U.S. patent application number 16/630294 was filed with the patent office on 2021-05-27 for compounds for tau protein degradation.
This patent application is currently assigned to Dana-Farber Cancer Institute, Inc.. The applicant listed for this patent is Dana-Farber Cancer Institute, Inc., The General Hospital Corporation D/B/A Massachusetts General Hospital, The General Hospital Corporation D/B/A Massachusetts General Hospital. Invention is credited to Quan Cai, Fleur M. Ferguson, Nathanael S. Gray, Stephen J. Haggarty, Maria Catarina Telo Baptista Lima da Silva, Tinghu Zhang.
Application Number | 20210154184 16/630294 |
Document ID | / |
Family ID | 1000005429001 |
Filed Date | 2021-05-27 |
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United States Patent
Application |
20210154184 |
Kind Code |
A1 |
Gray; Nathanael S. ; et
al. |
May 27, 2021 |
COMPOUNDS FOR TAU PROTEIN DEGRADATION
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.
Inventors: |
Gray; Nathanael S.; (Boston,
MA) ; Haggarty; Stephen J.; (Gloucester, MA) ;
Cai; Quan; (Shanghai, CN) ; Zhang; Tinghu;
(Brookline, MA) ; Telo Baptista Lima da Silva; Maria
Catarina; (Revere, MA) ; Ferguson; Fleur M.;
(Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dana-Farber Cancer Institute, Inc.
The General Hospital Corporation D/B/A Massachusetts General
Hospital |
Boston
Boston |
MA
MA |
US
US |
|
|
Assignee: |
Dana-Farber Cancer Institute,
Inc.
Boston
MA
The General Hospital Corporation D/B/A Massachusetts General
Hospital
Boston
MA
|
Family ID: |
1000005429001 |
Appl. No.: |
16/630294 |
Filed: |
July 12, 2018 |
PCT Filed: |
July 12, 2018 |
PCT NO: |
PCT/US18/41787 |
371 Date: |
January 10, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/28 20180101;
A61K 31/437 20130101; C07D 471/04 20130101; A61K 31/4545 20130101;
A61K 51/0455 20130101; G01N 33/6896 20130101; C07K 5/06034
20130101; G01N 33/534 20130101; A61K 38/05 20130101 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; A61K 31/437 20060101 A61K031/437; A61K 51/04 20060101
A61K051/04; A61P 25/28 20060101 A61P025/28; G01N 33/68 20060101
G01N033/68; G01N 33/534 20060101 G01N033/534; C07D 471/04 20060101
C07D471/04; A61K 38/05 20060101 A61K038/05; C07K 5/062 20060101
C07K005/062 |
Claims
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.sup.A)--, --S--,
--C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.A--,
--NR.sup.AC(.dbd.O)--, --NR.sup.AC(.dbd.O)R.sup.A--,
--C(.dbd.O)R.sup.A--, --NR.sup.AC(.dbd.O)O--,
--NR.sup.AC(.dbd.O)N(R.sup.A)--, --OC(.dbd.O)--, --OC(.dbd.O)O--,
--OC(.dbd.O)N(R.sup.A)--, --S(O).sub.2NR.sup.A--,
--NR.sup.AS(O).sub.2--, or a combination thereof; and each
occurrence of R.sup.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.sup.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: ##STR00216## wherein: L is N
or CR.sup.5; M is N or CR.sup.6; P is N or CR.sup.7; Q is N or
CR.sup.8; X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl; R.sup.9 is
hydrogen, --N.sub.3, alkynyl, OH, halogen, NH.sub.2, N(C.sub.1-6
alkyl).sub.2, aryl, heteroaryl, or a protecting group, wherein the
aryl and heteroaryl are optionally substituted with halogen,
SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl optionally substituted with
halogen or C.sub.3-8 cycloalkyl; R.sup.3 is
--(CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--; A is substituted or
unsubstituted heterocyclylene, substituted or unsubstituted
arylene, or substituted or unsubstituted heteroarylene; each of
R.sup.1, R.sup.2, and R.sup.4-R.sup.8 are independently hydrogen,
OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a leaving
group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl; and n is
0-12; wherein one or more carbon of R.sup.1-8 is optionally
replaced with C(O), O, S, SO.sub.2, NH, NH-C.sub.1-6 alkyl,
NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6 alkyl).sub.2.
3. The compound of claim 2, or a pharmaceutically acceptable salt
thereof, wherein T is of formula T-I-a: ##STR00217##
4. The compound of claim 2 or 3, or a pharmaceutically acceptable
salt thereof, wherein T is of formula T-I-b: ##STR00218##
5. The compound of any of claims 2-4, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
or -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
6. The compound of any of claims 2-5, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.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:
##STR00219##
8. The compound of any of claims 1-7, or a pharmaceutically
acceptable salt thereof, wherein T is of the formula:
##STR00220##
9. The compound of any of claims 1-8, or a pharmaceutically
acceptable salt thereof, wherein T is of the formula:
##STR00221##
10. The compound of any of claims 1-8, or a pharmaceutically
acceptable salt thereof, wherein T is of the formula:
##STR00222##
11. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein T is of Formula T-II: ##STR00223## wherein:
X.sup.1 is CH, N, NH, O, or S; X.sup.2 is CH, C, or N; X.sup.3 is
CR.sup.15 or N; X.sup.4 is CR.sup.15 or N; X.sup.5 is CR.sup.15 or
N; each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
R.sup.14 is --(CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.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.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or
N(C.sub.1-6alkyl).sub.2.
12. The compound of claim 11, or a pharmaceutically acceptable salt
thereof, wherein T is of Formula T-II-a: ##STR00224##
13. The compound of claim 11 or 12, or a pharmaceutically
acceptable salt thereof, wherein T is of Formula T-II-b:
##STR00225##
14. The compound of any of claims 11-13, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.14 is
-A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.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:
##STR00226##
16. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein T is of Formula T-III or T-IV: ##STR00227##
wherein: R.sup.20 and R.sup.21 are independently halogen, --OH,
--COOH, --SO.sub.3H, --NO.sub.2, --SH, --NR.sup.xR.sup.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.sup.22 (CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--; R.sup.23 is halogen,
--OH, --COOH, --SO.sub.3H, --NO.sub.2, --SH, --NR.sup.xR.sup.y,
substituted or unsubstituted alkyl, or substituted or unsubstituted
alkoxy; R.sup.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.sup.x and R.sup.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: ##STR00228##
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: ##STR00229##
19. The compound of any of claims 16-18, or a pharmaceutically
acceptable salt thereof, wherein: R.sup.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.sup.22
(CH.sub.2).sub.n--NR.sup.A-- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
20. The compound of any of claim 1 or 16-19, or a pharmaceutically
acceptable salt thereof, wherein T is of the formula:
##STR00230##
21. The compound of claim 16, or a pharmaceutically acceptable salt
thereof, wherein T is of Formula T-IV: ##STR00231##
22. The compound of claim 16 or 21, or a pharmaceutically
acceptable salt thereof, wherein T is of Formula T-IV-a:
##STR00232##
23. The compound of any of claim 16, 21, or 22, or a
pharmaceutically acceptable salt thereof, wherein: R.sup.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.sup.23
is NR.sup.xR.sup.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: ##STR00233##
25. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein T is of the formula: ##STR00234##
26. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein T is of the formula: ##STR00235## ##STR00236##
##STR00237## ##STR00238##
27. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein T is of the formula: ##STR00239## ##STR00240##
##STR00241##
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 ##STR00242## 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 ##STR00243## 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.sub.3-C.sub.12 alkylene or ##STR00244## 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:
##STR00245## wherein: Y is --(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--O--, --O(CH.sub.2).sub.k--,
--NR.sup.B(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--; X.sup.A is C(O) or
C(R.sup.3A).sub.2; X.sup.1-X.sup.2 is C(R.sup.3A)=N or
C(R.sup.3A).sub.2-C(R.sup.3A).sub.2; each R.sup.B is,
independently, hydrogen, or substituted or unsubstituted alkyl;
each R.sup.1A is, independently, halogen, OH, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 alkoxy; each R.sup.3A is, independently,
H or C.sub.1-C.sub.3 alkyl; each R.sup.3' is, independently,
C.sub.1-C.sub.3 alkyl; each R.sup.4A is, independently, H or
C.sub.1-C.sub.3 alkyl; or two R.sup.4A, together with the carbon
atom to which they are attached, form a C(O), C.sub.3-C.sub.6
carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or
2 heteroatoms selected from N and O; R.sup.5A is H, deuterium,
C.sub.1-C.sub.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: ##STR00246##
35. The compound of any of claims 1-32, or a pharmaceutically
acceptable salt thereof, wherein E is of the formula:
##STR00247##
36. The compound of any of claims 1-34, or a pharmaceutically
acceptable salt thereof, wherein E is of the formula:
##STR00248##
37. The compound of any of claims 1-32, or a pharmaceutically
acceptable salt thereof, wherein E is of the formula:
##STR00249##
38. The compound of any of claims 1-32, or a pharmaceutically
acceptable salt thereof, wherein E is of the formula:
##STR00250##
39. The compound of any of claims 1-37, or a pharmaceutically
acceptable salt thereof, wherein E is of the formula:
##STR00251##
40. The compound of any of claim 2, 3, 5, 6, or 28-39, wherein the
compound is of Formula I-a: ##STR00252## 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: ##STR00253## 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: ##STR00254## 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: ##STR00255## 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: ##STR00256## 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: ##STR00257## 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: ##STR00258## 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: ##STR00259## 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: ##STR00260## 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: ##STR00261## 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: ##STR00262## 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: ##STR00263## 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: ##STR00264## 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: ##STR00265## 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 ##STR00266##
##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271## or
a pharmaceutically acceptable salt thereof.
55. The compound of claim 1, wherein the compound is ##STR00272##
##STR00273## 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.
Description
RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application, U.S. Ser. No. 62/531,773,
filed Jul. 12, 2017, the entire content of which is incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to bifunctional
compounds that bind tau protein and promote its degradation via
recruitment of an E3 ubiquitin ligase, and uses of the compounds in
the treatment of neurological diseases (e.g., Alzheimer's
disease).
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) is characterized by progressive
loss of memory and other mental functions. Worldwide, nearly 35
million people suffer from AD. The exact mechanism for AD is not
fully understood, but two characteristic protein deposits, senile
plaques and neurofibrillary tangles (NFT), have been defined as
causative events for AD. While senile plaques include extracellular
aggregation of amyloid.beta. peptides (A.beta.), the NFTs are
composed of hyperphosphorylated tau protein. Since tau accumulation
begins before extensive neuronal loss, targeting tau protein has
become a strategy for treating AD. Hence, tau is not only a drug
target but also a biomarker for early diagnosis of AD by
measurement of brain tau loading. Positron emission tomography
(PET) is a molecular imaging technique that provides a non-invasive
diagnostic method for the detection of tau aggregation. Thus,
several tau radiotracers have been developed and tested in
humans.
[0004] Recently, a new therapeutic strategy to reduce and/or
eliminate proteins associated with certain pathological states,
PROTAC (proteolysis targeting chimeras; e.g., see U.S. Patent
Application, U.S. Ser. No. 14/792,414, filed Jul. 6, 2015), was
developed by creating bifunctional compounds that recruit target
proteins to E3 ubiquitin ligases, which subsequently induce
proteasome-mediated degradation of the target protein. E3 ubiquitin
ligases are proteins that, in combination with an E2
ubiquitin-conjugating enzyme, promote the attachment of ubiquitin
to a lysine on a target protein via an isopeptide bond (e.g., an
amide bond that is not present on the main chain of a protein). The
ubiquitination of the protein commonly results in degradation of
the target protein by the proteasome.
[0005] Currently, there are no clinically approved compounds that
target tau for the treatment of AD, and overall clinical failure is
much higher for AD compared to other diseases. Accordingly, an
ongoing need exists to identify drugs that effectively treat
neurological disorders, such as AD. In particular, drugs that can
take advantage of cellular machinery involved in protein
homeostasis (e.g., ubiquitination and proteasome degradation) may
find use as therapeutic agents.
SUMMARY OF THE INVENTION
[0006] PROTAC relies on a strategy of recruiting target protein to
an E3 ubiquitin ligase and subsequently inducing
proteasome-mediated degradation of the target protein. The present
disclosure describes the conjugation of tau binding moieties with
an E3 ubiquitin ligase binding moiety (e.g., lenalidomide,
thalidomide) to provide compounds that can induce the
ubiquitination of tau protein and promote its degradation in cells.
Accordingly, the present disclosure stems from the recognition that
the aggregation of tau protein, in particular hyperphosphorylated
tau protein, causes certain neurological disorders (e.g.,
tauopathies such as AD), and that by targeting both tau protein, or
any post-translationally modified form of tau, and recruiting an E3
ubiquitin ligase (e.g., Cereblon) to ubiquitinate the tau protein
and mark it for proteasome degradation, a single bifunctional
compound can promote the degradation of tau protein, thus providing
new compounds, compostions, and methods for the treatment of
neurological disease (e.g., tauopathies such as AD). Thus, the
present disclosure represents an important advance in the treatment
of neurological disease, particularly tauopathies.
[0007] In one aspect, provided are compounds of Formula I:
T-L-E I,
or pharmaceutically acceptable salts, co-crystals, tautomers,
stereoisomers, solvates, hydrates, polymorphs, isotopically
enriched derivatives, or prodrugs thereof, wherein:
[0008] T is a tau protein binding moiety;
[0009] E is an E3 ubiquitin ligase binding moiety;
[0010] 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.sup.A)--, --S--,
--C(.dbd.O)--, --C(.dbd.O)--, --C(.dbd.O)NR.sup.A--,
--NR.sup.AC(.dbd.O)--, --NR.sup.AC(.dbd.O)R.sup.A--,
--C(.dbd.O)R.sup.A--, --NR.sup.AC(.dbd.O)O--,
--NR.sup.AC(.dbd.O)N(R.sup.A)--, --C(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)N(R.sup.A)--, --S(O).sub.2NR.sup.A--,
--NR.sup.AS(O).sub.2--, or a combination thereof; and
[0011] each occurrence of R.sup.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.sup.A groups are
joined to form a substituted or unsubstituted heterocyclic
ring.
[0012] In certain embodiments, T is of Formula T-I:
##STR00001##
wherein:
[0013] L is N or CR.sup.5;
[0014] M is N or CR.sup.6;
[0015] P is N or CR.sup.7;
[0016] Q is N or CR.sup.8;
[0017] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0018] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0019] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A--S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0020] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0021] each of R.sup.1, R.sup.2, and R.sup.4-R.sup.8 are
independently hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2,
NO.sub.2, a leaving group, a protecting group, aryl, heteroaryl,
NHR.sup.12, N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0022] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0023] n is 0-12;
[0024] wherein one or more carbon of R.sup.1-8 is optionally
replaced with C(O), O, S, SO.sub.2, NH, NH--C.sub.1-6 alkyl,
NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6 alkyl).sub.2.
[0025] In certain embodiments of Formula T-I:
[0026] L is N or CR.sup.5;
[0027] M is N or CR.sup.6;
[0028] P is N or CR.sup.7;
[0029] Q is N or CR.sup.8;
[0030] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0031] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0032] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.nA-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A---S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0033] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0034] each of R.sup.1, R.sup.2, and R.sup.4-R.sup.8 are
independently hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2,
NO.sub.2, a leaving group, a protecting group, aryl, heteroaryl,
NHR.sup.12, N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0035] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0036] n is 0-12;
[0037] wherein one or more carbon of R.sup.1-8 is optionally
replaced with C(O), O, S, SO.sub.2, NH, NH--C.sub.1-6 alkyl,
NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6 alkyl).sub.2.
[0038] In certain embodiments, T is of formula T-II:
##STR00002##
wherein:
[0039] X.sup.1 is CH, N, NH, O, or S;
[0040] X.sup.2 is CH, C, or N;
[0041] X.sup.3 is CR.sup.15 or N;
[0042] X.sup.4 is CR.sup.15 or N;
[0043] X.sup.5 is CR.sup.15 or N;
[0044] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0045] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0046] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0047] n is 0-12;
[0048] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0049] In certain embodiments of Formula T-II:
[0050] X.sup.1 is CH, N, O, or S;
[0051] X.sup.2 is CH, C, or N;
[0052] X.sup.3 is CR.sup.15 or N;
[0053] X.sup.4 is CR.sup.15 or N;
[0054] X.sup.5 is CR.sup.15 or N;
[0055] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0056] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.nA-O--,
--(CH.sub.2).sub.nS----A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A-(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0057] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0058] n is 0-12;
[0059] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0060] In certain embodiments, T is of formula T-III or T-IV:
##STR00003##
wherein:
[0061] R.sup.20 and R.sup.21 are independently halogen, --OH,
--COOH, --SO.sub.3H, --NO.sub.2, --SH, --NR.sup.xR.sup.y,
substituted or unsubstituted alkyl, or substituted or unsubstituted
alkoxy;
[0062] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0063] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[0064] R.sup.23 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0065] R.sup.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;
[0066] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl;
[0067] n is 0-12;
[0068] t is 0, 1, 2, 3, or 4; and
[0069] r is 0, 1, or 2.
[0070] In certain embodiments, E is a cereblon E3 ubiquitin ligase
binding moiety or a VHL E3 ubiquitin ligase binding moiety.
[0071] In certain embodiments, E is a cereblon E3 ubiquitin ligase
binding moiety.
[0072] Exemplary compounds of Formula I include, but are not
limited to:
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009##
and pharmaceutically acceptable salts thereof.
[0073] In another aspect, provided are radiolabeled compounds
comprising a compound of Formula I, or a pharmaceutically
acceptable salt thereof, enriched with a radionuclide.
[0074] In another aspect, provided are pharmaceutical compositions
comprising a compound of Formula I, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[0075] In another aspect, provided are methods of treating a
neurological disorder in a subject in need thereof, the method
comprising administering a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition comprising a compound of Formula I, to the subject. In
certain embodiments, the neurological disorder is a
neurodegenerative disease. In certain embodiments, the
neurodegenerative disease is a tauopathy (e.g. Alzheimer's
disease).
[0076] In another aspect, provided are methods of promoting the
degradation of tau protein in a subject in need thereof, the method
comprising administering a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition comprising a compound of Formula I, to the subject.
[0077] In another aspect, provided are methods of detecting a
neurological disorder, the method comprising contacting a compound
of Formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising a compound of Formula I, with
a tissue.
[0078] In another aspect, provided are methods of detecting
pathological aggregation of tau protein in tissue, the method
comprising contacting a compound of Formula I, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition comprising a compound of Formula I, with a tissue.
[0079] In another aspect, provided are methods of diagnosing a
neurological disorder in a subject, the method comprising
contacting a compound of Formula I, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition comprising
a compound of Formula I, with a tissue of the subject.
[0080] In another aspect, provided are compounds of Formula I, or
pharmaceutically acceptable salts thereof, or pharmaceutical
compositions comprising a compound of Formula I, for use in
treating a neurological disorder in a subject in need thereof;
and/or promoting the degradation of tau protein.
[0081] In another aspect, provided are kits comprising a compound
of Formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising a compound of Formula I. In
certain embodiments, the kit further comprises instructions for
administration (e.g., human administration) and/or use.
[0082] The details of certain embodiments of the invention are set
forth in the Detailed Description of Certain Embodiments, as
described below. Other features, objects, and advantages of the
invention will be apparent from the Definitions, Examples, Figures,
and Claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0083] FIG. 1A is a series of western blot stains showing the
effect of exemplary compounds on levels of tau protein in a human
tau-A152T neuronal model, after 24 h treatment. FIG. 1B is a series
of bar graphs quantifying the total tau and hyperphosphorylated tau
from the western blots in FIG. 1A. These figures demonstrate the
significant tau lowering effects of the exemplary compounds, but
not lenalinomide, a CRBN-only binding compound.
[0084] FIG. 2A is a series of western blot stains showing the
effect of exemplary compounds on levels of tau protein in a human
tau-P301L neuronal model, after 24 h treatment. FIG. 2B is a series
of bar graphs quantifying the total tau and hyperphosphorylated tau
from the western blots in FIG. 2A. These figures demonstrate the
significant tau lowering effects of the exemplary compounds, but
not lenalinomide, a CRBN-only binding compound.
[0085] FIG. 3 is a series of western blot stains showing the effect
of T807, a known tau-binding compound, on levels of tau protein in
non-mutant human neurons (control) and human tau-A152T neurons. The
graph on the right shows the quantification of the blots. No
significant tau lowering activity of T807 was observed in either
cell line.
[0086] FIG. 4A is a series of western blot stains showing the
effect of exemplary compounds on levels of E3 ubiquitin ligases
Cereblon (CRBN), von Hippel-Lindau tumor suppressor (VHL), and C
terminus of HSC70-Interacting Protein (CHIP) in human tau-A152T and
tau-P301L neurons, after 24 h treatment. FIG. 4B is a series of bar
graphs quantifying CRBN from the western blots in FIG. 4A; CRBN
levels in the tau-A152T neurons are on the left (medium grey bars)
and CRBN levels in the tau-P301L neurons are on the right (black
bars). FIG. 4C is a series of bar graphs quantifying total tau from
the western blots in FIG. 4A; Tau5 (total tau) levels in the
tau-A152T neurons are on the left (medium grey bars) and Tau5
levels in the tau-P301L neurons are on the right (black bars). FIG.
4D is a series of bar graphs quantifying CHIP from the western
blots in FIG. 4A; CHIP levels in the tau-A152T neurons are on the
left (medium grey bars) and CHIP levels in the tau-P301L neurons
are on the right (black bars). FIG. 4E is a series of bar graphs
quantifying VHL from the western blots in FIG. 4A; VHL levels in
the tau-A152T neurons are on the left (medium grey bars) and VHL
levels in the tau-P301L neurons are on the right (black bars).
[0087] FIG. 5A is a series of western blot stains showing the
effect of exemplary compounds on levels of tau protein in human
non-mutant (control), human tau-A152T, and human tau-P301L neurons
at 6 weeks of differentiation. FIG. 5B is a series of bar graphs
quantifying total tau, hyperphosphorylated tau (upper graphs), and
CRBN (bottom graphs) from the western blots in FIG. 5A. FIG. 5C is
a series of bar graphs quantifying total tau, hyperphosphorylated
tau (upper graphs), and CRBN (bottom graphs) from an average of
three experiments of the western blots as represented in FIG.
5A.
[0088] FIG. 6A is a series of western blot stains showing the
effect of exemplary compounds in 6-week differentiated human
tau-A152T neurons. FIG. 6B is a series of bar graphs quantifying
total tau, hyperphosphorylated tau, and CRBN from the western blots
in FIG. 6A.
[0089] FIG. 7 is a bar graph quantifying the results of neuronal
cell viability assays for the ability of exemplary compounds to
provide protection from toxic stimuli associated with
neurodegeneration, here chosen to be .beta.-amyloid (1-42) peptide,
as a functional readout of having effectively degraded tau (at 8
weeks of differentiation). As shown by Silva et al. (Stem Cell
Reports, 2016, 7(3), 325-40; doi: 10.1016/j.stemcr.2016.08.001)
reduction of viability due to .beta.-amyloid (1-42) exposure is
dependent on tau. Left, schematic of experimental design, right,
graph of viability.
[0090] FIG. 8A is a series of western blot stains showing the
effect of exemplary compounds and T-807 on levels of tau protein in
a human tau-A152T neuronal model, after 24 h treatment. The control
is a non-mutant neuron (8330-8-RC1). FIG. 8B is a series of graphs
quantifying the total tau and hyperphosphorylated tau from the
western blots in FIG. 8A.
[0091] FIG. 9A is a series of western blot stains showing the
effect of exemplary compounds and T-807 on levels of tau protein in
a human tau-P301L neuronal model, after 24 h treatment. The control
is a non-mutant neuron (CTR2-L17-RC2). FIG. 9B is a series of
graphs quantifying the total tau and hyperphosphorylated tau from
the western blots in FIG. 9A.
[0092] FIG. 10 is a series of bar graphs quantifying the total tau
and hyperphosphorylated tau from the western blots in FIGS. 8A and
9A.
DEFINITIONS
Chemical Definitions
[0093] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Organic Chemistry, Thomas Sorrell, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rd Edition, Cambridge
University Press, Cambridge, 1987.
[0094] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various stereoisomeric
forms, e.g., enantiomers and/or diastereomers. For example, the
compounds described herein can be in the form of an individual
enantiomer, diastereomer or geometric isomer, or can be in the form
of a mixture of stereoisomers, including racemic mixtures and
mixtures enriched in one or more stereoisomer. Isomers can be
isolated from mixtures by methods known to those skilled in the
art, including chiral high pressure liquid chromatography (HPLC)
and the formation and crystallization of chiral salts; or preferred
isomers can be prepared by asymmetric syntheses. See, for example,
Jacques et al., Enantiomers, Racemates and Resolutions (Wiley
Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725
(1977); Eliel, E. L. Stereochemistry of Carbon Compounds
(McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving
Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, Ind. 1972). The invention
additionally encompasses compounds as individual isomers
substantially free of other isomers, and alternatively, as mixtures
of various isomers.
[0095] In a formula, is a single bond where the stereochemistry of
the moieties immediately attached thereto is not specified, is
absent or a single bond, and or is a single or double bond.
[0096] Unless otherwise stated, structures depicted herein are also
meant to include compounds that differ only in the presence of one
or more isotopically enriched atoms. For example, compounds having
the present structures except for the replacement of hydrogen by
deuterium or tritium, replacement of .sup.19F with .sup.18F, or the
replacement of .sup.12C with .sup.13C or .sup.14C are within the
scope of the disclosure. Such compounds are useful, for example, as
analytical tools or probes in biological assays.
[0097] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-.sub.4, C.sub.4-.sub.6,
C.sub.4-5, and C.sub.5-6 alkyl.
[0098] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and
carbocyclic groups. Likewise, the term "heteroaliphatic" refers to
heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic
groups.
[0099] The term "alkyl" refers to a radical of a straight-chain or
branched saturated hydrocarbon group having from 1 to 10 carbon
atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl group has
1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some embodiments, an
alkyl group has 1 to 8 carbon atoms ("C.sub.1-8 alkyl"). In some
embodiments, an alkyl group has 1 to 7 carbon atoms ("C.sub.1-7
alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon
atoms ("C.sub.1-6 alkyl"). In some embodiments, an alkyl group has
1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some embodiments, an
alkyl group has 1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some
embodiments, an alkyl group has 1 to 3 carbon atoms ("C.sub.1-3
alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon
atoms ("C.sub.1-2 alkyl"). In some embodiments, an alkyl group has
1 carbon atom ("C.sub.1 alkyl"). In some embodiments, an alkyl
group has 2 to 6 carbon atoms ("C.sub.2-6 alkyl"). Examples of
C.sub.1-6 alkyl groups include methyl (C.sub.1), ethyl (C.sub.2),
propyl (C.sub.3) (e.g., n-propyl, isopropyl), butyl (C.sub.4)
(e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C.sub.5)
(e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl,
tertiary amyl), and hexyl (C.sub.6) (e.g., n-hexyl). Additional
examples of alkyl groups include n-heptyl (C.sub.7), n-octyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkyl group is independently unsubstituted (an "unsubstituted
alkyl") or substituted (a "substituted alkyl") with one or more
substituents (e.g., halogen, such as F). In certain embodiments,
the alkyl group is an unsubstituted C.sub.1-10 alkyl (such as
unsubstituted C.sub.1-6 alkyl, e.g., --CH.sub.3 (Me), unsubstituted
ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl
(n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu,
e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl
(tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted
isobutyl (i-Bu)). In certain embodiments, the alkyl group is a
substituted C.sub.1-10 alkyl (such as substituted C.sub.1-6 alkyl,
e.g., --CF.sub.3, Bn).
[0100] The term "haloalkyl" is a substituted alkyl group, wherein
one or more of the hydrogen atoms are independently replaced by a
halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments,
the haloalkyl moiety has 1 to 8 carbon atoms ("C.sub.1-8
haloalkyl"). In some embodiments, the haloalkyl moiety has 1 to 6
carbon atoms ("C.sub.1-6 haloalkyl"). In some embodiments, the
haloalkyl moiety has 1 to 4 carbon atoms ("C.sub.1-4 haloalkyl").
In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms
("C.sub.1-3 haloalkyl"). In some embodiments, the haloalkyl moiety
has 1 to 2 carbon atoms ("C.sub.1-2 haloalkyl"). Examples of
haloalkyl groups include --CHF.sub.2, --CH.sub.2F, --CF.sub.3,
--CH.sub.2CF.sub.3, --CF.sub.2CF.sub.3, --CF.sub.2CF.sub.2CF.sub.3,
--CCl.sub.3, --CFCl.sub.2, --CF.sub.2Cl, and the like.
[0101] The term "heteroalkyl" refers to an alkyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkyl group refers to a saturated group having
from 1 to 20 carbon atoms and 1 or more heteroatoms within the
parent chain ("heteroC.sub.1-20 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 18 carbon atoms
and 1 or more heteroatoms within the parent chain
("heteroC.sub.1-18 alkyl"). In some embodiments, a heteroalkyl
group is a saturated group having 1 to 16 carbon atoms and 1 or
more heteroatoms within the parent chain ("heteroC.sub.1-16
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 14 carbon atoms and 1 or more heteroatoms within
the parent chain ("heteroC.sub.1-14 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 12 carbon atoms
and 1 or more heteroatoms within the parent chain
("heteroC.sub.1-12 alkyl"). In some embodiments, a heteroalkyl
group is a saturated group having 1 to 10 carbon atoms and 1 or
more heteroatoms within the parent chain ("heteroC.sub.1-10
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 8 carbon atoms and 1 or more heteroatoms within
the parent chain ("heteroC.sub.1-8 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 6 carbon atoms
and 1 or more heteroatoms within the parent chain ("heteroC.sub.1-6
alkyl"). In some embodiments, a heteroalkyl group is a saturated
group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the
parent chain ("heteroC.sub.1-4 alkyl"). In some embodiments, a
heteroalkyl group is a saturated group having 1 to 3 carbon atoms
and 1 heteroatom within the parent chain ("heteroC.sub.1-3 alkyl").
In some embodiments, a heteroalkyl group is a saturated group
having 1 to 2 carbon atoms and 1 heteroatom within the parent chain
("heteroC.sub.1-2 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 carbon atom and 1 heteroatom
("heteroC.sub.1 alkyl"). In some embodiments, the heteroalkyl group
defined herein is a partially unsaturated group having 1 or more
heteroatoms within the parent chain and at least one unsaturated
carbon, such as a carbonyl group. For example, a heteroalkyl group
may comprise an amide or ester functionality in its parent chain
such that one or more carbon atoms are unsaturated carbonyl groups.
Unless otherwise specified, each instance of a heteroalkyl group is
independently unsubstituted (an "unsubstituted heteroalkyl") or
substituted (a "substituted heteroalkyl") with one or more
substituents. In certain embodiments, the heteroalkyl group is an
unsubstituted heteroC.sub.1-20 alkyl. In certain embodiments, the
heteroalkyl group is an unsubstituted heteroC.sub.1-10 alkyl. In
certain embodiments, the heteroalkyl group is a substituted
heteroC.sub.1-20 alkyl. In certain embodiments, the heteroalkyl
group is an unsubstituted heteroC.sub.1-10 alkyl.
[0102] The term "alkenyl" refers to a radical of a straight-chain
or branched hydrocarbon group having from 2 to 10 carbon atoms and
one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double
bonds). In some embodiments, an alkenyl group has 2 to 9 carbon
atoms ("C.sub.2-9 alkenyl"). In some embodiments, an alkenyl group
has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In some embodiments,
an alkenyl group has 2 to 7 carbon atoms ("C.sub.2-7 alkenyl"). In
some embodiments, an alkenyl group has 2 to 6 carbon atoms
("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2
to 5 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an
alkenyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkenyl"). In
some embodiments, an alkenyl group has 2 to 3 carbon atoms
("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group has 2
carbon atoms ("C.sub.2 alkenyl"). The one or more carbon-carbon
double bonds can be internal (such as in 2-butenyl) or terminal
(such as in 1-butenyl). Examples of C.sub.2-4 alkenyl groups
include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl
(C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkenyl groups as well as
pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and
the like. Additional examples of alkenyl include heptenyl
(C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like.
Unless otherwise specified, each instance of an alkenyl group is
independently unsubstituted (an "unsubstituted alkenyl") or
substituted (a "substituted alkenyl") with one or more
substituents. In certain embodiments, the alkenyl group is an
unsubstituted C.sub.2-10 alkenyl. In certain embodiments, the
alkenyl group is a substituted C.sub.2-10 alkenyl. In an alkenyl
group, a C.dbd.C double bond for which the stereochemistry is not
specified (e.g., --CH.dbd.CHCH.sub.3 or
##STR00010##
may be an (E)- or (Z)-double bond.
[0103] The term "heteroalkenyl" refers to an alkenyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkenyl group refers to a group having from 2
to 10 carbon atoms, at least one double bond, and 1 or more
heteroatoms within the parent chain ("heteroC.sub.2-10 alkenyl").
In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms
at least one double bond, and 1 or more heteroatoms within the
parent chain ("heteroC.sub.2-9 alkenyl"). In some embodiments, a
heteroalkenyl group has 2 to 8 carbon atoms, at least one double
bond, and 1 or more heteroatoms within the parent chain
("heteroC.sub.2-8 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 7 carbon atoms, at least one double bond, and 1 or
more heteroatoms within the parent chain ("heteroC.sub.2-7
alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6
carbon atoms, at least one double bond, and 1 or more heteroatoms
within the parent chain ("heteroC.sub.2-6 alkenyl"). In some
embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at
least one double bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-5 alkenyl"). In some embodiments, a
heteroalkenyl group has 2 to 4 carbon atoms, at least one double
bond, and 1 or 2 heteroatoms within the parent chain
("heteroC.sub.2-4 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 3 carbon atoms, at least one double bond, and 1
heteroatom within the parent chain ("heteroC.sub.2-3 alkenyl"). In
some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at
least one double bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-6 alkenyl"). Unless otherwise specified, each
instance of a heteroalkenyl group is independently unsubstituted
(an "unsubstituted heteroalkenyl") or substituted (a "substituted
heteroalkenyl") with one or more substituents. In certain
embodiments, the heteroalkenyl group is an unsubstituted
heteroC.sub.2-10 alkenyl. In certain embodiments, the heteroalkenyl
group is a substituted heteroC.sub.2-10 alkenyl.
[0104] The term "alkynyl" refers to a radical of a straight-chain
or branched hydrocarbon group having from 2 to 10 carbon atoms and
one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple
bonds) ("C.sub.2-10 alkynyl"). In some embodiments, an alkynyl
group has 2 to 9 carbon atoms ("C.sub.2-9 alkynyl"). In some
embodiments, an alkynyl group has 2 to 8 carbon atoms ("C.sub.2-8
alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon
atoms ("C.sub.2-7 alkynyl"). In some embodiments, an alkynyl group
has 2 to 6 carbon atoms ("C.sub.2-6 alkynyl"). In some embodiments,
an alkynyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkynyl"). In
some embodiments, an alkynyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkynyl"). In some embodiments, an alkynyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkynyl"). In some embodiments, an
alkynyl group has 2 carbon atoms ("C.sub.2 alkynyl"). The one or
more carbon-carbon triple bonds can be internal (such as in
2-butynyl) or terminal (such as in 1-butynyl). Examples of
C.sub.2-4 alkynyl groups include, without limitation, ethynyl
(C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3), 1-butynyl
(C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of C.sub.2-6
alkenyl groups include the aforementioned C.sub.2-4 alkynyl groups
as well as pentynyl (C.sub.5), hexynyl (C.sub.6), and the like.
Additional examples of alkynyl include heptynyl (C.sub.7), octynyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkynyl group is independently unsubstituted (an
"unsubstituted alkynyl") or substituted (a "substituted alkynyl")
with one or more substituents. In certain embodiments, the alkynyl
group is an unsubstituted C.sub.2-10 alkynyl. In certain
embodiments, the alkynyl group is a substituted C.sub.2-10
alkynyl.
[0105] The term "heteroalkynyl" refers to an alkynyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkynyl group refers to a group having from 2
to 10 carbon atoms, at least one triple bond, and 1 or more
heteroatoms within the parent chain ("heteroC.sub.2-10 alkynyl").
In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms,
at least one triple bond, and 1 or more heteroatoms within the
parent chain ("heteroC.sub.2-9 alkynyl"). In some embodiments, a
heteroalkynyl group has 2 to 8 carbon atoms, at least one triple
bond, and 1 or more heteroatoms within the parent chain
("heteroC.sub.2-8 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 7 carbon atoms, at least one triple bond, and 1 or
more heteroatoms within the parent chain ("heteroC.sub.2-7
alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6
carbon atoms, at least one triple bond, and 1 or more heteroatoms
within the parent chain ("heteroC.sub.2-6 alkynyl"). In some
embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at
least one triple bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-5 alkynyl"). In some embodiments, a
heteroalkynyl group has 2 to 4 carbon atoms, at least one triple
bond, and 1 or 2 heteroatoms within the parent chain
("heteroC.sub.2-4 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 3 carbon atoms, at least one triple bond, and 1
heteroatom within the parent chain ("heteroC.sub.2-3 alkynyl"). In
some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at
least one triple bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-6 alkynyl"). Unless otherwise specified, each
instance of a heteroalkynyl group is independently unsubstituted
(an "unsubstituted heteroalkynyl") or substituted (a "substituted
heteroalkynyl") with one or more substituents. In certain
embodiments, the heteroalkynyl group is an unsubstituted
heteroC.sub.2-10 alkynyl. In certain embodiments, the heteroalkynyl
group is a substituted heteroC.sub.2-10 alkynyl.
[0106] The term "carbocyclyl" or "carbocyclic" refers to a radical
of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring
carbon atoms ("C.sub.3-14 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 10 ring carbon atoms ("C.sub.3-10 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms
("C.sub.3-8 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 7 ring carbon atoms ("C.sub.3-7 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 4 to 6 ring carbon atoms ("C.sub.4-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms
("C.sub.5-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 5 to 10 ring carbon atoms ("C.sub.5-10 carbocyclyl"). Exemplary
C.sub.3-6 carbocyclyl groups include, without limitation,
cyclopropyl (C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl
(C.sub.4), cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5),
cyclopentenyl (C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl
(C.sub.6), cyclohexadienyl (C.sub.6), and the like. Exemplary
C.sub.3-8 carbocyclyl groups include, without limitation, the
aforementioned C.sub.3-6 carbocyclyl groups as well as cycloheptyl
(C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl (C.sub.7),
cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8), cyclooctenyl
(C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7), bicyclo[2.2.2]octanyl
(C.sub.8), and the like. Exemplary C.sub.3-10 carbocyclyl groups
include, without limitation, the aforementioned C.sub.3-8
carbocyclyl groups as well as cyclononyl (C.sub.9), cyclononenyl
(C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl (C.sub.10),
octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl (C.sub.10),
spiro[4.5]decanyl (C.sub.10), and the like. As the foregoing
examples illustrate, in certain embodiments, the carbocyclyl group
is either monocyclic ("monocyclic carbocyclyl") or polycyclic
(e.g., containing a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic carbocyclyl") or tricyclic system
("tricyclic carbocyclyl")) and can be saturated or can contain one
or more carbon-carbon double or triple bonds. "Carbocyclyl" also
includes ring systems wherein the carbocyclyl ring, as defined
above, is fused with one or more aryl or heteroaryl groups wherein
the point of attachment is on the carbocyclyl ring, and in such
instances, the number of carbons continue to designate the number
of carbons in the carbocyclic ring system. Unless otherwise
specified, each instance of a carbocyclyl group is independently
unsubstituted (an "unsubstituted carbocyclyl") or substituted (a
"substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is an unsubstituted
C.sub.3-14 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-14 carbocyclyl.
[0107] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 14 ring carbon atoms
("C.sub.3-14 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 10 ring carbon atoms ("C.sub.3-10 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms
("C.sub.3-8 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms
("C.sub.4-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is an unsubstituted C.sub.3-14 cycloalkyl. In
certain embodiments, the cycloalkyl group is a substituted
C.sub.3-14 cycloalkyl.
[0108] The term "heterocyclyl" or "heterocyclic" refers to a
radical of a 3- to 14-membered non-aromatic ring system having ring
carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom
is independently selected from nitrogen, oxygen, and sulfur ("3-14
membered heterocyclyl"). In heterocyclyl groups that contain one or
more nitrogen atoms, the point of attachment can be a carbon or
nitrogen atom, as valency permits. A heterocyclyl group can either
be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a
fused, bridged or spiro ring system such as a bicyclic system
("bicyclic heterocyclyl") or tricyclic system ("tricyclic
heterocyclyl")), and can be saturated or can contain one or more
carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring
systems can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclyl ring, or ring systems wherein the heterocyclyl
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclyl ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclyl ring system. Unless otherwise specified, each instance
of heterocyclyl is independently unsubstituted (an "unsubstituted
heterocyclyl") or substituted (a "substituted heterocyclyl") with
one or more substituents. In certain embodiments, the heterocyclyl
group is an unsubstituted 3-14 membered heterocyclyl. In certain
embodiments, the heterocyclyl group is a substituted 3-14 membered
heterocyclyl.
[0109] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In
some embodiments, a heterocyclyl group is a 5-8 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some
embodiments, a heterocyclyl group is a 5-6 membered non-aromatic
ring system having ring carbon atoms and 1-4 ring heteroatoms,
wherein each heteroatom is independently selected from nitrogen,
oxygen, and sulfur ("5-6 membered heterocyclyl"). In some
embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected
from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6
membered heterocyclyl has 1 ring heteroatom selected from nitrogen,
oxygen, and sulfur.
[0110] Exemplary 3-membered heterocyclyl groups containing 1
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1
heteroatom include, without limitation, azetidinyl, oxetanyl, and
thietanyl. Exemplary 5-membered heterocyclyl groups containing 1
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing 2 heteroatoms include,
without limitation, dioxolanyl, oxathiolanyl and dithiolanyl.
Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms
include, without limitation, triazolinyl, oxadiazolinyl, and
thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing
1 heteroatom include, without limitation, piperidinyl,
tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary
6-membered heterocyclyl groups containing 2 heteroatoms include,
without limitation, piperazinyl, morpholinyl, dithianyl, and
dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3
heteroatoms include, without limitation, triazinyl. Exemplary
7-membered heterocyclyl groups containing 1 heteroatom include,
without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary
8-membered heterocyclyl groups containing 1 heteroatom include,
without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary
bicyclic heterocyclyl groups include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,
octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl,
naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl,
1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,
5,6-dihydro-4H-furo[3,2-b]pyrrolyl,
6,7-dihydro-5H-furo[3,2-b]pyranyl,
5,7-dihydro-4H-thieno[2,3-c]pyranyl,
2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,
2,3-dihydrofuro[2,3-b]pyridinyl,
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,
4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,
4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,
1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.
[0111] The term "aryl" refers to a radical of a monocyclic or
polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system
(e.g., having 6, 10, or 14 .pi. electrons shared in a cyclic array)
having 6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has 6 ring carbon atoms ("C.sub.6 aryl"; e.g., phenyl).
In some embodiments, an aryl group has 10 ring carbon atoms
("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has 14 ring carbon
atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also includes ring
systems wherein the aryl ring, as defined above, is fused with one
or more carbocyclyl or heterocyclyl groups wherein the radical or
point of attachment is on the aryl ring, and in such instances, the
number of carbon atoms continue to designate the number of carbon
atoms in the aryl ring system. Unless otherwise specified, each
instance of an aryl group is independently unsubstituted (an
"unsubstituted aryl") or substituted (a "substituted aryl") with
one or more substituents. In certain embodiments, the aryl group is
an unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl
group is a substituted C.sub.6-14 aryl.
[0112] "Aralkyl" is a subset of "alkyl" and refers to an alkyl
group substituted by an aryl group, wherein the point of attachment
is on the alkyl moiety.
[0113] The term "heteroaryl" refers to a radical of a 5-14 membered
monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic
ring system (e.g., having 6, 10, or 14 .pi. electrons shared in a
cyclic array) having ring carbon atoms and 1-4 ring heteroatoms
provided in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-14
membered heteroaryl"). In heteroaryl groups that contain one or
more nitrogen atoms, the point of attachment can be a carbon or
nitrogen atom, as valency permits. Heteroaryl polycyclic ring
systems can include one or more heteroatoms in one or both rings.
"Heteroaryl" includes ring systems wherein the heteroaryl ring, as
defined above, is fused with one or more carbocyclyl or
heterocyclyl groups wherein the point of attachment is on the
heteroaryl ring, and in such instances, the number of ring members
continue to designate the number of ring members in the heteroaryl
ring system. "Heteroaryl" also includes ring systems wherein the
heteroaryl ring, as defined above, is fused with one or more aryl
groups wherein the point of attachment is either on the aryl or
heteroaryl ring, and in such instances, the number of ring members
designates the number of ring members in the fused polycyclic
(aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein
one ring does not contain a heteroatom (e.g., indolyl, quinolinyl,
carbazolyl, and the like) the point of attachment can be on either
ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl)
or the ring that does not contain a heteroatom (e.g.,
5-indolyl).
[0114] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
unsubstituted (an "unsubstituted heteroaryl") or substituted (a
"substituted heteroaryl") with one or more substituents. In certain
embodiments, the heteroaryl group is an unsubstituted 5-14 membered
heteroaryl. In certain embodiments, the heteroaryl group is a
substituted 5-14 membered heteroaryl.
[0115] Exemplary 5-membered heteroaryl groups containing 1
heteroatom include, without limitation, pyrrolyl, furanyl, and
thiophenyl. Exemplary 5-membered heteroaryl groups containing 2
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing 3 heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing 4 heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing 1 heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing 2 heteroatoms include, without limitation, pyridazinyl,
pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups
containing 3 or 4 heteroatoms include, without limitation,
triazinyl and tetrazinyl, respectively. Exemplary 7-membered
heteroaryl groups containing 1 heteroatom include, without
limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary
5,6-bicyclic heteroaryl groups include, without limitation,
indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,
isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,
benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary
tricyclic heteroaryl groups include, without limitation,
phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl,
phenothiazinyl, phenoxazinyl, and phenazinyl.
[0116] "Heteroaralkyl" is a subset of "alkyl" and refers to an
alkyl group substituted by a heteroaryl group, wherein the point of
attachment is on the alkyl moiety.
[0117] The term "unsaturated bond" refers to a double or triple
bond.
[0118] The term "unsaturated" or "partially unsaturated" refers to
a moiety that includes at least one double or triple bond.
[0119] The term "saturated" refers to a moiety that does not
contain a double or triple bond, i.e., the moiety only contains
single bonds.
[0120] Affixing the suffix "-ene" to a group indicates the group is
a divalent moiety, e.g., alkylene is the divalent moiety of alkyl,
alkenylene is the divalent moiety of alkenyl, alkynylene is the
divalent moiety of alkynyl, heteroalkylene is the divalent moiety
of heteroalkyl, heteroalkenylene is the divalent moiety of
heteroalkenyl, heteroalkynylene is the divalent moiety of
heteroalkynyl, carbocyclylene is the divalent moiety of
carbocyclyl, heterocyclylene is the divalent moiety of
heterocyclyl, arylene is the divalent moiety of aryl, and
heteroarylene is the divalent moiety of heteroaryl.
[0121] A group is optionally substituted unless expressly provided
otherwise. The term "optionally substituted" refers to being
substituted or unsubstituted. In certain embodiments, alkyl,
alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are
optionally substituted. "Optionally substituted" refers to a group
which may be substituted or unsubstituted (e.g., "substituted" or
"unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl,
"substituted" or "unsubstituted" alkynyl, "substituted" or
"unsubstituted" heteroalkyl, "substituted" or "unsubstituted"
heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl,
"substituted" or "unsubstituted" carbocyclyl, "substituted" or
"unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl
or "substituted" or "unsubstituted" heteroaryl group). In general,
the term "substituted" means that at least one hydrogen present on
a group is replaced with a permissible substituent, e.g., a
substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, and includes any of the substituents described herein
that results in the formation of a stable compound. The present
invention contemplates any and all such combinations in order to
arrive at a stable compound. For purposes of this invention,
heteroatoms such as nitrogen may have hydrogen substituents and/or
any suitable substituent as described herein which satisfy the
valencies of the heteroatoms and results in the formation of a
stable moiety. The invention is not intended to be limited in any
manner by the exemplary substituents described herein.
[0122] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.3,
--CO.sub.2R.sup.aa, --C(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.O)N(Rbb).sub.2,
--NR.sup.bbC(.dbd.O).sub.Raa.sub., --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
C(.dbd.NR.sup.bb)--OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
OC(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --C(.dbd.O)SR.sup.aa, --SC(.dbd.O)OR.sup.aa,
--SC(.dbd.O)R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--OP(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--NR.sup.bbP(.dbd.O)(R.sup.aa).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, --P(R.sup.cc).sub.2,
--P(OR.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.3.sup.+X.sup.-, --P(R.sup.cc).sub.4,
--P(OR.sup.cc).sub.4, --OP(R.sup.cc).sub.2,
--OP(R.sup.cc).sub.3.sup.+X.sup.-, --OP(OR.sup.cc).sub.2,
--OP(OR.sup.cc).sub.3.sup.+X.sup.-, --OP(R.sup.cc).sub.4,
--OP(OR.sup.cc).sub.4, --B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2,
--BR.sup.aa(OR.sup.cc), C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X is a
counterion;
[0123] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0124] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.aa groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0125] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10 alkyl, heteroC.sub.2-10alkenyl, heteroC.sub.2-10
alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl,
C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two R.sup.bb
groups are joined to form a 3-14 membered heterocyclyl or 5-14
membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X is a
counterion;
[0126] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.CC groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0127] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR)R.sup.ee, --OC
(.dbd.NR.sup.ff)OR.sup.ee, --C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2 ,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi (R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O)(OR.sup.ee).sub.2, --P(.dbd.O)(R.sup.ee).sub.2, --OP
(.dbd.O)(R.sup.ee).sub.2, --OP (.dbd.O)(OR.sup.ee).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6 alkenyl,
heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups,
or two geminal R.sup.dd substituents can be joined to form .dbd.O
or .dbd.S; wherein X.sup.- is a counterion;
[0128] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6 alkenyl,
heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg
groups;
[0129] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6
alkenyl, heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10
membered heterocyclyl, C.sub.6-10 aryl and 5-10 membered
heteroaryl, or two R.sup.ff groups are joined to form a 3-10
membered heterocyclyl or 5-10 membered heteroaryl ring, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0130] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1
-6 alkyl, --ON(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.+, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--C(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC (.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC (.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C (.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC (.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6 alkyl),
--C(.dbd.NH)NH.sub.2, --NHC(.dbd.NH)N(C.sub.1-6 alkyl).sub.2,
--NHC(.dbd.NH)NH.sub.2, --NHSO.sub.2(C.sub.1-6 alkyl),
--SO.sub.2N(C.sub.1-6 alkyl).sub.2, --SO.sub.2NH(C.sub.1-6 alkyl),
--SO.sub.2NH.sub.2, SO.sub.2(C.sub.1-6 alkyl),
--SO.sub.2O(C.sub.1-6 alkyl), --OSO.sub.2(C.sub.1-6 alkyl),
--SO(C.sub.1-6 alkyl), --Si(C.sub.1-6 alkyl).sub.3, --OSi(C.sub.1-6
alkyl).sub.3 --C(.dbd.S)N(C.sub.1-6 alkyl).sub.2,
C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O)(OC.sub.1-6 alkyl).sub.2,
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6 alkenyl,
heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two
geminal R.sup.gg substituents can be joined to form .dbd.O or
.dbd.S; wherein X.sup.- is a counterion.
[0131] The term "halo" or "halogen" refers to fluorine (fluoro,
--F), chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine
(iodo, --I).
[0132] The term "hydroxyl" or "hydroxy" refers to the group --OH.
The term "substituted hydroxyl" or "substituted hydroxyl," by
extension, refers to a hydroxyl group wherein the oxygen atom
directly attached to the parent molecule is substituted with a
group other than hydrogen, and includes groups selected from
--OR.sup.aa, --ON(R.sup.bb).sub.2, --OC(.dbd.O)SR.sup.aa,
--OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--OC(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bbOR.sup.aa,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --OS(.dbd.O)R.sup.aa,
--OSO.sub.2R.sup.aa, --OSi(R.sup.aa).sub.3, --OP(R.sup.cc).sub.2,
--OP(R.sup.cc).sub.3.sup.+X.sup.-, --OP(OR.sup.cc).sub.2,
--OP(OR.sup.cc).sub.3.sup.+X.sup.-, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, and
--OP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein X.sup.-, R.sup.aa,
R.sup.bb, and R.sup.cc are as defined herein.
[0133] The term "amino" refers to the group --NH.sub.2. The term
"substituted amino," by extension, refers to a monosubstituted
amino, a disubstituted amino, or a trisubstituted amino. In certain
embodiments, the "substituted amino" is a monosubstituted amino or
a disubstituted amino group.
[0134] The term "monosubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with one hydrogen and one group other than hydrogen,
and includes groups selected from --NH(R.sup.bb),
--NHC(.dbd.O)R.sup.aa, --NHCO.sub.2R.sup.aa,
--NHC(.dbd.O)N(R.sup.bb).sub.2,
--NHC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --NHSO.sub.2R.sup.aa,
--NHP(.dbd.O)(OR.sup.cc).sub.2, and
--NHP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein R.sup.aa, R.sup.bb
and R.sup.cc are as defined herein, and wherein R.sup.bb of the
group --NH(R.sup.bb) is not hydrogen.
[0135] The term "disubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with two groups other than hydrogen, and includes
groups selected from --N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O).sub.R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
and --NR.sup.bbP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein
R.sup.aa, R.sup.bb, and R.sup.cc are as defined herein, with the
proviso that the nitrogen atom directly attached to the parent
molecule is not substituted with hydrogen.
[0136] The term "trisubstituted amino" refers to an amino group
wherein the nitrogen atom directly attached to the parent molecule
is substituted with three groups, and includes groups selected from
--N(R.sup.bb).sub.3 and --N(R.sup.bb).sub.3.sup.+X.sup.-, wherein
R.sup.bb and X.sup.- are as defined herein.
[0137] The term "sulfonyl" refers to a group selected from
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa, and
--SO.sub.2OR.sup.aa, wherein R.sup.aa and R.sup.bb are as defined
herein.
[0138] The term "sulfinyl" refers to the group --S(.dbd.O)R.sup.aa,
wherein R.sup.aa is as defined herein.
[0139] The term "acyl" refers to a group having the general formula
--C(.dbd.O)R.sup.X1, --C(.dbd.O)OR.sup.X1,
--C(.dbd.O)--O--C(.dbd.O)R.sup.X1, --C(.dbd.O)SR.sup.X1,
--C(.dbd.O)N(R.sup.X1).sub.2, --C(.dbd.S)R.sup.X1,
--C(.dbd.S)N(R.sup.X1).sub.2, --C(.dbd.S)O(R.sup.X1),
--C(.dbd.S)S(R.sup.X1), --C(.dbd.NR.sup.X1)R.sup.X1,
--C(.dbd.NR.sup.X1)OR.sup.X1, --C(.dbd.NR.sup.x1)SR.sup.X1, and
--C(--NR.sup.X1)N(R.sup.X1).sub.2, wherein R.sup.X1 is hydrogen;
halogen; substituted or unsubstituted hydroxyl; substituted or
unsubstituted thiol; substituted or unsubstituted amino;
substituted or unsubstituted acyl, cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; cyclic or acyclic, substituted or unsubstituted,
branched or unbranched alkyl; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched alkenyl; substituted or
unsubstituted alkynyl; substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, aliphaticoxy,
heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,
heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or
di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or
di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino,
or mono- or di-heteroarylamino; or two R.sup.X1 groups taken
together form a 5- to 6-membered heterocyclic ring. Exemplary acyl
groups include aldehydes (--CHO), carboxylic acids (--CO.sub.2H),
ketones, acyl halides, esters, amides, imines, carbonates,
carbamates, and ureas. Acyl substituents include, but are not
limited to, any of the substituents described herein, that result
in the formation of a stable moiety (e.g., aliphatic, alkyl,
alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl,
acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro,
hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino,
alkylamino, heteroalkylamino, arylamino, heteroarylamino,
alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy,
heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy,
heteroarylthioxy, acyloxy, and the like, each of which may or may
not be further substituted).
[0140] The term "carbonyl" refers a group wherein the carbon
directly attached to the parent molecule is sp.sup.2 hybridized,
and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a
group selected from ketones (e.g., --C(.dbd.O)R.sup.aa), carboxylic
acids (e.g., --CO.sub.2H), aldehydes (--CHO), esters (e.g.,
--CO.sub.2R.sup.aa, --C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa),
amides (e.g., --C(.dbd.O)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa,
--C(.dbd.S)N(R.sup.bb).sub.2), and imines (e.g.,
--C(.dbd.NR.sup.bb)R.sup.aa , --C(.dbd.NR.sup.bb)OR.sup.aa,
--(.dbd.NR.sup.bb).sub.N(R.sup.bb).sub.2), wherein R.sup.aa and
R.sup.bb are as defined herein.
[0141] The term "silyl" refers to the group --Si(R.sup.aa).sub.3,
wherein R.sup.aa is as defined herein.
[0142] The term "oxo" refers to the group .dbd.O, and the term
"thiooxo" refers to the group .dbd.S.
[0143] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quaternary nitrogen atoms. Exemplary nitrogen atom substituents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10 alkyl, heteroC.sub.2-10alkenyl,
heteroC.sub.2-10alkkynl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.CC groups attached to an N atom are joined to form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, and R.sup.dd are as defined
herein.
[0144] In certain embodiments, the substituent present on the
nitrogen atom is an nitrogen protecting group (also referred to
herein as an "amino protecting group"). Nitrogen protecting groups
include, but are not limited to, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, C(.dbd.NR.sup.cc)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g.,
aralkyl, heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10 alkyl, heteroC.sub.2-10 alkenyl, heteroC.sub.2-10
alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered heterocyclyl,
C.sub.6-14 aryl, and 5-14 membered heteroaryl groups, wherein each
alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined herein. Nitrogen protecting groups are well known in the
art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd
edition, John Wiley & Sons, 1999, incorporated herein by
reference.
[0145] For example, nitrogen protecting groups such as amide groups
(e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to,
formamide, acetamide, chloroacetamide, trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,
picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide,
o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0146] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,1
0-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate
(DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc),
allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc),
cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),
8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio
carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate,
diphenylmethylcarbamate, 2-methylthioethylcarbamate,
2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl
carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc),
4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl
carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc),
2-triphenylphosphonioisopropyl carbamate (Ppoc),
1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl
carbamate, p-(dihydroxyboryl)benzyl carbamate,
5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0147] Nitrogen protecting groups such as sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), .beta.-trimethylsilylethanesulfonamide
(SES), 9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0148] Other nitrogen protecting groups include, but are not
limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilypethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-ypamine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys). In certain embodiments, a
nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl
(BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc),
trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz),
p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl
(PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl
(Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl
(Tf), or dansyl (Ds).
[0149] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to herein as an
"hydroxyl protecting group"). Oxygen protecting groups include, but
are not limited to, --R.sup.aa, --N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.2, --P(OR.sup.cc).sub.3.sup.+X.sup.-,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, and
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein X.sup.-, R.sup.aa,
R.sup.bb, and R.sup.cc are as defined herein. Oxygen protecting
groups are well known in the art and include those described in
detail in Protecting Groups in Organic Synthesis, T. W. Greene and
P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999,
incorporated herein by reference.
[0150] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),
benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),
(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM),
t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl,
2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate,
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate,
vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc),
p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl
carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,
p-nitrobenzyl carbonate, S-benzyl thiocarbonate,
4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate,
2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate,
o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate,
2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, .alpha.-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts). In certain embodiments, an oxygen protecting group is silyl.
In certain embodiments, an oxygen protecting group is
t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS),
triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES),
trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac),
benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate
(Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM),
1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP),
2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM),
2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM),
tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl
(PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl
(DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl,
or pivaloyl (Piv).
[0151] In certain embodiments, the substituent present on a sulfur
atom is a sulfur protecting group (also referred to as a "thiol
protecting group"). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.2, --P(OR.sup.cc).sub.3.sup.+X.sup.-,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, and
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein R.sup.aa, R.sup.bb,
and R.sup.cc are as defined herein. Sulfur protecting groups are
well known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference. In certain embodiments, a sulfur protecting
group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl,
2-pyridine-sulfenyl, or triphenylmethyl.
[0152] A "counterion" or "anionic counterion" is a negatively
charged group associated with a positively charged group in order
to maintain electronic neutrality. An anionic counterion may be
monovalent (i.e., including one formal negative charge). An anionic
counterion may also be multivalent (i.e., including more than one
formal negative charge), such as divalent or trivalent. Exemplary
counterions include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-,
I.sup.-), NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-,
H.sub.2PO.sub.4.sup.-, HCO.sub.3 , HSO.sub.4.sup.-, sulfonate ions
(e.g., methansulfonate, trifluoromethanesulfonate,
p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,
naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,
ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions
(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,
glycolate, gluconate, and the like), BF.sub.4.sup.-,
PF.sub.4.sup.-, PF.sub.6.sup.-, AsF.sub.6.sup.-, SbF.sub.6.sup.-,
B[3,5-(CF.sub.3).sub.2C.sub.6H.sub.3].sub.4].sup.-,
B(C.sub.6F.sub.5).sub.4.sup.-, BPh.sub.4.sup.-,
Al(OC(CF.sub.3).sub.3).sub.4.sup.-, and carborane anions (e.g.,
CB.sub.11H.sub.12.sup.- or (HCB.sub.11Me.sub.5Br.sub.6).sup.-).
Exemplary counterions which may be multivalent include
CO.sub.3.sup.2-, HPO.sub.4.sup.2-, PO.sub.4.sup.3-,
B.sub.4O.sub.7.sup.2-, SO.sub.4.sup.2-, S.sub.2O.sub.3.sup.2-,
carboxylate anions (e.g., tartrate, citrate, fumarate, maleate,
malate, malonate, gluconate, succinate, glutarate, adipate,
pimelate, suberate, azelate, sebacate, salicylate, phthalates,
aspartate, glutamate, and the like), and carboranes.
[0153] The term "leaving group" is given its ordinary meaning in
the art of synthetic organic chemistry and refers to an atom or a
group capable of being displaced by a nucleophile. See, for
example, Smith, March's Advanced Organic Chemistry 6th ed.
(501-502). Examples of suitable leaving groups include, but are not
limited to, halogen (such as F, Cl, Br, or I (iodine)),
alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,
arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),
arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino,
pixyl, and haloformates. In some cases, the leaving group is a
sulfonic acid ester, such as toluenesulfonate (tosylate, --OTs),
methanesulfonate (mesylate, --OMs),p-bromobenzenesulfonyloxy
(brosylate, --OBs), --OS(.dbd.O).sub.2(CF.sub.2).sub.3CF.sub.3
(nonaflate, --ONf), or trifluoromethanesulfonate (triflate, --OTf).
In some cases, the leaving group is a brosylate, such as
p-bromobenzenesulfonyloxy. In some cases, the leaving group is a
nosylate, such as 2-nitrobenzenesulfonyloxy. The leaving group may
also be a phosphineoxide (e.g., formed during a Mitsunobu reaction)
or an internal leaving group such as an epoxide or cyclic sulfate.
Other non-limiting examples of leaving groups are water, ammonia,
alcohols, ether moieties, thioether moieties, zinc halides,
magnesium moieties, diazonium salts, and copper moieties. Further
exemplary leaving groups include, but are not limited to, halo
(e.g., chloro, bromo, iodo) and activated substituted hydroxyl
groups (e.g., --OC(.dbd.O)SR.sup.aa, --OC(.dbd.O)R.sup.aa,
--OCO.sub.2R.sup.aa, --OC(.dbd.O)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)R.sup.aa, --OC(.dbd.NR.sup.bb)OR.sup.aa,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --OS(.dbd.O)R.sup.aa,
--OSO.sub.hd 2R.sup.aa, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--OP(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --OP(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --OP(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein).
[0154] As used herein, use of the phrase "at least one instance"
refers to 1, 2, 3, 4, or more instances, but also encompasses a
range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2,
from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
[0155] A "non-hydrogen group" refers to any group that is defined
for a particular variable that is not hydrogen.
[0156] These and other exemplary substituents are described in more
detail in the Detailed Description, Examples, and claims. The
invention is not intended to be limited in any manner by the above
exemplary listing of substituents.
Other Definitions
[0157] The following definitions are more general terms used
throughout the present application.
[0158] As used herein, the term "salt" refers to any and all salts,
and encompasses pharmaceutically acceptable salts.
[0159] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al. describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,
incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids, such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid, and
perchloric acid or with organic acids, such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid, or
malonic acid or by using other methods known in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium, and N.sup.+(C.sub.1-4 alkyl).sub.4.sup.-
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate,
and aryl sulfonate.
[0160] The term "solvate" refers to forms of the compound, or a
salt thereof, that are associated with a solvent, usually by a
solvolysis reaction. This physical association may include hydrogen
bonding. Conventional solvents include water, methanol, ethanol,
acetic acid, DMSO, THF, diethyl ether, and the like. The compounds
described herein may be prepared, e.g., in crystalline form, and
may be solvated. Suitable solvates include pharmaceutically
acceptable solvates and further include both stoichiometric
solvates and non-stoichiometric solvates. In certain instances, the
solvate will be capable of isolation, for example, when one or more
solvent molecules are incorporated in the crystal lattice of a
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Representative solvates include hydrates,
ethanolates, and methanolates.
[0161] The term "hydrate" refers to a compound that is associated
with water. Typically, the number of the water molecules contained
in a hydrate of a compound is in a definite ratio to the number of
the compound molecules in the hydrate. Therefore, a hydrate of a
compound may be represented, for example, by the general formula
R.x H.sub.2O, wherein R is the compound, and x is a number greater
than 0. A given compound may form more than one type of hydrate,
including, e.g., monohydrates (x is 1), lower hydrates (x is a
number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5
H.sub.2O)), and polyhydrates (x is a number greater than 1, e.g.,
dihydrates (R.2 H.sub.2O) and hexahydrates (R.6 H.sub.2O)).
[0162] The term "tautomers" or "tautomeric" refers to two or more
interconvertible compounds resulting from at least one formal
migration of a hydrogen atom and at least one change in valency
(e.g., a single bond to a double bond, a triple bond to a single
bond, or vice versa). The exact ratio of the tautomers depends on
several factors, including temperature, solvent, and pH.
Tautomerizations (i.e., the reaction providing a tautomeric pair)
may catalyzed by acid or base. Exemplary tautomerizations include
keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine,
and enamine-to-(a different enamine) tautomerizations.
[0163] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers". Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers".
[0164] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0165] The term "polymorph" refers to a crystalline form of a
compound (or a salt, hydrate, or solvate thereof). All polymorphs
have the same elemental composition. Different crystalline forms
usually have different X-ray diffraction patterns, infrared
spectra, melting points, density, hardness, crystal shape, optical
and electrical properties, stability, and solubility.
Recrystallization solvent, rate of crystallization, storage
temperature, and other factors may cause one crystal form to
dominate. Various polymorphs of a compound can be prepared by
crystallization under different conditions.
[0166] The term "prodrugs" refers to compounds that have cleavable
groups and become by solvolysis or under physiological conditions
the compounds described herein, which are pharmaceutically active
in vivo. Such examples include, but are not limited to, choline
ester derivatives and the like, N-alkylmorpholine esters and the
like. Other derivatives of the compounds described herein have
activity in both their acid and acid derivative forms, but in the
acid sensitive form often offer advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well known to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides, and anhydrides derived
from acidic groups pendant on the compounds described herein are
particular prodrugs. In some cases it is desirable to prepare
double ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, aryl, C.sub.7-12 substituted aryl, and
C.sub.7-12 arylalkyl esters of the compounds described herein may
be preferred.
[0167] The terms "composition" and "formulation" are used
interchangeably.
[0168] A "subject" to which administration is contemplated refers
to a human (i.e., male or female of any age group, e.g., pediatric
subject (e.g., infant, child, or adolescent) or adult subject
(e.g., young adult, middle-aged adult, or senior adult)) or
non-human animal. In certain embodiments, the non-human animal is a
mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey),
commercially relevant mammal (e.g., cattle, pig, horse, sheep,
goat, cat, or dog), or bird (e.g., commercially relevant bird, such
as chicken, duck, goose, or turkey)). In certain embodiments, the
non-human animal is a fish, reptile, or amphibian. The non-human
animal may be a male or female at any stage of development. The
non-human animal may be a transgenic animal or genetically
engineered animal. The term "patient" refers to a human subject in
need of treatment of a disease. The subject may also be a plant. In
certain embodiments, the plant is a land plant. In certain
embodiments, the plant is a non-vascular land plant. In certain
embodiments, the plant is a vascular land plant. In certain
embodiments, the plant is a seed plant. In certain embodiments, the
plant is a cultivated plant. In certain embodiments, the plant is a
dicot. In certain embodiments, the plant is a monocot. In certain
embodiments, the plant is a flowering plant. In some embodiments,
the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat,
barley, rye, or millet. In some embodiments, the plant is a legume,
e.g., a bean plant, e.g., soybean plant. In some embodiments, the
plant is a tree or shrub.
[0169] The term "biological sample" refers to any sample including
tissue samples (such as tissue sections and needle biopsies of a
tissue); cell samples (e.g., cytological smears (such as Pap or
blood smears) or samples of cells obtained by microdissection);
samples of whole organisms (such as samples of yeasts or bacteria);
or cell fractions, fragments or organelles (such as obtained by
lysing cells and separating the components thereof by
centrifugation or otherwise). Other examples of biological samples
include blood, serum, urine, semen, fecal matter, cerebrospinal
fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied
tissue (e.g., obtained by a surgical biopsy or needle biopsy),
nipple aspirates, milk, vaginal fluid, saliva, swabs (such as
buccal swabs), or any material containing biomolecules that is
derived from a first biological sample.
[0170] The term "tissue" refers to any biological tissue of a
subject (including a group of cells, a body part, or an organ) or a
part thereof, including blood and/or lymph vessels, which is the
object to which a compound, particle, and/or composition of the
invention is delivered. A tissue may be an abnormal or unhealthy
tissue, which may need to be treated. A tissue may also be a normal
or healthy tissue that is under a higher than normal risk of
becoming abnormal or unhealthy, which may need to be prevented. In
certain embodiments, the tissue is the central nervous system. In
certain embodiments, the tissue is the brain.
[0171] The term "administer," "administering," or "administration"
refers to implanting, absorbing, ingesting, injecting, inhaling, or
otherwise introducing a compound described herein, or a composition
thereof, in or on a subject.
[0172] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, delaying the onset of, or inhibiting the
progress of a disease described herein. In some embodiments,
treatment may be administered after one or more signs or symptoms
of the disease have developed or have been observed. In other
embodiments, treatment may be administered in the absence of signs
or symptoms of the disease. For example, treatment may be
administered to a susceptible subject prior to the onset of
symptoms (e.g., in light of a history of symptoms). Treatment may
also be continued after symptoms have resolved, for example, to
delay or prevent recurrence.
[0173] The terms "condition," "disease," and "disorder" are used
interchangeably.
[0174] An "effective amount" of a compound described herein refers
to an amount sufficient to elicit the desired biological response.
An effective amount of a compound described herein may vary
depending on such factors as the desired biological endpoint, the
pharmacokinetics of the compound, the condition being treated, the
mode of administration, and the age and health of the subject. In
certain embodiments, an effective amount is a therapeutically
effective amount. In certain embodiments, an effective amount is a
prophylactic treatment. In certain embodiments, an effective amount
is the amount of a compound described herein in a single dose. In
certain embodiments, an effective amount is the combined amounts of
a compound described herein in multiple doses.
[0175] A "therapeutically effective amount" of a compound described
herein is an amount sufficient to provide a therapeutic benefit in
the treatment of a condition or to delay or minimize one or more
symptoms associated with the condition. A therapeutically effective
amount of a compound means an amount of therapeutic agent, alone or
in combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces, or avoids symptoms, signs, or
causes of the condition, and/or enhances the therapeutic efficacy
of another therapeutic agent. In certain embodiments, a
therapeutically effective amount is an amount sufficient for tau
protein binding and/or promoting the degradation of tau protein. In
certain embodiments, a therapeutically effective amount is an
amount sufficient for treating a neurological disorder (e.g., AD).
In certain embodiments, a therapeutically effective amount is an
amount sufficient for tau protein binding and/or promoting the
degradation of protein and treating a neurological disorder (e.g.,
AD).
[0176] A "prophylactically effective amount" of a compound
described herein is an amount sufficient to prevent a condition, or
one or more signs or symptoms associated with the condition, or
prevent its recurrence. A prophylactically effective amount of a
compound means an amount of a therapeutic agent, alone or in
combination with other agents, which provides a prophylactic
benefit in the prevention of the condition. The term
"prophylactically effective amount" can encompass an amount that
improves overall prophylaxis or enhances the prophylactic efficacy
of another prophylactic agent. In certain embodiments, a
prophylactically effective amount is an amount sufficient for tau
protein binding and/or promoting the degradation of tau protein. In
certain embodiments, a prophylactically effective amount is an
amount sufficient for treating a neurological disorder (e.g., AD).
n certain embodiments, a prophylactically effective amount is an
amount sufficient for tau protein binding and/or promoting the
degradation of tau protein and treating a neurological disorder
(e.g., AD).
[0177] The term "neurological disorder" refers to any disorder,
disease, or condition of the nervous system.
[0178] The term "tau protein" refers to a class of proteins that
stabilize microtubules. They are abundant in neurons of the central
nervous system and are less common elsewhere, but are also
expressed at very low levels in CNS astrocytes and
oligodendrocytes. The tau proteins are the product of alternative
splicing from a single gene that in humans is designated MAPT
(microtubule-associated protein tau) and is located on chromosome
17. Tau protein described herein include all post-translationally
modified forms of the protein.
[0179] The term "tauopathy" refers to a class of neurodegenerative
diseases associated with the pathological aggregation of tau
protein in neurofibrillary or gliofibrillary tangles in the human
brain. Primary tauopathies, i.e., conditions in which
neurofibrillary tangles (NFT) are predominantly observed, include,
but are not limited to, 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, and argyrophilic grain disease.
[0180] The terms "biologic," "biologic drug," and "biological
product" refer to a wide range of products such as vaccines, blood
and blood components, allergenics, somatic cells, gene therapy,
tissues, nucleic acids, and proteins. Biologics may include sugars,
proteins, or nucleic acids, or complex combinations of these
substances, or may be living entities, such as cells and tissues.
Biologics may be isolated from a variety of natural sources (e.g.,
human, animal, microorganism) and may be produced by
biotechnological methods and other technologies.
[0181] The term "small molecule" or "small molecule therapeutic"
refers to molecules, whether naturally occurring or artificially
created (e.g., via chemical synthesis) that have a relatively low
molecular weight. Typically, a small molecule is an organic
compound (i.e., it contains carbon). The small molecule may contain
multiple carbon-carbon bonds, stereocenters, and other functional
groups (e g , amines, hydroxyl, carbonyls, and heterocyclic rings,
etc.). In certain embodiments, the molecular weight of a small
molecule is not more than about 1,000 g/mol, not more than about
900 g/mol, not more than about 800 g/mol, not more than about 700
g/mol, not more than about 600 g/mol, not more than about 500
g/mol, not more than about 400 g/mol, not more than about 300
g/mol, not more than about 200 g/mol, or not more than about 100
g/mol. In certain embodiments, the molecular weight of a small
molecule is at least about 100 g/mol, at least about 200 g/mol, at
least about 300 g/mol, at least about 400 g/mol, at least about 500
g/mol, at least about 600 g/mol, at least about 700 g/mol, at least
about 800 g/mol, or at least about 900 g/mol, or at least about
1,000 g/mol. Combinations of the above ranges (e.g., at least about
200 g/mol and not more than about 500 g/mol) are also possible. In
certain embodiments, the small molecule is a therapeutically active
agent such as a drug (e.g., a molecule approved by the U.S. Food
and Drug Administration as provided in the Code of Federal
Regulations (C.F.R.)). The small molecule may also be complexed
with one or more metal atoms and/or metal ions. In this instance,
the small molecule is also referred to as a "small organometallic
molecule." Preferred small molecules are biologically active in
that they produce a biological effect in animals, preferably
mammals, more preferably humans. Small molecules include, but are
not limited to, radionuclides and imaging agents. In certain
embodiments, the small molecule is a drug. Preferably, though not
necessarily, the drug is one that has already been deemed safe and
effective for use in humans or animals by the appropriate
governmental agency or regulatory body. For example, drugs approved
for human use are listed by the FDA under 21 C.F.R. .sctn..sctn.
330.5, 331 through 361, and 440 through 460, incorporated herein by
reference; drugs for veterinary use are listed by the FDA under 21
C.F.R. .sctn..sctn. 500 through 589, incorporated herein by
reference. All listed drugs are considered acceptable for use in
accordance with the present invention.
[0182] The term "therapeutic agent" refers to any substance having
therapeutic properties that produce a desired, usually beneficial,
effect. For example, therapeutic agents may treat, ameliorate,
and/or prevent disease. Therapeutic agents, as disclosed herein,
may be biologics or small molecule therapeutics.
[0183] The term "E3 ubiquitin ligase" or "E3 ligase" refers to any
protein that recruits an E2 ubiquitin-conjugating enzyme that has
been loaded with ubiquitin, recognizes a protein substrate, and
assists or directly catalyzes the transfer of ubiquitin from the E2
protein to the protein substrate.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0184] Provided herein are bifunctional compounds that bind tau
protein and recruit an E3 ligase (e.g., Cereblon) to promote the
degradation of tau protein. In one aspect, the disclosure provides
compounds of Formula I, and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
pharmaceutical compositions thereof The compounds are useful for
the treatment and/or prevention of diseases associated with tau
protein aggregation (e.g., tauopathies (e.g., AD)) in a subject in
need thereof.
Compounds
[0185] The compounds described herein interact with tau protein and
an E3 ubiquitin ligase (e.g., Cereblon). As described herein, the
therapeutic effect may be a result of degradation, modulation,
binding, or modification of tau protein by a compound described
herein. Without wishing to be bound by any particular theory, the
therapeutic effect may be the result of modulation, targeting,
binding, or modification of an E3 ubiquitin ligase (e.g., Cereblon)
by a compound described herein. The therapeutic effect may be a
result of recruitment of an E3 ubiquitin ligase (e.g., Cereblon) by
modulation, targeting, binding, or modification of the E3 ubiquitin
ligase to ubiquitinate tau protein and mark it for proteasomal
degradation, by a compound. A compound may be provided for use in
any composition, kit, or method described herein as a
pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof.
[0186] In one aspect, disclosed is a compound of Formula I:
T-L-E I,
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[0187] T is a tau protein binding moiety;
[0188] E is an E3 ubiquitin ligase binding moiety;
[0189] 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.sup.A)--, --S--,
--C(.dbd.O)--, --C(.dbd.O)O--, --C(.dbd.O)NR.sup.A--,
--NR.sup.AC(.dbd.O)--, --NR.sup.AC(.dbd.O)R.sup.A--,
--C(.dbd.O)R.sup.A--, --NR.sup.AC(.dbd.O)O--,
--NR.sup.AC(.dbd.O)N(R.sup.A)--, --OC(.dbd.O)--, --OC(.dbd.O)O--,
--OC(.dbd.O)N(R.sup.A)--, --S(O).sub.2NR.sup.A--,
--NR.sup.AS(O).sub.2--, or a combination thereof; and
[0190] each occurrence of R.sup.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.sup.A groups are
joined to form a substituted or unsubstituted heterocyclic
ring.
Group T
[0191] In certain embodiments, T is any tau protein binding moiety.
In certain embodiments, T is any tau protein binding moiety derived
from the tau protein binding compounds described in U.S. Patent
Applications, U.S. Ser. No. 13/447,095, filed May 22, 2012; U.S.
Ser. No. 13/035,405, filed Feb. 25, 2011; U.S. Ser. No. 13/881,872,
filed Oct. 28, 2011; U.S. Ser. No. 09/378,662, filed Aug. 20, 1999;
and U.S. Ser. No. 14/346,914, filed Mar. 24, 2014, each of which is
incorporated herein by reference.
[0192] In certain embodiments, T is of Formula T-I:
##STR00011##
wherein:
[0193] L is N or CR.sup.5;
[0194] M is N or CR.sup.6;
[0195] P is N or CR.sup.7;
[0196] Q is N or CR.sup.8;
[0197] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl, optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0198] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0199] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.nA--(C.dbd.O)NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.nS(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0200] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0201] each of R.sup.1, R.sup.2, and R.sup.4-R.sup.8 are
independently hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2,
NO.sub.2, a leaving group, a protecting group, aryl, heteroaryl,
NHR.sup.12, N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0202] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0203] n is 0-12;
[0204] wherein one or more carbon of R.sup.1-8 is optionally
replaced with C(O), O, S, SO.sub.2, NH, NH--C.sub.1-6 alkyl,
NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alk.sub.Y.sup.1).sub.2.
[0205] In certain embodiments of Formula T-I:
[0206] L is N or CR.sup.5;
[0207] M is N or CR.sup.6;
[0208] P is N or CR.sup.7;
[0209] Q is N or CR.sup.8;
[0210] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl, optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0211] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0212] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.nA-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0213] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0214] each of R.sup.1, R.sup.2, and R.sup.4-R.sup.8 are
independently hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2,
NO.sub.2, a leaving group, a protecting group, aryl, heteroaryl,
NHR.sup.12, N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0215] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0216] n is 0-12;
[0217] wherein one or more carbon of R.sup.1-8 is optionally
replaced with C(O), O, S, SO.sub.2, NH, NH-C.sub.1-6 alkyl,
NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6 alkyl).sub.2.
[0218] In certain embodiments, L is N or CR.sup.5; M is N or
CR.sup.6; P is CR.sup.7; and Q is CR.sup.8. In certain embodiments,
L is CR.sup.5; M is N or CR.sup.6; P is CR.sup.7; and Q is
CR.sup.8. In certain embodiments, L is CR.sup.5; M is N; P is
CR.sup.7; and Q is CR.sup.8.
[0219] In certain embodiments, X is a bond.
[0220] In certain embodiments, R.sup.9 is hydrogen.
[0221] In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
or -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
--(CH.sub.2).sub.n-A-NR.sup.A--. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--; and A is substituted or
unsubstituted heterocyclylene, substituted or unsubstituted
arylene, or substituted or unsubstituted heteroarylene. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A-(C.dbd.O)NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is substituted
or unsubstituted heterocyclylene, substituted or unsubstituted
arylene, or substituted or unsubstituted heteroarylene. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A---; and A is substituted or
unsubstituted heteroarylene. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A-(C.dbd.O)NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is substituted
or unsubstituted heteroarylene. In certain embodiments, R.sup.3 is
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
or --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is substituted or
unsubstituted heteroarylene. In certain embodiments, R.sup.3 is
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is substituted
or unsubstituted heteroarylene. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-(CH.sub.2).sub.n--NR.sup.A--. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain embodiments,
R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--. In certain embodiments,
R.sup.3 is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-(CH.sub.2).sub.n--NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--; and A is
unsubstituted heteroarylene. In certain embodiments, R.sup.3 is
-A-(CH.sub.2).sub.n--NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene.
[0222] In certain embodiments, each of R.sup.1, R.sup.2, and
R.sup.4 are independently hydrogen, OH, halogen, NH.sub.2,
CH.sub.3, SO.sub.2, NO.sub.2, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12; and
R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl. In certain
embodiments, each of R.sup.1, R.sup.2, and R.sup.4 are
independently hydrogen.
[0223] In certain embodiments, T is of Formula T-I-a:
##STR00012##
wherein:
[0224] L is N or CR.sup.5;
[0225] M is N or CR.sup.6;
[0226] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0227] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0228] R.sup.3 is --(CH.sub.2).--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.nNR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.nA--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0229] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0230] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.nR.sup.12;
[0231] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0232] n is 0-12;
[0233] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NH-C.sub.1-6 alkyl, NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0234] In certain embodiments of formula T-I-a:
[0235] L is N or CR.sup.5;
[0236] M is N or CR.sup.6;
[0237] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0238] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0239] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.nA-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n--A-S(O).sub.2NR.sup.A--;
[0240] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0241] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0242] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
and
[0243] n is 0-12;
[0244] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NH--C.sub.1-6 alkyl, NC.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0245] In certain embodiments, T is of Formula T-I-b:
##STR00013##
wherein R.sup.3 is --(CH.sub.2).sub.n--O--,
-A4(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--.
[0246] In certain embodiments of Formula T-I-b, R.sup.3 is
--(CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--, --(CH.sub.2).sub.n--S--,
-A-(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n-A-S--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A--S(O).sub.2NR.sup.A--.
[0247] In certain embodiments of Formula T-I-b, R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
or -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
[0248] In certain embodiments of Formula T-I-b, R.sup.3 is
--(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
--(CH.sub.2).sub.n-A-NR.sup.A--. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-(CH.sub.2).sub.n--NR.sup.A--. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A-- or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In
certain embodiments, R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--. In
certain embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-(CH.sub.2).sub.n--NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-(CH.sub.2).sub.n--NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-(CH.sub.2).sub.n--NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.3 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene.
[0249] In certain embodiments, T is of the formula:
##STR00014##
[0250] In certain embodiments, T is of the formula:
##STR00015##
[0251] In certain embodiments, T is of the formula:
##STR00016##
[0252] In certain embodiments, T is of the formula:
##STR00017##
[0253] In certain embodiments, T is of the formula:
##STR00018##
[0254] In certain embodiments, T is of the formula:
##STR00019##
[0255] In certain embodiments, T is of the formula:
##STR00020##
[0256] In certain embodiments, T is of the formula:
##STR00021##
[0257] In certain embodiments, T is of the formula:
##STR00022##
[0258] In certain embodiments, T is of Formula T-II:
##STR00023##
[0259] wherein:
[0260] X.sup.1 is CH, N, NH, O, or S;
[0261] X.sup.2 is CH, C, or N;
[0262] X.sup.3 is CR.sup.15 or N;
[0263] X.sup.4 is CR.sup.15 or N;
[0264] X.sup.5 is CR.sup.15 or N;
[0265] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0266] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A-A;
[0267] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0268] n is 0-12;
[0269] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0270] In certain embodiments of Formula T-II:
[0271] X.sup.1 is CH, N, O, or S;
[0272] X.sup.2 is CH, C, or N;
[0273] X.sup.3 is CR.sup.15 or N;
[0274] X.sup.4 is CR.sup.15 or N;
[0275] X.sup.5 is CR.sup.15 or N;
[0276] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0277] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2) .sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n-(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0278] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0279] n is 0-12;
[0280] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0281] In certain embodiments, X.sup.1 and X.sup.2 are N.
[0282] In certain embodiments, at least one of X.sup.3, X.sup.4, or
X.sup.5 is N.
[0283] In certain embodiments, X.sup.5 is N; and X.sup.3 and
X.sup.4 are CH.
[0284] In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--; and A is unsubstituted
heterocyclylene. In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is
unsubstituted heterocyclylene. In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
piperidinylene or piperazinylene. In certain embodiments, R.sup.14
is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene.
[0285] In certain embodiments, T is of Formula T-II-a:
##STR00024##
wherein:
[0286] X.sup.3 is CR.sup.15 or N;
[0287] X.sup.4 is CR.sup.15 or N;
[0288] X.sup.5 is CR.sup.15 or N;
[0289] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0290] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.N-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0291] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0292] n is 0-12;
[0293] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0294] In certain embodiments of Formula T-II-a:
[0295] X.sup.3 is CR.sup.15 or N;
[0296] X.sup.4 is CR.sup.15 or N;
[0297] X.sup.5 is CR.sup.15 or N;
[0298] each occurrence of R.sup.13 and R.sup.15 is independently
hydrogen, halogen, hydroxy, nitro, cyano, amino, substituted or
unsubstituted alkyl, aralkyl, alkylamino, cycloalkylamino,
aminoalkyl, arylamino, aminoaryl, alkoxy,
--NR.sup.A(C.dbd.O)Oalkyl, --NR.sup.A(C.dbd.O)Oaryl,
--NR.sup.A(C.dbd.O)alkyl, --NR.sup.A(C.dbd.O)aryl,
--(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl, --(C.dbd.O)alkyl,
--(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or heterocyclyl;
[0299] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n-(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0300] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene; and
[0301] n is 0-12;
[0302] wherein one or more carbon of R.sup.13, R.sup.14, and
R.sup.15 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0303] In certain embodiments, T is of Formula T-II-b:
##STR00025##
wherein R.sup.14 is --(CH.sub.2).sub.n--O--, -A-(CH.sub.2) --O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--.
[0304] In certain embodiments of Formula T-II-b, R.sup.14 is
--(CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--, --(CH.sub.2).sub.n--S--,
-A-(CH.sub.2).sub.nS--, --(CH.sub.2).sub.n-A-S--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--.
[0305] In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--; and A is unsubstituted
heterocyclylene. In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain embodiments,
R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is
unsubstituted heterocyclylene. In certain embodiments, R.sup.14 is
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
piperidinylene or piperazinylene. In certain embodiments, R.sup.14
is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--. In certain
embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
heteroarylene. In certain embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene, pyrimidinylene, or pyridazinylene. In certain
embodiments, R.sup.14 is
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; and A is unsubstituted
pyridinylene.
[0306] In certain embodiments, T is of the formula:
##STR00026##
[0307] In certain embodiments, T is of the formula:
##STR00027##
[0308] In certain embodiments, T is of the formula:
##STR00028##
[0309] In certain embodiments, T is of the formula:
##STR00029##
[0310] In certain embodiments, T is of formula T-III or T-IV:
##STR00030##
wherein:
[0311] each of R.sup.20 and R.sup.21 is independently halogen,
--OH, --COOH, --SO.sub.3H, --NO.sub.2, --SH, --NR.sup.xR.sup.y,
substituted or unsubstituted alkyl, or substituted or unsubstituted
alkoxy;
[0312] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0313] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[0314] R.sup.23 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0315] R.sup.24 is substituted or unsubstituted alkylene, or
substituted or unsubstituted alkoxylene;
[0316] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl;
[0317] n is 0-12;
[0318] t is 0, 1, 2, 3, or 4; and
[0319] r is 0, 1, or 2.
[0320] In certain embodiments, T is of formula T-III:
##STR00031##
wherein:
[0321] R.sup.20 and R.sup.21 are independently halogen, --OH,
--COOH, --SO.sub.3H, --NO.sub.2, --SH, --NR.sup.xR.sup.y,
substituted or unsubstituted alkyl, or substituted or unsubstituted
alkoxy;
[0322] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0323] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[0324] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl;
[0325] n is 0-12;
[0326] t is 0, 1, 2, 3, or 4; and
[0327] r is 0, 1, or 2.
[0328] In certain embodiments, T is of formula T-III-a:
##STR00032##
wherein:
[0329] R.sup.20 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0330] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0331] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O).sub.NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[0332] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[0333] n is 0-12.
[0334] In certain embodiments, R.sup.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.sup.22 is
--(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
[0335] In certain embodiments, R.sup.2.degree. 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.sup.22 is
--(CH.sub.2).sub.n--NR.sup.A--.
[0336] In certain embodiments, G is unsubstituted arylene. In
certain embodiments, G is unsubstituted phenylene. In certain
embodiments, G is unsubstituted heteroarylene. In certain
embodiments, G is unsubstituted pyridinylene, pyrimidinylene,
pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or
thiazolylene. In certain embodiments, G is unsubstituted
pyridinylene or pyrazolinylene. In certain embodiments, G is
unsubstituted pyridinylene. In certain embodiments, G is
unsubstituted phenylene, pyridinylene, or pyrazolinylene.
[0337] In certain embodiments, R.sup.2.degree. 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.sup.22 is
--(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
[0338] In certain embodiments, R.sup.20 is
##STR00033##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
[0339] In certain embodiments, R.sup.20 is
##STR00034##
[0340] G is unsubstituted arylene or unsubstituted heteroarylene;
and R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--.
[0341] In certain embodiments, R.sup.20 is
##STR00035##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A--.
[0342] In certain embodiments, R.sup.20 is
##STR00036##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A--.
[0343] In certain embodiments, R.sup.20 is
##STR00037##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A--.
[0344] In certain embodiments, T is of the formula:
##STR00038##
[0345] In certain embodiments, T is of the formula:
##STR00039##
[0346] In certain embodiments, T is of the formula:
##STR00040##
[0347] In certain embodiments, T is of formula T-IV:
##STR00041##
wherein:
[0348] R.sup.21 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0349] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0350] R.sup.23 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0351] R.sup.24 is substituted or unsubstituted alkylene, or
substituted or unsubstituted alkoxylene;
[0352] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[0353] r is 0, 1, or 2.
[0354] In certain embodiments, T is of formula T-IV-a:
##STR00042##
wherein:
[0355] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0356] R.sup.23 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[0357] R.sup.24 is substituted or unsubstituted alkylene, or
substituted or unsubstituted alkoxylene; and
[0358] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl.
[0359] In certain embodiments, R.sup.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.sup.23 is NR.sup.xR.sup.y.
[0360] In certain embodiments, G is unsubstituted arylene. In
certain embodiments, G is unsubstituted phenylene. In certain
embodiments, G is unsubstituted heteroarylene. In certain
embodiments, G is unsubstituted pyridinylene, pyrimidinylene,
pyridazinylene, pyrazolinylene, imidazolylene, oxazolylene, or
thiazolylene. In certain embodiments, G is unsubstituted
pyridinylene or pyrazolinylene. In certain embodiments, G is
unsubstituted pyridinylene. In certain embodiments, G is
unsubstituted phenylene, pyridinylene, or pyrazolinylene.
[0361] In certain embodiments, R.sup.24 is
##STR00043##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.23 is NR.sup.xR.sup.y.
[0362] In certain embodiments, R.sup.24 is
##STR00044##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.23 is NR.sup.xR.sup.y.
[0363] In certain embodiments, R.sup.24 is
##STR00045##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.23 is NR.sup.xR.sup.y.
[0364] In certain embodiments, R.sup.24 is
##STR00046##
G is unsubstituted arylene or unsubstituted heteroarylene; and
R.sup.23 is NR.sup.xR.sup.y.
[0365] In certain embodiments, T is of the formula:
##STR00047##
[0366] In certain embodiments, T is of the formula:
##STR00048##
[0367] In certain embodiments, T is of the formula:
##STR00049##
[0368] In certain embodiments, T is of the formula:
##STR00050##
[0369] In certain embodiments, T is of the formula:
##STR00051##
[0370] In certain embodiments, T is of the formula:
##STR00052## ##STR00053## ##STR00054## ##STR00055##
[0371] In certain embodiments, T is of the formula:
##STR00056## ##STR00057## ##STR00058##
[0372] In certain embodiments, the tau binding moiety binds tau
protein with a K.sub.d of less than 100,000 nM, less than 50,000
nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM,
less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than
800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less
than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM,
less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM,
less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM,
less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM,
less than 2 nM, or less than 1 nM.
[0373] In certain embodiments, the tau binding moiety selectively
binds tau protein over another protein. In some embodiments, the
compound of Formula I selectively binds tau protein over amyloid
.beta.. In certain embodiments, the selectivity is between about
2-fold and about 5-fold. In certain embodiments, the selectivity is
between about 5-fold and about 10-fold. In certain embodiments, the
selectivity is between about 10-fold and about 20-fold. In certain
embodiments, the selectivity is between about 20-fold and about
50-fold. In certain embodiments, the selectivity is between about
50-fold and about 100-fold. In certain embodiments, the selectivity
is between about 100-fold and about 200-fold. In certain
embodiments, the selectivity is between about 200-fold and about
500-fold. In certain embodiments, the selectivity is between about
500-fold and about 1000-fold. In certain embodiments, the
selectivity is at least about 1000-fold.
Group L
[0374] L is a divalent moiety linking T and E. In certain
embodiments, 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.sup.A)--, --S--, --C(.dbd.O)--, --C(.dbd.O)O--,
--C(.dbd.O)NR.sup.A--, --NR.sup.AC(.dbd.O)--,
--NR.sup.AC(.dbd.O)R.sup.A--, --C(.dbd.O)R.sup.A--,
--NR.sup.AC(.dbd.O)O--, --NR.sup.AC(.dbd.O)N(R.sup.A)--,
--OC(.dbd.O)--, --OC(.dbd.O)O--, --OC(.dbd.O)N(R.sup.A)--,
--S(O).sub.2NR.sup.A--, --NR.sup.AS(O).sub.2--, or a combination
thereof.
[0375] In certain embodiments, L is any "L" group recited in U.S.
Patent Application, U.S. Ser. No. 14/792,414, filed Jul. 6, 2015,
which is incorporated herein by reference. In certain embodiments,
L is any "Linker" group recited in U.S. Patent Application, U.S.
Ser. No. 14/707,930, filed May 8, 2015, which is incorporated
herein by reference. In certain embodiments, L comprises up to 50
atoms, excluding hydrogen atoms. In certain embodiments, L
comprises up to 40 atoms, excluding hydrogen atoms. In certain
embodiments, L comprises up to 30 atoms, excluding hydrogen atoms.
In certain embodiments, L comprises up to 20 atoms, excluding
hydrogen atoms. In certain embodiments, L comprises up to 15 atoms,
excluding hydrogen atoms. In certain embodiments, L comprises up to
12 atoms, excluding hydrogen atoms. In certain embodiments, L
comprises up to 10 atoms, excluding hydrogen atoms. In certain
embodiments, L comprises up to 9 atoms excluding hydrogen atoms. In
certain embodiments, L comprises up to 6 atoms excluding hydrogen
atoms. In certain embodiments, L comprises up to 5 atoms excluding
hydrogen atoms. In certain embodiments, L comprises up to 3 atoms
excluding hydrogen atoms. In certain embodiments, any of the carbon
atoms in L can be substituted.
[0376] In certain embodiments, L is substituted or unsubstituted
alkylene, substituted or unsubstituted alkenylene, or substituted
or unsubstituted heteroalkylene.
[0377] In certain embodiments, L is substituted or unsubstituted
alkylene, or substituted or unsubstituted heteroalkylene. In
certain embodiments, L is a substituted or unsubstituted C.sub.1-30
alkylene. In certain embodiments, L is a substituted or
unsubstituted C.sub.1-20 alkylene. In certain embodiments, L is a
substituted or unsubstituted C.sub.1-10 alkylene. In certain
embodiments, L is a substituted or unsubstituted C.sub.1-30
heteroalkylene. In certain embodiments, L is a substituted or
unsubstituted C.sub.1-20 heteroalkylene. In certain embodiments, L
is a substituted or unsubstituted C.sub.1-10 heteroalkylene.
[0378] In certain embodiments, L is
##STR00059##
q is 1-12; u is 1-12; p is 1-10; and s is 1-10.
[0379] In certain embodiments, L is
##STR00060##
q is 1-12; p is 1-10; and s is 1-10.
[0380] In certain embodiments, L is
##STR00061##
q is 1-5; p is 2-5; and s is 1-5.
[0381] In certain embodiments, L is
##STR00062##
and q is 1-12. In certain embodiments, L is
##STR00063##
and q is 1-5. In certain embodiments, L is
##STR00064##
and q is 2. In certain embodiments, L is
##STR00065##
and q is 3. In certain embodiments, L is
##STR00066##
and q is 4. In certain embodiments, L is
##STR00067##
and q is 5.
[0382] In certain embodiments, L is
##STR00068##
and u is 1-12. In certain embodiments, L is
##STR00069##
and u is 1-5.
[0383] In certain embodiments, L is
##STR00070##
p is 1-10; and s is 1-10. In certain embodiments, L is
##STR00071##
p is 2-5; and s is 1-5. In certain embodiments, L is
##STR00072##
p is 3; and s is 2.
[0384] In certain embodiments, L is an unsubstituted
C.sub.3-C.sub.12 alkylene or
##STR00073##
wherein q is 1-12. In certain embodiments, L is an unsubstituted
C.sub.3-C.sub.12 alkylene or
##STR00074##
wherein q is 1-11. In certain embodiments, L is an unsubstituted
C.sub.4-C.sub.12 alkylene or
##STR00075##
wherein q is 1-11. In certain embodiments, L is an unsubstituted
C.sub.4-C.sub.10 alkylene or
##STR00076##
wherein q is 1-11. In certain embodiments, L is an unsubstituted
C.sub.5-C.sub.7 alkylene or
##STR00077##
wherein q is 1-11.
[0385] In certain embodiments, L is an unsubstituted
C.sub.5-C.sub.7 alkylene or
##STR00078##
wherein q is 1-6.
[0386] In certain embodiments, L is
##STR00079##
wherein q is 1-12. In certain embodiments, L is
##STR00080##
wherein q is 1-6. In certain embodiments, L is
##STR00081##
wherein q is 1. In certain embodiments, L is
##STR00082##
wherein q is 2. In certain embodiments, L is
##STR00083##
wherein q is 3. In certain embodiments, L is
##STR00084##
wherein q is 4. In certain embodiments, L is
##STR00085##
wherein q is 5. In certain embodiments, L is
##STR00086##
wherein q is 6. In certain embodiments, L is
##STR00087##
wherein q is 7. In certain embodiments, L is
##STR00088##
wherein q is 8. In certain embodiments, L is
##STR00089##
wherein q is 9. In certain embodiments, L is
##STR00090##
wherein q is 10. In certain embodiments, L is
##STR00091##
wherein q is 11. In certain embodiments, L is
##STR00092##
wherein q is 12.
[0387] In certain embodiments, L is an unsubstituted
C.sub.3-C.sub.12 alkylene. In certain embodiments, L is an
unsubstituted C.sub.4-C.sub.12 alkylene. In certain embodiments, L
is an unsubstituted C.sub.4-C.sub.10 alkylene. In certain
embodiments, L is an unsubstituted C.sub.5-C.sub.7 alkylene. In
certain embodiments, L is an unsubstituted C.sub.3 alkylene. In
certain embodiments, L is an unsubstituted C.sub.4 alkylene. In
certain embodiments, L is an unsubstituted C.sub.5 alkylene. In
certain embodiments, L is an unsubstituted C.sub.6 alkylene. In
certain embodiments, L is an unsubstituted C.sub.7 alkylene. In
certain embodiments, L is an unsubstituted C.sub.8 alkylene. In
certain embodiments, L is an unsubstituted C.sub.9 alkylene. In
certain embodiments, L is an unsubstituted C.sub.10 alkylene. In
certain embodiments, L is an unsubstituted C.sub.11 alkylene. In
certain embodiments, L is an unsubstituted C.sub.12 alkylene.
Group R.sup.A
[0388] In certain embodiments, R.sup.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, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two R.sup.A groups are joined to form
a substituted or unsubstituted heterocyclic ring. In certain
embodiments, R.sup.A is, independently, hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted heteroalkyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or two R.sup.A groups are joined
to form a substituted or unsubstituted heterocyclic ring. In
certain embodiments, R.sup.A is, independently, hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
heteroalkyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl, or
two R.sup.A groups are joined to form a substituted or
unsubstituted heterocyclic ring. In certain embodiments, R.sup.A
is, independently, hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted heteroalkyl, substituted or
unsubstituted 5-6 membered heterocyclyl, substituted or
unsubstituted phenyl, substituted or unsubstituted 5-6 membered
heteroaryl, or two R.sup.A groups are joined to form a substituted
or unsubstituted heterocyclic ring. In certain embodiments, R.sup.A
is, independently, hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, substituted or unsubstituted C.sub.1-30 heteroalkyl,
substituted or unsubstituted 5-6 membered heterocyclyl, substituted
or unsubstituted phenyl, substituted or unsubstituted 5-6 membered
heteroaryl, or two R.sup.A groups are joined to form a substituted
or unsubstituted heterocyclic ring. In certain embodiments, R.sup.A
is, independently, hydrogen, substituted or unsubstituted C.sub.1-6
alkyl, or substituted or unsubstituted C.sub.1-30 heteroalkyl. In
certain embodiments, R.sup.A is, independently, hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or substituted or
unsubstituted C.sub.1-20 heteroalkyl. In certain embodiments,
R.sup.A is, independently, hydrogen, or substituted or
unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is,
independently, hydrogen.
Group E
[0389] E is an E3 ubiquitin ligase binding moiety. E is inclusive
of all moieties that bind, or can bind, any E3 ubiquitin ligase.
For example, in certain embodiments, E is capable of binding an E3
ubiquitin ligase, such as Cereblon or von Hippel-Lindau tumor
suppressor (VHL). In certain embodiments, E is capable of binding
to multiple different E3 ubiquitin ligases. In certain embodiments,
E binds to Cereblon. In certain embodiments, E binds to VHL.
[0390] Human Cereblon (CRBN) is a protein of 442 amino acids with
an apparent molecular weight of .about.51 kDa (GenBank: AAH17419).
(For the CRBN protein sequence see: Higgins et al., Neurology.
2004, 63, 1927-31. For additional information related to the CRBN
structure see Hartmann et al., PLoS One. 2015, 10, e0128342.) Human
CRBN contains the N-terminal part (237-amino acids from 81 to 317)
of ATP-dependent Lon protease domain without the conserved Walker A
and Walker B motifs, 11 casein kinase II phosphorylation sites, 4
protein kinase C phosphorylation sites, 1 N-linked glycosylation
site, and 2 myristoylation sites. CRBN is widely expressed in
testis, spleen, prostate, liver, pancreas, placenta, kidney, lung,
skeletal muscle, ovary, small intestine, peripheral blood
leukocyte, colon, brain, and retina. CRBN is located in the
cytoplasm, nucleus, and peripheral membrane. (Chang et al., Int. J.
Biochem. Mol. Biol. 2011, 2, 287-94.)
[0391] Cereblon is an E3 ubiquitin ligase, and it forms an E3
ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1),
Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex
ubiquitinates a number of other proteins. Through a mechanism which
has not been completely elucidated, Cereblon ubiquitination of
target proteins results in increased levels of fibroblast growth
factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in
turn, regulates a number of developmental processes, such as limb
and auditory vesicle formation.
[0392] In certain embodiments, E is a modulator, binder, inhibitor,
or ligand of Cereblon. In certain embodiments, E is a modulator of
Cereblon. In certain embodiments, E is a binder of Cereblon. In
certain embodiments, E is an inhibitor of Cereblon. In certain
embodiments, E is a ligand of Cereblon. In certain embodiments, E
is any modulator, binder, inhibitor, or ligand of Cereblon
disclosed in U.S. Patent Application, U.S. Ser. No. 14/792,414,
filed Jul. 6, 2015, U.S. Patent Application, U.S. Ser. No.
14/707,930, filed May 8, 2015, and International Patent
Application, PCT/US2013/054663, filed Aug. 13, 2013, each of which
are incorporated herein by reference. In certain embodiments, E is
a modulator, binder, inhibitor, or ligand of a Cereblon variant. In
certain embodiments, E is a modulator, binder, inhibitor, or ligand
of a Cereblon isoform.
[0393] In certain embodiments, E comprises a heteroaryl ring. In
certain embodiments, E comprises a fused bicyclic heteroaryl ring.
In certain embodiments, E comprises a fused bicyclic heteroaryl
ring and a heterocyclic ring. In certain embodiments, E comprises a
phthalimido group, or an analogue or derivative thereof. In certain
embodiments, E comprises a phthalimido-glutarimide group, or an
analogue or derivative thereof.
[0394] In certain embodiments, E is of Formula E-I:
##STR00093##
wherein:
[0395] A is a substituted or unsubstituted heterocyclyl, or
substituted or unsubstituted heteroaryl ring;
[0396] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0397] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0398] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0399] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0400] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0401] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0402] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0403] k is 0, 1, 2, 3, 4, 5, or 6;
[0404] m is 0, 1, 2 or 3; and
[0405] n is 1 or 2.
[0406] In certain embodiments of Formula E-I:
[0407] A is a substituted or unsubstituted heterocyclyl, or
substituted or unsubstituted heteroaryl ring;
[0408] Y is --(CH.sub.2).sub.k-----(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0409] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0410] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0411] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0412] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0413] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0414] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0415] k is 0, 1, 2, 3, 4, 5, or 6;
[0416] m is 0, 1, 2 or 3; and
[0417] n is 1 or 2.
[0418] In certain embodiments, Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, --(CH.sub.2).sub.k--O--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--. In certain embodiments, Y
is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--. In certain embodiments, Y
is --(CH.sub.2).sub.k--NR.sup.B--, --(CH.sub.2).sub.k--O--, or
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--. In certain embodiments,
Y is --(CH.sub.2).sub.k--NH--. In certain embodiments, Y is --NH--.
In certain embodiments, Y is --(CH.sub.2).sub.k--O--. In certain
embodiments, Y is --O--. In certain embodiments, Y is
--NH(C.dbd.O)--(CH.sub.2)--O--. In certain embodiments, Y is
--NH--, --O--, or --NH(C.dbd.O)--(CH.sub.2)--O--.
[0419] In certain embodiments, E is of Formula E-II or E-III:
##STR00094##
wherein:
[0420] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0421] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0422] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2.sup.-C(R.sup.3A).sub.2;
[0423] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0424] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0425] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0426] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0427] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0428] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0429] k is 0, 1, 2, 3, 4, 5, or 6;
[0430] m is 0, 1, 2 or 3; and
[0431] n is 1 or 2.
[0432] In certain embodiments of Formula E-II or E-III:
[0433] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0434] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0435] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0436] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0437] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0438] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0439] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0440] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0441] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0442] k is 0, 1, 2, 3, 4, 5, or 6;
[0443] m is 0, 1, 2 or 3; and
[0444] n is 1 or 2.
[0445] In certain embodiments, E is of formula E-II:
##STR00095##
wherein:
[0446] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0447] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0448] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0449] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0450] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0451] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0452] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0453] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0454] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0455] k is 0, 1, 2, 3, 4, 5, or 6;
[0456] m is 0, 1, 2 or 3; and
[0457] n is 1 or 2.
[0458] In certain embodiments of formula E-II:
[0459] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0460] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0461] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0462] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0463] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0464] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0465] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0466] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0467] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0468] k is 0, 1, 2, 3, 4, 5, or 6;
[0469] m is 0, 1, 2 or 3; and
[0470] n is 1 or 2.
[0471] In certain embodiments of Formula E-II:
[0472] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0473] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0474] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0475] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0476] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0477] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0478] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0479] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0480] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0481] k is 0, 1, 2, 3, 4, 5, or 6;
[0482] m is 0, 1, 2 or 3; and
[0483] n is 1 or 2.
[0484] In certain embodiments of Formula E-II:
[0485] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0486] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0487] X.sup.1-X.sup.2 is C(R.sup.3A)=N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0488] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0489] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0490] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0491] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0492] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0493] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0494] k is 0, 1, 2, 3, 4, 5, or 6;
[0495] m is 0, 1, 2 or 3; and
[0496] n is 1 or 2.
[0497] In certain embodiments, E is of Formula E-II-a:
##STR00096##
wherein:
[0498] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0499] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0500] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0501] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0502] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0503] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0504] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0505] k is 0, 1, 2, 3, 4, 5, or 6; and
[0506] m is 0, 1, 2 or 3.
[0507] In certain embodiments of Formula E-II-a:
[0508] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0509] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0510] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0511] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0512] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0513] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0514] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0515] k is 0, 1, 2, 3, 4, 5, or 6; and
[0516] m is 0, 1, 2 or 3.
[0517] In certain embodiments, E is of Formula E-II-b:
##STR00097##
wherein:
[0518] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0519] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0520] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0521] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0522] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0523] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0524] k is 0, 1, 2, 3, 4, 5, or 6.
[0525] In certain embodiments of Formula E-II-b:
[0526] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0527] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0528] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0529] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0530] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0531] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0532] k is 0, 1, 2, 3, 4, 5, or 6.
[0533] In certain embodiments, E is of Formula E-II-c:
##STR00098##
wherein:
[0534] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0535] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0536] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0537] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0538] k is 0, 1, 2, 3, 4, 5, or 6.
[0539] In certain embodiments of Formula E-II-c:
[0540] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0541] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0542] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0543] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0544] k is 0, 1, 2, 3, 4, 5, or 6.
[0545] In certain embodiments, E is of Formula E-II-d:
##STR00099##
wherein:
[0546] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0547] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0548] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O
[0549] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0550] is 0, 1, 2, 3, 4, 5, or 6.
[0551] In certain embodiments of formula E-II-d:
[0552] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0553] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0554] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0555] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0556] k is 0, 1, 2, 3, 4, 5, or 6.
[0557] In certain embodiments, E is of formula E-II-e:
##STR00100##
wherein:
[0558] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0559] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0560] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;
and
[0561] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0562] In certain embodiments, E is of formula E-II-e-1:
##STR00101##
wherein:
[0563] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0564] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0565] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;
and
[0566] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0567] In certain embodiments, E is of formula E-II-e-1:
##STR00102##
wherein:
[0568] X.sup.A is C(O) or C(R.sup.3A).sub.2;
[0569] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0570] each R.sup.3A is, independently, H or C.sub.1-C.sub.3 alkyl;
and
[0571] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0572] In certain embodiments, E is of formula E-II-f:
##STR00103##
wherein:
[0573] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0574] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0575] In certain embodiments, E is of formula E-II-f-1:
##STR00104##
wherein:
[0576] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0577] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0578] In certain embodiments, E is of formula E-II-f-2:
##STR00105##
wherein:
[0579] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0580] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0581] In certain embodiments, E is of formula E-II-g:
##STR00106##
wherein:
[0582] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0583] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0584] In certain embodiments, E is of formula E-II-g-1:
##STR00107##
wherein:
[0585] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0586] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0587] In certain embodiments, E is of formula E-II-g-2:
##STR00108##
wherein:
[0588] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0589] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0590] In certain embodiments, E is of Formula E-III:
##STR00109##
wherein:
[0591] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sup.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0592] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0593] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0594] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0595] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0596] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0597] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0598] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0599] k is 0, 1, 2, 3, 4, 5, or 6;
[0600] m is 0, 1, 2 or 3; and
[0601] n is 1 or 2.
[0602] In certain embodiments of Formula E-III:
[0603] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sup.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0604] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0605] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0606] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0607] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0608] each R.sup.3' is, independently, C.sub.1-C.sub.3 alkyl;
[0609] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0610] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0611] k is 0, 1, 2, 3, 4, 5, or 6;
[0612] m is 0, 1, 2 or 3; and
[0613] n is 1 or 2.
[0614] In certain embodiments, Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, --(CH.sub.2).sub.k--O--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--. In certain embodiments, Y
is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--. In certain embodiments, Y
is --(CH.sub.2).sub.k--NR.sup.B--, --(CH.sub.2).sub.k--O--, or
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--. In certain embodiments,
Y is --(CH.sub.2).sub.k-NH--. In certain embodiments, Y is --NH--.
In certain embodiments, Y is --(CH.sub.2).sub.k--O--. In certain
embodiments, Y is --O--. In certain embodiments, Y is
--NH(C.dbd.O)--(CH.sub.2)--O--. In certain embodiments, Y is
--NH--, --O--, or --NH(C.dbd.O)--(CH.sub.2)--O--.
[0615] In certain embodiments, E is of formula E-III-a:
##STR00110##
wherein:
[0616] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0617] X.sup.l-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0618] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0619] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0620] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0621] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon
[0622] atom to which they are attached, form a C(O),
C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or 6-membered heterocycle
comprising 1 or 2 heteroatoms selected from N and O;
[0623] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0624] k is 0, 1, 2, 3, 4, 5, or 6; and
[0625] m is 0, 1, 2 or 3.
[0626] In certain embodiments of formula E-III-a:
[0627] Y is --(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--O--,
--O(CH.sub.2).sub.k--, --NR.sup.B(CH.sub.2).sub.k--,
--(CH.sub.2).sub.k--NR.sup.B--,
--(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--O(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--,
--NR.sup.B(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0628] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0629] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0630] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0631] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0632] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0633] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0634] k is 0, 1, 2, 3, 4, 5, or 6; and
[0635] m is 0, 1, 2 or 3.
[0636] In certain embodiments of formula E-III-a:
[0637] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0638] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0639] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0640] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0641] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0642] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0643] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0644] k is 0, 1, 2, 3, 4, 5, or 6; and
[0645] m is 0, 1, 2 or 3.
[0646] In certain embodiments of formula E-III-a:
[0647] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0648] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0649] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0650] each R.sup.1A is, independently, halogen, OH,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 alkoxy;
[0651] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0652] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0653] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl;
[0654] k is 0, 1, 2, 3, 4, 5, or 6; and
[0655] m is 0, 1, 2 or 3.
[0656] In certain embodiments, E is of formula E-III-b:
##STR00111##
wherein:
[0657] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0658] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0659] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0660] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0661] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0662] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0663] k is 0, 1, 2, 3, 4, 5, or 6.
[0664] In certain embodiments of formula E-III-b:
[0665] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0666] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0667] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0668] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0669] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0670] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0671] k is 0, 1, 2, 3, 4, 5, or 6.
[0672] In certain embodiments, E is of formula E-III-c:
##STR00112##
wherein:
[0673] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--,
--NR.sup.B(C.dbd.O)--(CH.sub.2).sub.k--O--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0674] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0675] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0676] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0677] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0678] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0679] k is 0, 1, 2, 3, 4, 5, or 6.
[0680] In certain embodiments of formula E-III-c:
[0681] Y is --(CH.sub.2).sub.k--NR.sup.B--,
--O(CH.sub.2).sub.k--(C.dbd.O)NR.sup.B--, or
--(CH.sub.2).sub.k--NR.sup.B(C.dbd.O)--;
[0682] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0683] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0684] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0685] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O;
[0686] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or Cl;
and
[0687] k is 0, 1, 2, 3, 4, 5, or 6.
[0688] In certain embodiments, E is of formula E-III-d:
##STR00113##
wherein:
[0689] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0690] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0691] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0692] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0693] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0694] In certain embodiments, E is of formula E-III-d-1:
##STR00114##
wherein:
[0695] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0696] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0697] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0698] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0699] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0700] In certain embodiments, E is of formula E-III-d-2:
##STR00115##
wherein:
[0701] X.sup.1-X.sup.2 is C(R.sup.3A).dbd.N or
C(R.sup.3A).sub.2--C(R.sup.3A).sub.2;
[0702] each R.sup.B is, independently, hydrogen, or substituted or
unsubstituted alkyl;
[0703] each R.sup.3A is, independently, H or C.sub.1-C.sub.3
alkyl;
[0704] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0705] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0706] In certain embodiments, E is of formula E-III-e:
##STR00116##
wherein:
[0707] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0708] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0709] In certain embodiments, E is of formula E-III-e-1:
##STR00117##
wherein:
[0710] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0711] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0712] In certain embodiments, E is of formula E-III-e-2:
##STR00118##
wherein:
[0713] each R.sup.4A is, independently, H or C.sub.1-C.sub.3 alkyl;
or two R.sup.4A, together with the carbon atom to which they are
attached, form a C(O), C.sub.3-C.sub.6 carbocycle, or a 4-, 5-, or
6-membered heterocycle comprising 1 or 2 heteroatoms selected from
N and O; and
[0714] R.sup.5A is H, deuterium, C.sub.1-C.sub.3 alkyl, F, or
Cl.
[0715] In certain embodiments, E is thalidomide, lenalidomide,
pomalidomide, CC-885 (Matyskiela et al., Nature 2016, 535,
252-257),
3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yppiperidine-2,6-dione,
or an analogue or derivative thereof.
[0716] In certain embodiments, E is
##STR00119##
[0717] In certain embodiments, E is
##STR00120##
[0718] In certain embodiments, E is
##STR00121##
[0719] In certain embodiments, E is
##STR00122##
[0720] In certain embodiments, E is
##STR00123##
[0721] In certain embodiments, E is
##STR00124##
[0722] In certain embodiments, E is
##STR00125##
[0723] The von Hippel-Lindau tumor suppressor (VHL) is an E3
ubiquitin ligase. VHL comprises the substrate recognition
subunit/E3 ubiquitin ligase complex VCB, which includes elongins B
and C, and a complex including Cullin-2 and Rbxl. The primary
substrate of VHL is Hypoxia Inducible Factor 1.alpha.
(HIF-1.alpha.), a transcription factor that upregulates genes, such
as the pro-angiogenic growth factor VEGF and the red blood
cell-inducing cytokine, erythropoietin, in response to low oxygen
levels. VCB is a known target in cancer, chronic anemia, and
ischemia.
[0724] The full-length von Hippel-Lindau tumor suppressor protein
(VHL) contains 213 amino acids. (For the VHL protein sequence see:
Duan et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6459-63. For
additional information related to the VHL structure see Stebbins et
al., Science 1999, 284, 455-61 and Minervini et al., Sci. Rep.
2015, 5, 12605.) A second VHL-gene product arises by internal
translation initiation from the codon 54 methionine, producing a
160 amino-acid protein ("pVHL19"). VHL has two main structural
domains: an N-terminal domain composed mainly of .beta.-sheets
(.alpha.-domain) and a smaller C-terminal domain between amino
acids 155-192 composed mainly of .alpha. helices (.alpha.-domain).
The .alpha.-domain consists of three a helices that combines with a
fourth .alpha. helix donated by elongin C. The .beta.-domain is on
the opposite side of the a domain and is free to contact other
protein.
[0725] In certain embodiments, E is a modulator, binder, inhibitor,
or ligand of VHL. In certain embodiments, E is a modulator of VHL.
In certain embodiments, E is a binder of VHL. In certain
embodiments, E is an inhibitor of VHL. In certain embodiments, E is
a ligand of Cereblon. In certain embodiments, E is any ligand of
VHL listed in Galdeano, C. et al. J. Med. Chem. 2014, 57, 8657,
which is incorporated herein by reference. In certain embodiments,
E is a modulator, binder, inhibitor, or ligand of a VHL variant. In
certain embodiments, E is a modulator, binder, inhibitor, or ligand
of a VHL isoform. In certain embodiments, E is a modulator, binder,
inhibitor, or ligand of a VHL gene-product (e.g., pVHL19).
[0726] In certain embodiments, E comprises a peptide backbone
structure. In certain embodiments, E is of the formula:
##STR00126##
wherein R.sup.5 is a heteroaryl ring, and R.sup.6 is hydrogen or
C.sub.1 -4 alkyl. In certain embodiments, R.sup.5 is a 5-membered
heteroaryl ring comprising at least one nitrogen. In certain
embodiments, R.sup.5 is substituted or unsubstituted oxazolinyl, or
substituted or unsubstituted thiazolinyl.
[0727] In certain embodiments, E is of the formula:
##STR00127##
[0728] In certain embodiments, E is of the formula:
##STR00128##
[0729] In certain embodiments, E is of the formula:
##STR00129##
[0730] In certain embodiments, E is of the formula:
##STR00130##
[0731] In certain embodiments, E is of the formula:
##STR00131##
[0732] In certain embodiments, E is of the formula:
##STR00132##
[0733] In certain embodiments, the E3 ligase binding moiety binds
an E3 ubiquitin ligase with a K.sub.d of less than 100,000 nM, less
than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than
5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM,
less than 800 nM, less than 700 nM, less than 600 nM, less than 500
nM, less than 400 nM, less than 300 nM, less than 200 nM, less than
100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less
than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less
than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less
than 3 nM, less than 2 nM, or less than 1 nM.
[0734] In certain embodiments, the E3 ligase binding moiety binds
Cereblon with a K.sub.d of less than 100,000 nM, less than 50,000
nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM,
less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than
800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less
than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM,
less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM,
less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM,
less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM,
less than 2 nM, or less than 1 nM.
[0735] In certain embodiments, the E3 ligase binding moiety binds
VHL with a K.sub.d of less than 100,000 nM, less than 50,000 nM,
less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less
than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800
nM, less than 700 nM, less than 600 nM, less than 500 nM, less than
400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less
than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less
than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less
than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less
than 2 nM, or less than 1 nM.
[0736] In certain embodiments, the E3 ligase binding moiety
selectively binds an E3 ubiquitin ligase as compared to another
protein. In some embodiments, the E3 ligase binding moiety
selectively binds Cereblon over another protein. In some
embodiments, the E3 ligase binding moiety selectively binds
Cereblon over another E3 ubiquitin ligase. In some embodiments, the
E3 ligase binding moiety selectively binds VHL over another
protein. In some embodiments, the E3 ligase binding moiety
selectively binds VHL over another E3 ubiquitin ligase. In certain
embodiments, the selectivity is between about 2-fold and about
5-fold. In certain embodiments, the selectivity is between about
5-fold and about 10-fold. In certain embodiments, the selectivity
is between about 10-fold and about 20-fold. In certain embodiments,
the selectivity is between about 20-fold and about 50-fold. In
certain embodiments, the selectivity is between about 50-fold and
about 100-fold. In certain embodiments, the selectivity is between
about 100-fold and about 200-fold. In certain embodiments, the
selectivity is between about 200-fold and about 500-fold. In
certain embodiments, the selectivity is between about 500-fold and
about 1000-fold. In certain embodiments, the selectivity is at
least about 1000-fold.
Further Embodiments of Formula I
[0737] In certain embodiments, the compound of Formula I is a
compound of Formula I-a:
##STR00133##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[0738] E is an E3 ubiquitin ligase binding moiety;
[0739] L is N or CR.sup.5;
[0740] M is N or CR.sup.6;
[0741] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0742] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0743] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0744] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0745] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0746] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0747] n is 0-12; and
[0748] q is 1-6;
[0749] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0750] In certain embodiments of the compound of Formula I-a,
[0751] E is an E3 ubiquitin ligase binding moiety;
[0752] L is N or CR.sup.5;
[0753] M is N or CR.sup.6;
[0754] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0755] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0756] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2) -A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0757] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0758] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0759] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0760] n is 0-12; and
[0761] q is 1-5;
[0762] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0763] In certain embodiments of the compound of Formula I-a,
[0764] L is CR.sup.5;
[0765] M is N;
[0766] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0767] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0768] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0769] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0770] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0771] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0772] n is 0-12; and
[0773] q is 1-6;
[0774] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0775] In certain embodiments of the compound of Formula I-a,
[0776] L is CR.sup.5;
[0777] M is N;
[0778] X is a bond or substituted or unsubstituted C.sub.1-12
alkylene, wherein one or more carbon is optionally replaced with
C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl optionally
substituted with halogen, OH, or C.sub.1-6 alkyl;
[0779] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0780] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.nA-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.nA-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.6-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0781] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0782] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0783] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0784] n is 0-12; and
[0785] q is 1-5;
[0786] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-.sub.6
alkyl).sub.2.
[0787] In certain embodiments of the compound of Formula I-a,
[0788] L is CR.sup.5;
[0789] M is N;
[0790] X is a bond;
[0791] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0792] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0793] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0794] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0795] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0796] n is 0-12; and
[0797] q is 1-6;
[0798] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-.sub.6
alkyl).sub.2.
[0799] In certain embodiments of the compound of Formula I-a,
[0800] L is CR.sup.5;
[0801] M is N;
[0802] X is a bond;
[0803] R.sup.9 is hydrogen, --N.sub.3, alkynyl, OH, halogen,
NH.sub.2, N(C.sub.1-6 alkyl).sub.2, aryl, heteroaryl, or a
protecting group, wherein the aryl and heteroaryl are optionally
substituted with halogen, SO.sub.2, NH.sub.2, or C.sub.1-6 alkyl
optionally substituted with halogen or C.sub.3-8 cycloalkyl;
[0804] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.nA-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.nS--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0805] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0806] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0807] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0808] n is 0-12; and
[0809] q is 1-5;
[0810] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0811] In certain embodiments of the compound of Formula I-a,
[0812] L is CR.sup.5;
[0813] M is N;
[0814] X is a bond;
[0815] R.sup.9 is hydrogen;
[0816] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0817] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0818] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0819] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0820] n is 0-12; and
[0821] q is 1-6;
[0822] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0823] In certain embodiments of the compound of Formula I-a,
[0824] L is CR.sup.5;
[0825] M is N;
[0826] X is a bond;
[0827] R.sup.9 is hydrogen;
[0828] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n--A-S(O).sub.2NR.sup.A--;
[0829] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0830] each R.sup.2, R.sup.7, and R.sup.8 are independently
hydrogen, OH, halogen, NH.sub.2, CH.sub.3, SO.sub.2, NO.sub.2, a
leaving group, a protecting group, aryl, heteroaryl, NHR.sup.12,
N(R.sup.12).sub.2C.sub.3-8 cycloalkyl,
N(R.sup.12).sub.2heterocyclyl, or --(CH.sub.2).sub.n--R.sup.12;
[0831] R.sup.12 is hydrogen, --CH.sub.3, aryl, or heteroaryl;
[0832] n is 0-12; and
[0833] q is 1-5;
[0834] wherein one or more carbon of R.sup.2, R.sup.3, R.sup.7, and
R.sup.8 is optionally replaced with C(O), O, S, SO.sub.2, NH,
NC.sub.1-6 alkyl, NH--C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0835] In certain embodiments of the compound of Formula I-a,
[0836] L is CR.sup.5;
[0837] M is N;
[0838] X is a bond;
[0839] R.sup.9 is hydrogen;
[0840] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0841] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0842] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0843] n is 0-12; and
[0844] q is 1-6;
[0845] wherein one or more carbon of R.sup.3 is optionally replaced
with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[0846] In certain embodiments of the compound of Formula I-a,
[0847] L is CR.sup.5;
[0848] M is N;
[0849] X is a bond;
[0850] R.sup.9 is hydrogen;
[0851] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n--A-S(O).sub.2NR.sup.A--;
[0852] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0853] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0854] n is 0-12; and
[0855] q is 1-5;
[0856] wherein one or more carbon of R.sup.3 is optionally replaced
with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[0857] In certain embodiments of the compound of Formula I-a,
[0858] L is CR.sup.5;
[0859] M is N;
[0860] X is a bond;
[0861] R.sup.9 is hydrogen;
[0862] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--, or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--; A is substituted or
unsubstituted arylene, or substituted or unsubstituted
heteroarylene;
[0863] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0864] n is 0-12; and
[0865] q is 1-6.
[0866] In certain embodiments of the compound of Formula I-a,
[0867] L is CR.sup.5;
[0868] M is N;
[0869] X is a bond;
[0870] R.sup.9 is hydrogen;
[0871] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--, or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0872] A is substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0873] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0874] n is 0-12; and
[0875] q is 1-5.
[0876] In certain embodiments of the compound of Formula I-a,
[0877] L is CR.sup.5;
[0878] M is N;
[0879] X is a bond;
[0880] R.sup.9 is hydrogen;
[0881] R.sup.3 is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0882] A is substituted or unsubstituted heteroarylene;
[0883] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0884] n is 0-12; and
[0885] q is 1-6.
[0886] In certain embodiments of the compound of Formula I-a,
[0887] L is CR.sup.5;
[0888] M is N;
[0889] X is a bond;
[0890] R.sup.9 is hydrogen;
[0891] R.sup.3 is -A-(CH.sub.2),,--NR.sup.A--;
[0892] A is substituted or unsubstituted heteroarylene;
[0893] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0894] n is 0-12; and
[0895] q is 1-6.
[0896] In certain embodiments of the compound of Formula I-a,
[0897] L is CR.sup.5;
[0898] M is N;
[0899] X is a bond;
[0900] R.sup.9 is hydrogen;
[0901] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--;
[0902] A is substituted or unsubstituted heteroarylene;
[0903] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0904] n is 0-12; and
[0905] q is 1-5.
[0906] In certain embodiments of the compound of Formula I-a,
[0907] L is CR.sup.5;
[0908] M is N;
[0909] X is a bond;
[0910] R.sup.9 is hydrogen;
[0911] R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0912] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0913] n is 0-12; and
[0914] q is 1-6.
[0915] In certain embodiments of the compound of Formula I-a,
[0916] L is CR.sup.5;
[0917] M is N;
[0918] X is a bond;
[0919] R.sup.9 is hydrogen;
[0920] R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0921] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0922] n is 0-12; and
[0923] q is 1-5.
[0924] In certain embodiments of the compound of Formula I-a,
[0925] L is CR.sup.5;
[0926] M is N;
[0927] X is a bond;
[0928] R.sup.9 is hydrogen;
[0929] R.sup.3 is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0930] each R.sup.2, R.sup.7, and R.sup.8 is hydrogen;
[0931] n is 0-12; and
[0932] q is 1-6.
[0933] In certain embodiments, the compound of Formula I is a
compound of Formula I-b:
##STR00134##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[0934] E is an E3 ubiquitin ligase binding moiety;
[0935] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0936] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0937] n is 0-12; and
[0938] q is 1-6;
[0939] wherein one or more carbon of R.sup.3 is optionally replaced
with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[0940] In certain embodiments of the compound of Formula I-b,
[0941] E is an E3 ubiquitin ligase binding moiety;
[0942] R.sup.3 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0943] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0944] n is 0-12; and
[0945] q is 1-5;
[0946] wherein one or more carbon of R.sup.3 is optionally replaced
with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[0947] In certain embodiments of the compound of Formula I-b,
[0948] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--, or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0949] A is substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0950] n is 0-12; and
[0951] q is 1-6.
[0952] In certain embodiments of the compound of Formula I-b,
[0953] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--, or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0954] A is substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0955] n is 0-12; and
[0956] q is 1-5.
[0957] In certain embodiments of the compound of Formula I-b,
[0958] R.sup.3 is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0959] A is substituted or unsubstituted heteroarylene;
[0960] n is 0-12; and
[0961] q is 1-6.
[0962] In certain embodiments of the compound of Formula I-b,
[0963] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--;
[0964] A is substituted or unsubstituted heteroarylene;
[0965] n is 0-12; and
[0966] q is 1-6.
[0967] In certain embodiments of the compound of Formula I-b,
[0968] R.sup.3 is -A-(CH.sub.2).sub.n--NR.sup.A--;
[0969] A is substituted or unsubstituted heteroarylene;
[0970] n is 0-12; and
[0971] q is 1-5.
[0972] In certain embodiments of the compound of Formula I-b,
[0973] R.sup.3 is --(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[0974] n is 0-12; and
[0975] q is 1-6.
[0976] In certain embodiments of the compound of Formula I-b,
[0977] R.sup.3 is --(CH.sub.2).--(C.dbd.O)NR.sup.A--;
[0978] n is 0-12; and
[0979] q is 1-5.
[0980] In certain embodiments, the compound of Formula I-b is a
compound of Formula I-b-1:
##STR00135##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-6.
[0981] In certain embodiments of the compound of Formula I-b-1, E
is an E3 ubiquitin ligase binding moiety; and q is 1-5.
[0982] In certain embodiments, the compound of Formula I-b is a
compound of Formula I-b-2:
##STR00136##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-6.
[0983] In certain embodiments of the compound of Formula I-b-2, E
is an E3 ubiquitin ligase binding moiety; and q is 1-5.
[0984] In certain embodiments, the compound of Formula I-b is a
compound of Formula I-b-3:
##STR00137##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-4.
[0985] In certain embodiments, the compound of Formula I-b is a
compound of Formula I-b-4:
##STR00138##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-6.
[0986] In certain embodiments, the compound of Formula I-b is a
compound of Formula I-b-5:
##STR00139##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-4.
[0987] In certain embodiments, the compound of Formula I is a
compound of Formula I-c:
##STR00140##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[0988] E is an E3 ubiquitin ligase binding moiety;
[0989] X.sup.3 is CR.sup.15 or N;
[0990] X.sup.4 is CR.sup.15 or N;
[0991] X.sup.5 is CR.sup.15 or N;
[0992] each occurrence of R.sup.15 is independently hydrogen,
halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted
alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino,
aminoaryl, alkoxy, --NR.sup.A(C.dbd.O)Oalkyl,
--NR.sup.A(C.dbd.O)Oaryl, --NR.sup.A(C.dbd.O)alkyl,
--NR.sup.A(C.dbd.O)aryl, --(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl,
--(C.dbd.O)alkyl, --(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl;
[0993] R.sup.14 (CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[0994] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[0995] n is 0-12; and
[0996] q is 1-6;
[0997] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[0998] In certain embodiments of the compound Formula I-c,
[0999] E is an E3 ubiquitin ligase binding moiety;
[1000] X.sup.3 is CR.sup.15 or N;
[1001] X.sup.4 is CR.sup.15 or N;
[1002] X.sup.5 is CR.sup.15 or N;
[1003] each occurrence of R.sup.15 is independently hydrogen,
halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted
alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino,
aminoaryl, alkoxy, --NR.sup.A(C.dbd.O)Oalkyl,
--NR.sup.A(C.dbd.O)Oaryl, --NR.sup.A(C.dbd.O)alkyl,
--NR.sup.A(C.dbd.O)aryl, --(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl,
--(C.dbd.O)alkyl, --(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl;
[1004] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1005] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1006] n is 0-12; and
[1007] q is 1-5;
[1008] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2
[1009] In certain embodiments of the compound of Formula I-c,
[1010] X.sup.3 is CR.sup.15;
[1011] X.sup.4 is CR.sup.15;
[1012] X.sup.5 is N;
[1013] each occurrence of R.sup.15 is independently hydrogen,
halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted
alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino,
aminoaryl, alkoxy, --NR.sup.A(C.dbd.O)Oalkyl,
--NR.sup.A(C.dbd.O)Oaryl, --NR.sup.A(C.dbd.O)alkyl,
--NR.sup.A(C.dbd.O)aryl, --(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl,
--(C.dbd.O)alkyl, --(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl;
[1014] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1015] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene or substituted or
unsubstituted heteroarylene;
[1016] n is 0-12; and
[1017] q is 1-6;
[1018] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[1019] In certain embodiments of the compound of Formula I-c,
[1020] X.sup.3 is CR.sup.15;
[1021] X.sup.4 is CR.sup.15;
[1022] X.sup.5 is N;
[1023] each occurrence of R.sup.15 is independently hydrogen,
halogen, hydroxy, nitro, cyano, amino, substituted or unsubstituted
alkyl, aralkyl, alkylamino, cycloalkylamino, aminoalkyl, arylamino,
aminoaryl, alkoxy, --NR.sup.A(C.dbd.O)Oalkyl,
--NR.sup.A(C.dbd.O)Oaryl, --NR.sup.A(C.dbd.O)alkyl,
--NR.sup.A(C.dbd.O)aryl, --(C.dbd.O)Oalkyl, --(C.dbd.O)Oaryl,
--(C.dbd.O)alkyl, --(C.dbd.O)aryl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl;
[1024] R.sup.14 (CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--, --(CH.sub.2).sub.n--S--,
-A-(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n-A-S--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1025] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene or substituted or
unsubstituted heteroarylene;
[1026] n is 0-12; and
[1027] q is 1-5;
[1028] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[1029] In certain embodiments of the compound of Formula I-c,
[1030] X.sup.3 is CR.sup.15;
[1031] X.sup.4 is CR.sup.15;
[1032] X.sup.5 is N;
[1033] each occurrence of R.sup.15 is hydrogen;
[1034] R.sup.14 is (CH.sub.2).sub.n--O--, -A-(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1035] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1036] n is 0-12; and
[1037] q is 1-6;
[1038] wherein one or more carbon of R.sup.14 is optionally
replaced with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[1039] In certain embodiments of the compound of Formula I-c,
[1040] X.sup.3 is CR.sup.15;
[1041] X.sup.4 is CR.sup.15;
[1042] X.sup.5 is N;
[1043] each occurrence of R.sup.15 is hydrogen;
[1044] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1045] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1046] n is 0-12; and
[1047] q is 1-5;
[1048] wherein one or more carbon of R.sup.14 is optionally
replaced with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[1049] In certain embodiments of the compound of Formula I-c,
[1050] X.sup.3 is CR.sup.15;
[1051] X.sup.4 is CR.sup.15;
[1052] X.sup.5 is N;
[1053] each occurrence of R.sup.15 is hydrogen;
[1054] R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--;
[1055] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene or substituted or
unsubstituted heteroarylene;
[1056] n is 0-12; and
[1057] q is 1-5;
[1058] wherein one or more carbon of R.sup.14 is optionally
replaced with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[1059] In certain embodiments of the compound of Formula I-c,
[1060] X.sup.3 is CR.sup.15;
[1061] X.sup.4 is CR.sup.15;
[1062] X.sup.5 is N;
[1063] each occurrence of R.sup.15 is hydrogen;
[1064] R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[1065] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1066] n is 0-12; and
[1067] q is 1-5.
[1068] In certain embodiments of the compound of Formula I-c,
[1069] X.sup.3 is CR.sup.15;
[1070] X.sup.4 is CR.sup.15;
[1071] X.sup.5 is N;
[1072] each occurrence of R.sup.15 is hydrogen;
[1073] R.sup.14 is -A-(CH.sub.2).--(C.dbd.O)NR.sup.A--;
[1074] A is substituted or unsubstituted heterocyclylene;
[1075] n is 0-12; and
[1076] q is 1-5.
[1077] In certain embodiments of the compound of Formula I-c,
[1078] X.sup.3 is CR.sup.15;
[1079] X.sup.4 is CR.sup.15;
[1080] X.sup.5 is N;
[1081] each occurrence of R.sup.15 is hydrogen;
[1082] R.sup.14 is -A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[1083] A is substituted or unsubstituted heteroarylene;
[1084] n is 0-12; and
[1085] q is 1-6.
[1086] In certain embodiments, the compound of Formula I is a
compound of Formula I-d:
##STR00141##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1087] E is an E3 ubiquitin ligase binding moiety;
[1088] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
-A-O--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--,
-A-S--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--NR.sup.A--, -A-(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n-A-NR.sup.A--,
-A-NR.sup.A--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1089] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1090] n is 0-12; and
[1091] q is 1-6;
[1092] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[1093] In certain embodiments of the compound of Formula I-d,
[1094] E is an E3 ubiquitin ligase binding moiety;
[1095] R.sup.14 is --(CH.sub.2).sub.n--O--,
-A-(CH.sub.2).sub.n--O--, --(CH.sub.2).sub.n-A-O--,
--(CH.sub.2).sub.n--S--, -A-(CH.sub.2).sub.n--S--,
--(CH.sub.2).sub.n-A-S--, --(CH.sub.2).sub.n--NR.sup.A--,
-A-(CH.sub.2).sub.n--NR.sup.A--, --(CH.sub.2).sub.n-A-NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
-A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--,
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--,
-A-(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--, or
--(CH.sub.2).sub.n-A-S(O).sub.2NR.sup.A--;
[1096] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1097] n is 0-12; and
[1098] q is 1-5;
[1099] wherein one or more carbon of R.sup.14 and R.sup.15 is
optionally replaced with C(O), O, S, SO.sub.2, NH, NC.sub.1-6
alkyl, NH-C.sub.1-6 alkyl, NH.sub.2, or N(C.sub.1-6
alkyl).sub.2.
[1100] In certain embodiments of the compound of Formula I-d,
[1101] R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A- or
--(CH.sub.2).sub.n-A--(C.dbd.O)NR.sup.A--;
[1102] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1103] n is 0-12; and
[1104] q is 1-5;
[1105] wherein one or more carbon of R.sup.14 is optionally
replaced with C(O), O, S, SO.sub.2, NH, or NC.sub.1-6 alkyl.
[1106] In certain embodiments of the compound of Formula I-d,
[1107] R.sup.14 is -A-(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[1108] A is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene or substituted or
unsubstituted heteroarylene;
[1109] n is 0-12; and
[1110] q is 1-5.
[1111] In certain embodiments of the compound of Formula I-d,
[1112] R.sup.14 is -A-(CH.sub.2).--(C.dbd.O)NR.sup.A--;
[1113] A is substituted or unsubstituted heterocyclylene;
[1114] n is 0-12; and
[1115] q is 1-5.
[1116] In certain embodiments of the compound of Formula I-d,
[1117] R.sup.14 is -A-O--(CH.sub.2).--(C.dbd.O)NR.sup.A--;
[1118] A is substituted or unsubstituted heteroarylene;
[1119] n is 0-12; and
[1120] q is 1-6.
[1121] In certain embodiments, the compound of Formula I-d is a
compound of Formula I-d-1:
##STR00142##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-6.
[1122] In certain embodiments of the compound of Formula I-d-1, E
is an E3 ubiquitin ligase binding moiety; and q is 1-5.
[1123] In certain embodiments, the compound of Formula I is a
compound of Formula I-e:
##STR00143##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1124] E is an E3 ubiquitin ligase binding moiety;
[1125] R.sup.20 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[1126] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1127] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[1128] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl;
[1129] n is 0-12; and
[1130] q is 1-5.
[1131] In certain embodiments of the compound of Formula I-e,
[1132] R.sup.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;
[1133] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1134] R.sup.22 is --(CH.sub.2).sub.n--O--,
--(CH.sub.2).sub.n--S--, --(CH.sub.2).sub.n--NR.sup.A--,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--, or
--(CH.sub.2).sub.n--S(O).sub.2NR.sup.A--;
[1135] n is 0-12; and
[1136] q is 1-5.
[1137] In certain embodiments of the compound of Formula I-e,
[1138] R.sup.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;
[1139] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1140] R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[1141] n is 0-12; and
[1142] q is 1-5.
[1143] In certain embodiments of the compound of Formula I-e,
[1144] R.sup.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;
[1145] G is unsubstituted arylene or unsubstituted
heteroarylene;
[1146] R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A- or
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.A--;
[1147] n is 0-12; and
[1148] q is 1-5.
[1149] In certain embodiments of the compound of Formula I-e,
[1150] R.sup.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;
[1151] G is unsubstituted arylene or unsubstituted
heteroarylene;
[1152] R.sup.22 is --(CH.sub.2).sub.nn--NR.sup.A--;
[1153] n is 0-12; and
[1154] q is 1-5.
[1155] In certain embodiments of the compound of Formula I-e,
[1156] R.sup.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;
[1157] G is unsubstituted heteroarylene;
[1158] R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A--;
[1159] n is 0-12; and
[1160] q is 1-5.
[1161] In certain embodiments of the compound of Formula I-e,
[1162] R.sup.20 is alkoxy substituted with one or more halogen or
hydroxy groups;
[1163] G is unsubstituted heteroarylene;
[1164] R.sup.22 is --(CH.sub.2).sub.n--NR.sup.A--;
[1165] n is 0-12; and
[1166] q is 1-5.
[1167] In certain embodiments, the compound of Formula I-e is a
compound of Formula I-e-1:
##STR00144##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein R.sup.20 is alkoxy
substituted with one or more halogen or hydroxy groups; E is an E3
ubiquitin ligase binding moiety; and q is 1-5.
[1168] In certain embodiments, the compound of Formula I-e is a
compound of Formula I-e-2:
##STR00145##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-5.
[1169] In certain embodiments, the compound of Formula I-e is a
compound of Formula I-e-3:
##STR00146##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-5.
[1170] In certain embodiments, the compound of Formula I is a
compound of Formula I-f:
##STR00147## [1171] or a pharmaceutically acceptable salt,
co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,
isotopically enriched derivative, or prodrug thereof, [1172]
wherein:
[1173] E is an E3 ubiquitin ligase binding moiety;
[1174] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1175] R.sup.23 is halogen, --OH, --COOH, --SO.sub.3H, --NO.sub.2,
--SH, --NR.sup.xR.sup.y, substituted or unsubstituted alkyl, or
substituted or unsubstituted alkoxy;
[1176] R.sup.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;
[1177] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[1178] q is 1-5.
[1179] In certain embodiments of the compound of Formula I-f,
[1180] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1181] R.sup.23 is -NR.sup.xR.sup.y;
[1182] R.sup.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;
[1183] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[1184] q is 1-5.
[1185] In certain embodiments of the compound of Formula I-f,
[1186] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1187] R.sup.23 is --NR.sup.xR.sup.y;
[1188] R.sup.24 is substituted or unsubstituted alkylene, or
substituted or unsubstituted alkoxylene;
[1189] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[1190] q is 1-5.
[1191] In certain embodiments of the compound of Formula I-f,
[1192] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1193] R.sup.23 is --NR.sup.xR.sup.y;
[1194] R.sup.24 is substituted or unsubstituted alkoxylene;
[1195] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and q is 1-5.
[1196] In certain embodiments of the compound of Formula I-f,
[1197] G is substituted or unsubstituted heterocyclylene,
substituted or unsubstituted arylene, or substituted or
unsubstituted heteroarylene;
[1198] R.sup.23 is --NR.sup.xR.sup.y;
[1199] R.sup.24 is alkoxylene substituted with one or more halogen
or hydroxy groups;
[1200] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and q is 1-5.
[1201] In certain embodiments of the compound of Formula I-f,
[1202] G is substituted or unsubstituted heteroarylene;
[1203] R.sup.23 is --NR.sup.xR.sup.y;
[1204] R.sup.24 is alkoxylene substituted with one or more halogen
or hydroxy groups;
[1205] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and q is 1-5.
[1206] In certain embodiments of the compound of Formula I-f,
[1207] G is unsubstituted heteroarylene;
[1208] R.sup.23 is --NR.sup.xR.sup.y;
[1209] R.sup.24 is alkoxylene substituted with one or more halogen
or hydroxy groups;
[1210] R.sup.x and R.sup.y are independently hydrogen, or
substituted or unsubstituted alkyl; and
[1211] q is 1-5.
[1212] In certain embodiments, the compound of Formula I-f is a
compound of Formula I-f-1:
##STR00148##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; G is unsubstituted heteroarylene; R.sup.23 is
--NR.sup.xR.sup.y; R.sup.x and R.sup.y are independently hydrogen,
or substituted or unsubstituted alkyl; and q is 1-5.
[1213] In certain embodiments, the compound of Formula I-f is a
compound of Formula I-f-2:
##STR00149##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-5.
[1214] In certain embodiments, the compound of Formula I-f is a
compound of Formula I-f-3:
##STR00150##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein E is an E3 ubiquitin ligase
binding moiety; and q is 1-5.
[1215] In certain embodiments, the compound of Formula I is a
compound of Formula I-g:
##STR00151##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1216] T is a tau protein binding moiety; and
[1217] q is 1-6.
[1218] In certain embodiments, the compound of Formula I is a
compound of Formula I-h:
##STR00152##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1219] T is a tau protein binding moiety; and
[1220] q is 1-6.
[1221] In certain embodiments, the compound of Formula I is a
compound of Formula I-i:
##STR00153##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1222] T is a tau protein binding moiety; and
[1223] q is 1-6.
[1224] In certain embodiments, the compound of Formula I is a
compound of Formula I-j:
##STR00154##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1225] T is a tau protein binding moiety; and
[1226] q is 1-4.
[1227] In certain embodiments, the compound of Formula I is a
compound of Formula I-k:
##STR00155##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1228] T is a tau protein binding moiety; and
[1229] q is 1-4.
[1230] In certain embodiments, the compound of Formula I is a
compound of Formula I-1:
##STR00156##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1231] T is a tau protein binding moiety; and
[1232] q is 1-4.
[1233] In certain embodiments, the compound of Formula I is a
compound of Formula I-m:
##STR00157##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1234] T is a tau protein binding moiety; and
[1235] q is 1-6.
[1236] In certain embodiments, the compound of Formula I is a
compound of Formula I-n:
##STR00158##
or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug thereof, wherein:
[1237] T is a tau protein binding moiety; and
[1238] q is 1-4.
[1239] In certain embodiments, the compound of Formula I is a
compound of Table 1, or a pharmaceutically acceptable salt,
co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,
isotopically enriched derivative, or prodrug thereof.
TABLE-US-00001 TABLE 1 ##STR00159## ##STR00160## ##STR00161##
##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166##
##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171##
##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176##
##STR00177## ##STR00178## ##STR00179## ##STR00180##
##STR00181##
[1240] In certain embodiments, the compound of Formula I is a
compound of Table 2, or a pharmaceutically acceptable salt,
co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,
isotopically enriched derivative, or prodrug thereof.
TABLE-US-00002 TABLE 2 ##STR00182## ##STR00183## ##STR00184##
##STR00185## ##STR00186## ##STR00187##
[1241] In certain embodiments, the compound of Formula I comprises
a radionuclide. In certain embodiments, the compound of Formula I
is substituted with a radionuclide. In certain embodiments, the
compound of Formula I is enriched with a radionuclide. In certain
embodiments, the compound of Formula I is useful as an imaging
agent (e.g., for use in positron emission tomography). The
radionuclide, such as a halogen atom, for example, may be readily
introduced into the compound using a number of different methods
well known in the art. Accordingly, the radiolabeled compounds of
Formula I may be prepared using standard methods known in the art
for preparing such radiolabeled compounds having a particular
substituent, wherein the compound may be incorporated with a
particular radionuclide selected from the group consisting of
.sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.123I, .sup.124I,
.sup.125I, .sup.131I, and 11C, 13.sub.N, 15.sub.0 18.sub.F,
123.sub./ 124.sub./ 125-.sub., 1 .sup.131k, and .sup.77Br.
[1242] In certain embodiments, the compound of Formula I binds tau
protein with a K.sub.d of less than 100,000 nM, less than 50,000
nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM,
less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than
800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less
than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM,
less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM,
less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM,
less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM,
less than 2 nM, or less than 1 nM.
[1243] In certain embodiments, the compound of Formula I
selectively binds tau protein over another protein. In some
embodiments, the compound of Formula I selectively binds tau
protein over amyloid R. In certain embodiments, the selectivity is
between about 2-fold and about 5-fold. In certain embodiments, the
selectivity is between about 5-fold and about 10-fold. In certain
embodiments, the selectivity is between about 10-fold and about
20-fold. In certain embodiments, the selectivity is between about
20-fold and about 50-fold. In certain embodiments, the selectivity
is between about 50-fold and about 100-fold. In certain
embodiments, the selectivity is between about 100-fold and about
200-fold. In certain embodiments, the selectivity is between about
200-fold and about 500-fold. In certain embodiments, the
selectivity is between about 500-fold and about 1000-fold. In
certain embodiments, the selectivity is at least about
1000-fold.
[1244] In certain embodiments, the compound of Formula I binds an
E3 ubiquitin ligase with a IQ of less than 100,000 nM, less than
50,000 nM, less than 20,000 nM, less than 10,000 nM, less than
5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM,
less than 800 nM, less than 700 nM, less than 600 nM, less than 500
nM, less than 400 nM, less than 300 nM, less than 200 nM, less than
100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less
than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less
than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less
than 3 nM, less than 2 nM, or less than 1 nM.
[1245] In certain embodiments, the compound of Formula I binds
Cereblon with a K.sub.d of less than 100,000 nM, less than 50,000
nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM,
less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than
800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less
than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM,
less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM,
less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM,
less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM,
less than 2 nM, or less than 1 nM.
[1246] In certain embodiments, the compound of Formula I
selectively binds an E3 ubiquitin ligase as compared to another
protein. In some embodiments, the compound of Formula I selectively
binds Cereblon over another protein. In some embodiments, the
compound of Formula I selectively binds Cereblon over another E3
ubiquitin ligase. In certain embodiments, the selectivity is
between about 2-fold and about 5-fold. In certain embodiments, the
selectivity is between about 5-fold and about 10-fold. In certain
embodiments, the selectivity is between about 10-fold and about
20-fold. In certain embodiments, the selectivity is between about
20-fold and about 50-fold. In certain embodiments, the selectivity
is between about 50-fold and about 100-fold. In certain
embodiments, the selectivity is between about 100-fold and about
200-fold. In certain embodiments, the selectivity is between about
200-fold and about 500-fold. In certain embodiments, the
selectivity is between about 500-fold and about 1000-fold. In
certain embodiments, the selectivity is at least about
1000-fold.
[1247] In certain embodiments, the compound of Formula I promotes
the degradation of up to 10%, up to 15%, up to 20%, up to 25%, up
to 30%, up to 35%, up to 40%, up to 45%, up to 50%, up to 55%, up
to 60%, up to 65%, up to 70%, up to 75%, up to 80%, up to 85%, up
to 90%, up to 95%, up to 99%, or up to 100% of tau protein at a
concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM
or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less,
2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less,
700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300
nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or
less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less,
30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or
less, 3 nM or less, 2 nM or less, or 1 nM or less.
[1248] In certain embodiments, the compound of Formula I increases
the rate of tau protein degradation of up to 10%, up to 15%, up to
20%, up to 25%, up to 30%, up to 35%, up to 40%, up to 45%, up to
50%, up to 55%, up to 60%, up to 65%, up to 70%, up to 75%, up to
80%, up to 85%, up to 90%, up to 95%, up to 99%, or up to 100% at a
concentration of 100,000 nM or less, 50,000 nM or less, 20,000 nM
or less, 10,000 nM or less, 5,000 nM or less, 3,500 nM or less,
2,500 nM or less, 1,000 nM or less, 900 nM or less, 800 nM or less,
700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300
nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or
less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less,
30 nM or less, 20 nM or less, 10 nM or less, 5 nM or less, 4 nM or
less, 3 nM or less, 2 nM or less, or 1 nM or less.
Pharmaceutical Compositions, Kits, and Administration
[1249] The present disclosure provides pharmaceutical compositions
comprising a compound of Formula I, or a pharmaceutically
acceptable salt, co-crystal, tautomer, stereoisomer, solvate,
hydrate, polymorph, isotopically enriched derivative, or prodrug
thereof, and optionally a pharmaceutically acceptable excipient. In
certain embodiments, the pharmaceutical composition described
herein comprises a compound of Formula I, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
excipient.
[1250] In certain embodiments, the compound of Formula I is
provided in an effective amount in the pharmaceutical composition.
In certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount. In certain embodiments, the
effective amount is an amount effective for treating a neurological
disorder in a subject in need thereof. In certain embodiments, the
effective amount is an amount effective for preventing a
neurological disorder in a subject in need thereof. In certain
embodiments, the effective amount is an amount effective for
treating a neurodegenerative disease in a subject in need thereof.
In certain embodiments, the effective amount is an amount effective
for preventing a neurodegenerative disease in a subject in need
thereof In certain embodiments, the effective amount is an amount
effective for treating a tauopathy in a subject in need thereof In
certain embodiments, the effective amount is an amount effective
for preventing a tauopathy in a subject in need thereof. In certain
embodiments, the effective amount is an amount effective for
reducing the risk of developing a disease (e.g., neurological
disorder, neurodegenerative disease, or tauopathy) in a subject in
need thereof
[1251] In certain embodiments, the subject is an animal. The animal
may be of either sex and may be at any stage of development. In
certain embodiments, the subject described herein is a human. In
certain embodiments, the subject is a non-human animal. In certain
embodiments, the subject is a mammal In certain embodiments, the
subject is a non-human mammal In certain embodiments, the subject
is a domesticated animal, such as a dog, cat, cow, pig, horse,
sheep, or goat. In certain embodiments, the subject is a companion
animal, such as a dog or cat. In certain embodiments, the subject
is a livestock animal, such as a cow, pig, horse, sheep, or goat.
In certain embodiments, the subject is a zoo animal. In another
embodiment, the subject is a research animal, such as a rodent
(e.g., mouse, rat), dog, pig, or non-human primate. In certain
embodiments, the animal is a genetically engineered animal. In
certain embodiments, the animal is a transgenic animal (e.g.,
transgenic mice and transgenic pigs). In certain embodiments, the
subject is a fish or reptile.
[1252] In certain embodiments, the effective amount is an amount
effective for promoting the degradation of at least about 10%, at
least about 20%, at least about 30%, at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least about
80%, at least about 90%, at least about 95%, at least about 98%, or
at least about 99% of tau protein. In certain embodiments, the
effective amount is an amount effective for promoting the
degradation of tau protein by a range between a percentage
described in this paragraph and another percentage described in
this paragraph, inclusive.
[1253] The present disclosure provides pharmaceutical compositions
comprising a compound that interacts with tau protein and/or an E3
ubiquitin ligase (e.g., Cereblon) for use in treating a
neurological disorder in a subject in need thereof In certain
embodiments, the composition is for use in treating a
neurodegenerative disease. In certain embodiments, the composition
is for use in treating a tauopathy. In certain embodiments, the
composition is for use in treating 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. In
certain embodiments, the composition is for use in treating
Alzheimer's disease.
[1254] A compound or composition, as described herein, can be
administered in combination with one or more additional
pharmaceutical agents (e.g., therapeutically and/or
prophylactically active agents). The compounds or compositions can
be administered in combination with additional pharmaceutical
agents that improve their activity (e.g., activity (e.g., potency
and/or efficacy) in treating a disease in a subject in need
thereof, in preventing a disease in a subject in need thereof,
and/or in reducing the risk to develop a disease in a subject in
need thereof), improve bioavailability, improve their ability to
cross the blood-brain barrier, improve safety, reduce drug
resistance, reduce and/or modify metabolism, inhibit excretion,
and/or modify distribution in a subject or cell. It will also be
appreciated that the therapy employed may achieve a desired effect
for the same disorder, and/or it may achieve different effects. In
certain embodiments, a pharmaceutical composition described herein
including a compound described herein and an additional
pharmaceutical agent exhibit a synergistic effect that is absent in
a pharmaceutical composition including one of the compound and the
additional pharmaceutical agent, but not both.
[1255] The compound or composition can be administered concurrently
with, prior to, or subsequent to one or more additional
pharmaceutical agents, which may be useful as, e.g., combination
therapies. Pharmaceutical agents include therapeutically active
agents. Pharmaceutical agents also include prophylactically active
agents. Pharmaceutical agents include small organic molecules such
as drug compounds (e.g., compounds approved for human or veterinary
use by the U.S. Food and Drug Administration as provided in the
Code of Federal Regulations (CFR)), peptides, proteins,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides
or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells. In certain embodiments, the additional
pharmaceutical agent is a pharmaceutical agent useful for treating
and/or preventing a disease (e.g., neurological disorder,
neurodegenerative disease, and/or tauopathy). Each additional
pharmaceutical agent may be administered at a dose and/or on a time
schedule determined for that pharmaceutical agent. The additional
pharmaceutical agents may also be administered together with each
other and/or with the compound or composition described herein in a
single dose or administered separately in different doses. The
particular combination to employ in a regimen will take into
account compatibility of the compound described herein with the
additional pharmaceutical agent(s) and/or the desired therapeutic
and/or prophylactic effect to be achieved. In general, it is
expected that the additional pharmaceutical agent(s) in combination
be utilized at levels that do not exceed the levels at which they
are utilized individually. In some embodiments, the levels utilized
in combination will be lower than those utilized individually.
[1256] In certain embodiments, the compound or pharmaceutical
composition is a solid. In certain embodiments, the compound or
pharmaceutical composition is a powder. In certain embodiments, the
compound or pharmaceutical composition can be dissolved in a liquid
to make a solution. In certain embodiments, the compound or
pharmaceutical composition is dissolved in water to make an aqueous
solution. In certain embodiments, the pharmaceutical composition is
a liquid for parental injection. In certain embodiments, the
pharmaceutical composition is a liquid for oral administration
(e.g., ingestion). In certain embodiments, the pharmaceutical
composition is a liquid (e.g., aqueous solution) for intravenous
injection. In certain embodiments, the pharmaceutical composition
is a liquid (e.g., aqueous solution) for subcutaneous
injection.
[1257] After formulation with an appropriate pharmaceutically
acceptable excipient in a desired dosage, the pharmaceutical
compositions of this invention can be administered to humans and
other animals orally, parenterally, intracisternally,
intraperitoneally, topically, bucally, or the like, depending on
the disease or condition being treated.
[1258] In certain embodiments, a pharmaceutical composition
comprising a compound of Formula I is administered, orally or
parenterally, at dosage levels of each pharmaceutical composition
sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in
one or more dose administrations for one or several days (depending
on the mode of administration). In certain embodiments, the
effective amount per dose varies from about 0.001 mg/kg to about
200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg
to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic and/or prophylactic effect. In certain embodiments, the
compounds described herein may be at dosage levels sufficient to
deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001
mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg,
from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1
mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about
30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1
mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to
about 25 mg/kg, of subject body weight per day, one or more times a
day, to obtain the desired therapeutic and/or prophylactic effect.
The desired dosage may be delivered three times a day, two times a
day, once a day, every other day, every third day, every week,
every two weeks, every three weeks, or every four weeks. In certain
embodiments, the desired dosage may be delivered using multiple
administrations (e.g., two, three, four, five, six, seven, eight,
nine, ten, eleven, twelve, thirteen, fourteen, or more
administrations). In certain embodiments, the composition described
herein is administered at a dose that is below the dose at which
the agent causes non-specific effects.
[1259] In certain embodiments, the pharmaceutical composition is
administered at a dose of about 0.001 mg to about 1000 mg per unit
dose. In certain embodiments, the pharmaceutical composition is
administered at a dose of about 0.01 mg to about 200 mg per unit
dose. In certain embodiments, the pharmaceutical composition is
administered at a dose of about 0.01 mg to about 100 mg per unit
dose. In certain embodiments, pharmaceutical composition is
administered at a dose of about 0.01 mg to about 50 mg per unit
dose. In certain embodiments, the pharmaceutical composition is
administered at a dose of about 0.01 mg to about 10 mg per unit
dose. In certain embodiments, the pharmaceutical composition is
administered at a dose of about 0.1 mg to about 10 mg per unit
dose.
[1260] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include the steps of bringing the composition
comprising a compound of Formula I into association with a carrier
and/or one or more other accessory ingredients, and then, if
necessary and/or desirable, shaping and/or packaging the product
into a desired single- or multi-dose unit.
[1261] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. As used herein, a "unit dose" is a discrete
amount of the pharmaceutical composition comprising a predetermined
amount of the active ingredient. The amount of the active
ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage, such as, for example,
one-half or one-third of such a dosage.
[1262] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition of the invention will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. By way of example, the
composition may comprise between 0.1% and 100% (w/w) active
ingredient.
[1263] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[1264] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and mixtures thereof.
[1265] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose, and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and
mixtures thereof.
[1266] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g. acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene
sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween
60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan
monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan
tristearate (Span 65), glyceryl monooleate, sorbitan monooleate
(Span 80)), polyoxyethylene esters (e.g. polyoxyethylene
monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil,
polyethoxylated castor oil, polyoxymethylene stearate, and
Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid
esters (e.g. Cremophor.TM.), polyoxyethylene ethers, (e.g.
polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium
oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,
sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[1267] Exemplary binding agents include starch (e.g. cornstarch and
starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose,
dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and
synthetic gums (e.g. acacia, sodium alginate, extract of Irish
moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and
larch arabogalactan), alginates, polyethylene oxide, polyethylene
glycol, inorganic calcium salts, silicic acid, polymethacrylates,
waxes, water, alcohol, and/or mixtures thereof.
[1268] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
alcohol preservatives, acidic preservatives, and other
preservatives. In certain embodiments, the preservative is an
antioxidant. In other embodiments, the preservative is a chelating
agent.
[1269] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[1270] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[1271] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid.
[1272] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[1273] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[1274] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115,
Germaben II, Neolone, Kathon, and Euxyl.
[1275] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof
[1276] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[1277] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and mixtures thereof.
[1278] Liquid dosage forms for oral and parenteral administration
include, but are not limited to, pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups, and
elixirs. In addition to the active agents, the liquid dosage forms
may contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents. In certain
embodiments for parenteral administration, agents of the invention
are mixed with solubilizing agents such CREMOPHOR EL.RTM.
(polyethoxylated castor oil), alcohols, oils, modified oils,
glycols, polysorbates, cyclodextrins, polymers, and combinations
thereof
[1279] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. Sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[1280] Injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[1281] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active agent is mixed with at least one inert, pharmaceutically
acceptable excipient or carrier such as sodium citrate or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose,
sucrose, glucose, mannitol, and silicic acid, b) binders such as,
for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[1282] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner Examples of embedding compositions
which can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polyethylene
glycols and the like.
[1283] The active agents can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active agent may be admixed with at least one inert diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as
is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets, and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner Examples of
embedding compositions which can be used include polymeric
substances and waxes.
[1284] Formulations suitable for topical administration include
liquid or semi-liquid preparations such as liniments, lotions,
gels, applicants, oil-in-water or water-in-oil emulsions such as
creams, ointments, or pastes; or solutions or suspensions such as
drops. Formulations for topical administration to the skin surface
can be prepared by dispersing the drug with a dermatologically
acceptable carrier such as a lotion, cream, ointment, or soap.
Useful carriers are capable of forming a film or layer over the
skin to localize application and inhibit removal. For topical
administration to internal tissue surfaces, the agent can be
dispersed in a liquid tissue adhesive or other substance known to
enhance adsorption to a tissue surface. For example,
hydroxypropylcellulose or fibrinogen/thrombin solutions can be used
to advantage. Alternatively, tissue-coating solutions, such as
pectin-containing formulations can be used. Ophthalmic formulation,
ear drops, and eye drops are also contemplated as being within the
scope of this invention. Additionally, the present disclosure
contemplates the use of transdermal patches, which have the added
advantage of providing controlled delivery of an agent to the body.
Such dosage forms can be made by dissolving or dispensing the agent
in the proper medium. Absorption enhancers can also be used to
increase the flux of the agent across the skin. The rate can be
controlled by either providing a rate controlling membrane or by
dispersing the agent in a polymer matrix or gel.
[1285] Additionally, the carrier for a topical formulation can be
in the form of a hydroalcoholic system (e.g., quids and gels), an
anhydrous oil or silicone based system, or an emulsion system,
including, but not limited to, oil-in-water, water-in-oil,
water-in-oil-in-water, and oil-in-water-in-silicone emulsions. The
emulsions can cover a broad range of consistencies including thin
lotions (which can also be suitable for spray or aerosol delivery),
creamy lotions, light creams, heavy creams, and the like. The
emulsions can also include microemulsion systems. Other suitable
topical carriers include anhydrous solids and semisolids (such as
gels and sticks); and aqueous based mousse systems.
[1286] Also encompassed by the disclosure are kits (e.g.,
pharmaceutical packs). The kits provided may comprise a
pharmaceutical composition or compound described herein and a
container (e.g., a vial, ampule, bottle, syringe, and/or dispenser
package, or other suitable container). In some embodiments,
provided kits may optionally further include a second container
comprising a pharmaceutical excipient for dilution or suspension of
a pharmaceutical composition or compound described herein. In some
embodiments, the pharmaceutical composition or compound described
herein provided in the first container and the second container are
combined to form one unit dosage form.
[1287] Thus, in one aspect, provided are kits including a first
container comprising a compound or pharmaceutical composition
described herein. In certain embodiments, the kits are useful for
treating a disease (e.g., neurological disorder, neurodegenerative
disease, or tauopathy) in a subject in need thereof In certain
embodiments, the kits are useful for preventing a disease (e.g.,
neurological disorder, neurodegenerative disease, or tauopathy) in
a subject in need thereof In certain embodiments, the kits are
useful for reducing the risk of developing a disease (e.g.,
neurological disorder, neurodegenerative disease, or tauopathy) in
a subject in need thereof In certain embodiments, the kits are
useful for promoting the degradation of tau protein in a subject or
cell. In certain embodiments, the kits are useful for imaging
and/or detecting a neurological disorder in any human tissue (e.g.,
through use of a radiolabeled compound of Formula I). In certain
embodiments, the kits are useful for promoting the degradation of
tau protein in a subject or cell. In certain embodiments, the kits
are useful for imaging and/or detecting a neurological disorder in
the central nervous system (e.g., through use of a radiolabeled
compound of Formula I). In certain embodiments, the kits are useful
for promoting the degradation of tau protein in a subject or cell.
In certain embodiments, the kits are useful for imaging and/or
detecting a neurological disorder in the brain (e.g., through use
of a radiolabeled compound of Formula I). In certain embodiments,
the kits are useful for imaging and/or detecting pathological
aggregation of tau protein in any human tissue (e.g., through use
of a radiolabeled compound of Formula I). In certain embodiments,
the kits are useful for imaging and/or detecting pathological
aggregation of tau protein in the central nervous system (e.g.,
through use of a radiolabeled compound of Formula I). In certain
embodiments, the kits are useful for imaging and/or detecting
pathological aggregation of tau protein in the brain (e.g., through
use of a radiolabeled compound of Formula I).
[1288] In certain embodiments, a kit described herein further
includes instructions for using the kit. A kit described herein may
also include information as required by a regulatory agency such as
the U.S. Food and Drug Administration (FDA). In certain
embodiments, the information included in the kits is prescribing
information. In certain embodiments, the kits and instructions
provide for treating a disease (e.g., neurological disorder,
neurodegenerative disease, or tauopathy) in a subject in need
thereof In certain embodiments, the kits and instructions provide
for preventing a disease (e.g., neurological disorder,
neurodegenerative disease, or tauopathy) in a subject in need
thereof In certain embodiments, the kits and instructions provide
for reducing the risk of developing a disease (e.g., neurological
disorder, neurodegenerative disease, or tauopathy) in a subject in
need thereof. In certain embodiments, the kits and instructions
provide for promoting the degradation of tau protein in a subject
or cell. In certain embodiments, the kits and instructions provide
for diagnosing a neurological disorder in the central nervous
system (e.g., through use of a radiolabeled compound of Formula I).
In certain embodiments, the kits and instructions provide for
imaging and/or detecting a neurological disorder in the central
nervous system (e.g., through use of a radiolabeled compound of
Formula I). In certain embodiments, the kits and instructions
provide for imaging and/or detecting pathological aggregation of
tau protein in the central nervous system (e.g., through use of a
radiolabeled compound of Formula I). A kit described herein may
include one or more additional pharmaceutical agents described
herein as a separate composition.
Methods of Treatment
[1289] Major neuropathology observations of postmortem examination
of Alzheimer's disease (AD) brains confirm the presence of AD
through the detection of intracellular neurofibrillary tangles
(NFT). NFTs derive from filaments of aggregated hyperphosphorylated
tau proteins. The presence and severity of NFTs generally but not
always correlates with the severity of dementia and cognitive
impairment, and it has become clear that the pathological process
of AD begins before the presentation of the clinical symptoms of
dementia and the late stage NFTs. Therefore, reduction and/or
elimination of aberrant tau species preceding NFTs, or NFTs
themselves, by tau protein degradation is an attractive method for
the treatment of AD and other tauopathies.
[1290] Immunomodulatory agents, including thalidomide and
lenalidomide, bind Cereblon. Accordingly, use of a bifunctional
compound that binds tau protein and an E3 ubiquitin ligase (e.g.,
Cereblon) provides a strategy for treating diseases associated with
tau protein aggregation, also known as tauopathies. bp The present
disclosure provides methods for treating neurological disorders. In
certain embodiments, the application provides a method of treating
neurodegenerative disease. In certain embodiments, the application
provides a method of treating a tauopathy. In certain embodiments,
the application provides a method of treating 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. In
certain embodiments, the application provides a method of treating
Alzheimer's disease.
[1291] The present disclosure provides methods for preventing
neurological disorders. In certain embodiments, the application
provides a method of preventing neurodegenerative disease. In
certain embodiments, the application provides a method of
preventing a tauopathy. In certain embodiments, the application
provides a method of preventing 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. In
certain embodiments, the application provides a method of
preventing Alzheimer's disease.
[1292] In certain embodiments, the application provides a method of
promoting the degradation of tau protein (e.g., in a cell). In
certain embodiments, the application provides a method of promoting
the degradation of tau protein in a subject in need thereof. In
certain embodiments, the application provides a method of binding
an E3 ubiquitin ligase and promoting the degradation of tau
protein. In certain embodiments, the E3 ubiquitin ligase targeted
is Cereblon.
[1293] In certain embodiments, the methods comprise administering
to a subject in need thereof (e.g., a subject with a
neurodegenerative disease) a compound that interacts with tau
protein, for example, a compound that is a modulator of tau
protein, a binder of tau protein, a compound that modifies tau
protein, or a compound that promotes the degradation of tau
protein. The compound may also be an inhibitor of an E3 ubiquitin
ligase, a modulator of an E3 ubiquitin ligase, a binder of an E3
ubiquitin ligase, a compound that modifies an E3 ubiquitin ligase,
or a compound that disrupts the interaction of the E3 ubiquitin
ligase with another protein. In certain embodiments, the methods
comprise administering a compound of Formula I, or a
pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug, or composition thereof, to a subject in
need thereof. In some embodiments, the method comprises
administering a pharmaceutical composition comprising a compound of
Formula I, or a pharmaceutically acceptable salt, co-crystal,
tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically
enriched derivative, or prodrug, or composition thereof, to a
subject in need thereof.
[1294] The present disclosure also provides a compound of Formula
I, or a pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug, or composition thereof, for use in the
treatment of a neurological disorder. In certain embodiments, the
neurological disorder is a neurodegenerative disease. In certain
embodiments, the neurodegenerative disease is a tauopathy. In
certain embodiments, the 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. In
certain embodiments, the tauopathy is Alzheimer's disease.
[1295] The present disclosure also provides uses of a compound of
Formula I, or a pharmaceutically acceptable salt, co-crystal,
tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically
enriched derivative, or prodrug, or composition thereof, in the
manufacture of a medicament for the treatment of a neurological
disorder. In certain embodiments, the neurological disorder is a
neurodegenerative disease. In certain embodiments, the
neurodegenerative disease is a tauopathy. In certain embodiments,
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. In
certain embodiments, the tauopathy is Alzheimer's disease.
[1296] In certain embodiments, the methods of the disclosure
comprise administering to the subject an effective amount of a
compound of Formula I, or a pharmaceutically acceptable salt,
co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,
isotopically enriched derivative, or prodrug, or composition
thereof. In some embodiments, the effective amount is a
therapeutically effective amount. In some embodiments, the
effective amount is a prophylactically effective amount.
[1297] In certain embodiments, the subject being treated is an
animal. The animal may be of either sex and may be at any stage of
development. In certain embodiments, the subject is a mammal In
certain embodiments, the subject being treated is a human. In
certain embodiments, the subject is a domesticated animal, such as
a dog, cat, cow, pig, horse, sheep, or goat. In certain
embodiments, the subject is a companion animal, such as a dog or
cat. In certain embodiments, the subject is a livestock animal,
such as a cow, pig, horse, sheep, or goat. In certain embodiments,
the subject is a zoo animal. In another embodiment, the subject is
a research animal such as a rodent (e.g., mouse, rat), dog, pig, or
non-human primate. In certain embodiments, the animal is a
genetically engineered animal. In certain embodiments, the animal
is a transgenic animal.
[1298] Certain methods described herein may comprise administering
one or more additional pharmaceutical agent(s) in combination with
the compounds described herein. The additional pharmaceutical
agent(s) may be administered at the same time as the compound of
Formula I, or at different times than the compound of Formula I.
For example, the compound of Formula I and any additional
pharmaceutical agent(s) may be on the same dosing schedule or
different dosing schedules. All or some doses of the compound of
Formula I may be administered before all or some doses of an
additional pharmaceutical agent, after all or some does an
additional pharmaceutical agent, within a dosing schedule of an
additional pharmaceutical agent, or a combination thereof. The
timing of administration of the compound of Formula I and
additional pharmaceutical agents may be different for different
additional pharmaceutical agents.
[1299] In certain embodiments, the additional pharmaceutical agent
comprises an agent useful in the treatment of a neurological
disorder. In certain embodiments, the additional pharmaceutical
agent is useful in the treatment of a neurodegenerative disease. In
certain embodiments, the additional pharmaceutical agent is useful
in the treatment of a tauopathy. In certain embodiments, the
additional pharmaceutical agent is useful in the treatment of
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. In certain embodiments, the
additional pharmaceutical agent is useful in the treatment of a
non-Hodgkin's lymphoma. In certain embodiments, the additional
pharmaceutical agent is useful in the treatment of Alzheimer's
disease.
[1300] In another aspect, the present disclosure provides methods
for promoting the degradation of tau protein, the method comprising
administering to the subject a compound of Formula I, or a
pharmaceutically acceptable salt, co-crystal, tautomer,
stereoisomer, solvate, hydrate, polymorph, isotopically enriched
derivative, or prodrug, or composition thereof
[1301] In another aspect, the present disclosure provides methods
for binding an E3 ubiquitin ligase and promoting the degradation of
tau protein, the method comprising administering to the subject a
compound of Formula I, or a pharmaceutically acceptable salt,
co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph,
isotopically enriched derivative, or prodrug, or composition
thereof. In certain embodiments, the E3 ubiquitin ligase is
Cereblon.
Diagnostic Methods
[1302] The pathological development of tauopathies often begin
before presentation of clinical symptoms, thus in vivo imaging of
aberrant and/or aggregated tau protein may be useful for the early
and accurate diagnosis of neurological disease. In particular, the
pathological process of AD begins before the presentation of the
clinical symptoms of dementia, and in vivo imaging of aberrant tau
and NFTs may be useful for the early and accurate diagnosis of AD.
Quantitative evaluation of tau pathology could also be helpful for
tracking and predicting severity of dementia, because the formation
of neuritic pathology correlates with clinical severity of
dementia. The compounds of the present disclosure recognize
pathological forms of tau, which includes forms containing
excessively phosphorylated tau protein as a constituent ingredient
as well as aberrant high-molecular weight species formed from tau
and other post-translational modifications, and thus the compounds
can be used as a probe for the detection of aberrant tau relevant
to neurodegeneration. Thus, imaging techniques in conjunction with
novel treatments that prevent or reduce the pathological formation
of neurofibrillary pathology would be useful for the evaluation of
treatment efficacy.
[1303] In certain embodiments, the present disclosure relates to
radiolabeled compounds of Formula I as imaging agents. These
imaging agents are useful as they contain tau protein binding
moieties that interact with and bind to tau protein, providing the
ability to image aggregated tau protein in vivo. As the compounds
of Formula I lead to the degradation of tau protein by regular
administration, progression of the therapeutic effect of the
compounds of Formula I may be monitored through the use of
radiolabeled forms of the compounds or other known imaging agents
for tau protein.
[1304] In certain embodiments, the imaging is achieved by employing
a fluorescence imaging technique or a nuclear imaging technique
selected from the group consisting of positron emission tomography
(PET) and single photon emission computed tomography (SPECT), the
fluorescence imaging technique and/or nuclear imaging technique for
monitoring or visualizing a distribution of the radiolabeled or
tagged compound within the central nervous system or within a
portion thereof (e.g., the brain).
[1305] PET and SPECT utilize radiolabeled compounds. PET and SPECT
are sensitive techniques and require small quantities of
radiolabeled compounds, or tracers. The labeled compounds are
transported, accumulated and converted in vivo in exactly the same
way as the corresponding non-radioactively compound. Tracers, or
probes, can be radiolabeled with a radionuclide useful for PET
imaging, such as .sup.11C, .sup.13N, .sup.15O, .sup.18F, .sup.64Cu
and .sup.124I, or with a radionuclide useful for SPECT imaging,
such as .sup.99Tc, .sup.77Br, .sup.61Cu, .sup.153Gd, .sup.123I,
.sup.125I, .sup.131I and .sup.32P.
[1306] PET creates images based on the distribution of molecular
imaging tracers carrying positron-emitting isotopes in the tissue
of the patient. The PET method has the potential to detect
malfunction on a cellular level in the investigated tissues or
organs. PET has been used in clinical oncology, such as for the
imaging of tumors and metastases, and has been used for diagnosis
of certain brain diseases, as well as mapping brain and heart
function. Similarly, SPECT can be used to complement any gamma
imaging study, where a true 3D representation can be helpful, for
example, imaging tumor, infection (leukocyte), thyroid or
bones.
[1307] The present disclosure provides methods for detecting a
neurological disorder, the method comprising contacting a compound
of Formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising a compound of Formula I, with
tissue of the central nervous system. In certain embodiments, the
neurological disorder is a neurodegenerative disease. In certain
embodiments, the neurodegenerative disease is a tauopathy. In
certain embodiments, 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. In
certain embodiments, the tauopathy is Alzheimer's disease.
[1308] The present disclosure provides methods for detecting
pathological aggregation of tau protein in the central nervous
system (e.g., brain), the method comprising contacting a compound
of Formula I, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising a compound of Formula I, with
tissue of the central nervous system. In certain embodiments,
contacting includes administration of the compound of Formula I, or
a pharmaceutically acceptable salt thereof, to a subject and
allowing the compound to distribute into the central nervous
system.
[1309] The present disclosure also provides methods for imaging tau
protein in a subject, the method comprising administering a
compound of Formula I, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition comprising a compound of
Formula I, to a subject. In certain embodiments, the methods
comprise imaging pathological aggregation of tau protein in the
central nervous system (e.g., brain).
[1310] The present disclosure also provides methods for diagnosing
a neurological disorder in a subject, the method comprising
contacting a compound of Formula I, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition comprising
a compound of Formula I, with tissue of the central nervous system.
In certain embodiments, the neurological disorder is a
neurodegenerative disease. In certain embodiments, the
neurodegenerative disease is a tauopathy. In certain embodiments,
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. In
certain embodiments, the tauopathy is Alzheimer's disease.
[1311] In certain embodiments, the tissue of the central nervous
system is brain tissue. In certain embodiments, the compound is
contacted with the tissue in vivo. In other embodiments, the
compound is contacted with the tissue in vitro. In certain
embodiments, the compound contacts the tissue after administration
of the compound to a subject and allowing the compound to
distribute into the central nervous system.
EXAMPLES
[1312] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
examples described in this application are offered to illustrate
the compounds, pharmaceutical compositions, and methods provided
herein and are not to be construed in any way as limiting their
scope.
[1313] Compounds of Formula I may be prepared using the synthetic
schemes and procedures described in detail below.
Preparation of Synthetic Intermediates
##STR00188## ##STR00189##
[1315] 3-(4-(4-Nitropyridin-3-yl)phenyl)propan-1-ol (C): A solution
of
3-(4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-1-ol
(A) (1.65 g, 6.29 mmol), 3-bromo-4-nitropyridine (B) (1.16 g, 5.72
mmol), Na.sub.2CO.sub.3 (1.52 g, 14 3 mmol), and
Pd(PPh.sub.3).sub.4 (330 mg, 0.286 mmol) in 1,4-dioxane (40 mL) and
H.sub.2O (10 mL) was stirred at 110.degree. C. for 16 h before it
was quenched with NH.sub.4Cl (sat. aq., 100 mL). The resulting
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.80 mL), the
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. The residue was purified
by flash column chromatography to give the title compound (950 mg,
3.68 mmol, 64% yield).
[1316]
3-(4-(3-((tert-Butyldiphenylsilyl)oxy)propyl)phenyl)-4-nitropyridin-
e (D): To a stirred solution of C (950 mg, 3.68 mmol) in
CH.sub.2Cl.sub.2 (35 mL) at 25.degree. C. was added imidazole (751
mg, 11.04 mmol) and TBDPSCl (2.01 g, 7.36 mmol). After stirring at
this temperature for 3 h, the reaction was quenched with NH.sub.4Cl
(sat. aq., 100 mL). The resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL), the combined organic phases were
washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. The residue was purified
by flash column chromatography to give the title compound (1.62 g,
3.26 mmol, 89% yield).
[1317]
7-(3-((tert-Butyldiphenylsilyl)oxy)propyl)-5H-pyrido[4,3-b]indole
(E): A solution of D (1.62 g, 3.26 mmol) in P(OEt).sub.3 (20 mL)
was stirred at 110.degree. C. for 3 h before it was concentrated
under reduced pressure. The residue was purified by flash column
chromatography to give the title compound (1.32 g, 2.84 mmol, 87%
yield).
[1318] tert-Butyl
7-(3-((tert-butyldiphenylsilyl)oxy)propyl)-5H-pyrido[4,3-b]indole-5-carbo-
xylate (F): To a stirred solution of E (1.32 g, 2.84 mmol) and DMAP
(213 mg, 1.75 mmol) in CH.sub.2Cl.sub.2 (30 mL) at 25.degree. C.
was added Et.sub.3N (1.06 g, 10.47 mmol) and (Boc).sub.2O (1.52 g,
6.98 mmol). After stirring at this temperature for 2 h, the
reaction was quenched with NH.sub.4Cl (sat. aq., 100 mL). The
resulting mixture was extracted with CH.sub.2Cl.sub.2 (2.times.50
mL), the combined organic phases were washed with brine (100 mL),
dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography to give the title compound (1.42 g, 2.52 mmol, 89%
yield).
[1319] tert-Butyl
7-(3-hydroxypropyl)-5H-pyrido[4,3-b]indole-5-carboxylate (G): To a
stirred solution of F (1.42 g, 2.52 mmol) in THF (25 mL) at
0.degree. C. was added TBAF (1.0 M in THF, 3.8 mL, 3.8 mmol)
dropwise. After stirring at this temperature for 2 h, the reaction
was quenched with acetic acid (0.2 mL). The mixture was
concentrated under reduced pressure. The residue was purified by
flash column chromatography to give the title compound (670 mg,
2.05 mmol, 81% yield).
[1320] tert-butyl
7-(3-oxopropyl)-5H-pyrido[4,3-b]indole-5-carboxylate (H): To a
stirred solution of DMSO (1.30 g, 16 6 mmol) in CH.sub.2Cl.sub.2 (7
mL) at -78.degree. C. was added oxalyl chloride (783 mg, 6.16 mmol)
in CH.sub.2Cl.sub.2 (6 mL) dropwise. After stirring at this
temperature for 0.5 h, a solution of G (670 mg, 2.05 mmol) in
CH.sub.2Cl.sub.2 (6 mL) was added dropwise. The mixture was stirred
at this temperature for 2 h followed by the addition of Et.sub.3N
(1.035 g, 10.25 mmol) dropwise. The reaction mixture was slowly
warmed to 0.degree. C. over 1 h, and was quenched with NH.sub.4Cl
(sat. aq., 30 mL). The resulting mixture was extracted with
CH.sub.2Cl.sub.2 (2.times.30 mL), the combined organic phases were
washed with brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure to provide the title
compound. The crude product of H was used in the next step without
further purification.
[1321]
3-(5-(tert-Butoxycarbonyl)-5H-pyrido[4,3-b]indol-7-yl)propanoic
acid (I): To a stirred solution of the above residue of H in THF
(10 mL), t-BuOH (5 mL) and H.sub.2O (5 mL) at 25.degree. C. was
added NaH.sub.2PO.sub.4.H.sub.2O (2.55 g, 18.5 mmol),
2-methyl-butene (5 mL) and sodium chlorite (1.64 g, 18.5 mmol).
After stirring at this temperature for 2 h, the reaction was
diluted with H.sub.2O (50 mL). The resulting mixture was extracted
with CH.sub.2Cl.sub.2 (2.times.50 mL), the combined organic phases
were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure to provide the title compound. The crude product
of I was used in the next step without further purification.
[1322] 3-(5H-Pyrido[4,3-b]indol-7-yl)propanoic acid (J): A solution
of the crude product of I in CH.sub.2Cl.sub.2 (12 mL) and TFA (6
mL) was stirred at 25.degree. C. for 12 h before it was
concentrated under reduced pressure. The residue was dissolved in
NaOH (0.5 M, aq., 20 mL) and was extracted with CH.sub.2Cl.sub.2
(4.times.15 mL). The water phase was added HCl (aq., 1.0 M)
dropwise to adjust the pH to 6-7. The resulting mixture was
extracted with CHCl.sub.3/i-PrOH (4/1, 3.times.30 mL), the combined
organic phases were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure to afford the title compound
(357 mg, 1.48 mmol, 73% yield over 3 steps).
Preparation of Exemplary Compounds
N-(6-02-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-3--
(5H-pyrido[4,3-b]indol-7-yl)propanamide (1; QC-01-178))
##STR00190##
[1324]
N-(6-42-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)he-
xyl)-3-(5H-pyrido[4,3-b]indol-7-yl)propanamide (1): To a stirred
solution of carboxylic acid J (6.8 mg, 0.02 mmol), EDCI (11.5 mg,
0.06 mmol), DMAP (2.2 mg, 0.02 mmol) and DIPEA (14.3 mg, 0.12 mmol)
in CH.sub.2Cl.sub.2 (0.6 mL) at 25.degree. C. was added
4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
(K) (9.7 mg, 0.26 mmol). The resulting reaction mixture was stirred
at this temperature for 4 h, and then concentrated under reduced
pressure. The residue was purified by reverse-phase HPLC to give
the title compound as the TFA salt (9.6 mg, 0.014 mmol, 70% yield).
.sup.1H NMR (500 MHz, DMSO) .delta. 13.03 (s, 1H), 11.10 (s, 1H),
9.68 (s, 1H), 8.61 (d, J=6.8 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.96
(d, J=6.7 Hz, 1H), 7.80 (t, J=5.6 Hz, 1H), 7.59 (s, 1H), 7.57 (dd,
J=8.5, 7.2 Hz, 1H), 7.36 (dd, J=8.2, 1.0 Hz, 1H), 7.03 (d, J=3.9
Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.46 (t, J=5.1 Hz, 1H), 5.05 (dd,
J=12.8, 5.4 Hz, 1H), 3.20 (dd, J=12.4, 6.5 Hz, 2H), 3.06-3.00 (m,
4H), 2.89 (ddd, J=17.0, 13.9, 5.4 Hz, 1H), 2.66-2.52 (m, 2H), 2.48
(t, J=7.6 Hz, 2H), 2.06-2.01 (m, 1H), 1.49-1.43 (m, 2H), 1.37-1.31
(m, 2H), 1.29-1.23 (m, 2H), 1.22-1.16 (m, 2H).
[1325] Example compounds 2-7 were prepared in an analogous manner
to compound 1, employing the corresponding amine starting materials
and carboxylic acid J.
TABLE-US-00003 Structure/Name Characterization 2 ##STR00191##
.sup.1H NMR (500 MHz, DMSO) .delta. 13.00 (s, 1H), 11.08 (s, 1H),
9.65 (s, 1H), 8.61 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H),
7.95 (d, J = 6.7 Hz, 1H), 7.88 (t, J = 5.6 Hz, 1H), 7.58 (s, 1H),
7.55 (dd, J = 8.4, 7.2 Hz, 1H), 7.34 (dd, J = 8.2, 1.0 Hz, 1H),
7.06 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.53 (t, J =
5.6 Hz, 1H), 5.02 (dd, J = 12.9, 5.4 Hz, 1H), 3.54 (t, J = 5.4 Hz,
2H), 3.42 (t, J = 5.8 Hz, 2H), 3.39-3.36 (m, 2H), 3.23-3.19 (m,
2H), 3.04 (t, J = 7.5 Hz, 2H), 2.83 (ddd, J = 17.4, 14.1, 5.3 Hz,
1H), 2.56- 2.48 (m, 4H), 2.02-1.97 (m, 1H). 3 ##STR00192## .sup.1H
NMR (500 MHz, DMSO) .delta. 13.04 (s, 1H), 11.09 (s, 1H), 9.67 (s,
1H), 8.62 (d, J = 6.6 Hz, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.96 (d, J
= 6.7 Hz, 1H), 7.90 (t, J = 5.6 Hz, 1H), 7.58 (s, 1H), 7.56 (dd, J
= 8.3, 7.4 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.11 (d, J = 8.6 Hz,
1H), 7.01 (d, J = 7.0 Hz, 1H), 6.57 (t, J = 5.7 Hz, 1H), 5.05 (dd,
J = 12.7, 5.4 Hz, 1H), 3.58 (t, J = 5.7 Hz, 2H), 3.52- 3.50 (m,
2H), 3.47-3.42 (m, 6H), 3.20-3.17 (m, 2H), 3.03 (t, J = 7.6 Hz,
2H), 2.87 (ddd, J = 16.9, 13.8, 5.3 Hz, 1H), 2.60-2.55 (m, 1H),
2.54-2.47 (m, 3H), 2.01 (ddd, J = 10.0, 6.7, 4.0 Hz, 1H). 4
##STR00193## .sup.1H NMR (500 MHz, DMSO) .delta. 13.02 (s, 1H),
11.09 (s, 1H), 9.67 (s, 1H), 8.62 (d, J = 6.7 Hz, 1H), 8.32 (d, J =
8.1 Hz, 1H), 7.96 (d, J = 6.7 Hz, 1H), 7.91 (t, J = 5.6 Hz, 1H),
7.59 (s, 1H), 7.56 (dd, J = 8.4, 7.2 Hz, 1H), 7.34 (d, J = 9.0 Hz,
1H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.57 (br
s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.60 (t, J = 5.4 Hz, 2H),
3.55-3.53 (m, 2H), 3.50-3.48 (m, 2H), 3.46-3.42 (m, 6H), 3.35 (t, J
= 5.8 Hz, 2H), 3.19-3.16 (m, J = 5.7 Hz, 2H), 3.03 (t, J = 7.6 Hz,
2H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.60-2.56 (m, 1H),
2.54-2.47 (m, 3H), 2.06-1.96 (m, 1H). 5 ##STR00194## .sup.1H NMR
(500 MHz. DMSO) .delta. 13.01 (s, 1H), 9.67 (s, 1H), 8.62 (d, J =
6.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 6.7 Hz, 1H),
7.91 (t, J = 5.6 Hz, 1H), 7.59 (s, 1H), 7.56 (dd, J = 8.5, 7.2 Hz,
1H), 7.35 (dd, J = 8.2, 1.1 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02
(d, J = 6.9 Hz, 1H), 6.58 (t, J = 5.7 Hz, 1H), 5.05 (dd, J = 12.8,
5.4 Hz, 1H), 3.60 (t, J = 5.5 Hz, 2H), 3.56- 3.54 (m, 2H),
3.52-3.37 (m, 16H), 3.35 (t, J = 5.9 Hz, 3H), 3.20- 3.16 (m, 2H),
3.04 (t, J = 7.6 Hz, 2H), 2.91-2.84 (m, 1H), 2.60-2.60 (m, 1H),
2.53-2.47 (m, 3H), 2.04-2.00 (m, 1H). 6 ##STR00195## .sup.1H NMR
(500 MHz, DMSO) .delta. 13.03 (s, 1H), 11.09 (s, 1H), 9.67 (s, 1H),
8.62 (d, J = 6.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.97 (d, J =
6.7 Hz, 1H), 7.92 (t, J = 5.6 Hz, 1H), 7.59 (s, 1H), 7.57 (dd, J =
9.5, 8.2 Hz, 1H), 7.35 (dd, J = 8.2, 1.1 Hz, 1H), 7.13 (d, J = 8.6
Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.05
(dd, J = 12.8, 5.4 Hz, 1H), 3.61 (t, J = 5.4 Hz, 2H), 3.56-3.54 (m,
2H), 3.52-3.43 (m, 20H), 3.35 (t, J = 5.8 Hz, 2H), 3.20-3.16 (m,
1H), 3.04 (t, J = 7.6 Hz, 1H), 2.88 (ddd, J = 16.9, 13.8, 5.4 Hz,
1H), 2.60-2.56 (m, 1H), 2.54- 2.47 (m, 3H), 2.04-1.99 (m, 1H). 7
##STR00196## .sup.1H NMR (500 MHz, DMSO) .delta. 13.02 (s, 1H),
11.09 (s, 1H), 9.68 (s, 1H), 8.62 (d, J = 6.7 Hz, 1H), 8.32 (d, J =
8.1 Hz, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.92 (t, J = 5.6 Hz, 1H),
7.59 (s, 1H), 7.57 (dd, J = 8.6, 7.3 Hz, 1H), 7.35 (d, J = 8.1 Hz,
1H), 7.13 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.59 (br
s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.61 (t, J = 5.4 Hz, 2H),
3.57-3.55 (m, 2H), 3.53-3.43 (m, 36H), 3.35 (t, J = 5.8 Hz, 2H),
3.18 (q, J = 5.7 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H), 2.88 (ddd, J =
16.9, 13.8, 5.4 Hz, 1H), 2.60-2.56 (m, 1H), 2.52 (dd, J = 18.3,
13.8 Hz, 3H), 2.04-2.00 (m, 1H).
(2S,4R)-1-[(2S)-3,3-Dimethyl-2-(3-{2-[2-(3-{5H-pyrido[4,3-b]indol-7-yl}pro-
panamido)ethoxy]ethoxy}propanamido)butanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-met-
hyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-earboxamide (8;
FMF-05-129-1)
##STR00197##
[1327] (M): To a stirred solution of carboxylic acid 10 (30 mg,
0.125 mmol), HATU (53 mg, 1.38 mmol) and DIPEA (70 .mu.L, 0.375
mmol) in DMF (5 mL) at 25.degree. C. was added the corresponding
primary amine (33 mg, 0.138 mmol). The reaction mixture was stirred
for 16 h, diluted with 0.1 N aqueous NaOH (15 mL) and extracted
with CH.sub.2Cl.sub.2(3.times.20 mL). The combined organic phases
were dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (0-5% MeOH in DCM) to give compound M (18 mg, 0.040
mmol, 32% yield). MS (ESI) m/z 456 (M+H).sup.+
[1328] (N): A solution of M (18 mg, 0.04 mmol) in CH.sub.2Cl.sub.2
(2 mL) and TFA (1 mL) was stirred at 25.degree. C. for 12 h before
it was concentrated under reduced pressure to give compound N (20
mg, 0.04 mmol, quant. yield). MS (ESI) m/z 400 (M+H).sup.+
[1329]
(2S,4R)-1-[(2S)-3,3-Dimethyl-2-(3-{2-[2-(3-{5H-pyrido[4,3-b]indol-7-
-yl}propanamido)ethoxy]ethoxy}propanamido)butanoyl]-4-hydroxy-N-[(1S)-1-[4-
-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
(8): Compound O (25 mg, 0.06 mmol) was added to a stirred solution
of carboxylic acid N (20 mg, 0.04 mmol), HATU (27 mg, 0.07 mmol)
and DIPEA (35 .mu.L, 0.18 mmol) in DMF (2 mL) at 25.degree. C. The
reaction mixture was stirred for 16 h, diluted with saturated
aqueous NaHCO.sub.3 (15 mL) and extracted with CH.sub.2Cl.sub.2
(3.times.20 mL). The combined organic phases were dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure.
The residue was purified by reverse-phase HPLC to give compound 8
(FMF-05-129-1) (10 mg, 0.01 mmol, 25% yield). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .beta. 9.67 (s, 1H), 8.99 (s, 1H), 8.82 (d, J=6.1 Hz,
1H), 8.37 (dd, J=9.9, 7.9 Hz, 2H), 7.97 (t, J=5.6 Hz, 1H), 7.86 (d,
J=9.3 Hz, 1H), 7.75 (d, J=6.1 Hz, 1H), 7.49 (dd, J=8.1, 1.3 Hz,
1H), 7.44 (dd, J=8.2, 1.7 Hz, 3H), 7.40-7.37 (m, 3H), 4.91 (h,
J=7.0 Hz, 1H), 4.50 (dd, J=26.0, 9.0 Hz, 1H), 4.43 (t, J=8.1 Hz,
1H), 4.36-4.25 (m, 2H), 3.66-3.56 (m, 3H), 3.54 (s, 6H), 3.51-3.35
(m, 6H), 3.21 (q, J=5.8 Hz, 2H), 3.09 (t, J=7.6 Hz, 2H), 2.82 (s,
5H), 2.59-2.52 (m, 2H), 2.46 (s, 4H), 2.34 (dt, J=14.8, 6.2 Hz,
1H), 2.19-1.97 (m, 1H), 1.76 (dddd, J=38.8, 13.3, 8.9, 4.4 Hz, 1H),
1.38 (d, J=7.0 Hz, 4H), 1.07 (s, 4H), 0.93 (d, J=5.1 Hz, 9H). MS
(ESI) m/z 827 (M+H).sup.+
[1330] Example compounds 9-14 were prepared in an analogous manner
to compound 8, employing the corresponding amine starting materials
and carboxylic acid J.
TABLE-US-00004 Structure/Name Characterization 9 ##STR00198##
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.02 (s, 1H), 9.69 (s,
1H), 8.99 (s, 1H), 8.63 (d, J = 6.8 Hz, 1H), 8.36 (dd, J = 20.7,
7.9 Hz, 2H), 7.98 (d, J = 6.7 Hz, 1H), 7.93 (t, J = 5.6 Hz, 1H),
7.86 (d, J = 9.3 Hz, 1H), 7.60 (s, 1H), 7.47-7.41 (m, 2H), 7.41-
7.30 (m, 3H), 4.92 (p, J = 7.0 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H),
4.43 (t, J = 8.1 Hz, 1H), 4.29 (d, J = 4.4 Hz, 1H), 3.59 (dddd, J =
18.5, 15.9, 7.8, 5.3 Hz, 4H), 3.51-3.38 (m, 8H), 3.37 (t, J = 5.9
Hz, 2H), 3.25- 3.14 (m, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.46 (s,
3H), 2.35 (dt, J = 14.7, 6.1 Hz, 1H), 2.06-1.97 (m, 1H), 1.80 (ddd,
J = 12.9, 8.5, 4.6 Hz, 1H), 1.37 (d, J = 7.0 Hz, 3H), 0.93 (d, J =
5.1 Hz, 9H). MS (ESI) m/z 871 (M + H).sup.+ FMF-05-129-2
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[3-(2-{2-[2-(3-{5H-pyrido[4,3-b]indol-7-
yl}propanamido)ethoxy]ethoxy}ethoxy)propanamido]butanoyl]-4-hydroxy-N
[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxam-
ide 10 ##STR00199## .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
13.04 (s, 1H), 9.69 (s, 1H), 8.99 (s, 1H), 8.68-8.56 (m, 1H), 8.36
(dd, J = 21.4, 7.9 Hz, 2H), 7.98 (d, J = 6.8 Hz, 1H), 7.95-7.80 (m,
2H), 7.65-7.55 (m, 1H), 7.48-7.30 (m, 5H), 4.92 (p, J = 7.0 Hz,
1H), 4.53 (d, J = 9.4 Hz, 1H), 4.43 (t, J = 8.1 Hz, 1H), 4.28 (s,
1H), 3.65- 3.55 (m, 4H), 3.55-3.41 (m, 14H), 3.41-3.31 (m, 2H),
3.19 (qd, J = 5.7, 2.1 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.95 (s,
3H), 2.79 (s, 3H), 2.46 (d, J = 2.8 Hz, 3H), 2.38- 2.26 (m, 1H),
2.02 (td, J = 9.5, 8.2, 4.5 Hz, 1H), 1.96 (s, 3H), 1.80 (ddd, J =
12.9, 8.5, 4.6 Hz, 1H), 1.47 (s, 1H), 1.43-1.32 (m, 3H), 0.94 (s,
9H). MS (ESI) m/z 915 (M + H).sup.+ FMF-05-129-3
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[1-(3-{5H-pyrido[4,3-b]indol-7-yl}propanam-
ido)-
3,6,9,12-tetraoxapentadecan-15-amido]butanoyl]-4-hydroxy-N-[(1S)-
1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
11 ##STR00200## .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.80
(s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.90 (d, J = 6.3 Hz, 1H), 8.47
(d, J = 7.6 Hz, 1H), 8.39 (dd, J = 15.6, 7.9 Hz, 2H), 7.97 (t, J =
5.7 Hz, 1H), 7.88 (dd, J = 20.7, 7.8 Hz, 2H), 7.53 (dd, J = 8.1,
1.3 Hz, 1H), 7.45-7.43 (m, 4H), 7.39-7.35 (m, 3H), 6.96 (d, J = 6.0
Hz, 1H), 4.97-4.84 (m, 2H), 4.57-4.39 (m, 3H), 4.37-4.25 (m, 2H),
4.19 (d, J = 6.1 Hz, 1H), 3.86 (d, J = 11.4 Hz, 1H), 3.61 (ddt, J =
14.1, 11.1, 2.7 Hz, 3H), 3.55 (s, 6H), 3.52-3.46 (m, 15H),
3.43-3.37 (m, 2H), 3.26-3.19 (m, 2H), 3.10 (t, J = 7.6 Hz, 2H),
2.83 (s, 6H), 2.59-2.52 (m, 2H), 2.46 (s, 5H), 2.35 (dt, J = 14.6,
6.1 Hz, 1H), 2.15 (dd, J = 13.1, 8.0 Hz, 1H), 2.02 (ddd, J = 12.2,
8.2, 2.2 Hz, 1H), 1.76 (dddd, J = 38.8, 13.2, 8.9, 4.4 Hz, 1H),
1.38 (dd, J = 7.0, 1.7 Hz, 5H), 1.07 (s, 5H), 0.93 (d, J = 6.0 Hz,
9H). MS (ESI) m/z 959 (M + H).sup.+ 12 ##STR00201## .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 11.11 (s, 1H), 9.81 (s, 1H), 9.00
(d, J = 3.3 Hz, 1H), 8.91-8.85 (m, 1H), 8.40 (dd, J = 14.9, 7.9 Hz,
2H), 8.01 (t, J = 5.6 Hz, 1H), 7.88 (dd, J = 20.0, 7.8 Hz, 2H),
7.55- 7.46 (m, 1H), 7.45-7.42 (m, 2H), 7.39 (dq, J = 8.7, 2.2 Hz,
2H), 4.96-4.87 (m, 1H), 4.56-4.46 (m, 1H), 4.43 (t, J = 8.0 Hz,
1H), 4.30- 4.23 (m, 1H), 3.55 (s, 5H), 3.52- 3.42 (m, 14H), 3.38
(t, J = 5.8 Hz, 1H), 3.21 (d, J = 5.0 Hz, 2H), 3.15 (d, J = 20.9
Hz, 2H), 3.10 (t, J = 7.6 Hz, 1H), 2.83 (s, 5H), 2.46 (s, 3H),
1.41-1.34 (m, 4H), 1.00 (s, 3H), 0.94 (s, 9H). MS (ESI) m/z 1003 (M
+ H).sup.+ FMF-05-129-5
(2S,4R)-1-[(2S)-3,3-dimethyl-2-[1-(3-{5H-pyrido[4,3-b]indol-7-yl}propanam-
ido)-
3,6,9,12,15,18-hexaoxahenicosan-21-amido]butanoyl]-4-hydroxy-N-[(1S)-
1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
13 ##STR00202## .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.05
(s, 1H), 9.69 (s, 1H), 8.99 (s, 1H), 8.63 (d, J = 6.8 Hz, 1H), 8.37
(d, J = 7.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 6.7 Hz,
1H), 7.84-7.74 (m, 2H), 7.59 (s, 1H), 7.45-7.42 (m, 2H), 7.40-7.36
(m, 3H), 4.92 (p, J = 7.2 Hz, 1H), 4.51 (d, J = 9.3 Hz, 1H), 4.43
(t, J = 8.0 Hz, 1H), 4.29 (s, 1H), 4.07-3.96 (m, 2H), 3.07-2.98 (m,
5H), 2.55 (s, 1H), 2.46 (d, J = 2.3 Hz, 4H), 2.25-2.16 (m, 1H),
2.10-1.95 (m, 3H), 1.80 (ddd, J = 12.8, 8.5, 4.6 Hz, 1H), 1.38 (dd,
J = 6.8, 3.8 Hz, 5H), 1.24 (s, 3H), 1.08-0.97 (m, 3H), 0.93 (s,
9H). MS (ESI) m/z 809 (M + H).sup.+ FMF-06-066-1
(2S,4R)-1-((S)-2-(8-(3-(5H-pyrido[4,3-b]indol-7-yl)propanamido)octanamido-
)-3,3- dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-
yl)phenyl)ethyl)pyrrolidine-2-carboxamide 14 ##STR00203## .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 13.07 (s, 1H), 9.68 (s, 1H),
8.99 (d, J = 6.4 Hz, 2H), 8.62 (d, J = 6.8 Hz, 1H), 8.33 (d, J =
8.2 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.99-7.96 (m, 2H), 7.59 (s,
1H), 7.44 (d, J = 3.5 Hz, 4H), 7.38-7.33 (m, 1H), 4.92 (dt, J =
14.5, 7.1 Hz, 2H), 4.45-4.27 (m, 4H), 3.38-3.31 (m, 2H), 3.04 (t, J
= 7.8 Hz, 2H), 2.79 (s, 2H), 2.47-2.43 (m, 5H), 2.29 (dt, J = 13.4,
6.2 Hz, 2H), 2.11-1.86 (m, 4H), 1.31 (d, J = 7.2 Hz, 3H), 1.24 (s,
3H), 1.10 (t, J = 7.0 Hz, 1H), 1.00 (d, J = 2.1 Hz, 5H), 0.96 (d, J
= 3.1 Hz, 9H). MS (ESI) m/z 871 (M + H).sup.+ FMF-06-064-1
(2R,4S)-1-((S)-2-(tert-butyl)-4,17-dioxo-19-(5H-pyrido[4,3-b]indol-7-yl)--
7,10,13-
trioxa-3,16-diazanonadecanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-
5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide
2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]oxy-
}-N-{2-[2-(2-{2-[(5-{5H-pyrido[4,3-b]indol-7-yl}pyridin-2-yl)oxy]acetamido-
}ethoxy)ethoxy]ethyl}acetamide (15; FMF-05-183-1)
##STR00204## ##STR00205##
[1332] (R): Compound P (500 mg, 2.02 mmol), compound Q (655 mg,
2.23 mmol), NaHCO.sub.3 (510 mg, 6.06 mmol), and
Pd(dppf).sub.2Cl.sub.2 (70 mg) in MeCN and H.sub.2O (4:1, 10 mL)
were stirred at 90.degree. C. for 30 min. The reaction mixture was
cooled to r.t., diluted with H.sub.2O (50 mL), and extracted with
DCM (3.times.100 mL). The organics were combined and concentrated
in vacuo. The resulting solid was washed with cold DCM (3 mL) to
afford compound R as a white powder, which was used without further
purification (340 mg, 1.02 mmol, 51%). MS (ESI) m/z 334
(M+H).sup.+
[1333] (S): Compound R (340 mg, 1.02 mmol) was dissolved in MeCN (1
mL) and 1 N aqueous NaOH (1 mL), and stirred at 60.degree. C. for
16 h. The reaction mixture was cooled to 0.degree. C. and acidified
to pH 5 with conc. HCl (36%). The resulting precipitate was
filtered off to afford the compound S as a white solid which was
used without further purification. (309 mg, 0.97 mmol, 95%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 9.58 (s, 1H), 8.62 (d,
J=4.3 Hz, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.42 (d, J=8.2 Hz, 2H), 8.16
(dd, J=8.8, 2.6 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=6.1 Hz, 1H), 7.66
(d, J=8.3 Hz, 1H), 7.41 (dd, J=8.4, 4.3 Hz, 1H), 7.03 (d, J=8.6 Hz,
1H), 4.89 (s, 2H). MS (ESI) m/z 320 (M+H).sup.+
[1334] (U): Compound S (50 mg, 0.15 mmol), compound T (42 mg, 0.17
mmol), HATU (72 mg, 0.19 mmol), DIPEA (61 uL, 0.47 mmol), and DMF
(3 mL) were stirred at 60.degree. C. for 30 mins, cooled to r.t.
and stirred for 16 h. The reaction mixture was diluted with sat.
aq. NaHCO.sub.3 (30 mL) and extracted with DCM (3.times.50 mL). The
combined organic phases were dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. The residue was purified
by flash column chromatography (0-15% MeOH in DCM) to afford
compound U (36 mg, 0.065 mmol, 44%). .sup.1H NMR (500 MHz,
Methanol-d.sub.4) .delta. 9.20 (s, 1H), 8.43 (d, J=2.5 Hz, 1H),
8.37 (d, J=5.8 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 8.03 (dd, J=8.6,
2.6 Hz, 1H), 7.67 (d, J=1.4 Hz, 1H), 7.50-7.45 (m, 2H), 7.02 (d,
J=8.6 Hz, 1H), 3.58 (dd, J=6.6, 4.4 Hz, 6H), 3.48 (q, J=5.4 Hz,
4H), 3.37 (s, 2H), 3.33 (p, J=1.7 Hz, 1H), 3.21 (t, J=5.8 Hz, 2H),
1.42 (s, 9H). MS (ESI) m/z 550 (M+H).sup.+
[1335] (V): Compound U (41 mg, 0.07 mmol), TFA (1 mL) and DCM (1
mL) were stirred at r.t. for 2 h. The reaction mixture was
concentrated under reduced pressure to afford compound V as a TFA
salt (42 mg, 0.07 mmol) which was used without further
purification. MS (ESI) m/z 450 (M+H).sup.+
[1336]
2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-
-yl]oxy}-N-{2-[2-(2-{2-[(5-{5H-pyrido[4,3-b]indol-7-yl}pyridin-2-yl)oxy]ac-
etamido}ethoxy)ethoxy]ethyl}acetamide: Compound V (42 mg, 0.07
mmol), compound W (27 mg, 0.08 mmol), HATU (32 mg, 0.08 mmol), and
DIPEA (40 uL, 0.21 mmol) were stirred in DMF (1 mL) at r.t. for 16
h. The reaction mixture was filtered and purified by HPLC to afford
compound 15 (FMF-05-183-1) as a TFA salt (35 mg, 0.04, 54%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.24 (s, 1H), 11.12
(s, 1H), 9.76 (s, 1H), 8.67 (d, J=6.7 Hz, 1H), 8.59 (d, J=2.6 Hz,
1H), 8.52 (d, J=8.2 Hz, 1H), 8.21 (dd, J=8.6, 2.6 Hz, 1H), 8.09 (t,
J=5.7 Hz, 1H), 8.04-7.99 (m, 3H), 7.81-7.77 (m, 2H), 7.47 (d, J=7.2
Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 5.11 (dd,
J=12.8, 5.5 Hz, 1H), 4.79 (d, J=11.1 Hz, 4H), 3.52 (s, 4H), 3.46
(dt, J=7.9, 5.8 Hz, 4H), 3.30 (dq, J=17.7, 5.8 Hz, 4H), 2.94-2.83
(m, 1H), 2.62-2.56 (m, 1H), 2.04 (dtd, J=13.0, 5.4, 2.3 Hz, 1H),
1.30-1.16 (m, 1H). MS (ESI) m/z 765 (M+H).sup.+
[1337] Example compounds 16-18 were prepared in an analogous manner
to compound 15, employing the corresponding amine starting
materials and carboxylic acid S.
TABLE-US-00005 Structure/Name Characterization 16 ##STR00206##
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.20 (s, 1H), 11.11
(s, 1H), 9.75 (s, 1H), 8.66 (d, J = 6.6 Hz, 1H), 8.58 (d, J = 2.6
Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.19 (dd, J = 8.6, 2.6 Hz, 1H),
8.08 (t, J = 5.7 Hz, 1H), 8.03- 7.97 (m, 3H), 7.81-7.77 (m, 2H),
7.46 (d, J = 7.3 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.06 (d, J =
8.6 Hz, 1H), 5.11 (dt, J = 12.6, 5.2 Hz, 1H), 4.79 (d, J = 8.5 Hz,
4H), 3.47 (t, J = 5.8 Hz, 4H), 3.31 (p, J = 5.9 Hz, 4H), 2.89 (ddd,
J = 16.7, 13.7, 5.4 Hz, 1H), 2.63-2.56 (m, 1H), 2.06-2.00 (m, 1H),
1.22-1.11 (m, 1H). MS (ESI) m/z 721 (M + H).sup.+ 17 ##STR00207##
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.20 (s, 1H), 11.12
(s, 1H), 9.75 (s, 1H), 8.66 (d, J = 6.7 Hz, 1H), 8.60 (d, J = 2.7
Hz, 1H), 8.51 (d, J = 8.2 Hz, 1H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H),
8.09 (t, J = 5.8 Hz, 1H), 8.04- 7.94 (m, 3H), 7.82-7.72 (m, 2H),
7.48 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.07 (d, J =
8.7 Hz, 1H), 5.15- 5.07 (m, 1H), 4.79 (d, J = 11.4 Hz, 4H), 3.50
(d, J = 4.6 Hz, 7H), 3.44 (t, J = 5.5 Hz, 3H), 3.29 (dq, J = 15.7,
5.8 Hz, 3H), 2.95-2.84 (m, 1H), 2.63-2.57 (m, 1H), 2.04 (ddd, J =
10.5, 5.7, 3.3 Hz, 1H), 1.22-1.15 (m, 3H). MS (ESI) m/z 709 (M +
H).sup.+ 18 ##STR00208## .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.11 (s, 1H), 9.71 (s, 1H), 8.64 (d, J = 6.7 Hz, 1H), 8.59
(d, J = 2.7 Hz, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.20 (dd, J = 8.6,
2.6 Hz, 1H), 8.07 (t, J = 5.7 Hz, 1H), 8.00-7.92 (m, 3H), 7.80-7.74
(m, 2H), 7.45 (d, J = 7.3 Hz, 1H), 7.36-7.33 (m, 1H), 7.08- 7.05
(m, 1H), 5.14-5.08 (m, 1H), 4.76 (d, J = 19.9 Hz, 3H), 3.19-3.10
(m, 4H), 2.90 (ddd, J = 18.5, 13.8, 5.4 Hz, 1H), 2.67-2.60 (m, 1H),
2.09-2.00 (m, 1H), 1.44 (d, J = 3.8 Hz, 4H), 1.22-1.10 (m, 2H). MS
(ESI) m/z 704 (M + H).sup.+
N-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4--
yl]amino}ethoxy)ethyl]-2-[(5-{5H-pyrido
[4,3-b]indol-7-yl}pyridirt-2-yl)oxy]acetamide (19;
FMF-05-167-1)
##STR00209##
[1339] The title compound was prepared in an analogous manner to
compound 1, employing the corresponding amine starting materials
and compound S. Compound S (50 mg, 0.15 mmol), the corresponding
amine (61 mg, 0.17 mmol), HATU (18 mg, 0.05 mmol), and DIPEA (30
uL, 0.15 mmol) were stirred in DMF (1 mL) at r.t. for 16 h. The
reaction mixture was filtered and purified by HPLC to afford
compound 19 (FMF-05-167-1) as a TFA salt (7 mg, 0.009, 23%).
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.19 (s, 1H), 11.09
(s, 1H), 9.77 (d, J=3.6 Hz, 1H), 8.68 (d, J=6.7 Hz, 1H), 8.59 (d,
J=2.6 Hz, 1H), 8.52 (dd, J=8.2, 4.4 Hz, 1H), 8.22-8.18 (m, 1H),
8.09 (t, J=5.7 Hz, 1H), 8.04-7.99 (m, 2H), 7.82-7.77 (m, 1H),
7.58-7.54 (m, 1H), 7.12 (d, J=8.6 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H),
7.01 (d, J=7.0 Hz, 1H), 6.60 (t, J=6.0 Hz, 1H), 5.09-4.98 (m, 1H),
4.81 (s, 1H), 3.66-3.57 (m, 4H), 3.54-3.43 (m, 4H), 3.31 (q, J=5.9
Hz, 1H), 3.15 (qd, J=7.4, 4.3 Hz, 2H), 2.60-2.54 (m, 1H), 2.06-1.97
(m, 1H), 1.35 (d, J=28.5 Hz, 1H). MS (ESI) m/z 663 (M+H).sup.+
[1340]
N-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-i-
soindol-4-yl]oxy}ethoxy)ethoxy]ethyl}-3-{5H-pyrido
[4,3-b]indol-7-yl}propanamide (20; FMF-06-038-1)
##STR00210##
[1341] (AA): Compound X (100 mg, 0.61mmol), compound Y (256 mg,
0.92 mmol), and Et.sub.3N (430 uL, 3.06 mmol) were stirred in DMF
(2 mL) at 90.degree. C. for 16 h. The reaction mixture was cooled
to room temperature and filtered. The precipitate was washed with
EtOAc (20 mL) and the combined filtrate and organics were
concentrated under reduced pressure to 2 mL volume. Et.sub.3N (430
uL, 3.06 mmol) and compound Z (250 mg, 0.53 mmol) were added to the
concentrated filtrates and the reaction mixture heated at
90.degree. C. for 3 h. The reaction was concentrated under reduced
pressure and purified by flash chromatography to afford the title
compound (270 mg, 0.57 mmol, 93%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 11.10 (s, 1H), 7.82 (dd, J=8.5, 7.2 Hz, 1H),
7.56-7.51 (m, 1H), 7.46 (d, J=7.2 Hz, 1H), 6.77-6.70 (m, 1H), 5.09
(dd, J=12.8, 5.5 Hz, 1H), 4.37-4.33 (m, 2H), 3.84-3.79 (m, 2H),
3.64 (dd, J=5.8, 3.8 Hz, 2H), 3.54-3.48 (m, 4H), 3.37 (d, J=6.2 Hz,
2H), 3.06 (q, J=5.8 Hz, 3H), 2.60 (ddd, J=17.0, 4.4, 2.4 Hz, 1H),
2.03 (dtd, J=13.0, 5.3, 2.2 Hz, 1H), 1.36 (s, 9H). MS (ESI) m/z 506
(M+H).sup.-
[1342] (BB): Compound AA (156 mg, 0.31 mmol) was dissolved in 2 mL
DCM and 2 mL TFA, and stirred at r.t. for 2 h. The reaction mixture
was concentrated under reduced pressure to afford the compound BB
(161mg, 0.31 mmol, 100%), which was used without further
purification. MS (ESI) m/z 406 (M+H).sup.+
[1343]
N-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-i-
soindol-4-yl]oxy}ethoxy)ethoxy]ethyl}-3-{5H-pyrido[4,3-b]indol-7-yl}propan-
amide: Compound BB (10 mg, 0.042 mmol), Compound J (24 mg, 0.046
mmol), HATU (20 mg, 0.05 mmol), and DIPEA (26 uL, 0.126 mmol) were
dissolved in DMF (2 mL) and stirred at r.t. for 4 h. The reaction
mixture was filtered and purified by HPLC to afford compound 20
(FMF-06-038-1) as a TFA salt. (3 mg, 0.004 mmol, 10%). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 13.05 (s, 1H), 11.10 (s, 1H), 9.68
(s, 1H), 8.62 (d, J=6.7 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 7.97 (d,
J=6.7 Hz, 1H), 7.93 (q, J=5.6 Hz, 1H), 7.81-7.77 (m, 1H), 7.59 (d,
J=4.2 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.45-7.41 (m, 1H), 7.37-7.32
(m, 1H), 5.08 (dd, J=12.8, 5.3 Hz, 1H), 4.33-4.27 (m, 2H),
3.64-3.59 (m, 6H), 3.17-3.13 (m, 6H), 3.07-3.02 (m, 2H), 2.90-2.84
(m, 2H), 2.61-2.57 (m, 1H), 2.06-2.01 (m, 1H). MS (ESI) m/z 626
(M-H).sup.-
[1344] Example compounds 21-24 were prepared in an analogous manner
to compound 20, employing the corresponding amine starting
materials and carboxylic acid J.
TABLE-US-00006 Structure/Name Characterization 21 ##STR00211##
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 13.04 (s, 1H), 11.10
(s, 1H), 9.67 (s, 1H), 8.61 (d, J = 6.7 Hz, 1H), 8.33 (d, J = 8.0
Hz, 1H), 7.97 (d, J = 6.6 Hz, 1H), 7.81 (dd, J = 8.4, 7.2 Hz, 1H),
7.70 (s, 1H), 7.60 (s, 1H), 7.46 (dd, J = 13.7, 7.9 Hz, 2H), 7.36
(dd, J = 8.3, 1.3 Hz, 1H), 5.08 (dd, J = 12.8, 5.5 Hz, 1H),
4.23-3.99 (m, 3H), 3.03 (dq, J = 12.4, 6.6, 5.9 Hz, 4H), 2.77 (d, J
= 12.2 Hz, 2H), 1.64 (t, J = 7.5 Hz, 1H), 1.53 (d, J = 7.2 Hz, 1H),
1.46 (dd, J = 15.6, 6.6 Hz, 1H), 1.37-1.33 (m, 5H), 1.23 (d, J =
11.1 Hz, 2H), 1.11-1.04 (m, 3H). MS (ESI) m/z 596 (M + H).sup.+ 22
##STR00212## MS (ESI) m/z 672 (M + H)+ FMF-06-050-2
N-(2-{2-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-
1H-isoindol-4-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl)-3-{5H-pyrido[4,3-
b]indol-7-yl}propanamide 23 ##STR00213## .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 12.98 (s, 1H), 11.10 (s, 1H), 9.66 (s, 1H),
8.61 (s, 1H), 8.32 (dd, J = 11.7, 8.1 Hz, 1H), 7.92 (t, J = 5.7 Hz,
1H), 7.80 (dd, J = 8.5, 7.3 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.5
Hz, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.33 (dd, J = 8.1, 1.4 Hz, 1H),
5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.33 (t, J = 4.7 Hz, 2H), 3.79 (t,
J = 4.6 Hz, 2H), 3.63 (dd, J = 5.8, 3.7 Hz, 2H), 3.58-3.41 (m,
13H), 3.18 (q, J = 5.7 Hz, 2H), 3.04 (t, J = 7.7 Hz, 2H), 2.06-1.99
(m, 0H), 1.26-1.23 (m, 2H), 1.18-0.82 (m, 2H). MS (ESI) m/z 716 (M
+ H)+ 24 ##STR00214## .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
13.12 (s, 1H), 11.10 (s, 1H), 9.66 (s, 1H), 8.60 (d, J = 6.8 Hz,
1H), 8.33 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 6.9 Hz, 1H), 7.85 (t, J
= 5.7 Hz, 1H), 7.79 (dd, J = 8.4, 7.3 Hz, 1H), 7.59 (s, 1H), 7.43
(dd, J = 7.9, 4.3 Hz, 2H), 7.35 (dd, J = 8.2, 1.4 Hz, 1H), 5.06
(dd, J = 12.7, 5.4 Hz, 1H), 4.07 (t, J = 6.4 Hz, 2H), 3.08-3.01 (m,
4H), 2.92-2.85 (m, 4H), 1.67 (p, J = 6.6 Hz, 2H), 1.41 (p, J = 6.9
Hz, 2H), 1.33 (p, J = 7.6 Hz, 1H), 1.29-1.21 (m, 4H). MS (ESI) m/z
582 (M + H)+
Tau Degradation Assays
[1345] Assays were performed to demonstrate the ability of the
exemplary compounds to degrade tau in human cells. Compounds
employed as controls in the experiments described below include the
following:
##STR00215##
[1346] Example compounds 1-12 were evaluated for their ability to
degrade tau protein in cultured human differentiated frontotemporal
lobar dementia (FTD) neurons. Several exemplary compounds
significantly degraded hyperphosphorylated tau and total tau in
human tau-A152T neurons (5-week differentiated) and tau-P301L
neurons (8-week differentiated) after treatment of the neurons with
the compounds for 24 hours (FIGS. 1, 2, and 8-10). For each
condition, 1 well of differentiated neuronal cells (6 well-plate)
was washed and collected in PBS, pelleted and lysed in RIPA buffer
(Boston Bio-Products) with 2% SDS (Sigma), protease inhibitors
(Roche Complete Mini tablets), and phosphatase inhibitors (Sigma),
followed by sonication in a water sonicator (Bransonic Ultrasonic
Baths, Thomas Scientific) for 5 min, and centrifugation at 20,000 g
for 15 min. Supernatants were transferred to new tubes, total
protein concentration was quantified with the Pierce BCA Protein
Assay Kit (Thermo), and SDS-PAGE gels were loaded with lOug total
protein per well (pre-boiled samples). Western blots were performed
with the Novex NuPAGE SDS-PAGE Gel System (Invitrogen). All samples
were resolved in 7% Tris-Acetate gels with Tris-Acetate running
buffer (Invitrogen). Blots were probed with antibodies against
total tau (TAUS) and phosphosrylated tau (Ser396), along with
.beta.-actin as a loading control; followed by corresponding
HRP-linked secondary antibodies (Cell Signaling Technology), and
SuperSignal West Pico Chemiluminescent Substrate (Thermo)
detection. Membranes were exposed to autoradiographic film
(LabScientific) and films were scanned using an Epson Perfection
V800 Photo Scanner. Protein band intensities (pixel mean intensity)
were quantified using Adobe Photoshop CS5 Histogram function.
Whereas the vehicle alone (DMSO) had no effect on tau, varying
degrading activity was observed amongst the compounds, however with
overall similar relative levels of degrading activity between
tau-A152T neurons and tau-P301L neurons. Compounds were added at
the doses indicated of either 0.1, 1, 5, or 10 .mu.M. Lenalidomide
(1 .mu.M or 10 .mu.M) was also evaluated as a control in some
experiments since it binds CRBN but should not engage tau, as
confirmed by having no effect on tau levels.
[1347] The effect of the tau binding moiety, T807, was also
evaluated in a control experiment since it should not recruit tau
to CRBN as it does not bind CRBN. Four-week differentiated neurons,
both non-mutant (8330-8) and tau-A152T (19-5-RC6) were employed.
The neurons were treated with T807 for 24 hours (at 10
.mu.g/mL=59.4 .mu.M). One well of differentiated neuronal cells (6
well-plate, treated or untreated) was washed and collected in PBS,
pelleted and directly lysed in 200 .mu.L of Sample Buffer (New
England Biolabs) supplemented with 3.times. DTT, boiled for 15 min
and 10 .mu.L of each lysate was run by SDS-PAGE in a 4-12% Bis-Tris
Gel, with MOPS running buffer. Blots were probed with antibodies to
total tau (DA9) and phosphorylated tau (Ser396, PHF1, AT8) along
with GAPDH as a loading control. The results of this experiment
showed that T807 had no effect on tau levels and did not degrade
tau (FIG. 3). Complementarily, FIG. 5 also showed no effect of T807
on tau and phosphorylated tau, when treated concomitantly with
other exemplary compounds at the same dose of 1 .mu.M.
[1348] Example compounds 2-5 were reevaluated for their ability to
degrade tau protein in human FTD neurons as well as evaluate their
effect on E3 ubiquitin ligases CRBN, VHL, and CHIP (FIG. 4A-E). For
each control and treatment, 1 well of differentiated neuronal cells
(6 well-plate) was washed and collected in PBS, pelleted and lysed
in RIPA buffer (Boston Bio-Products) with 2% SDS (Sigma), protease
inhibitors (Roche Complete Mini tablets), and phosphatase
inhibitors (Sigma), followed by sonication in a water sonicator
(Bransonic Ultrasonic Baths, Thomas Scientific) for 5 min, and
centrifugation at 20,000 g for 15 min. Supernatants were
transferred to new tubes, total protein concentration was
quantified with the Pierce BCA Protein Assay Kit (Thermo), and
SDS-PAGE gels were loaded with 10 pg total protein per well
(pre-boiled samples). Western blots were performed with the Novex
NuPAGE SDS-PAGE Gel System (Invitrogen), with gradient 4-12%
Bis-Tris gels with MOPS running buffer (Invitrogen). Blots were
probed with antibodies to CRBN, VHL, CHIP and total tau (TAUS),
along with (3-actin as a loading control; followed by corresponding
HRP-linked secondary antibodies (Cell Signaling Technology), and
SuperSignal West Pico Chemiluminescent Substrate (Thermo)
detection. Membranes were exposed to autoradiographic film
(LabScientific) and films were scanned using an Epson Perfection
V800 Photo Scanner. Protein band intensities (pixel mean intensity)
were quantified using Adobe Photoshop CS5 Histogram function.
Whereas the vehicle alone (DMSO) had no effect on tau, several of
the compounds significantly degraded hyperphosphorylated tau and
total tau in human tau-A152T neurons (5-week differentiated) and
tau-P301L neurons (8-week differentiated). Lenalidomide was also
evaluated as a control, and it had no effect on tau levels. In
addition, the exemplary compounds did not have an effect on CRBN,
but did have an effect on VHL and CHIP. The assay also confirmed
significant tau accumulation in A152T and P301L neurons. In FTD
neurons (A152T and P301L), tau accumulation leads to disruption of
specific proteostasis pathways, which include upregulation of CHIP
and VHL. For CHIP, the compounds with highest potency for tau
degradation also caused a decrease in CHIP levels. This may be an
indication that CRBN is a stable and useful target for degraders of
tau protein in human neurons.
[1349] Example compounds 2-5 were again evaluated in tau
degradation assays in non-mutant control, A152T and P301L neurons
(6-week differentiated). Non-mutant neurons were employed as a
negative control since derivatives of T807 should not recognize
non-disease states of tau based upon how the series was identified,
using selection for binding to pathological forms of tau in
post-mortem brain lysates and tissue slices. In addition, T807,
lenalidomide, and QC-03-075 were employed as controls along with
the vehicle (DMSO). As QC-03-075 does not bind to CRBN it should
act as a negative control. For each condition, 1 well of
differentiated neuronal cells (6 well-plate) was washed and
collected in PBS, pelleted and lysed in RIPA buffer (Boston
Bio-Products) with 2% SDS (Sigma), protease inhibitors (Roche
Complete Mini tablets), and phosphatase inhibitors (Sigma),
followed by sonication in a water sonicator (Bransonic Ultrasonic
Baths, Thomas Scientific) for 5 min, and centrifugation at 20,000 g
for 15 min. Supernatants were transferred to new tubes, total
protein concentration was quantified with the Pierce BCA Protein
Assay Kit (Thermo), and SDS-PAGE gels were loaded with 10 .mu.g
total protein per well (pre-boiled samples). Western blots were
performed with the Novex NuPAGE SDS-PAGE Gel System (Invitrogen)
and samples were resolved in 7% Tris-Acetate gels with Tris-Acetate
running buffer (Invitrogen). Blots were probed with antibodies to
total tau (TAU5), phospho-tau (S396) and CRBN along with GAPDH as a
loading control; followed by corresponding HRP-linked secondary
antibodies (Cell Signaling Technology), and SuperSignal West Pico
Chemiluminescent Substrate (Thermo) detection. Membranes were
exposed to autoradiographic film (LabScientific) and films were
scanned using an Epson Perfection V800 Photo Scanner. Protein band
intensities (pixel mean intensity) were quantified using Adobe
Photoshop CS5 Histogram function. Assay results again confirmed the
ability of the exemplary compounds to be effective degraders of
pathological forms of tau while having little effect on levels of
tau in non-mutant tau neurons (FIG. 5A-C). These results were
confirmed by three biological replicates (FIG. 5C).
[1350] Example compounds 2, 3, and 5 were evaluated to determine
time and dose-dependency effect on the degradation of tau in 6-week
differentiated A152T neurons (FIG. 6A-B). For each condition, one
well of differentiated neuronal cells (6 well-plate, treated or
untreated) was washed and collected in PBS, pelleted and directly
lysed in 150 .mu.L of Sample Buffer (New England Biolabs)
supplemented with 3.times. DTT, boiled for 15 min and 10 .mu.L of
each lysate was run by SDS-PAGE in a Novex NuPAGE SDS-PAGE System
(Invitrogen) with 7% Tris-Acetate gels and Tris-Acetate running
buffer (Invitrogen). Blots were probed with antibodies to total tau
(TAUS), and phospho-tau (S396), along with GAPDH as a loading
control; followed by HRP-linked secondary antibodies (Cell
Signaling Technology), and SuperSignal West Pico Chemiluminescent
Substrate (Thermo) detection. Membranes were exposed to
autoradiographic film (LabScientific) and films were scanned using
an Epson Perfection V800 Photo Scanner. Protein band intensities
(pixel mean intensity) were quantified using Adobe Photoshop CS5
Histogram function. Upon compound treatment, no toxicity or
detachment were detected. The results confirmed the findings of the
previous assays described above and showed that compounds 2 and 3
have a dose dependent effect on tau after treatment for 24
hours.
[1351] Example compounds 2, 3, and 5 were also evaluated for their
ability to rescue stress vulnerability in Al 52T neurons
differentiated for 8 weeks. QC-03-075 was employed as negative
control. Compound 3 showed that it is effective at rescuing stress
vulnerability caused by exposure of neurons to 10 .mu.M
.beta.-amyloid (1-42) peptide for 16 h, when these neurons were
pre-treated with Compound 3 for 8h prior to stress exposure (FIG.
7). The results also demonstrated that example Compounds 2, 3, and
5 had no effect on neuronal viability (FIG. 7) as for Silva et al.
(Stem Cell Reports, 2016, 7(3), 325-40; doi:
10.1016/j.stemcr.2016.08.001) reduction of viability due to
.beta.-amyloid (1-42) exposure is dependent on tau levels.
In Vivo Assay
[1352] To determine whether the compounds of the present disclosure
are capable of crossing the blood brain barrier (BBB), a key
property for use of these compounds as CNS therapeutics, compound 3
was administered to mice in a pharmacokinetic study of plasma and
brain tissue. A stable formulation compatible with chronic
administration was prepared prior to administration, and analytical
methods for measuring concentration of the compound in plasma and
brain tissue were developed. Mice were additionally monitored for
tolerability for up to 24 hours.
[1353] Animal Husbandry: Male CD-1 mice were group housed during a
2-3 day acclimation prior to the study at an animal room
environment with a controlled environment (target conditions:
temperature 18-26.degree. C., relative humidity 30-70%, 12 hours
artificial light and 12 hours dark). All animals had access to
Certified Rodent Diet and water ad libitum.
[1354] Formulation & Dosing: Compound 3 (QC-01-175) was
formulated at 5.00 mg/mL in 20% PEG400 in water producing a clear,
stable solution. For intraperitoneal (IP) dosing, the dose
formulation was administered with a dose volume determined by the
animals' body weight collected on the morning of dosing day.
[1355] Sample Collection & Processing:
[1356] Blood Samples: A blood sample (about 0.03 mL per time point)
was collected from each mouse into polypropylene tubes at each
timepoint. All blood samples were transferred into pre-chilled
commercial EDTA-K2 tubes or pre-chilled plastic microcentrifuge
tubes containing 2 .mu.L of EDTA-K2 as anti-coagulant and placed on
wet ice until centrifugation. Each collected blood sample was
centrifuged for 15 minutes at 4.degree. C. and 3000 g for plasma
collection. Plasma from each mouse was transferred into a
pre-labeled polypropylene tube in dry ice at each time point. After
terminal collection, all plasmas were stored at approximately
-80.degree. C. until bioanalysis.
[1357] Brain Samples: Whole brain was dissected at each designated
time point and rinsed twice cold in deionized water before
processing. They were then blotted on filter paper, weighed and
homogenized with 5-fold of cold 15 mM PBS/MeOH (V:V, 2:1) using
mechanical method. The samples were kept with ice water when
homogenizing, and further stored at -80.degree. C. until
bioanalysis.
[1358] Bioanalytical Method Development: A LC-MS/MS method was
developed and used for the quantitative determination of test
compound concentration in blood and brain with a calibration curve
applied to determine the limits of quantification.
[1359] In Vivo Sample Analysis: Plasma and brain concentration
versus time data along with C.sub.max, T.sub.max, T.sub.1/2, and
AUC(.sub.0-t) was analyzed by non-compartmental approaches using
the Phoenix WinNonlin 6 3 software program.
[1360] Results: As summarized in Table 3, Compound 3 was capable of
brain penetration when systemically administered to male CD-1 mice
via intraperitoneal injection (n=3 per group) at a dose of 30 mg/kg
in a vehicle of 20% PEG400/water. Additionally, mice were monitored
for up to 24 hours and no adverse effects were observed.
TABLE-US-00007 TABLE 3 In vivo pharmacokinetic profile of compound
3 Mean Plasma Mean Brain C.sub.max (ng/mL) 4640 56.4 T.sub.max (h)
1.00 0.500 T.sub.1/2 (h) 7.23 0.766 AUC.sub.0-last (ng h/mL) 6938
74.3
[1361] Compound 3 was well tolerated and is capable of crossing the
blood-brain barrier. The dose achieved in brain is within the
concentration range estimated from the ex vivo cellular studies to
allow efficient tau degradation.
Equivalents And Scope
[1362] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[1363] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[1364] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[1365] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *