 . The method of claim 59 , wherein the neurodegenerative disease is a tauopathy.
61 . The method of claim 60 , wherein the tauopathy is primary age-related tauopathy (PART)/neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease.
62 . A method of promoting the degradation of tau protein in a subject in need thereof, the method comprising administering a compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 to the subject.
63 . A method of detecting a neurological disorder, the method comprising contacting a compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 with a tissue.
64 . A method of detecting pathological aggregation of tau protein, the method contacting a compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 with a tissue.
65 . A method of diagnosing a neurological disorder in a subject, the method comprising contacting a compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 with a tissue of the subject.
66 . The method of any of claims 63 - 65 , wherein the tissue is tissue of the central nervous system.
67 . The method of claim 66 , wherein the tissue of the central nervous system is brain tissue.
68 . The compound of any one of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 for use in the treatment of a neurological disorder in a subject in need thereof.
69 . The compound or pharmaceutical composition of claim 68 , wherein the neurological disorder is a neurodegenerative disease.
70 . The compound or pharmaceutical composition of claim 69 , wherein the neurodegenerative disease is a tauopathy.
71 . The compound or pharmaceutical composition of claim 70 , wherein the tauopathy is primary age-related tauopathy (PART)/neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease.
72 . The compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 , for use in promoting the degradation of tau protein in a subject in need thereof.
73 . A kit comprising the compound of any of claims 1 - 56 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 57 ; and instructions for administering the compound, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition to a subject.Join the waitlist — get patent alerts
Track US2021154184A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.