U.S. patent application number 17/457733 was filed with the patent office on 2022-03-24 for fused thiophene compounds.
The applicant listed for this patent is BioTheryX, Inc.. Invention is credited to Kyle W.H. Chan, Aparajita Hoskote Chourasia, Paul E. Erdman, Leah M. Fung, Frank Mercurio, Robert W. Sullivan.
Application Number | 20220088025 17/457733 |
Document ID | / |
Family ID | 1000006009997 |
Filed Date | 2022-03-24 |
United States Patent
Application |
20220088025 |
Kind Code |
A1 |
Chan; Kyle W.H. ; et
al. |
March 24, 2022 |
FUSED THIOPHENE COMPOUNDS
Abstract
The present disclosure provides compounds that modulate protein
function, to restore protein homeostasis, and cell-cell adhesion.
The disclosure provides methods of modulating protein-mediated
diseases, such as cytokine-mediated diseases, disorders,
conditions, or responses. Compositions, including in combination
with other cytokine and inflammatory mediators, are provided.
Methods of treatment, amelioration, or prevention of diseases,
disorders, or conditions associated with a protein, are
provided.
Inventors: |
Chan; Kyle W.H.; (San Diego,
CA) ; Chourasia; Aparajita Hoskote; (San Diego,
CA) ; Erdman; Paul E.; (San Diego, CA) ; Fung;
Leah M.; (San Diego, CA) ; Mercurio; Frank;
(Rancho Santa Fe, CA) ; Sullivan; Robert W.;
(Vista, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BioTheryX, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000006009997 |
Appl. No.: |
17/457733 |
Filed: |
December 6, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16438244 |
Jun 11, 2019 |
11191769 |
|
|
17457733 |
|
|
|
|
62684495 |
Jun 13, 2018 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 495/04 20130101;
A61K 31/454 20130101; A61K 31/5377 20130101; A61P 35/02
20180101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61P 35/02 20060101 A61P035/02; A61K 31/454 20060101
A61K031/454; C07D 495/04 20060101 C07D495/04 |
Claims
1. A compound of Formula (I): ##STR00095## or a pharmaceutically
acceptable salt thereof, wherein Q.sub.1, Q.sub.2, and Q.sub.3, are
independently CR.sup.1, CR.sup.2, or --S--; wherein one of Q.sub.1,
Q.sub.2, and Q.sub.3 is --S--; one of Q.sub.1, Q.sub.2, and Q.sub.3
is CR.sup.1; and one of Q.sub.1, Q.sub.2, and Q.sub.3 is CR.sup.2;
each - - - is a carbon-carbon single bond, a carbon-carbon double
bond, or a carbon-sulfur single bond; R.sup.1 is H, deuterium,
hydroxyl, halogen, cyano, nitro, optionally substituted
C.sub.1-C.sub.6 alkoxy, optionally substituted C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, optionally
substituted amino, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), (C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, or optionally substituted
C.sub.3-C.sub.8 carbocyclyl; R.sup.2 is ##STR00096## R.sup.3 is H,
deuterium, an optionally substituted C.sub.1-C.sub.6 alkyl,
##STR00097## X is C.dbd.O, CHR.sup.4A, or CR.sup.4AR.sup.4B; each
R.sup.4A and R.sup.4B is independently H, deuterium, or
C.sub.1-C.sub.6 alkyl; X.sub.1 is H, deuterium, fluoro, or
C.sub.1-C.sub.6 alkyl; each of X.sub.A, X.sub.B, and X.sub.C is
independently a bond, (CH.sub.2).sub.m, (CF.sub.2).sub.m, O, S, and
NH; wherein none of X.sub.A--X.sub.B, X.sub.A--X.sub.C, or
X.sub.B--X.sub.C is a bond selected from N--N, N--O, N--S, O--N,
S--N, O--O, S--S, or N.dbd.N; wherein, not more than one of
X.sub.A, X.sub.B, and X.sub.C can be a bond; and wherein any
hydrogen of the (CH.sub.2).sub.m and NH groups can be substituted
by one or more R.sup.5; R.sup.5 is hydrogen, deuterium, halogen,
C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl; m is 1, 2, or
3; n is 0, 1, or 2; R.sup.6 is C.sub.6-C.sub.10 aryl, 5 to 10
membered heteroaryl, C.sub.3 to C.sub.8 carbocyclyl, or 3 to 10
membered heterocyclyl, each optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxyl, optionally substituted C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, amino(C.sub.1-C.sub.6 alkyl),
--C(.dbd.O)NR.sup.16aR.sup.16b, optionally substituted
C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl), optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10
aryl(C.sub.1-C.sub.6 alkyl), optionally substituted 5 to 10
membered heteroaryl, optionally substituted 5 to 10 membered
heteroaryl(C.sub.1-C.sub.6 alkyl), optionally substituted
heterocyclyl, and optionally substituted
heterocyclyl(C.sub.1-C.sub.6 alkyl); each R.sup.16a and R.sup.16b
is independently H or C.sub.1-C.sub.6 alkyl, or R.sup.16a and
R.sup.16b together with the nitrogen atom to which they are
attached form 5 or 6 membered heterocyclyl optionally substituted
with one or more R.sup.9; each R.sup.9 is independently
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, (C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, optionally substituted amino,
halogen, or cyano; or two geminal R.sup.9 form oxo (.dbd.O); and
each of R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and
R.sup.15 is independently H, an optionally substituted
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl; or R.sup.14
and R.sup.15 together with the nitrogen atom to which they are
attached form an optionally substituted 5 or 6 membered
heterocyclyl.
2. The compound of claim 1, having the structure of Formula (Ia),
(Ib), (Ic), (Id), (Ie), or (If): ##STR00098## or a pharmaceutically
acceptable salt thereof.
3. The compound of claim 1 or 2, wherein n is 1.
4. The compound of any one of claims 1 to 3, wherein X is
C.dbd.O.
5. The compound of any one of claims 1 to 3, wherein X is
CH.sub.2.
6. The compound of any one of claims 1 to 5, wherein X.sub.1 is
H.
7. The compound of any one of claims 1 to 6, wherein R.sup.3 is
H.
8. The compound of any one of claims 1 to 7, wherein R.sup.2 is
##STR00099## X.sub.B is a bond, O, S, or NR.sup.5E; each of
R.sup.5A, R.sup.5B, R.sup.5C, R.sup.5D, and R.sup.5E is
independently hydrogen, deuterium, halogen, C.sub.1 to C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl; and each m1 and m2 is
independently 1, 2, or 3.
9. The compound of claim 8, wherein R.sup.2 is ##STR00100## and
wherein each m1 and m2 is independently 1 or 2.
10. The compound of claim 9, wherein X.sub.B is a bond, O, or
NR.sup.5E.
11. The compound of claim 8, wherein R.sup.2 is ##STR00101## and
wherein m1 is 1 or 2.
12. The compound of claim 11, wherein X.sub.B is O or
NR.sup.5E.
13. The compound of claim 8, wherein R.sup.2 is ##STR00102## and
wherein m2 is 1 or 2.
14. The compound of claim 13, wherein X.sub.B is O or
NR.sup.5E.
15. The compound of any one of claims 9 to 14, wherein each of
R.sup.5A, R.sup.5B, R.sup.5C, R.sup.5D is hydrogen.
16. The compound of any one of claims 9 to 14, wherein at least one
of R.sup.5A, R.sup.5B, R.sup.5C, R.sup.5D is halogen or
C.sub.1-C.sub.6 alkyl.
17. The compound of any one of claims 9 to 16, wherein each
R.sup.5E is independently hydrogen or methyl.
18. The compound of any one of claims 1 to 17, wherein R.sup.1 is
H.
19. The compound of any one of claims 1 to 18, wherein R.sup.6 is
C.sub.6-C.sub.10 aryl, 5 to 10 membered heteroaryl, C.sub.3 to
C.sub.8 carbocyclyl, or 3 to 10 membered heterocyclyl, each
optionally substituted with one or more substituents independently
selected from the group consisting of halogen, hydroxyl, optionally
substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, amino(C.sub.1-C.sub.6 alkyl),
--C(.dbd.O)NR.sup.16aR.sup.16b, C.sub.3-C.sub.7 cycloalkyl
optionally substituted with one or more R.sup.9, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, C.sub.6-C.sub.10 aryl optionally substituted with
one or more R.sup.9, C.sub.6-C.sub.10 aryl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9, 5 or 6 membered
heteroaryl optionally substituted with one or more R.sup.9, 5 or 6
membered heteroaryl(C.sub.1-C.sub.6 alkyl) optionally substituted
with one or more R.sup.9, heterocyclyl optionally substituted with
one or more R.sup.9, and heterocyclyl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9.
20. The compound of claim 19, wherein R.sup.6 is a phenyl
substituted with one, two, or three substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.7 cycloalkyl optionally
substituted with one or more R.sup.9, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, 5 or 6 membered heterocyclyl optionally
substituted with one or more R.sup.9, and 5 or 6 membered
heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9.
21. The compound of claim 19 or 20, wherein R.sup.6 is a phenyl
substituted with ##STR00103## each optionally substituted with one
or more R.sup.9.
22. The compound of claim 19 or 20, wherein R.sup.6 is a phenyl
substituted with ##STR00104## each optionally substituted with one
or more R.sup.9.
23. The compound of any one of claims 20 to 22, wherein R.sup.9 is
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6haloalkyl.
24. The compound of claim 19 or 20, wherein R.sup.6 is a phenyl
substituted with --NH(C.sub.1-C.sub.4 alkyl) or --N(C.sub.1-C.sub.4
alkyl).sub.2.
25. The compound of claim 19 or 20, wherein R.sup.6 is a phenyl
substituted with --(CH.sub.2).sub.1-3--NH(C.sub.1-C.sub.4 alkyl) or
--(CH.sub.2).sub.1-3--N(C.sub.1-C.sub.4 alkyl).sub.2.
26. The compound of claim 19 or 20, wherein R.sup.6 is a phenyl
substituted with one, two, or three substituents independently
selected from the group consisting of fluoro, chloro, methyl,
ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, --NH(Me),
--NH(Et), --N(Me).sub.2, --N(Et).sub.2, ##STR00105##
27. The compound of claim 19, wherein R.sup.6 is a pyridyl
substituted with one, two, or three substituents independently
selected from the group consisting of halogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.7 cycloalkyl optionally
substituted with one or more R.sup.9, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, 5 or 6 membered heterocyclyl optionally
substituted with one or more R.sup.9, and 5 or 6 membered
heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9.
28. The compound of claim 27, wherein R.sup.6 is a pyridyl
substituted with one, two, or three substituents independently
selected from the group consisting of fluoro, chloro, methyl,
ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, --NH(Me),
--NH(Et), --N(Me).sub.2, --N(Et).sub.2, ##STR00106##
29. The compound of claim 1, selected from the group consisting of
##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111##
##STR00112## ##STR00113## ##STR00114## ##STR00115## ##STR00116##
and pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition, comprising a compound of any one
of claims 1 to 29, or a pharmaceutically acceptable salt thereof,
and at least one pharmaceutically acceptable carrier or
excipient.
31. A method of treating, ameliorating, or preventing a
hematological malignancy or a solid tumor in a subject, comprising
administering a therapeutically effective amount of a compound of
any one of claims 1 to 29, or a pharmaceutically acceptable salt
thereof, or the pharmaceutical composition of claim 30, to the
subject in need thereof.
32. The method of claim 31, wherein the hematological malignancy or
the solid tumor is small cell lung cancer, non-small cell lung
cancer, breast cancer, prostate cancer, head and neck cancer,
pancreatic cancer, colon cancer, rectal cancer, teratoma, ovarian
cancer, gastric cancer, endometrial cancer, brain cancer,
retinoblastoma, leukemia, skin cancer, melanoma, squamous cell
carcinoma, liposarcoma, lymphoma, multiple myeloma, testicular
cancer, liver cancer, esophageal cancer, kidney carcinoma,
astrogliosis, multiple myeloma, or neuroblastoma.
33. The method of claim 32, wherein the hematological malignancy is
leukemia, lymphoma, or multiple myeloma.
34. The method of any one of claims 31 to 33, wherein the
hematological malignancy or the solid tumor is associated with one
or more proteins selected from the group consisting of IL-1.beta.,
IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1, aiolos, ikaros, and
helios, and combinations thereof.
35. A method of treating, ameliorating, or preventing a disease,
disorder, or condition in a subject, comprising administering a
therapeutically effective amount of a compound of any one of claims
1 to 29, or a pharmaceutically acceptable salt thereof, or the
pharmaceutical composition of claim 30, to the subject in need
thereof; and wherein the disease, disorder, or condition is a
neurodegenerative disease, fibrosis, lupus, fibromyalgia,
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, uveitis, or chronic obstructive
pulmonary disease, or combinations thereof.
36. The method of claim 34, wherein the disease, disorder, or
condition is multiple sclerosis, Alzheimer's disease, Parkinson's
disease, fibrosis, lupus, fibromyalgia, rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic
arthritis, Crohn's disease, or ulcerative colitis, or combinations
thereof.
37. The method of claim 34 or 36, wherein the disease, disorder, or
condition is associated with one or more proteins selected from the
group consisting of IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha.,
GSPT1, aiolos, ikaros, and helios, and combinations thereof.
38. The method of any one of claims 31 to 37, wherein the compound,
pharmaceutically acceptable salt thereof, or pharmaceutical
composition is co-administered to the subject with a second
therapeutic agent.
39. A method of modulating activity of a protein in a biological
sample, comprising contacting the biological sample with a compound
of any one of claims 1 to 29, or a pharmaceutically acceptable salt
thereof, wherein the protein is IL-1.beta., IL-2, IL-6, TNF.alpha.,
CK1.alpha., GSPT1, aiolos, ikaros, or helios.
40. The method of claim 39, wherein the method inhibits the
activity of the protein.
41. The method of claim 39, wherein the method induces IL-2.
42. The method of any one of claims 39 to 41, wherein the
biological sample comprises one or more cells selected from the
group consisting of small cell lung cancer cell, non-small cell
lung cancer cell, breast cancer cell, prostate cancer cell, head
and neck cancer cell, pancreatic cancer cell, colon cancer cell,
rectal cancer cell, teratoma cell, ovarian cancer cell, gastric
cancer cell, endometrial cancer cell, brain cancer cell,
retinoblastoma cell, leukemia cell, skin cancer cell, melanoma
cell, squamous cell carcinoma cell, liposarcoma cell, lymphoma
cell, multiple myeloma cell, testicular cancer cell, liver cancer
cell, esophageal cancer cell, kidney carcinoma cell, astrogliosis
cell, multiple myeloma cell, and neuroblastoma cell.
Description
INCORPORATION BY REFERENCE TO PRIORITY APPLICATIONS
[0001] The present application is a divisional of U.S. application
Ser. No. 16/438,244, filed Jun. 11, 2019; which claims the benefit
of U.S. Provisional Application No. 62/684,495, filed Jun. 13,
2018; the disclosure of each of which is incorporated herein by
reference in its entirety.
BACKGROUND
Field
[0002] Compounds, methods of making such compounds, pharmaceutical
compositions and medicaments comprising such compounds, and uses of
such compounds to treat, prevent or diagnose diseases, disorders,
or conditions associated with protein malfunction are provided.
[0003] Aberrant protein function, and/or protein imbalance is a
hallmark of many disease states. For example, the functioning of
the immune system is finely balanced by the activities of
pro-inflammatory and anti-inflammatory mediators or cytokines. Some
cytokines promote inflammation (pro-inflammatory cytokines),
whereas other cytokines suppress the activity of the
pro-inflammatory cytokines (anti-inflammatory cytokines). For
example, IL-4, IL-10, and IL-13 are potent activators of B
lymphocytes, and also act as anti-inflammatory agents. They are
anti-inflammatory cytokines by virtue of their ability to suppress
genes for pro-inflammatory cytokines such as IL-1, TNF, and
chemokines.
[0004] Unregulated activities of these mediators can lead to the
development of serious inflammatory conditions. For example,
autoimmune diseases arise when immune system cells (lymphocytes,
macrophages) become sensitized against the "self." Lymphocytes, as
well as macrophages, are usually under control in this system.
However, a misdirection of the system toward the body's own tissues
may happen in response to still unexplained triggers. One
hypothesis is that lymphocytes recognize an antigen which mimics
the "self" and a cascade of activation of different components of
the immune system takes place, ultimately leading to tissue
destruction. Genetic predisposition has also been postulated to be
responsible for autoimmune disorders.
[0005] Tumor necrosis factor-alpha (TNF-alpha, or TNF-.alpha.) and
interleukin-1 (IL-1) are pro-inflammatory cytokines that mediate
inflammatory responses associated with infectious agents and other
cellular stresses. Overproduction of these cytokines is believed to
underlie the progression of many inflammatory diseases including
rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel
disease, endotoxin shock, osteoporosis, neurodegenerative diseases
(such as multiple sclerosis, Alzheimer's disease, Parkinson's
disease), congestive heart failure, and psoriasis among others.
[0006] Recent data from clinical trials support the use of protein
antagonists of cytokines, for example soluble TNF-.alpha. receptor
fusion protein (etanercept) or the monoclonal TNF-.alpha. antibody
(infliximab), for the treatment of rheumatoid arthritis, Crohn's
disease, juvenile chronic arthritis and psoriatic arthritis. Thus,
the reduction of pro-inflammatory cytokines such as TNF-.alpha. and
interleukin-1 (IL-I) has become an accepted therapeutic approach
for potential drug intervention in these conditions.
[0007] Moreover, IL-2 is now FDA approved for the treatment of
renal cancer and melanoma patients, with durable, complete
remissions achieved with IL-2 up to 148 months. However, the short
half-life of IL-2 in serum requires that large amounts of IL-2 be
injected to achieve therapeutic levels. Many attempts have been
made to minimize side effects of systemic IL-2 treatment, for
example, introducing IL-2 directly into the tumor, though this
complicates treatment, and has largely been unsuccessful.
[0008] Local delivery of cytokines is appealing compared to
systemic delivery for a variety of reasons. It takes advantage of
the natural biology of cytokines that have evolved to act locally
in a paracrine or autocrine fashion. Local expression also
dramatically minimizes many of the side effects of systemic
delivery of cytokines. Thus, compounds and methods to increase
local expression of IL-2 would be better tolerated than high dose
IL-2 treatment, which would expand therapeutic utility of
strategies that increase IL-2.
[0009] Additional targets include several candidate genes involved
in apoptosis and cell survival, including the translation
termination factor GSPT1 (eRF3a), casein kinase 1.alpha.
(CK1.alpha.), and the zinc-finger transcription factors aiolos,
helios, and ikaros. Aiolos, helios, and ikaros are transcription
factors whose expression is restricted to lymphoid lineages. For
example, aiolos binds to the Bcl-2 promoter, and also interacts
with the Bcl-2 and Bcl-XL proteins to promote cell survival.
Upregulation of aiolos expression, for example, can reduce
apoptosis of HIV-1 infected cells.
[0010] Likewise, expression of aiolos in lung and breast cancers
predicts significantly reduced patient survival. Aiolos decreases
expression of a large set of adhesion-related genes, disrupting
cell-cell and cell-matrix interactions, facilitating metastasis.
Aiolos may also function as an epigenetic driver of lymphocyte
mimicry in certain metastatic epithelial cancers. Similarly,
aberrant ikaros and helios expression may promote Bcl-XL
expression, driving the development of hematopoietic malignancies.
Thus, down-regulation of aiolos, ikaros, and/or helios may reduce
or eliminate metastasis.
[0011] GSPT1 mediates stop codon recognition and facilitates
release of a nascent peptide from the ribosome and is also involved
in several other critical cellular processes, such as cell cycle
regulation, cytoskeleton organization and apoptosis. Accordingly,
decreased levels of GSPT1 may impair control of cell proliferation
and facilitate cell migration and scar formation. Indeed, GSPT1 has
been implicated as an oncogenic driver of several different cancer
types, including breast cancer, hepatocellular carcinoma, gastric
cancer, and prostate cancer. See, e.g., Brito, et al.,
Carcinogenesis, Vol. 26, No. 12, pp. 2046-49 (2005); Brito, et al.,
Canc. Geneti. Cytogen., Vol. 195, pp. 132-42 (2009); Tavassoli, et
al., Med. Oncol., Vol. 29, pp. 1581-85 (2011); Wright and Lange,
Rev. Urol., Vol. 9, No. 4, pp. 207-213 (2007); Hoshino, et al.,
Apoptosis, Vol. 17, pp. 1287-99 (2012); Liu, et. al., PLOS One,
Vol. 9, No. 1, e86371 (2014); and Jean-Jean, et al., Mol. Cell.
Bio., Vol. 27, No. 16, pp. 5619-29 (2007). GSPT1 also contributes
to glial scar formation and astrogliosis after a central nervous
system (CNS) injury. See, e.g., Ishii et al., J. Biol. Chem., Vol.
292, No. 4, pp. 1240-50 (2017).
[0012] Casein kinase 1.alpha. (CK1.alpha.) is a component of the
.beta.-catenin-degradation complex and a critical regulator of the
Wnt signaling pathway, and its ablation induces both Wnt and p53
activation. Schittek and Sinnberg, Mol. Cancer. 2014, 13, 231;
Cheong and Virshup, J. Biochem. Cell Biol. 2011, 43, 465-469;
Elyada et al., Nature 2011, 470, 409-413. CK1.alpha. phosphorylates
.beta.-catenin, which is subsequently further phosphorylated by
GSK-30. This destabilizes .beta.-catenin and marks the protein for
ubiquitination and proteasomal degradation. Thus, CK1.alpha.
functions as a molecular switch for the Wnt pathway. Amit et al.,
Genes Dev. 2002, 16, 1066-1076. CK1.alpha. is critical for
embryogenesis and plays an important role in tissue development and
response to DNA damage, at least partly coordinated with p53.
Elyada et al., Nature 2011, 470, 409-413; Schneider et al., Cancer
Cell 2014, 26, 509-520. Levine and Oren, Nat. Rev. Cancer 2009, 9,
749-758.
[0013] Indeed, CK1.alpha. also phosphorylates p53, which inhibits
binding to MDM2 (a p53 inhibitor) and stabilizes p53's binding
interactions with the transcriptional machinery. Huart, et al., J.
Biol. Chem. 2009, 284, 32384-32394. Thus, inhibiting CK1.alpha.
activity increases cellular levels of p53. This is of particular
importance for skin cancer, which has killed more people since 1980
than all other types of cancer combined. Stern, Arch Dermatol.
2010, 146, 279-282.
[0014] One mechanism to disrupt protein drivers of disease is to
decrease the cellular concentration of these proteins. For example,
proteolytic degradation of cellular proteins is essential to normal
cell function. Hijacking this process, by targeting specific
disease-related proteins, presents a novel mechanism for the
treatment of disease. The irreversible nature of proteolysis makes
it well-suited to serve as a regulatory switch for controlling
unidirectional processes.
[0015] Ubiquitin-mediated proteolysis begins with ligation of one
or more ubiquitin molecules to a particular protein substrate.
Ubiquitination occurs through the activity of ubiquitin-activating
enzymes (E1), ubiquitin-conjugating enzymes (E2), and
ubiquitin-protein ligases (E3), acting sequentially to attach
ubiquitin to lysine residues of substrate proteins. The E3 ligases
confer specificity to ubiquitination reactions by binding directly
to particular substrates.
SUMMARY
[0016] The compounds is the present disclosure have been discovered
to exert surprising and unexpected biological effects. In
particular, the compounds disclosed in the present application
modulate protein function and/or rodulae protein levels to restore
protein homeostasis.
[0017] Some embodiments of the present disclosure provide a
compound of Formula (I):
##STR00001##
[0018] or a pharmaceutically acceptable salt thereof, wherein
[0019] Q.sub.1, Q.sub.2, and Q.sub.3, are independently CR.sup.1,
CR.sup.2, or --S--;
[0020] wherein one of Q.sub.1, Q.sub.2, and Q.sub.3 is --S--; one
of Q.sub.1, Q.sub.2, and Q.sub.3 is CR.sup.1; and one of Q.sub.1,
Q.sub.2, and Q.sub.3 is CR.sup.2;
[0021] each - - - is a carbon-carbon single bond, a carbon-carbon
double bond, or a carbon-sulfur single bond;
[0022] R.sup.1 is H, deuterium, hydroxyl, halogen, cyano, nitro,
optionally substituted C.sub.1-C.sub.6 alkoxy, optionally
substituted C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, optionally substituted amino, C.sub.1-C.sub.6
alkylamino, amino(C.sub.1-C.sub.6 alkyl), (C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, or optionally substituted
C.sub.3-C.sub.8 carbocyclyl;
[0023] R.sup.2 is
##STR00002##
[0024] R.sup.3 is H, deuterium, an optionally substituted
C.sub.1-C.sub.6 alkyl,
##STR00003##
[0025] X is C.dbd.O, CHR.sup.4A, or CR.sup.4AR.sup.4B;
[0026] each of R.sup.4A and R.sup.4B is independently H, deuterium,
or C.sub.1-C.sub.6 alkyl;
[0027] X.sub.1 is H, deuterium, fluoro, or C.sub.1-C.sub.6
alkyl;
[0028] each of X.sub.A, X.sub.B, and X.sub.C is independently a
bond, (CH.sub.2).sub.m, (CF.sub.2).sub.m, O, S, and NH; wherein
none of X.sub.A--X.sub.B, X.sub.A--X.sub.C, or X.sub.B--X.sub.C is
a bond selected from N--N, N--O, N--S, O--N, S--N, O--O, S--S, or
N.dbd.N; wherein, not more than one of X.sub.A, X.sub.B, and
X.sub.C can be a bond; and wherein any hydrogen of the
(CH.sub.2).sub.m and NH groups can be substituted by one or more
R.sup.5;
[0029] R.sup.5 is hydrogen, deuterium, halogen, C.sub.1-C.sub.6
alkyl, or C.sub.1-C.sub.6 haloalkyl;
[0030] m is 1, 2, or 3;
[0031] n is 0, 1, or 2;
[0032] R.sup.6 is C.sub.6-C.sub.10 aryl, 5 to 10 membered
heteroaryl, C.sub.3 to C.sub.8 carbocyclyl, or 3 to 10 membered
heterocyclyl, each optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, hydroxyl, optionally substituted C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkylamino, amino(C.sub.1-C.sub.6 alkyl),
--C(.dbd.O)NR.sup.16aR.sup.16b, optionally substituted
C.sub.3-C.sub.7 cycloalkyl, optionally substituted C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl), optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.6-C.sub.10
aryl(C.sub.1-C.sub.6 alkyl), optionally substituted 5 to 10
membered heteroaryl, optionally substituted 5 to 10 membered
heteroaryl(C.sub.1-C.sub.6 alkyl), optionally substituted
heterocyclyl, and optionally substituted
heterocyclyl(C.sub.1-C.sub.6 alkyl);
[0033] each R.sup.16a and R.sup.16b is independently H or
C.sub.1-C.sub.6 alkyl, or R.sup.16a and R.sup.16b together with the
nitrogen atom to which they are attached form 5 or 6 membered
heterocyclyl optionally substituted with one or more R.sup.9;
[0034] each R.sup.9 is independently C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, (C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl, optionally
substituted amino, halogen, or cyano; or two geminal R.sup.9 form
oxo (.dbd.O); and
[0035] each of R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14,
and R.sup.15 is independently H, an optionally substituted
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.6 cycloalkyl; or R.sup.14
and R.sup.15 together with the nitrogen atom to which they are
attached form an optionally substituted 5 or 6 membered
heterocyclyl. In some embodiments, R.sup.6 is C.sub.6-C.sub.10
aryl, 5 to 10 membered heteroaryl, C.sub.3 to C.sub.8 carbocyclyl,
or 3 to 10 membered heterocyclyl, each optionally substituted with
one or more substituents independently selected from the group
consisting of halogen, hydroxyl, optionally substituted
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), --C(.dbd.O)NR.sup.16aR.sup.16b,
C.sub.3-C.sub.7 cycloalkyl optionally substituted with one or more
R.sup.9, C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9, C.sub.6-C.sub.10
aryl optionally substituted with one or more R.sup.9,
C.sub.6-C.sub.10 aryl(C.sub.1-C.sub.6 alkyl) optionally substituted
with one or more R.sup.9, 5 or 6 membered heteroaryl optionally
substituted with one or more R.sup.9, 5 or 6 membered
heteroaryl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, heterocyclyl optionally substituted with one or
more R.sup.9, and heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally
substituted with one or more R.sup.9.
[0036] In some embodiments, the compound of Formula (I) is also
represented by Formula (Ia), (Ib), (Ic), (Id), (Ie), or (If):
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0037] Some embodiments of the present disclosure provide a
pharmaceutical composition, comprising a compound of Formula (I) or
(Ia)-(If), or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable carrier.
[0038] Some embodiments of the present disclosure provide a method
of modulating the activity of a protein in a biological sample,
comprising contacting the biological sample with a compound of
Formula (I) or (Ia)-(If), or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition thereof; wherein the
protein is IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1,
aiolos, ikaros, or helios. In some embodiments, the method inhibits
the activity of the protein.
[0039] Some further embodiments the present disclosure provide a
method of treating, ameliorating, or preventing a hematological
malignancy or a solid tumor in a subject, the method comprising
administering a therapeutically effective amount of a compound of
Formula (I) or (Ia)-(If), or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition thereof to the subject in
need thereof. In some embodiments, the hematological malignancy or
the solid tumor is associated with one or more proteins selected
from a IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1,
aiolos, ikaros, and helios, and combinations of any of the
foregoing. In some further embodiments, the hematological
malignancy is leukemia, lymphoma, or multiple myeloma.
[0040] Some further embodiments of the present disclosure provide a
method of treating, ameliorating, or preventing a disease,
disorder, or condition, the method comprising administering a
therapeutically effective amount of a compound of Formula (I) or
(Ia)-(If), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition thereof to the subject; wherein the
disease, disorder, or condition is a neurodegenerative disease,
fibrosis, lupus, fibromyalgia, rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic
arthritis, inflammatory bowel disease, Crohn's disease, ulcerative
colitis, uveitis, or chronic obstructive pulmonary disease. In some
embodiments, the disease, disorder or condition is associated with
one or more proteins selected from the group consisting of
IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1, aiolos,
ikaros, and helios, and combinations of any of the foregoing.
DETAILED DESCRIPTION
[0041] Disclosed herein are compounds useful for the treatment of
various diseases, disorders, or conditions, such as inflammatory
diseases and cancers. In some embodiments, these compounds are
modulators of various protein activities, for example, a cytokine
(such as IL-1.beta., IL-2, and IL-6), TNF.alpha., aiolos, ikaros,
helios, CK1.alpha., or GSPT1. In some aspects, these compounds are
inhibitors of the protein activities. In other aspects, certain
compounds described herein may induce protein activities (e.g.,
IL-2).
[0042] The section headings used herein are for organizational
purposes only and are not to be construed as limiting the subject
matter described.
Definitions
[0043] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications referenced herein are
incorporated by reference in their entirety unless stated
otherwise. In the event that there are a plurality of definitions
for a term herein, those in this section prevail unless stated
otherwise. As used in the specification and the appended claims,
the singular forms "a," "an" and "the" include plural referents
unless the context clearly dictates otherwise. Unless otherwise
indicated, conventional methods of mass spectroscopy, NMR, HPLC,
protein chemistry, biochemistry, recombinant DNA techniques and
pharmacology are employed. The use of "or" or "and" means "and/or"
unless stated otherwise. Furthermore, use of the term "including"
as well as other forms, such as "include", "includes," and
"included," is not limiting.
[0044] All references cited herein are incorporated herein by
reference in their entirety. To the extent publications and patents
or patent applications incorporated by reference contradict the
disclosure contained in the specification, the specification is
intended to supersede and/or take precedence over any such
contradictory material.
[0045] Unless otherwise defined, all terms (including technical and
scientific terms) are to be given their ordinary and customary
meaning to a person of ordinary skill in the art, and are not to be
limited to a special or customized meaning unless expressly so
defined herein. It should be noted that the use of particular
terminology when describing certain features or aspects of the
disclosure should not be taken to imply that the terminology is
being re-defined herein to be restricted to include any specific
characteristics of the features or aspects of the disclosure with
which that terminology is associated.
[0046] Where a range of values is provided, it is understood that
the upper and lower limit, and each intervening value between the
upper and lower limit of the range is encompassed within the
embodiments.
[0047] As used herein, common organic abbreviations are defined as
follows:
[0048] ACN acetonitrile
[0049] AcOH acetic acid
[0050] CCl.sub.4 carbon tetrachloride
[0051] CDI 1,1'-carbonyldiimidazole, N,N'-carbonyldiimidazole
[0052] d day, days
[0053] DCM dichloromethane, methylene chloride
[0054] DEAD diethyl azodicarboxylate
[0055] DIEA N,N-diisopropylethylamine
[0056] DMA N,N-dimethylamide
[0057] DMF N,N-dimethylformamide
[0058] DMSO dimethylsulfoxide
[0059] EDAC-HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
[0060] EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
[0061] Ether diethyl ether
[0062] EA ethyl acetate
[0063] EtOH ethanol
[0064] K.sub.2CO.sub.3 potassium carbonate
[0065] LiAH lithium aluminium hydride
[0066] LiCl lithium chloride
[0067] LiOH lithium hydroxide
[0068] h hour, hours
[0069] H.sub.2 hydrogen
[0070] HCl hydrochloric acid, hydrochloride
[0071] HOBt 1-hydroxybenzotriazole
[0072] MeOH MeOH
[0073] m minute, minutes
[0074] NaHCO.sub.3 sodium bicarbonate
[0075] Na.sub.2SO.sub.4 sodium sulfate
[0076] NBS N-bromosuccinimide
[0077] N.sub.2 nitrogen
[0078] Pd/C palladium on activated carbon
[0079] PE petroleum ether
[0080] RT room temperature
[0081] TEA triethylamine
[0082] TFA trifluoroacetic acid
[0083] THF tetrahydrofuran
[0084] quant quantitative yield
[0085] The terms "effective amount" and "therapeutically effective
amount" are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and are
not to be limited to a special or customized meaning), and refer
without limitation to a sufficient amount of an agent or a compound
being administered which will relieve to some extent one or more of
the symptoms of the disease or condition being treated. The result
can be reduction and/or alleviation of the signs, symptoms, or
causes of a disease, or any other desired alteration of a
biological system. For example, an "effective amount" for
therapeutic uses is the amount of the composition comprising a
compound as disclosed herein required to provide a clinically
significant decrease in disease symptoms. An appropriate
"effective" amount in any individual case may be determined using
techniques, such as a dose escalation study. Where a drug has been
approved by the U.S. Food and Drug Administration (FDA) or a
counterpart foreign medicines agency, a "therapeutically effective
amount" optionally refers to the dosage approved by the FDA or its
counterpart foreign agency for treatment of the identified disease
or condition.
[0086] The terms "treat," "treatment," or "treating," as used
herein refers to administering a compound or pharmaceutical
composition to a subject for prophylactic and/or therapeutic
purposes. The term "prophylactic treatment" refers to treating a
subject who does not yet exhibit symptoms of a disease or
condition, but who is susceptible to, or otherwise at risk of, a
particular disease or condition, whereby the treatment reduces the
likelihood that the patient will develop the disease or condition.
The term "therapeutic treatment" refers to administering treatment
to a subject already suffering from a disease or condition.
[0087] The terms "co-administration" and similar terms as used
herein are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and are
not to be limited to a special or customized meaning), and refer
without limitation to administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0088] As used herein, any "R" group(s) represent substituents that
can be attached to the indicated atom. An R group may be
substituted or unsubstituted. If two "R" groups are described as
being "taken together" the R groups and the atoms they are attached
to can form a cycloalkyl, aryl, heteroaryl, or heterocycle. For
example, without limitation, if R.sup.a and R.sup.a, and the atom
to which it is attached, are indicated to be "taken together" or
"joined together" it means that they are covalently bonded to one
another to form a ring:
##STR00005##
[0089] Whenever a group is described as being "optionally
substituted" that group may be unsubstituted or substituted with
one or more of the indicated substituents. Likewise, when a group
is described as being "unsubstituted or substituted" if
substituted, the substituent may be selected from one or more the
indicated substituents. If no substituents are indicated, it is
meant that the indicated "optionally substituted" or "substituted"
group may be individually and independently substituted with one or
more group(s) individually and independently selected from alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroaralkyl,
heterocyclyl(alkyl), hydroxy, alkoxy, cycloalkoxy, aryloxy, acyl,
mercapto, alkylthio, arylthio, cyano, halogen, C-amido, N-amido,
C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato,
nitro, haloalkyl, haloalkoxy, amino, and alkylamino. When a group
is not described as "optionally substituted," "unsubstituted" or
"substituted," such group is unsubstituted unless the definition of
such group states otherwise.
[0090] As used herein, "C.sub.a to C.sub.b" in which "a" and "b"
are integers refer to the number of carbon atoms in an alkyl group,
or the number of ring atoms of a cycloalkyl, aryl, heteroaryl or
heterocyclyl group. That is, the alkyl, ring of the cycloalkyl, and
ring of the aryl, can contain from "a" to "b", inclusive, carbon
atoms. Likewise, the ring of the heteroaryl and ring of the
heterocyclyl can contain from "a" to "b", inclusive, total ring
atoms. Thus, for example, a "C.sub.1 to C.sub.4 alkyl" group refers
to all alkyl groups having from 1 to 4 carbons, that is,
CH.sub.3--, CH.sub.3CH.sub.2--, CH.sub.3CH.sub.2CH.sub.2--,
(CH.sub.3).sub.2CH--, CH.sub.3CH.sub.2CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2CH(CH.sub.3)-- and (CH.sub.3).sub.3C--; a C.sub.3
to C.sub.4 cycloalkyl group refers to all cycloalkyl groups having
from 3 to 4 carbon atoms, that is, cyclopropyl and cyclobutyl.
Similarly, a "4 to 6 membered heterocyclyl" group refers to all
heterocyclyl groups with 4 to 6 total ring atoms, for example,
azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine,
morpholine, and the like. If no "a" and "b" are designated with
regard to an alkyl, cycloalkyl aryl, heteroaryl or heterocyclyl
group, the broadest range described in these definitions is to be
assumed. As used herein, the term "C.sub.1-C.sub.6" includes
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5 and C.sub.6, and a
range defined by any of the two numbers. For example,
C.sub.1-C.sub.6 alkyl includes C.sub.1, C.sub.2, C.sub.3, C.sub.4,
C.sub.5 and C.sub.6 alkyl, C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.3
alkyl, etc. Similarly, C.sub.3-C.sub.8 carbocyclyl or cycloalkyl
each includes hydrocarbon ring containing 3, 4, 5, 6, 7 and 8
carbon atoms, or a range defined by any of the two numbers, such as
C.sub.3-C.sub.7 cycloalkyl or C.sub.5-C.sub.6 cycloalkyl.
[0091] As used herein, "alkyl" refers to a straight or branched
hydrocarbon chain that comprises a fully saturated (no double or
triple bonds) hydrocarbon group. The alkyl group may have 1 to 20
carbon atoms (whenever it appears herein, a numerical range such as
"1 to 20" refers to each integer in the given range; e.g., "1 to 20
carbon atoms" means that the alkyl group may consist of 1 carbon
atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20
carbon atoms, although the present definition also covers the
occurrence of the term "alkyl" where no numerical range is
designated). The alkyl group may also be a medium size alkyl having
1 to 10 carbon atoms. The alkyl group could also be a lower alkyl
having 1 to 6 carbon atoms. The alkyl group of the compounds may be
designated as "C.sub.1-C.sub.4 alkyl" or similar designations. By
way of example only, "C.sub.1-C.sub.4 alkyl" indicates that there
are one to four carbon atoms in the alkyl chain, i.e., the alkyl
chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include,
but are in no way limited to, methyl, ethyl, n-propyl, isopropyl,
butyl, isobutyl, tertiary butyl, pentyl (straight chain or
branched), and hexyl (straight chain or branched). The alkyl group
may be substituted or unsubstituted.
[0092] The term "alkenyl" used herein refers to a monovalent
straight or branched chain radical of from two to twenty carbon
atoms containing a carbon double bond(s) including, but not limited
to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,
2-butenyl and the like. An alkenyl group may be unsubstituted or
substituted.
[0093] The term "alkynyl" used herein refers to a monovalent
straight or branched chain radical of from two to twenty carbon
atoms containing a carbon triple bond(s) including, but not limited
to, 1-propynyl, 1-butynyl, 2-butynyl and the like. An alkynyl group
may be unsubstituted or substituted.
[0094] As used herein, "cycloalkyl" refers to a completely
saturated (no double or triple bonds) mono- or multi-cyclic
hydrocarbon ring system. When composed of two or more rings, the
rings may be joined together in a fused, bridged or spiro fashion.
As used herein, the term "fused" refers to two rings which have two
atoms and one bond in common. As used herein, the term "bridged
cycloalkyl" refers to compounds wherein the cycloalkyl contains a
linkage of one or more atoms connecting non-adjacent atoms. As used
herein, the term "spiro" refers to two rings which have one atom in
common and the two rings are not linked by a bridge. Cycloalkyl
groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in
the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the
ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be
unsubstituted or substituted. Examples of monocyclic cycloalkyl
groups include, but are in no way limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Examples of bicyclic fused cycloalkyl groups are
decahydronaphthalenyl, dodecahydro-1H-phenalenyl and
tetradecahydroanthracenyl; examples of bicyclic bridged cycloalkyl
groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and
examples of bicyclic spiro cycloalkyl groups include
spiro[3.3]heptane and spiro[4.5]decane.
[0095] As used herein, "carbocyclyl" refers to a non-aromatic a
mono- or multi-cyclic hydrocarbon ring system. When composed of two
or more rings, the rings may be joined together in a fused, bridged
or spiro fashion, as described herein. Carbocyclyl groups can
contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s),
3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6
atoms in the ring(s). A carbocyclyl group may be unsubstituted or
substituted. Examples of carbocyclyl groups include, but are in no
way limited to, cycloalkyl groups, as defined herein, and the
non-aromatic portions of 1,2,3,4-tetrahydronaphthalene,
2,3-dihydro-1H-indene, 5,6,7,8-tetrahydroquinoline and
6,7-dihydro-5H-cyclopenta[b]pyridine.
[0096] As used herein, "aryl" refers to a carbocyclic (all carbon)
monocyclic or multicyclic aromatic ring system (including fused
ring systems where two carbocyclic rings share a chemical bond)
that has a fully delocalized pi-electron system throughout all the
rings. The number of carbon atoms in an aryl group can vary. For
example, the aryl group can be a C.sub.6-C.sub.14 aryl group, a
C.sub.6-C.sub.10 aryl group or a C.sub.6 aryl group. Examples of
aryl groups include, but are not limited to, benzene, naphthalene
and azulene. An aryl group may be substituted or unsubstituted.
[0097] As used herein, "heteroaryl" refers to a monocyclic or
multicyclic aromatic ring system (a ring system with fully
delocalized pi-electron system) that contain(s) one or more
heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an
element other than carbon, including but not limited to, nitrogen,
oxygen and sulfur. The number of atoms in the ring(s) of a
heteroaryl group can vary. For example, the heteroaryl group can
contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s)
or 5 to 6 atoms in the ring(s), such as nine carbon atoms and one
heteroatom; eight carbon atoms and two heteroatoms; seven carbon
atoms and three heteroatoms; eight carbon atoms and one heteroatom;
seven carbon atoms and two heteroatoms; six carbon atoms and three
heteroatoms; five carbon atoms and four heteroatoms; five carbon
atoms and one heteroatom; four carbon atoms and two heteroatoms;
three carbon atoms and three heteroatoms; four carbon atoms and one
heteroatom; three carbon atoms and two heteroatoms; or two carbon
atoms and three heteroatoms. Furthermore, the term "heteroaryl"
includes fused ring systems where two rings, such as at least one
aryl ring and at least one heteroaryl ring or at least two
heteroaryl rings, share at least one chemical bond. Examples of
heteroaryl rings include, but are not limited to, furan, furazan,
thiophene, benzothiophene, phthalazine, pyrrole, oxazole,
benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole,
1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole,
benzimidazole, indole, indazole, pyrazole, benzopyrazole,
isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole,
thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,
purine, pteridine, quinoline, isoquinoline, quinazoline,
quinoxaline, cinnoline and triazine. A heteroaryl group may be
substituted or unsubstituted.
[0098] As used herein, "heterocyclyl" refers to three-, four-,
five-, six-, seven-, eight-, nine-, ten-, up to 18-membered
monocyclic, bicyclic and tricyclic ring system wherein carbon atoms
together with from 1 to 5 heteroatoms constitute said ring system.
A heterocycle may optionally contain one or more unsaturated bonds
situated in such a way, however, that a fully delocalized
pi-electron system does not occur throughout all the rings (i.e.,
heterocyclyl groups are not aromatic). The heteroatom(s) is an
element other than carbon including, but not limited to, oxygen,
sulfur and nitrogen. A heterocycle may further contain one or more
carbonyl functionalities, so as to make the definition include
oxo-systems such as lactams, lactones, and cyclic carbamates. When
composed of two or more rings, the rings may be joined together in
a fused, bridged or spiro fashion. As used herein, the term "fused"
refers to two rings which have two atoms and one bond in common. As
used herein, the term "bridged heterocyclyl" refers to compounds
wherein the heterocyclyl contains a linkage of one or more atoms
connecting non-adjacent atoms. As used herein, the term "spiro"
refers to two rings which have one atom in common and the two rings
are not linked by a bridge. Heterocyclyl groups can contain 3 to 30
atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms
in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the
ring(s). For example, five carbon atoms and one heteroatom; four
carbon atoms and two heteroatoms; three carbon atoms and three
heteroatoms; four carbon atoms and one heteroatom; three carbon
atoms and two heteroatoms; two carbon atoms and three heteroatoms;
one carbon atom and four heteroatoms; three carbon atoms and one
heteroatom; or two carbon atoms and one heteroatom. Additionally,
any nitrogens in a heterocyclyl group may be quaternized.
Heterocyclyl groups can be linked to the rest of the molecule via a
carbon atom in the heterocyclyl group (C-linked) or by a heteroatom
in the heterocyclyl group, such as a nitrogen atom (N-linked).
Heterocyclyl groups may be unsubstituted or substituted. Examples
of such "heterocyclyl" groups include but are not limited to,
aziridine, oxirane, thiirane, azetidine, oxetane, 1,3-dioxin,
1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane,
1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane,
1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline,
imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane,
piperidine N-oxide, piperidine, piperazine, pyrrolidine, azepane,
pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,
2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,
thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone
and their benzo-fused analogs (e.g., benzimidazolidinone,
tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of
spiro heterocyclyl groups include 2-azaspiro[3.3]heptane,
2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane,
2,6-diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and
2-azaspiro[3.4]octane.
[0099] "Alkylene groups" are straight-chained --CH.sub.2--
tethering groups, forming bonds to connect molecular fragments via
their terminal carbon atoms. Alkylene groups contain from 1 to 10
carbon atoms. Examples include but are not limited to methylene
(--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--), propylene
(--CH.sub.2CH.sub.2CH.sub.2--), and butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--). An alkylene group can be
substituted by replacing one or more hydrogen of the alkylene group
with a substituent(s) listed under the definition of
"substituted."
[0100] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl
group, as defined above, connected, as a substituent, via an
alkylene group, as described above. The alkylene and aryl group of
an aralkyl may be substituted or unsubstituted. Examples include
but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl, and
naphthylalkyl.
[0101] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)"
refer to a heteroaryl group, as defined above, connected, as a
substituent, via an alkylene group, as defined above. The alkylene
and heteroaryl group of heteroaralkyl may be substituted or
unsubstituted. Examples include but are not limited to
2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl,
pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl,
and their benzo-fused analogs.
[0102] As used herein, "heterocyclyl(alkyl)" or "heterocyclylalkyl"
refers to a heterocyclic or a heterocyclyl group, as defined above,
connected, as a substituent, via an alkylene group, as defined
above. The alkylene and heterocyclyl groups of a
heterocyclyl(alkyl) may be substituted or unsubstituted. Examples
include but are not limited to tetrahydrofuranylmethyl,
piperazinylmethyl, and morpholinylethyl. When a heterocyclylalkyl
group contains a secondary amino group (i.e., --NH--), the alkyl
portion of the heterocyclylalkyl may replace the hydrogen on the
nitrogen in the heterocyclyl ring, such that the heterocyclyl ring
is linked to the alkyl portion of the heterocyclylalkyl group via
the nitrogen atom.
[0103] As used herein, "cycloalkyl(alkyl)" refers to a cycloalkyl
group, as defined above, connected, as a substituent, via an
alkylene group, as defined above. The alkylene and cycloalkyl
portion of a cycloalkyl(alkyl) may be substituted or unsubstituted.
Examples include but are not limited to
##STR00006##
[0104] As used herein, "alkoxy" refers to the formula --OR wherein
R is an alkyl group, as defined herein. A non-limiting list of
alkoxys is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy),
n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy may be
substituted or unsubstituted.
[0105] As used herein, "cycloalkoxy" refers to the formula --OR
wherein R is a cycloalkyl group, as defined herein. A non-limiting
list of cycloalkoxys is cyclopropoxy, cyclobutoxy, cyclopentoxy,
and cyclohexoxy. A cycloalkoxy may be substituted or
unsubstituted.
[0106] As used herein, "acyl" refers to a hydrogen, alkyl, aryl,
heteroaryl, or heterocyclyl group, as defined above, connected, as
substituents, via a carbonyl group. Examples include formyl,
acetyl, propanoyl, and benzoyl. An acyl may be substituted or
unsubstituted. A "carbonyl" group refers to a C.dbd.O group.
[0107] As used herein, "hydroxyalkyl" refers to an alkyl group in
which one or more of the hydrogen atoms are replaced by a hydroxy
group. Exemplary hydroxyalkyl groups include but are not limited
to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and
2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or
unsubstituted.
[0108] As used herein, "haloalkyl" refers to an alkyl group in
which one or more of the hydrogen atoms are replaced by a halogen
(e.g., mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such
groups include but are not limited to, chloromethyl, fluoromethyl,
difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, and
2-fluoroisobutyl. A haloalkyl may be substituted or
unsubstituted.
[0109] As used herein, "haloalkoxy" refers to an alkoxy group in
which one or more of the hydrogen atoms are replaced by a halogen
(e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such
groups include but are not limited to, chloromethoxy,
fluoromethoxy, difluoromethoxy, trifluoromethoxy,
1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. A haloalkoxy may
be substituted or unsubstituted.
[0110] As used herein, "alkoxyalkyl" or "(alkoxy)alkyl" refers to
an alkoxy group connected via an lower alkylene group, such as
C.sub.2-C.sub.8 alkoxyalkyl, or (C.sub.1-C.sub.6
alkoxy)C.sub.1-C.sub.6 alkyl, for example,
--(CH.sub.2).sub.1-3--OCH.sub.3.
[0111] As used herein, "--O-alkoxyalkyl" or "--O-(alkoxy)alkyl"
refers to an alkoxy group connected via an --O-(lower alkylene)
group, such as --O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
for example, --O--(CH.sub.2).sub.1-3--OCH.sub.3.
[0112] As used herein, "aryloxy" and "arylthio" refers to RO-- and
RS--, in which R is an aryl, as defined above, such as but not
limited to phenyl. Both an aryloxy and arylthio may be substituted
or unsubstituted.
[0113] As used herein, an "O-carboxy" group refers to a
"RC(.dbd.O)O--*" group in which R can be hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or
heterocyclyl(alkyl), as defined herein, and wherein "*" denotes the
connect of the O-carboxy group to the rest of the molecule. An
O-carboxy may be substituted or unsubstituted.
[0114] As used herein, "ester" and "C-carboxy" refer to a
"*--C(.dbd.O)OR" group in which R can be hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or
heterocyclyl(alkyl), as defined herein, and wherein "*" denotes the
connect of the C-carboxy (or ester) group to the rest of the
molecule. A C-carboxy or ester group may be substituted or
unsubstituted.
[0115] As used herein, "amino" or "optionally substituted amino,"
as used herein refer to --NR.sub.AR.sub.B where R.sub.A and R.sub.B
are independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
An unsubstituted amino is --NH.sub.2.
[0116] As used herein, "alkylamino" or "(alkyl)amino" refers to
"--NR.sub.AR.sub.B" where R.sub.A and R.sub.B are hydrogen or alkyl
as defined above, and at least one of R.sub.A and R.sub.B is alkyl.
The alkyl portion of the (alkyl)amino, includes, for example,
C.sub.1-C.sub.6 alkyl groups. Examples of alkylamino groups
include, but are not limited to methylamino (--NHMe), ethylamino
(--NHEt), dimethylamino (--N(Me).sub.2, methylethylamino
(--N(Me)(Et)), and isopropylamino (--NHiPr).
[0117] As used herein, "aminoalkyl" or "amino(alkyl)" refers to an
alkyl group in which one or more of the hydrogen atoms are replaced
by an amino group or "--NR.sub.AR.sub.B" group as defined herein.
The alkyl portion of the amino(alkyl), includes, for example,
C.sub.1-C.sub.6 alkyl. Examples of aminoalkyl groups include, but
are not limited to --(CH.sub.2).sub.1-4NH.sub.2,
--(CH.sub.2).sub.1-4--NHCH.sub.3,
--(CH.sub.2).sub.1-4--NHC.sub.2H.sub.5,
--(CH.sub.2).sub.1-4--N(CH.sub.3).sub.2,
--(CH.sub.2).sub.1-4--N(C.sub.2H.sub.5).sub.2,
--(CH.sub.2).sub.1-4--NH--CH(CH.sub.3).sub.2,
--(CH.sub.2).sub.1-4N(CH.sub.3)C.sub.2H.sub.5, and
--CH(NH.sub.2)CH.sub.3.
[0118] As used herein, the term "hydroxy" refers to a --OH
group.
[0119] A "cyano" group refers to a "--CN" group.
[0120] The term "azido" as used herein refers to a --N.sub.3
group.
[0121] An "isocyanato" group refers to a "--NCO" group.
[0122] A "thiocyanato" group refers to a "--CNS" group.
[0123] An "isothiocyanato" group refers to an "--NCS" group.
[0124] A "mercapto" group refers to an "--SH" group.
[0125] A "C-amido" group refers to a
"*--C(.dbd.O)N(R.sub.AR.sub.B)" group in which R and R.sub.A can be
independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,
heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined above,
and wherein "*" denotes the connect of the C-amido group to the
rest of the molecule. A C-amido may be substituted or
unsubstituted.
[0126] An "N-amido" group refers to a "RC(.dbd.O)N(R.sub.A)--*"
group in which R and R.sub.A can be independently hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or
heterocyclyl(alkyl), as defined above, and wherein "*" denotes the
connect of the N-amido group to the rest of the molecule. An
N-amido may be substituted or unsubstituted.
[0127] A "urea" group refers to a
"--N(R.sub.AR.sub.B)--C(.dbd.O)--N(R.sub.AR.sub.B)--" group in
which R.sub.A and R.sub.B can be independently hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or
heterocyclyl(alkyl), as defined above. A urea group may be
substituted or unsubstituted.
[0128] A "thiourea" group refers to a
"--N(R.sub.AR.sub.B)--C(.dbd.S)--N(R.sub.AR.sub.B)--" group in
which R.sub.A and R.sub.B can be independently hydrogen, alkyl,
cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, or
heterocyclyl(alkyl), as defined above. A thiourea group may be
substituted or unsubstituted.
[0129] The term "halogen atom" or "halogen" as used herein, means
any one of the radio-stable atoms of column 7 of the Periodic Table
of the Elements, such as, fluorine, chlorine, bromine, and
iodine.
[0130] Where the numbers of substituents is not specified (e.g.,
haloalkyl), there may be one or more substituents present. For
example "haloalkyl" may include one or more of the same or
different halogens. As another example, "C.sub.1-C.sub.3
alkoxyphenyl" may include one or more of the same or different
alkoxy groups containing one, two, or three atoms.
[0131] As used herein, the abbreviations for any protective groups,
amino acids and other compounds, are, unless indicated otherwise,
in accord with their common usage, recognized abbreviations, or the
IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.
11:942-944 (1972)).
[0132] The terms "protecting group" and "protecting groups" as used
herein refer to any atom or group of atoms that is added to a
molecule in order to prevent existing groups in the molecule from
undergoing unwanted chemical reactions. Examples of protecting
group moieties are described in T. W. Greene and P. G. M. Wuts,
Protective Groups in Organic Synthesis, 3. Ed. John Wiley &
Sons, 1999, and in J. F. W. McOmie, Protective Groups in Organic
Chemistry Plenum Press, 1973, both of which are hereby incorporated
by reference for the limited purpose of disclosing suitable
protecting groups. The protecting group moiety may be chosen in
such a way, that they are stable to certain reaction conditions and
readily removed at a convenient stage using methodology known from
the art. A non-limiting list of protecting groups include benzyl;
substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl (BOC),
acetyl, or isobutyryl); arylalkylcarbonyls (e.g., benzyloxycarbonyl
or benzoyl); substituted methyl ether (e.g., methoxymethyl ether);
substituted ethyl ether; a substituted benzyl ether;
tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl,
triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, or
t-butyldiphenylsilyl); esters (e.g., benzoate ester); carbonates
(e.g., methoxymethylcarbonate); sulfonates (e.g., tosylate or
mesylate); acyclic ketal (e.g., dimethyl acetal); cyclic ketals
(e.g., 1,3-dioxane or 1,3-dioxolanes); acyclic acetal; cyclic
acetal; acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals
(e.g., 1,3-dithiane or 1,3-dithiolane); and triarylmethyl groups
(e.g., trityl; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl
(DMTr); or 4,4',4''-trimethoxytrityl (TMTr)).
[0133] The term "leaving group" as used herein refers to any atom
or moiety that is capable of being displaced by another atom or
moiety in a chemical reaction. More specifically, in some
embodiments, "leaving group" refers to the atom or moiety that is
displaced in a nucleophilic substitution reaction. In some
embodiments, "leaving groups" are any atoms or moieties that are
conjugate bases of strong acids. Examples of suitable leaving
groups include, but are not limited to, tosylates and halogens.
Non-limiting characteristics and examples of leaving groups can be
found, for example in Organic Chemistry, 2d ed., Francis Carey
(1992), pages 328-331; Introduction to Organic Chemistry, 2d ed.,
Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171;
and Organic Chemistry, 5' ed., John McMurry (2000), pages 398 and
408; all of which are incorporated herein by reference for the
limited purpose of disclosing characteristics and examples of
leaving groups.
[0134] The term "pharmaceutically acceptable salt" as used herein
is a broad term, and is to be given its ordinary and customary
meaning to a person of ordinary skill in the art (and is not to be
limited to a special or customized meaning), and refers without
limitation to a salt of a compound that does not cause significant
irritation to an organism to which it is administered and does not
abrogate the biological activity and properties of the compound. In
some embodiments, the salt is an acid addition salt of the
compound. Pharmaceutical salts can be obtained by reacting a
compound with inorganic acids such as hydrohalic acid (e.g.,
hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid,
and phosphoric acid. Pharmaceutical salts can also be obtained by
reacting a compound with an organic acid such as aliphatic or
aromatic carboxylic or sulfonic acids, for example formic acid,
acetic acid (AcOH), propionic acid, glycolic acid, pyruvic acid,
malonic acid, maleic acid, fumaric acid, trifluoroacetic acid
(TFA), benzoic acid, cinnamic acid, mandelic acid, succinic acid,
lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,
nicotinic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid,
butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid,
1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,
benzenesulfonic acid, 2-naphthalenesulfonic acid, or
naphthalenesulfonic acid. Pharmaceutical salts can also be obtained
by reacting a compound with a base to form a salt such as an
ammonium salt, an alkali metal salt, such as a lithium, sodium or a
potassium salt, an alkaline earth metal salt, such as a calcium,
magnesium or aluminum salt, a salt of organic bases such as
dicyclohexylamine, N-methyl-D-glucamine,
tris(hydroxymethyl)methylamine, (C.sub.1-C.sub.7 alkyl)amine,
cyclohexylamine, dicyclohexylamine, triethanolamine,
ethylenediamine, ethanolamine, diethanolamine, triethanolamine,
tromethamine, and salts with amino acids such as arginine and
lysine; or a salt of an inorganic base, such as aluminum hydroxide,
calcium hydroxide, potassium hydroxide, sodium carbonate, sodium
hydroxide, or the like.
[0135] The term "prodrug" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a compound or
a pharmaceutical composition that can be administered to a patient
in a less active or inactive form, which can then be metabolized in
vivo into a more active metabolite. In certain embodiments, upon in
vivo administration, a prodrug is chemically converted to the
biologically, pharmaceutically, or therapeutically active form of
the compound. In certain embodiments, a prodrug is enzymatically
metabolized by one or more steps or processes to the biologically,
pharmaceutically, or therapeutically active form of the compound.
Certain compounds described herein are prodrugs.
[0136] It is understood that, in any compound described herein
having one or more chiral centers, if an absolute stereochemistry
is not expressly indicated, then each center may independently be
of R-configuration or S-configuration or a mixture thereof. Thus,
the compounds provided herein may be enantiomerically pure,
enantiomerically enriched, or may be stereoisomeric mixtures, and
include all diastereomeric, and enantiomeric forms. In addition it
is understood that, in any compound described herein having one or
more double bond(s) generating geometrical isomers that can be
defined as E or Z, each double bond may independently be E or Z a
mixture thereof. Stereoisomers are obtained, if desired, by methods
such as, stereoselective synthesis and/or the separation of
stereoisomers by chiral chromatographic columns.
[0137] Likewise, it is understood that, in any compound described,
all tautomeric forms are also intended to be included.
[0138] Wherever a substituent is depicted as a di-radical (i.e.,
has two points of attachment to the rest of the molecule), it is to
be understood that the substituent can be attached in any
directional configuration unless otherwise indicated. Thus, for
example, a substituent depicted as -AE- or
##STR00007##
includes the substituent being oriented such that the A is attached
at the leftmost attachment point of the molecule as well as the
case in which A is attached at the rightmost attachment point of
the molecule.
[0139] It is to be understood that where compounds disclosed herein
have unfilled valencies, then the valencies are to be filled with
hydrogens and/or deuteriums.
[0140] It is understood that the compounds described herein can be
labeled isotopically or by another other means, including, but not
limited to, the use of chromophores or fluorescent moieties,
bioluminescent labels, or chemiluminescent labels. Substitution
with isotopes such as deuterium may afford certain therapeutic
advantages resulting from greater metabolic stability, such as, for
example, increased in vivo half-life or reduced dosage
requirements. Each chemical element as represented in a compound
structure may include any isotope of said element. For example, in
a compound structure a hydrogen atom may be explicitly disclosed or
understood to be present in the compound. At any position of the
compound that a hydrogen atom may be present, the hydrogen atom can
be any isotope of hydrogen, including but not limited to hydrogen-1
(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,
reference herein to a compound encompasses all potential isotopic
forms unless the context clearly dictates otherwise.
[0141] It is understood that the methods and formulations described
herein include the use of pharmaceutically acceptable salts and/or
conformers of compounds of preferred embodiments, as well as
metabolites and active metabolites of these compounds having the
same type of activity. A conformer is a structure that is a
conformational isomer. Conformational isomerism is the phenomenon
of molecules with the same structural formula but different
conformations (conformers) of atoms about a rotating bond.
[0142] Likewise, it is understood that the compounds described
herein, such as compounds of preferred embodiments, include the
compound in any of the forms described herein (e.g.,
pharmaceutically acceptable salts, prodrugs, enantiomeric forms,
tautomeric forms, and the like).
Compounds
[0143] Some embodiments provide a compound of Formula (I):
##STR00008##
[0144] or a pharmaceutically acceptable salt thereof as described
herein. In some embodiments, R.sup.1 is H, deuterium, hydroxyl,
halogen, cyano, nitro, an optionally substituted amino, an
optionally substituted C.sub.1-C.sub.6 alkoxy, or an optionally
substituted C.sub.1-C.sub.6 alkyl. In some embodiments, R.sup.5 is
hydrogen, deuterium, or methyl. In some embodiments, R.sup.6 is
or
##STR00009##
each of p and q is independently 1, 2, or 3; each of R.sup.7 and
R.sup.8 is independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), heterocyclyl optionally substituted
with one or more R.sup.9, or heterocyclyl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9. In some further
embodiments, each of R.sup.7 and R.sup.8 is independently halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylamino, unsubstituted heterocyclyl, heterocyclyl substituted
with C.sub.1-C.sub.6 alkyl, unsubstituted
heterocyclyl(C.sub.1-C.sub.6 alkyl), and
heterocyclyl(C.sub.1-C.sub.6 alkyl) substituted with
C.sub.1-C.sub.6 alkyl. In some further embodiments, R.sup.1 is H,
deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted
amino, optionally substituted C.sub.1-C.sub.6 alkoxy, or optionally
substituted C.sub.1-C.sub.6 alkyl; R.sup.5 is hydrogen, deuterium,
or methyl; R.sup.6 is or
##STR00010##
each of p and q is independently 1, 2, or 3; each R.sup.7 and
R.sup.8 is independently halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6alkylamino, unsubstituted
heterocyclyl, heterocyclyl substituted with C.sub.1-C.sub.6 alkyl,
unsubstituted heterocyclyl(C.sub.1-C.sub.6 alkyl), and
heterocyclyl(C.sub.1-C.sub.6 alkyl) substituted with
C.sub.1-C.sub.6 alkyl.
[0145] In some embodiments of the compound of Formula (I), the
compound is also represented by
##STR00011##
or a pharmaceutically acceptable salt of any of the foregoing. In
one embodiment, the compound has Formula (Ia). In another
embodiment, the compound has Formula (Ie).
[0146] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), n is 1. In other embodiments, n is
2. In still other embodiments, n is 0.
[0147] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), X is C.dbd.O. In other
embodiments, X is CHR.sup.4A. In still other embodiments, X is
CR.sup.4AR.sup.4B In some embodiments, each R.sup.4A is H or
deuterium. In still other embodiments, each R.sup.4A is
C.sub.1-C.sub.6 alkyl, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, t-butyl, pentyl (straight chain or
branched), or hexyl (straight chain or branched). In one
embodiment, R.sup.4A is methyl. In some embodiments, each R.sup.4B
is H or deuterium. In still other embodiments, each R.sub.4B is
C.sub.1-C.sub.6 alkyl, such as those described herein. In some
embodiments, each R.sub.4B is methyl. In one embodiment, both
R.sup.4A and R.sup.4B are hydrogen.
[0148] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), X.sub.1 is H. In some embodiments,
X.sub.1 is D. In some embodiments, X.sub.1 is fluoro. In some
embodiments, X.sub.1 is C.sub.1-C.sub.6 alkyl, such as those
described herein. In some embodiments, X.sub.1 is methyl.
[0149] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), R.sup.3 is H. In other
embodiments, R.sub.3 is deuterium or an optionally substituted
C.sub.1-C.sub.6 alkyl, such as those described herein. In some
embodiments, R.sub.3 is methyl. In some other embodiments, R.sup.3
is
##STR00012##
In some such embodiments, each R.sup.10 and R.sup.11 is
independently H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl). In some such embodiments, at least one of R.sup.10 and
R.sup.11 is H or C.sub.1-C.sub.6 alkyl. In one embodiment, both
R.sup.10 and R.sup.11 are C.sub.1-C.sub.6 alkyl (e.g., isopropyl).
In some other embodiments, R.sub.3 is
##STR00013##
In some such embodiments, each R.sup.12 and R.sup.13 is
independently H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl, such as those described herein. In some such
embodiments, at least one of R.sup.12 and R.sup.13 is H or
C.sub.1-C.sub.6 alkyl. In one embodiment, both R.sup.12 and
R.sup.13 are H. In another embodiment, R.sup.12 is H and R.sup.13
is C.sub.1-C.sub.6 alkyl (e.g., isopropyl). In some such
embodiments, each R.sup.14 and R.sup.15 is independently H,
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl, such as those
described herein. In some such embodiments, at least one of
R.sup.14 and R.sup.15 is H or C.sub.1-C.sub.6 alkyl. In one
embodiment, both R.sup.14 and R.sup.15 are H. In other embodiments,
R.sup.14 and R.sup.15 together with the nitrogen atom to which they
are attached form an optionally substituted 5 or 6 membered
heterocyclyl, for example, a 5 or 6 membered monocyclic
heterocyclyl group containing one or two nitrogen atoms, one or two
oxygen atoms, or one nitrogen atom and one oxygen atom. In some
further embodiments, R.sup.14 and R.sup.15 come together to form a
pyrrolidine, a piperidine, a piperazine, or a morpholine.
[0150] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), R.sup.1 is an optionally
substituted C.sub.1-C.sub.6 alkyl including C.sub.1-C.sub.6
haloalkyl (such as trifluoromethyl), an optionally substituted
C.sub.1-C.sub.6 alkoxy including C.sub.1-C.sub.6 haloalkoxy (such
as methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, sec-butoxy, t-butoxy, pentoxy (straight chain or
branched), or hexoxy (straight chain or branched)), or an
optionally substituted amino (such as an unsubstituted amino, or an
amino substituted with one or two groups selected from
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, 3 to 6
membered heterocyclyl, or 5 to 6 membered heteroaryl). In other
embodiments, R.sup.1 is halogen. In other embodiments, R.sup.1 is
H.
[0151] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), R.sup.2 is
##STR00014##
where X.sub.A is a bond; X.sub.B is O, S, NH, (CF.sub.2).sub.m or
(CH.sub.2).sub.m; and X.sub.C is (CF.sub.2).sub.m or
(CH.sub.2).sub.m. In some other embodiments, X.sub.A is
(CF.sub.2).sub.m or (CH.sub.2).sub.m; X.sub.B is O, S, NH,
(CF.sub.2).sub.m or (CH.sub.2).sub.m; and X.sub.C is a bond. In
some other embodiments, X.sub.A is (CH.sub.2).sub.m; X.sub.B is O,
S, or NH; and X.sub.C is (CH.sub.2).sub.m. In any of the
embodiments, NH is optionally substituted with one R.sup.5, e.g.,
methyl. In any of the embodiments, (CH.sub.2).sub.m is optionally
substituted by one or two R.sup.5, e.g., methyl or halogen. In any
of the embodiments, m is 1, 2, or 3. In one embodiment, m is 1. In
another embodiment, m is 2.
[0152] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), R.sup.2 is
##STR00015##
where X.sub.B is a bond, O, S, or NR.sup.5E; each of R.sup.5A,
R.sup.5B, R.sup.5C, R.sup.5D, and R.sup.5E is independently
hydrogen, deuterium, halo, C.sub.1 to C.sub.6 alkyl, or
C.sub.1-C.sub.6haloalkyl; and each m1 and m2 is independently 1, 2,
or 3. In some embodiments, R.sup.2 is
##STR00016##
and wherein each m1 and m2 is independently 1 or 2. In some such
embodiments, X.sub.B is a bond, O, or NR.sup.5E. In some
embodiments, R.sup.2 is
##STR00017##
wherein m1 is 1 or 2. In some such embodiments, X.sub.B is O or
NR.sup.5E. In some embodiments, R.sup.2 is
##STR00018##
wherein m2 is 1 or 2. In some such embodiments, X.sub.B is O or
NR.sup.5E. In some embodiments, each of R.sup.5A, R.sup.5B,
R.sup.5C, R.sup.5D, and R.sup.5E is independently hydrogen,
deuterium, or C.sub.1-C.sub.6 alkyl (e.g., methyl). In some
embodiments, each of R.sup.5A, R.sup.5B, R.sup.5C, R.sup.5D is
independently hydrogen, deuterium, halogen, or C.sub.1-C.sub.6
alkyl. In one embodiment, each of R.sup.5A, R.sup.5B, R.sup.5C,
R.sup.5D is hydrogen. In other embodiments, at least one of
R.sup.5A, R.sup.5B, R.sup.5C, R.sup.5D is halogen or
C.sub.1-C.sub.6 alkyl. In any such embodiments, R.sup.5E is
independently hydrogen or methyl.
[0153] In some further embodiments, X.sub.A, X.sub.B, and X.sub.C
are selected as shown in Table A below.
TABLE-US-00001 TABLE A X.sub.A X.sub.B X.sub.C (CH.sub.2).sub.1-3
(CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 NH
(CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 O (CH.sub.2).sub.1-3
(CH.sub.2).sub.1-3 S (CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 Bond
(CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 NH
(CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 O (CH.sub.2).sub.1-3
(CH.sub.2).sub.1-3 S (CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 Bond NH
(CH.sub.2).sub.1-3 (CH.sub.2).sub.1-3 NH (CH.sub.2).sub.1-3 Bond NH
(CH.sub.2).sub.1-3 O NH (CH.sub.2).sub.1-3 NH NH (CH.sub.2).sub.1-3
S NH Bond (CH.sub.2).sub.1-3 O (CH.sub.2).sub.1-3
(CH.sub.2).sub.1-3 O (CH.sub.2).sub.1-3 Bond O (CH.sub.2).sub.1-3 O
O (CH.sub.2).sub.1-3 NH O Bond (CH.sub.2).sub.1-3 Bond NH
(CH.sub.2).sub.1-3 Bond O (CH.sub.2).sub.1-3 Bond
(CH.sub.2).sub.1-3 NH Bond (CH.sub.2).sub.1-3 O Bond
(CH.sub.2).sub.1-3 S
[0154] In some embodiments of the compounds of Formula (I), (Ia),
(Ib), (Ic), (Id), (Ie), or (If), R.sup.6 is an optionally
substituted phenyl, optionally substituted 5 to 10 membered
heteroaryl (e.g., five or six-membered heteroaryl containing one,
two or three heteroatoms selected from O, N or S; including but not
limited to pyridyl, pyrimidyl, thienyl, furyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, isothiazolyl, diathiazolyl, oxazolyl, and
isoxazolyl), optionally substituted C.sub.3 to C.sub.8 carbocyclyl
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or
optionally substituted 3 to 10 membered heterocyclyl (e.g., four to
six-membered monocyclic heterocyclyl containing one, two or three
heteroatoms selected from O, N or S; including but not limited to
pyrrolidine, piperidine, piperazine, or morpholine); where the
substituents are independently selected from the group consisting
of halogen, hydroxyl, optionally substituted C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.1-C.sub.6 alkylamino, amino(C.sub.1-C.sub.6
alkyl), optionally substituted C.sub.3-C.sub.7 cycloalkyl,
optionally substituted C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6
alkyl), optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.6-C.sub.10 aryl(C.sub.1-C.sub.6 alkyl),
optionally substituted 5 to 10 membered heteroaryl, optionally
substituted 5 to 10 membered heteroaryl(C.sub.1-C.sub.6 alkyl),
optionally substituted heterocyclyl, and optionally substituted
heterocyclyl(C.sub.1-C.sub.6 alkyl). In some further embodiments,
the one or more substituents of R.sup.6 is independently selected
from the group consisting of halogen, hydroxyl, optionally
substituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6
alkylamino, amino(C.sub.1-C.sub.6 alkyl),
--C(.dbd.O)NR.sup.16aR.sup.16b, C.sub.3-C.sub.7 cycloalkyl
optionally substituted with one or more R.sup.9, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, C.sub.6-C.sub.10 aryl optionally substituted with
one or more R.sup.9, C.sub.6-C.sub.10 aryl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9, 5 or 6 membered
heteroaryl optionally substituted with one or more R.sup.9, 5 or 6
membered heteroaryl(C.sub.1-C.sub.6 alkyl) optionally substituted
with one or more R.sup.9, heterocyclyl optionally substituted with
one or more R.sup.9, and heterocyclyl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9; wherein each
R.sup.9 is independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy,
(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkoxy)C.sub.1-C.sub.6 alkyl, optionally
substituted amino, halogen, or cyano; or two geminal R.sup.9 form
oxo (.dbd.O). In some embodiments, R.sup.6 is unsubstituted. In
other embodiments, R.sup.6 is substituted with one, two or three
substituents described herein. Non-limiting embodiments of the
heterocyclyl and heterocyclyl(C.sub.1-C.sub.6 alkyl) substituents
include
##STR00019##
each optionally substituted with one or more R.sup.9. Non-limiting
embodiments of the C.sub.3-C.sub.7 cycloalkyl and C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) substituents include
##STR00020##
each optionally substituted with one or more R.sup.9. Non-limiting
embodiments of C.sub.6-C.sub.10 aryl and C.sub.6-C.sub.10
aryl(C.sub.1-C.sub.6 alkyl) substituents include phenyl and benzyl,
each optionally substituted with one or more R.sup.9. Non-limiting
embodiments of 5 or 6 heteroaryl and 5 or 6 heteroaryl
(C.sub.1-C.sub.6 alkyl) substituents include pyridyl, pyrimidyl,
thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
isothiazolyl, diathiazolyl, oxazolyl, isoxazolyl,
--(CH.sub.2).sub.1-3-pyridyl, --(CH.sub.2).sub.1-3-pyrimidyl,
--(CH.sub.2).sub.1-3-thienyl, --(CH.sub.2).sub.1-3-furyl,
--(CH.sub.2).sub.1-3-pyrrolyl, --(CH.sub.2).sub.1-3-pyrazolyl,
--(CH.sub.2).sub.1-3-imidazolyl, --(CH.sub.2).sub.1-3-thiazolyl,
--(CH.sub.2).sub.1-3-isothiazolyl,
--(CH.sub.2).sub.1-3-diathiazolyl, --(CH.sub.2).sub.1-3-oxazolyl,
and --(CH.sub.2).sub.1-3-isoxazolyl, each optionally substituted
with one or more R.sup.9. In some further embodiments, R.sup.9 is
halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl (e.g.,
trifluoromethyl).
[0155] In some further embodiments, R.sup.6 is phenyl substituted
with one, two or three R.sup.7, where each R.sup.7 is independently
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylamino, amino(C.sub.1-C.sub.6 alkyl),
heterocyclyl optionally substituted with one or more R.sup.9 (e.g.,
optionally substituted with C.sub.1-C.sub.6alkyl or halogen), or
heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9 (e.g., optionally substituted with C.sub.1-C.sub.6
alkyl or halogen). In some embodiments, R.sup.7 is halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylamino, unsubstituted heterocyclyl, heterocyclyl substituted
with C.sub.1-C.sub.6 alkyl, unsubstituted
heterocyclyl(C.sub.1-C.sub.6 alkyl), or
heterocyclyl(C.sub.1-C.sub.6 alkyl) substituted with
C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.7 is halogen
(e.g., fluoro or chloro). In some such embodiments, R.sup.7 is
C.sub.1-C.sub.6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, or
t-butyl). In some such embodiments, R.sup.7 is C.sub.1-C.sub.6
haloalkyl (such as --CH.sub.2F, --CHF.sub.2, --CF.sub.3,
--CH.sub.2CF.sub.3, and --CF.sub.2C.sub.1). In some such
embodiments, R.sup.7 is C.sub.1-C.sub.6 alkylamino (e.g.,
--NH(C.sub.1-C.sub.4 alkyl), --N(C.sub.1-C.sub.4 alkyl).sub.2,
methylamino, dimethylamino, ethylamino, diethylamino,
n-propylamino, di-n-propylamino, isopropylamino, diisopropylamino,
methylethylamino, or methylisopropylamino). In some such
embodiments, R.sup.7 is optionally substituted
amino(C.sub.1-C.sub.6 alkyl) (e.g.,
--(CH.sub.2).sub.1-3--NH(C.sub.1-C.sub.4 alkyl) or
--(CH.sub.2).sub.1-3--N(C.sub.1-C.sub.4 alkyl).sub.2). In some such
embodiments, R.sup.7 is a heterocyclyl optionally substituted with
one or more R.sup.9 (e.g., a four, five or six-membered monocyclic
heterocyclyl group containing one or two heteroatoms (e.g., N, O or
S), optionally substituted with one or more R.sup.9). In some
further embodiments, the heterocyclyl a 5 or 6 membered monocyclic
heterocyclyl group, such as pyrrolidine, piperidine, piperazine, or
morpholine, for example,
##STR00021##
each optionally substituted with one or two R.sup.9 (such as
methyl, ethyl, isopropyl or t-butyl). In some further embodiments,
R.sup.7 is heterocyclyl(C.sub.1-C.sub.6alkyl) optionally
substituted with one or more R.sup.9 (e.g., the heterocyclyl
portion may be a four, five or six-membered monocyclic heterocyclyl
group containing one or two heteroatoms (e.g., N, O, or S),
optionally substituted with one or more R.sup.9). Non-limiting
examples includes
##STR00022##
each optionally substituted with one or two R (such as methyl,
ethyl, isopropyl or t-butyl). When heterocyclyl or the heterocyclyl
portion of heterocyclyl(C.sub.1-C.sub.6 alkyl) contains a secondary
amine moiety, the nitrogen atom of such amine moiety may be
substituted with R.sup.9 (e.g.,
##STR00023##
where R.sup.9 is C.sub.1-C.sub.6 alkyl such as methyl, ethyl,
isopropyl or t-butyl). In some other embodiments, R.sup.7 is an
unsubstituted heterocyclyl or heterocyclyl(C.sub.1-C.sub.6 alkyl)
described herein. In some embodiments, R.sup.6 is a phenyl
substituted with C.sub.3-C.sub.7 cycloalkyl or C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl). Non-limiting examples
include
##STR00024##
each optionally substituted with one or more R.sup.9 (where R.sup.9
is halogen, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6 haloalkyl
(e.g., trifluoromethyl)). In some further embodiments, R.sup.6 is a
phenyl substituted with one, two, or three substituents
independently selected from the group consisting of fluoro, chloro,
methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl,
--NH(Me), --NH(Et), --N(Me).sub.2, --N(Et).sub.2,
##STR00025##
In some further embodiments, R.sup.6 is substituted with one or two
substituents described herein. When R.sup.6 is substituted with one
substituent, such substituent may be at the para position
##STR00026##
or meta position
##STR00027##
When R.sup.6 is substituted with two substituents, such
substituents may be at the para and otho positions
##STR00028##
or at the para and meta positions
##STR00029##
[0156] In some other embodiments, R.sup.6 is naphthyl substituted
with one, two or three R.sup.8, where each R.sup.8 is independently
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylamino, amino(C.sub.1-C.sub.6 alkyl),
C.sub.3-C.sub.7 cycloalkyl optionally substituted with one or more
R.sup.9, C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6 alkyl)
optionally substituted with one or more R.sup.9, heterocyclyl
optionally substituted with one or more R.sup.9 (e.g., optionally
substituted with C.sub.1-C.sub.6 alkyl or halogen), or
heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9 (e.g., optionally substituted with C.sub.1-C.sub.6
alkyl or halogen). In some further embodiments, In some
embodiments, R.sup.7 is halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylamino,
unsubstituted heterocyclyl, heterocyclyl substituted with
C.sub.1-C.sub.6 alkyl, unsubstituted heterocyclyl(C.sub.1-C.sub.6
alkyl), or heterocyclyl(C.sub.1-C.sub.6 alkyl) substituted with
C.sub.1-C.sub.6 alkyl. In some further embodiments, R.sup.6 is
substituted with one, two, or three substituents independently
selected from the group consisting of fluoro, chloro, methyl,
ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, --NH(Me),
--NH(Et), --N(Me).sub.2, --N(Et).sub.2,
##STR00030##
[0157] In some other embodiments, R.sup.6 is a pyridyl substituted
with one, two, or three substituents independently selected from
the group consisting of halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkylamino,
amino(C.sub.1-C.sub.6 alkyl), C.sub.3-C.sub.7 cycloalkyl optionally
substituted with one or more R.sup.9, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9, 5 or 6 membered heterocyclyl optionally
substituted with one or more R.sup.9, and 5 or 6 membered
heterocyclyl(C.sub.1-C.sub.6 alkyl) optionally substituted with one
or more R.sup.9. In some further embodiments, R.sup.6 is a pyridyl
substituted with one, two, or three substituents independently
selected from the group consisting of fluoro, chloro, methyl,
ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, --NH(Me),
--NH(Et), --N(Me).sub.2, --N(Et).sub.2,
##STR00031##
[0158] In some embodiments the compound of Formula (I) is:
##STR00032##
or a pharmaceutically acceptable salt of any of the foregoing. In
some embodiments, X is C.dbd.O or CH.sub.2. In some embodiments, X
is C.dbd.O. In other embodiments, X is CH.sub.2. In some
embodiments, one of X.sub.A and X.sub.C is a bond. In other
embodiments, both X.sub.A and X.sub.C are --CH.sub.2--. In some
such embodiments, R.sup.2 is --CH.sub.2--CH.sub.2--R.sup.6. In some
such embodiments, R.sup.2 is --O--CH.sub.2--R.sup.6. In other
embodiments, R.sup.2 is --S--CH.sub.2--R.sup.6. In still other
embodiments, R.sup.2 is --NH--CH.sub.2--R.sup.6. In some such
embodiments, R.sup.2 is --CH.sub.2--O--R.sup.6. In other
embodiments, R.sup.2 is --CH.sub.2--S--R.sup.6. In still other
embodiments, R.sup.2 is --CH.sub.2--NH--R.sup.6. In some such
embodiments, R.sup.2 is --CH.sub.2--O--CH.sub.2--R.sup.6. In other
embodiments, R.sup.2 is --CH.sub.2--S--CH.sub.2--R.sup.6. In still
other embodiments, R.sup.2 is --CH.sub.2--NH--CH.sub.2--R.sup.6. In
some embodiments, R.sup.6 is phenyl substituted with one or two
substituents. In some such embodiments, when R.sup.6 is phenyl
substituted with one substituent, such substituent is fluoro,
chloro, methyl, ethyl, isopropyl or t-butyl. In some such
embodiments, when R.sup.6 is phenyl substituted with one
substituent, such substituent is --N(Me).sub.2, --N(Et).sub.2,
--(CH.sub.2).sub.1-2--N(Me).sub.2, or
--(CH.sub.2).sub.1-2N(Et).sub.2. In some such embodiments, when
R.sup.6 is phenyl substituted with one substituent, such
substituent is
##STR00033##
each optionally substituted with one or more R.sup.9, for example,
C.sub.1-C.sub.6 alkyl. In some such embodiments, when R.sup.6 is
phenyl substituted with one substituent, such substituent is
##STR00034##
In some such embodiments, when R.sup.6 is phenyl substituted with
two substituents, such substituents are independently fluoro,
chloro, methyl, trifluoromethyl, ethyl, isopropyl or t-butyl. In
some such embodiments, when R.sup.6 is phenyl substituted with two
substituents, one such substituent is --N(Me).sub.2, --N(Et).sub.2,
--(CH.sub.2).sub.1-2--N(Me).sub.2, or
--C.sub.2).sub.1-2N(Et).sub.2; and the other such substituent is
fluoro, chloro, methyl, trifluoromethyl, ethyl, isopropyl or
t-butyl. In some such embodiments, when R.sup.6 is phenyl
substituted with two substituents, one such substituent is
##STR00035##
each optionally substituted with one or more R.sup.9 (for example,
C.sub.1-C.sub.6 alkyl); and the other such substituent is fluoro,
chloro, methyl, trifluoromethyl, ethyl, isopropyl, t-butyl,
--N(Me).sub.2, --N(Et).sub.2, --(CH.sub.2).sub.1-2--N(Me).sub.2, or
--(CH.sub.2).sub.1-2N(Et).sub.2.
[0159] In some embodiments, the compound of Formula (I) is selected
from Compounds 1-31 of Table B, and pharmaceutically acceptable
salts thereof.
TABLE-US-00002 TABLE B Exemplary Compounds of Formula (I) COMPD No.
Structure COMPD No. Structure 1 ##STR00036## 2 ##STR00037## 3
##STR00038## 4 ##STR00039## 5 ##STR00040## 6 ##STR00041## 7
##STR00042## 8 ##STR00043## 9 ##STR00044## 10 ##STR00045## 11
##STR00046## 12 ##STR00047## 13 ##STR00048## 14 ##STR00049## 15
##STR00050## 16 ##STR00051## 17 ##STR00052## 18 ##STR00053## 19
##STR00054## 20 ##STR00055## 21 ##STR00056## 22 ##STR00057## 23
##STR00058## 24 ##STR00059## 25 ##STR00060## 26 ##STR00061## 27
##STR00062## 28 ##STR00063## 29 ##STR00064## 30 ##STR00065## 31
##STR00066##
[0160] Some embodiments provide a pharmaceutical composition,
comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie),
or (If), or a pharmaceutically acceptable salt thereof, and at
least one pharmaceutically acceptable carrier or excipient.
[0161] In any embodiments of the compounds described herein, when a
substituent is selected from a carbocyclyl (e.g., C.sub.3-C.sub.8
carbocyclyl, it includes C.sub.3-C.sub.8 cycloalkyl. When a
substituent is select from 3 to 7 membered heterocyclyl, it
includes 3 to 7 membered monocyclic heterocycle rings with no
double or triple bond within the ring structure.
[0162] In some embodiments, the compound of Formula (I) (including
Formula (Ia)-(If)) is formed as a pharmaceutically acceptable salt.
In some embodiments, the pharmaceutically acceptable salt is a
trifluoroacetic acid salt. In some embodiments, the compound of
Formula (I) (including Formula (Ia)-(If)), or a pharmaceutically
acceptable salt of any of the foregoing, is racemic. In some
embodiments, the compound of Formula (I) (including Formula
(Ia)-(If)), or a pharmaceutically acceptable salt of any of the
foregoing, has an S-configuration or a R-configuration (for
example, at the carbon atom with an asterisk
##STR00067##
In some embodiments, the compound of Formula (I) (including Formula
(Ia)-(If)), or a pharmaceutically acceptable salt of any of the
foregoing, is enriched in one enantiomer over another enantiomer,
for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, 95%, or 99%, or a range defined by any two preceding
values. In some embodiments, the compound of Formula (I) (including
Formula (Ia)-(If)) or a pharmaceutically acceptable salt of any of
the foregoing, is enriched in one diastereomer over another
diastereomer for example, enriched by about 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, 95%, or 99%, or a range defined by any two
preceding values. In some embodiments, the compound of Formula (I)
(including Formula (Ia)-(If)) is a pharmaceutically acceptable
solvate.
Methods of Treatment/Uses
[0163] Some embodiments provide a method of modulating the activity
of a protein in a biological sample, comprising contacting the
biological sample with a compound of Formula (I) (including (Ia),
(Ib), (Ic), (Id), (Ie), or (If)), or a pharmaceutically acceptable
salt thereof; wherein the protein is IL-1.beta., IL-2, IL-6,
TNF.alpha., CK1.alpha., GSPT1, aiolos, ikaros, or helios, or
combinations thereof. Some embodiments provide the use of a
compound of Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie), or
(If)), or a pharmaceutically acceptable salt thereof, for
modulating the activity of a protein in a biological sample,
comprising contacting the biological sample with a compound of
Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie), or (If)) or a
pharmaceutically acceptable salt thereof; wherein the protein is
IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1, aiolos,
ikaros, or helios, or combinations thereof. In some embodiments,
the protein is wild-type. In other embodiments, the protein is a
mutant form of the protein. In some embodiments, the protein is
overexpressed. In some aspect, the method or use inhibits the
activity of the protein. In another aspect, the method of use
induces the activity of the protein, for example, IL-2. In some
embodiments, the biological sample contains one or more cancer
cells. In some embodiments, the cells are small cell lung cancer
cells, non-small cell lung cancer cells, breast cancer cells,
prostate cancer cells, head and neck cancer cells, pancreatic
cancer cells, colon cancer cells, rectal cancer cells, teratoma
cells, ovarian cancer cells, gastric cancer cells, endometrial
cancer cells, brain cancer cells, retinoblastoma cells, leukemia
cells, skin cancer cells, melanoma cells, squamous cell carcinoma
cells, liposarcoma cells, lymphoma cells, multiple myeloma cells,
testicular cancer cells, liver cancer cells, esophageal cancer
cells, kidney carcinoma cells, astrogliosis cells, multiple myeloma
cells (relapsed/refractory), or neuroblastoma cells. In some
further embodiments, the biological sample contains leukemia cells,
lymphoma cells, or multiple myeloma cells.
[0164] Some embodiments provide a method of treating, ameliorating,
or preventing a disease, disorder, or condition associated with a
protein in a subject, the protein is IL-1.beta., IL-2, IL-6,
TNF.alpha., CK1.alpha., GSPT1, aiolos, ikaros, or helios, or
combinations of any of the foregoing; the method comprising
administering a therapeutically effective amount of a compound of
Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof to the subject; wherein the disease, disorder,
or condition is a hematological malignancy or a solid tumor. Some
embodiments provide the use of a compound of Formula (I) (including
(Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition thereof
for treating, ameliorating, or preventing a disease, disorder, or
condition associated with a protein; wherein the protein is
IL-1.beta., IL-2, IL-6, TNF.alpha., CK1.alpha., GSPT1, aiolos,
ikaros, or helios, combinations of any of the foregoing; and
wherein the disease, disorder, or condition is a hematological
malignancy or a solid tumor. In some embodiments, the protein is
wild-type. In other embodiments, the protein is a mutant form of
the protein. In some embodiments, the protein is overexpressed.
[0165] Some other embodiments provide a method of treating,
ameliorating, or preventing a hematological malignancy or a solid
tumor in a subject, comprising administering a therapeutically
effective amount of a compound of Formula (I) (including (Ia),
(Ib), (Ic), (Id), (Ie), or (If)), or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition thereof to the
subject. Some embodiments provide the use of a compound of Formula
(I) (including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof for treating, ameliorating, or preventing a
hematological malignancy or a solid tumor. In some embodiments, the
hematological malignancy or the solid tumor is associated with a
protein, wherein the protein is IL-1.beta., IL-2, IL-6, TNF.alpha.,
CK1.alpha., GSPT1, aiolos, ikaros, or helios, combinations of any
of the foregoing. In some embodiments, the protein is wild-type. In
other embodiments, the protein is a mutant form of the protein. In
some embodiments, the protein is overexpressed.
[0166] In some embodiments of the methods or uses described herein,
the hematological malignancy or a solid tumor is small cell lung
cancer, non-small cell lung cancer, breast cancer, prostate cancer,
head and neck cancer, pancreatic cancer, colon cancer, rectal
cancer, teratoma, ovarian cancer, gastric cancer, endometrial
cancer, brain cancer, retinoblastoma, leukemia, skin cancer,
melanoma, squamous cell carcinoma, liposarcoma, lymphoma, multiple
myeloma, testicular cancer, liver cancer, esophageal cancer, kidney
carcinoma, astrogliosis, multiple myeloma (relapsed/refractory), or
neuroblastoma. In some further embodiments, the hematological
malignancy is leukemia, lymphoma, or multiple myeloma.
[0167] Some additional embodiments provide a method of treating,
ameliorating, or preventing a disease, disorder, or condition
associated with a protein in a subject, the protein is IL-10, IL-2,
IL-6, TNF.alpha., CK1.alpha., GSPT1, aiolos, ikaros, or helios, or
combinations of any of the foregoing; the method comprising
administering a therapeutically effective amount of a compound of
Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof to the subject; wherein the disease, disorder,
or condition is a neurodegenerative disease, fibrosis, lupus,
fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, uveitis, or chronic
obstructive pulmonary disease. In some further embodiments, the
neurodegenerative disease may include multiple sclerosis,
Alzheimer's disease, Parkinson's disease and other chronic
inflammatory diseases of the central nervous system. In some
further embodiments, fibrosis may include renal fibrosis, pulmonary
fibrosis, and hepatic fibrosis. Some embodiments provide the use of
a compound of Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie),
or (If)), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition thereof for treating, ameliorating, or
preventing a disease, disorder, or condition associated with a
protein; wherein the protein is IL-1.beta., IL-2, IL-6, TNF.alpha.,
CK1.alpha., GSPT1, aiolos, ikaros, or helios, or combinations of
any of the foregoing; and wherein the disease, disorder, or
condition is a neurodegenerative disease, fibrosis, lupus,
fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, uveitis, or chronic
obstructive pulmonary disease. In some embodiments, the disease,
disorder, or condition is multiple sclerosis, Alzheimer's disease,
Parkinson's disease, lupus, fibromyalgia, rheumatoid arthritis,
osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic
arthritis, Crohn's disease, or ulcerative colitis. In some
embodiments, the protein is wild-type. In other embodiments, the
protein is a mutant form of the protein. In some embodiments, the
protein is overexpressed.
[0168] Some embodiments provide a method of treating, ameliorating,
or preventing an inflammatory disease, disorder or condition in a
subject, comprising administering a therapeutically effective
amount of a compound of Formula (I) (including (Ia), (Ib), (Ic),
(Id), (Ie), or (If)), or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition thereof to the subject.
Some embodiments provide the use of a compound of Formula (I)
(including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof for treating, ameliorating, or preventing an
inflammatory disease, disorder or condition. In some embodiments,
the inflammatory disease, disorder or condition is a
neurodegenerative disease (such as multiple sclerosis, Alzheimer's
disease, Parkinson's disease), pulmonary fibrosis, lupus,
fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing
spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, uveitis, or chronic
obstructive pulmonary disease. In some embodiments, the
inflammatory disease, disorder or condition is associated with a
protein, wherein the protein is IL-1.beta., IL-2, IL-6, TNF.alpha.,
CK1.alpha., GSPT1, aiolos, ikaros, or helios, combinations of any
of the foregoing. In some embodiments, the protein is wild-type. In
other embodiments, the protein is a mutant form of the protein. In
some embodiments, the protein is overexpressed.
Additional Therapeutic Agents
[0169] Some embodiments provide pharmaceutical compositions
comprising a compound of Formula (I) (including (Ia), (Ib), (Ic),
(Id), (Ie), or (If)) or a pharmaceutically acceptable salt of any
of the foregoing and a second therapeutic agent. In some
embodiments, the second therapeutic agent is an anti-inflammatory
agent. In some embodiments, the second therapeutic agent is a
non-steroidal anti-inflammatory agent. In some embodiments, the
second therapeutic agent is an anti-cancer agent. In some
embodiments, the second therapeutic agent is an immunostimulatory
agent. In some embodiments, the second therapeutic agent is an
immunosuppressive agent. In some embodiments, the second
therapeutic agent is an antibody.
[0170] In some embodiments, the second therapeutic agent is
selected from aspirin; diflunisal; salsalate; acetaminophen;
ibuprofen; dexibuprofen; naproxen; fenoprofen; ketoprofen;
dexketoprofen; flurbiprofen; oxaprozin; loxoprofen; indomethacin;
tolmetin; sulindac; etodolac; ketorolac; diclofenac; aceclofenac;
nabumetone; enolic acid; piroxicam; meloxicam; tenoxicam; droxicam;
lornoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic
acid; tolfenamic acid; sulfonanilides; clonixin; licofelone;
dexamethasone; and prednisone. In some embodiments, the second
therapeutic agent is mechlorethamine; cyclophosphamide; melphalan;
chlorambucil; ifosfamide; busulfan; N-nitroso-N-methylurea (MNU);
carmustine (BCNU); lomustine (CCNU); semustine (MeCCNU);
fotemustine; streptozotocin; dacarbazine; mitozolomide;
temozolomide; thiotepa; mytomycin; diaziquone (AZQ); cisplatin;
carboplatin; or oxaliplatin. In some embodiments, the second
therapeutic agent is vincristine; vinblastine; vinorelbine;
vindesine; vinflunine; paclitaxel; docetaxel; etoposide;
teniposide; tofacitinib; ixabepilone; irinotecan; topotecan;
camptothecin; doxorubicin; mitoxantrone; or teniposide. In some
embodiments, the second therapeutic agent is actinomycin;
bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin;
idarubicin; pirarubicin; aclarubicin; mitoxantrone;
cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone;
folinic acid; methotrexate; melphalan; capecitabine;
mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide;
bendamustine; 6-mercaptopurine; or procarbazine. In some
embodiments, the second therapeutic agent is cladribine;
pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine;
cladribine; clofarabine; ytarabine; decitabine; cytarabine;
cytarabine liposomal; pralatrexate; floxuridine; fludarabine;
colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel;
tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed;
pemetrexed; carmofur; or floxuridine. In some embodiments, the
second therapeutic agent is azacitidine; decitabine;
hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide;
aclarubicin; epirubicin; idarubicin; amrubicin; pirarubicin;
valrubicin; zorubicin; mitoxantrone; pixantrone; mechlorethamine;
chlorambucil; prednimustine; uramustine; estramustine; carmustine;
lomustine; fotemustine; nimustine; ranimustine; carboquone;
thioTEPA; triaziquone; or triethylenemelamine. In some embodiments,
the second therapeutic agent is nedaplatin; satraplatin;
procarbazine; dacarbazine; temozolomide; altretamine; mitobronitol;
pipobroman; actinomycin; bleomycin; plicamycin; aminolevulinic
acid; methyl aminolevulinate; efaproxiral; talaporfin; temoporfin;
verteporfin; alvocidib; seliciclib; palbociclib; bortezomib;
carfilzomib; anagrelide; masoprocol; olaparib; belinostat;
panobinostat; romidepsin; vorinosta; idelalisib; atrasentan;
bexarotene; testolactone; amsacrine; trabectedin; alitretinoin;
tretinoin; demecolcine; elsamitrucin; etoglucid; lonidamine;
lucanthone; mitoguazone; mitotane; oblimersen; omacetaxine
mepesuccinate; or eribulin. In some embodiments, the second
therapeutic agent is azathioprine; mycophenolic acid; leflunomide;
teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus;
gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra;
sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus;
zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab
pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab;
faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept;
otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab;
zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; or
ocrelizumab. In some embodiments, the second therapeutic agent is
pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab;
aselizumab; galiximab; gavilimomab; ruplizumab; belimumab;
blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab;
metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab;
daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab;
fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab;
rovelizumab; siplizumab; talizumab; telimomab; vapaliximab;
vepalimomab; abatacept; belatacept; pegsunercept; aflibercept;
alefacept; or rilonacept.
Dosing Regimes
[0171] In some embodiments, about 1 mg to about 5 grams, or any
amount in between, of a compound of Formula (I) (including (Ia),
(Ib), (Ic), (Id), (Ie), or (If)), or a pharmaceutically acceptable
salt of any of the foregoing is administered each day, each week,
or each cycle of treatment.
[0172] In some embodiments, a compound of Formula (I) (including
(Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a pharmaceutically
acceptable salt of any of the foregoing is administered once per
day, twice per day, three times per day, four times per day, or
more than four times per day. In some embodiments, a compound of
Formula (I) (including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt of any of the foregoing is
administered once per day, twice per day, three times per day, four
times per day, or more than four times per cycle of treatment.
[0173] In some embodiments, each cycle of treatment lasts from 1
day to 14 days, or any value in between. In some embodiments, each
cycle of treatment has from at least one day up to fourteen days,
or any value in between, between administration. In some
embodiments, each cycle of treatment includes one or more
additional therapeutic agents, as described herein. In some
embodiments, a compound of Formula (I) (including (Ia), (Ib), (Ic),
(Id), (Ie), or (If)), or a pharmaceutically acceptable salt of any
of the foregoing is provided intravenously over about 10 minutes to
over about 4 hours, or any value in between.
Pharmaceutical Compositions
[0174] Some embodiments described herein relate to a pharmaceutical
composition, that can include an effective amount of one or more
compounds described herein (for example, a compound of Formula (I)
(including (Ia), (Ib), (Ic), (Id), (Ie), or (If)), or a
pharmaceutically acceptable salt thereof) and at least one
pharmaceutically acceptable excipient or carrier.
[0175] The term "pharmaceutical composition" refers to a mixture of
one or more compounds and/or salts disclosed herein with other
chemical components, such as one or more excipients. The
pharmaceutical composition facilitates administration of the
compound to an organism. Pharmaceutical compositions can also be
obtained by reacting compounds with inorganic or organic acids such
as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, and salicylic acid. Pharmaceutical
compositions will generally be tailored to the specific intended
route of administration.
[0176] As used herein, an "excipient" refers to essentially inert
substances that are added to a pharmaceutical composition to
provide, without limitation, bulk, consistency, stability, binding
ability, lubrication, disintegrating ability etc., to the
composition. For example, stabilizers such as anti-oxidants and
metal-chelating agents are excipients. Excipients also include
ingredients in a pharmaceutical composition that lack appreciable
pharmacological activity but may be pharmaceutically necessary or
desirable. For example, to increase the bulk of a potent drug whose
mass is too small for manufacture and/or administration. It may
also be a liquid for the dissolution of a drug to be administered
by injection, ingestion or inhalation. For example, a buffered
aqueous solution such as, without limitation, phosphate buffered
saline that mimics the pH and isotonicity of human blood.
[0177] The pharmaceutical compositions described herein can be
administered to a human patient per se, or in pharmaceutical
compositions where they are mixed with other active ingredients, as
in combination therapy, or excipients, or combinations thereof.
Proper formulation is dependent upon the route of administration
chosen. Techniques for formulation and administration of the
compounds described herein are known to those skilled in the
art.
[0178] The pharmaceutical compositions disclosed herein may be
manufactured in a manner that is itself known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or tableting
processes. Additionally, the active ingredients are contained in an
amount effective to achieve its intended purpose. Many of the
compounds used in the pharmaceutical combinations disclosed herein
may be provided as salts with pharmaceutically compatible
counterions.
[0179] One or more of the compounds of preferred embodiments can be
provided in the form of pharmaceutically acceptable salts, active
metabolites, tautomers, or prodrugs thereof. Some embodiments can
be provided in pharmaceutical compositions comprising a
therapeutically effective amount of the compound. In some
embodiments, the pharmaceutical composition also contains at least
one pharmaceutically acceptable inactive ingredient. The
pharmaceutical composition can be formulated for intravenous
injection, subcutaneous injection, oral administration, buccal
administration, inhalation, nasal administration, topical
administration, transdermal administration, ophthalmic
administration, or otic administration. The pharmaceutical
composition can be in the form of a tablet, a pill, a capsule, a
liquid, an inhalant, a nasal spray solution, a suppository, a
suspension, a gel, a colloid, a dispersion, a solution, an
emulsion, an ointment, a lotion, an eye drop, or an ear drop.
[0180] Multiple techniques of administering a compound, salt and/or
composition exist in the art including, but not limited to, oral,
rectal, pulmonary, topical, aerosol, injection, infusion and
parenteral delivery, including intramuscular, subcutaneous,
intravenous, intramedullary injections, intrathecal, direct
intraventricular, intraperitoneal, intranasal and intraocular
injections. In some embodiments, a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, can be administered
orally.
[0181] One may also administer the compound, salt and/or
composition in a local rather than systemic manner, for example,
via injection or implantation of the compound directly into the
affected area, often in a depot or sustained release formulation.
Furthermore, one may administer the compound in a targeted drug
delivery system, for example, in a liposome coated with a
tissue-specific antibody. The liposomes will be targeted to and
taken up selectively by the organ. For example, intranasal or
pulmonary delivery to target a respiratory disease or condition may
be desirable.
[0182] The compositions may, if desired, be presented in a pack or
dispenser device which may contain one or more unit dosage forms
containing the active ingredient. The pack may for example comprise
metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with
a notice associated with the container in form prescribed by a
governmental agency regulating the manufacture, use, or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the drug for human or veterinary
administration. Such notice, for example, may be the labeling
approved by the U.S. Food and Drug Administration for prescription
drugs, or the approved product insert. Compositions that can
include a compound and/or salt described herein formulated in a
compatible pharmaceutical excipient may also be prepared, placed in
an appropriate container, and labeled for treatment of an indicated
condition.
EXAMPLES
[0183] Additional embodiments are disclosed in further detail in
the following schemes, which are not in any way intended to limit
the scope of the claims.
[0184] Characterization of the compounds disclosed herein is
performed with Bruker AV-500 and Bruker DRX-500 NMR spectrometers
and a Perkin Elmer PE-SCIEX API-150 mass spectrometer.
General Synthesis
##STR00068##
##STR00069##
##STR00070##
##STR00071##
##STR00072##
##STR00073##
[0185] Example 1
Compound 1:
(S)-3-(1-((4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrr-
ol-5(6H)-yl)piperidine-2,6-dione
##STR00074##
[0187] To a solution of methyl 4-methylthiophene-3-carboxylate (5.0
g, 32 mmol) in DMF (25 mL) at 0.degree. C. was added NBS (6.0 g, 34
mmol). The mixture was stirred at RT overnight then poured into
water and extracted with EA. The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give methyl 5-bromo-4-methylthiophene-3-carboxylate
(7.2 g, crude) as an oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.06 (s, 1H), 3.86 (s, 3H), 2.42 (s, 3H).
[0188] To a solution of methyl
5-bromo-4-methylthiophene-3-carboxylate (7.2 g, 30 mmol, crude) in
CCl.sub.4 (70 mL) was added NBS (5.75 g, 32.3 mmol) and benzoyl
peroxide (2.18 g, 9.00 mmol). After heating at 80.degree. C. for 5
h, the mixture was filtered, and the filtrate was concentrated. The
residue was purified using silica gel eluting with PE/EA (1:1) to
give methyl 5-bromo-4-(bromomethyl)thiophene-3-carboxylate (4.4 g,
46% yield) as an oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.04 (s, 1H), 4.77 (s, 2H), 3.83 (s, 3H).
[0189] To a solution of methyl
5-bromo-4-(bromomethyl)thiophene-3-carboxylate (4.4 g, 1.0 mmol)
and (S)-tert-butyl 4,5-diamino-5-oxopentanoate (4.00 g, 16.9 mmol)
in DMF (40 mL) was added TEA (4 mL). The mixture was stirred at
40.degree. C. for 3 h then quenched with water and extracted with
DCM. The combined organic layers were washed with aqueous 1M LiCl,
and brine, then dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give (S)-methyl
4-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bromoth-
iophene-3-carboxylate (5.70 g, 93% yield) as an oil. MS (ESI) m/z
435.1 [M+H].sup.+.
[0190] To a solution of (S)-methyl
4-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bromoth-
iophene-3-carboxylate (5.70 g, 13.1 mmol) in THF (80 mL) at
0.degree. C. was added aqueous 0.6 M LiOH (33 mL). The mixture was
stirred at 0.degree. C. for 2 h then concentrated. The residue was
dissolved in water and washed with EA. The aqueous layer was
adjusted to a pH of 6 using 1N HCl. The resulting precipitate was
collected by filtration to give
(S)-4-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)--
5-bromothiophene-3-carboxylic acid (2.2 g, 40% yield) as a solid.
MS (ESI) m/z 421.1 [M+H].sup.+.
[0191] To a mixture of
(S)-4-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bro-
mothiophene-3-carboxylic acid (2.2 g, 5.2 mmol) in DMF was added
2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (4.00 g, 10.4 mmol) and DIEA (2.6 mL). After 2
h, the mixture was quenched with water and extracted with EA. The
combined organic layers were washed with 1M aqueous LiCl, saturated
NaHCO.sub.3, and brine, then dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified using silica gel eluting
with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(2.5 g, quant) as a solid. MS (ESI) m/z 403.0 [M+H].sup.+.
[0192] To a solution of (S)-tert-butyl
5-amino-4-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.20 g, 3.00 mmol) in DMF (6 mL) was added
1,1'-bis(diphenylphosphino)ferrocene (333 mg, 0.60 mmol), zinc
cyanide (388 mg, 3.30 mmol) and
tris(dibenzylideneacetone)dipalladium (275 mg, 0.30 mmol). After
N.sub.2 purge, the mixture was stirred at 150.degree. C. under
microwave for 1 h. The mixture was diluted with water and extracted
with EA. The combined organic layers were washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified using silica gel eluting with PE/EA (1:2) to give
(S)-tert-butyl
5-amino-4-(1-cyano-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(260 mg, 26% yield) as a solid. MS (ESI) m/z 350.1
[M+Na].sup.+.
[0193] To (S)-tert-butyl
5-amino-4-(1-cyano-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(260 mg, 0.74 mmol) in a solution of AcOH (2 mL), pyridine (4 mL),
and water (2 mL) was added sodium hypophosphite (320 mg, 3.72 mmol)
and Raney Ni (50 mg). After 1 h, the mixture was filtered. The
filtrate was concentrated, diluted with DCM, washed with 1N HCl,
and brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified using silica gel eluting with PE/EA (1:2)
to give (S)-tert-butyl
5-amino-4-(1-formyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (130 mg, 50% yield) as a solid. MS (ESI) m/z 353.1
[M+H].sup.+.
[0194] To a solution of (S)-tert-butyl
5-amino-4-(1-formyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (130 mg, 0.37 mmol) in MeOH (4 mL) at 0.degree. C. was added
sodium borohydride (8.5 g, 0.22 mmol). The mixture was stirred at
RT for 3 h then concentrated and purified by prep-TLC eluting with
EA to give (S)-tert-butyl
5-amino-4-(1-(hydroxymethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (100 mg, 76% yield) as solid. MS (ESI) m/z 355.1
[M+Na].sup.+.
[0195] To a solution of (S)-tert-butyl
5-amino-4-(1-(hydroxymethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (100 mg, 0.28 mmol), 4-dimethylaminopyridine (3.5 mg,
0.028 mmol) and TEA (57 mg, 0.56 mmol) in DCM (4 mL) was added
tosyl chloride (108 mg, 0.56 mmol). The mixture was stirred for 2 h
then concentrated to give (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (80 mg, crude) as a solid. MS (ESI) m/z 373.1
[M+H].sup.+.
[0196] To a solution 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) and
morpholine (1 mL) in DCM (20 mL) was added sodium
triacetoxyborohydride (3.50 g, 16.4 mmol). After heating at RT
overnight, the mixture was washed with saturated aqueous
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified using silica gel eluting
with PE/EA (1:1) to give 4-(morpholinomethyl)phenol (1.0 g, 63%
yield) as a solid. MS (ESI) m/z 194.1 [M+H].sup.+.
[0197] To a solution of (S-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (80 mg, 0.21 mmol, crude) and 4-(morpholinomethyl)phenol
(81 mg, 0.42 mmol) in ACN (4 mL) was added K.sub.2CO.sub.3 (60 mg,
0.42 mmol). The mixture was stirred at 80.degree. C. for 2 h then
concentrated, and the residue was purified using silica gel eluting
with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (60 mg, 52% yield) as an oil. MS
(ESI) m/z 530.2 [M+H].sup.+.
[0198] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (60 mg, 0.11 mmol) in DCM (4 mL)
was added TFA (1 mL). The mixture was stirred for 1 h then
concentrated to give
(S)-5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thie-
no[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (0.11 mmol, crude) as
a solid, which was used in the next step without further
purification.
[0199] To a solution
(S)-5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (0.11 mmol, crude) in ACN
(4 mL) was added CDI (72 mg, 0.44 mmol). The mixture was stirred at
95.degree. C. for 3 h then concentrated and purified by prep-TLC
eluting with EA to afford Compound 1 (26.8 mg, 53% yield) as a
solid. MS (ESI) m/z 456.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.99 (s, 1H), 8.02 (s, 1H), 7.23 (d, J=8.4
Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 5.02 (dd, J=4.8,
13.2 Hz, 1H), 4.35 (d, J=15.6 Hz, 1H), 4.22 (d, J=16.0 Hz, 1H),
3.55 (d, J=4.0 Hz, 4H), 3.37-3.40 (m, 2H), 2.84-2.93 (m, 1H),
2.56-2.60 (m, 1H), 2.29-2.37 (m, 5H), 1.96-2.00 (m, 1H).
Example 2
Compound 2:
(S)-3-(3-((4-(morpholinomethyl)benzyl)oxy)-6-oxo-4H-thieno[2,3-c]pyrrol-5-
(6H)-yl)piperidine-2,6-dione
##STR00075##
[0201] To a solution of methyl
4-bromo-3-methylthiophene-2-carboxylate (15.0 g, 64.1 mmol) in THF
(100 mL) and MeOH (50 mL) at 0.degree. C. was added LiOH (163
mmol). The mixture was stirred at RT overnight then concentrated.
The residue was acidified with 2M HCl to a pH of approximately 3 to
4. The mixture was filtered and the filter cake was dried to give
4-bromo-3-methylthiophene-2-carboxylic acid (12.5 g, 89% yield) as
a solid.
[0202] To a solution of 4-bromo-3-methylthiophene-2-carboxylic acid
(11.5 g, 52.3 mmol) in DCM (100 mL) at 0.degree. C. was added
(COCl).sub.2 (13.3 g, 549 mmol) and DMF (1 mL) dropwise. After 2 h,
the mixture was concentrated. The residue was dissolved in THF (100
mL) and a solution of t-BuOK (17.6 g, 157 mmol) in THF (50 mL) was
added. The mixture was stirred for 1 h then quenched with water and
extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give tert-butyl
4-bromo-3-methylthiophene-2-carboxylate (9.2 g, 64% yield) as an
oil.
[0203] To a solution of tert-butyl
4-bromo-3-methylthiophene-2-carboxylate (8.60 g, 31.3 mmol) in
1,4-dioxane (150 mL) was added KOAc (9.20 g, 93.8 mmol) and
bis(pinacolato)diboron (11.9 g, 46.9 mmol). After N.sub.2 purge,
Pd(PPh.sub.3)Cl.sub.2 (4.6 g, 6.3 mmol) was added and the mixture
was heated at 100.degree. C. overnight. After concentration, the
residue was purified using silica gel eluting with PE/EA (1:2) to
give tert-butyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbo-
xylate (6.45 g, 64% yield) as a solid.
[0204] To a solution of tert-butyl
3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carbo-
xylate (6.97 g, 21.5 mmol) in acetone (90 mL) and water (90 mL) at
0.degree. C. was added NaIO.sub.4 (13.8 g, 64.5 mmol) and
NH.sub.4OAc (3.3 g, 43 mmol). The mixture was stirred at RT
overnight then concentrated. The residue was purified using silica
gel eluting with PE/EA (1:1) to give
(5-(tert-butoxycarbonyl)-4-methylthiophen-3-yl)boronic acid (2.08
g, 40% yield) as a solid.
[0205] To a solution of
(5-(tert-butoxycarbonyl)-4-methylthiophen-3-yl)boronic acid (2.08
g, 8.39 mmol) in ether (50 mL) at 0.degree. C. was added
H.sub.2O.sub.2(2.5 mL). After 2 h, the reaction was quenched with
saturated Na.sub.2SO.sub.3 and exacted with EA. The combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified using silica
gel eluting with PE/EA (1:1) to give tert-butyl
4-hydroxy-3-methylthiophene-2-carboxylate (1.6 g, 89% yield) as a
gum.
[0206] To a solution of tert-butyl
4-hydroxy-3-methylthiophene-2-carboxylate (1.50 g, 7.01 mmol) in
DMF (3 mL) was added imidazole (1.43 g, 21.0 mmol) and TBDMSCl
(1.58 g, 10.51 mmol). After heating at 60.degree. C. for 1 h, water
was added, and the mixture was extracted with methyl tert-butyl
ether. The combined organic layers were washed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified using silica gel eluting with PE/EA (1:1) to give
tert-butyl
4-((tert-butyldimethylsilyl)oxy)-3-methylthiophene-2-carboxylate
(2.23 g, 97% yield) as an oil.
[0207] To a solution of tert-butyl
4-((tert-butyldimethylsilyl)oxy)-3-methylthiophene-2-carboxylate
(1.93 g, 5.88 mmol) in CCl.sub.4 (50 mL) was added NBS (1.10 g,
6.18 mmol) and AIBN (506 mg, 2.94 mmol). After heating at reflux
overnight, the mixture was concentrated. The residue was dissolved
in water and extracted with EA. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified using silica gel eluting with PE/EA (1:1) to
give tert-butyl 3-(bromomethyl)-4-((tert-butyldimethylsilyl)
oxy)thiophene-2-carboxylate (2.0 g, 84% yield) as an oil.
[0208] To a solution of (S)-methyl 4,5-diamino-5-oxopentanoate (1.7
g, 6.2 mmol) in DMF (50 mL) at 0.degree. C. was added DIEA (1.85 g,
14.33 mmol) and tert-butyl
3-(bromomethyl)-4-((tert-butyldimethylsilyl)
oxy)thiophene-2-carboxylate (1.94 g, 4.78 mmol). After stirring at
RT overnight, the mixture was diluted with water and extracted with
EA. The combined layers were dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified using silica gel eluting
with PE/EA (1:2) to give (S)-tert-butyl
3-(((1-amino-5-methoxy-1,5-dioxopentan-2-yl)amino)methyl)-4-((tert-butyld-
imethylsilyl)oxy)thiophene-2-carboxylate (815 mg, 35% yield) as an
oil. MS (ESI) m/z 487 [M+H].sup.+.
[0209] To a solution of (S)-tert-butyl
3-(((1-amino-5-methoxy-1,5-dioxopentan-2-yl)amino)methyl)-4-((tert-butyld-
imethylsilyl)oxy)thiophene-2-carboxylate (715 mg, 1.47 mmol) in DCM
(10 mL) at 0.degree. C. was added TFA (3 mL). The mixture was
stirred at RT for 8 h then concentrated to give
(S)-3-(((1-amino-5-methoxy-1,5-dioxopentan-2-yl)amino)methyl)-4-((tert-bu-
tyldimethylsilyl)oxy)thiophene-2-carboxylic acid (633 mg, quant) as
an oil. MS (ESI) m/z 431 [M+H].sup.+.
[0210] To a solution of
(S)-3-(((1-amino-5-methoxy-1,5-dioxopentan-2-yl)amino)methyl)-4-((tert-bu-
tyldimethylsilyl)oxy)thiophene-2-carboxylic acid (633 mg, 1.47
mmol) in DMF (15 mL) at 0.degree. C. was added HATU (670.8 g, 1.765
mmol) and DIEA (474.4 mg, 3.678 mmol). After 8 h, the mixture was
diluted with water and extracted with DCM. The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was triturated with EA to give (S)-methyl
5-amino-4-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-4H-thieno[2,3-c]pyrrol--
5(6H)-yl)-5-oxopentanoate (606 mg, quant) as a solid. MS (ESI) m/z
413 [M+H].sup.+.
[0211] To a solution of (S)-methyl
5-amino-4-(3-((tert-butyldimethylsilyl)oxy)-6-oxo-4H-thieno[2,3-c]pyrrol--
5(6H)-yl)-5-oxopentanoate (606 mg, 1.47 mmol) in DMF (14 mL) was
added TBAF (463.3 mg, 1.471 mmol). After heating at 40.degree. C.
for 1 h, the mixture was cooled to RT then
4-(4-(chloromethyl)benzyl)morpholine (845 mg, 3.24 mmol) and
K.sub.2CO.sub.3 (304.5 mg, 2.206 mmol) were added. The mixture was
heated at 50.degree. C. overnight then cooled to RT, quenched with
water, and extracted with EA. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was triturated with EA to give (S)-methyl
5-amino-4-(3-((4-(morpholinomethyl)benzyl)oxy)-6-oxo-4H-thieno[2,3-c]pyrr-
ol-5(6H)-yl)-5-oxopentanoate (80 mg, 11% yield) as a solid. MS
(ESI) m/z 488 [M+H].sup.+.
[0212] To a solution of (S)-methyl
5-amino-4-(3-((4-(morpholinomethyl)benzyl)oxy)-6-oxo-4H-thieno[2,3-c]pyrr-
ol-5(6H)-yl)-5-oxopentanoate (80 mg, 0.16 mmol) in THF (5 mL) at
0.degree. C. was added LiOH (0.5 mL, 0.49 mmol). After 2 h, the
mixture was concentrated. The residue was acidified with 2M HCl to
a pH of approximately 4 to 5 and extracted with EA. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give
(S)-5-amino-4-(3-((4-(morpholinomethyl)benzyl)oxy)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoic acid (77.7 mg, crude) as a solid,
which was used in the next step without further purification.
[0213] To a solution of
(S)-5-amino-4-(3-((4-(morpholinomethyl)benzyl)oxy)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoic acid (77.7 mg, 0.164 mmol) in ACN
(5 mL) was added CDI (106.4 mg, 0.6568 mmol). The mixture was
heated to 80.degree. C. overnight then concentrated. The residue
was purified using silica gel eluting with EA in petroleum from 0%
to 90% and further purified by prep-HPLC (5 .mu.M C18 column, 0.1%
TFA in H.sub.2O, 0.1% TFA in ACN, 5%-95%) to afford Compound 2
(12.7 mg, 17% yield) as a solid. MS (ESI) m/z 456 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H),
7.32-7.43 (m, 4H), 7.18 (s, 1H), 5.11 (s, 2H), 4.96-5.00 (m, 1H),
4.15-4.37 (m, 2H), 3.55-3.57 (m, 4H), 3.46 (s, 2H), 2.83-2.92 (m,
1H), 2.55-2.59 (m, 1H), 2.34 (s, 5H), 1.97-2.00 (m, 1H).
Example 3
Compound 3:
(S)-3-(3-((4-(morpholinomethyl)benzyl)amino)-6-oxo-4H-thieno[2,3-c]pyrrol-
-5(6H)-yl)piperidine-2,6-dione
##STR00076##
[0215] To a mixture of (S)-tert-butyl
5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.00 g, 2.48 mmol), (4-(morpholinomethyl)phenyl)methanamine (1.00
g, 4.96 mmol) and cesium carbonate (2.40 g, 7.44 mmol) in
N,N-dimethylethanolamine (5 mL) was added Pd-peppsi-IpentCl (208
mg, 0.248 mmol). After purging with N.sub.2, the mixture was
stirred at 120.degree. C. under microwave for 3 h. The mixture was
diluted with water and extracted with EA. The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by prep-TLC
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(3-((4-(morpholinomethyl)benzyl)amino)-6-oxo-4H-thieno[2,
3-c]pyrrol-5(6H)-yl)-5-oxopentanoate (100 mg, 8% yield) as a solid.
MS (ESI) m/z 529.3 [M+H].sup.+.
[0216] To a solution of (S)-tert-butyl
5-amino-4-(3-((4-(morpholinomethyl)benzyl)-amino)-6-oxo-4H-thieno[2,3-c]p-
yrrol-5(6H)-yl)-5-oxopentanoate (100 mg, 0.19 mmol) in DCM (4 mL)
was added TFA (1 mL). The mixture was stirred for 1 h then
concentrated to give
(S)-5-amino-4-(3-((4-(morpholinomethyl)benzyl)amino)-6-oxo-4H-thieno-
[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (0.19 mmol, crude) as a
solid, which was used in the next step without further
purification.
[0217] To a solution
(S)-5-amino-4-(3-((4-(morpholinomethyl)benzyl)amino)-6-oxo-4H-thieno[2,3--
c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (0.19 mmol, crude) in ACN (4
mL) was added CDI (125 mg, 0.771 mmol). After heating at 95.degree.
C. for 3 h, the mixture was concentrated and purified by prep-HPLC
as previously described to afford Compound 3 (10.2 mg, 12% yield)
as a solid. MS (ESI) m/z 455.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.94 (s, 1H), 7.23-7.35 (m, 4H), 6.29-6.32
(m, 2H), 4.97 (dd, J=5.2, 13.2 Hz, 1H), 4.15-4.22 (m, 4H), 3.55 (t,
J=4.8 Hz, 4H), 3.41 (s, 2H), 2.83-2.92 (m, 1H), 2.56-2.61 (m, 1H),
2.25-2.33 (m, 5H), 1.99-2.04 (m, 1H).
Example 4
Compound 4:
S)-3-(3-(4-(morpholinomethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H-
)-yl)piperidine-2,6-dione
##STR00077##
[0219] To 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.34 g,
2.31 mmol) in THF (40 mL) was added cuprous chloride (230 mg, 2.31
mmol) and sodium tert-butoxide (445 mg, 4.62 mmol). After 30 m
under N.sub.2, a solution of
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.6
g, 0.077 mol) in THF (20 mL) was added. After 10 m, a solution of
4-ethynylbenzaldehyde (10.0 g, 0.077 mol) in THF (40 mL) was added.
The mixture was stirred overnight then concentrated, and the
residue was purified using silica gel eluting with PE/EA (50:1) to
give
(E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde
(2.4 g, 12% yield) as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.99 (s, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.62 (d, J=8.0 Hz,
2H), 7.42 (d, J=18.4 Hz, 1H), 6.32 (d, J=18.4 Hz, 1H), 1.26 (s,
12H).
[0220] To a solution of (S)-tert-butyl
5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(700 mg, 1.74 mmol) and
(E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde
(900 mg, 3.48 mmol) in 1,4-dioxane (9 mL) and water (1 mL) was
added potassium phosphate (1.10 g, 5.22 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (254
mg, 0.35 mmol). The mixture was heated at 110.degree. C. overnight
under N.sub.2 then water was added, and the mixture was extracted
with EA. The combined organic layers were washed with brine, dried
over Na.sub.2SO.sub.4, and concentrated. The residue was purified
using silica gel eluting with PE/EA (1:1 to 100% EA) to give
(S,E)-tert-butyl
5-amino-4-(3-(4-formylstyryl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-ox-
opentanoate (370 mg, 47% yield) as a solid. MS (ESI) m/z=477.1
[M+Na].sup.+.
[0221] To a solution of (S,E)-tert-butyl
5-amino-4-(3-(4-formylstyryl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-ox-
opentanoate (370 mg, 0.81 mmol) in isopropanol (10 mL) was added
10% Pd/C (740 mg). The mixture was stirred overnight under H.sub.2
then filtered and concentrated to give (S)-tert-butyl
5-amino-4-(3-(4-(hydroxymethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(-
6H)-yl)-5-oxopentanoate (371 mg, crude) which was used for the next
step without purification. MS (ESI) m/z=459.2 [M+H].sup.+.
[0222] To a solution of (S)-tert-butyl
5-amino-4-(3-(4-(hydroxymethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(-
6H)-yl)-5-oxopentanoate (371 mg, 0.81 mmol, crude) in DCM (10 mL)
was added Dess-Martin (345 mg, 0.81 mmol). After 2 h, aqueous
saturated sodium thiosulfate was added, and the mixture was
extracted with EA. The combined organic layers were washed with
saturated NaHCO.sub.3 followed by brine then dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give (S)-tert-butyl
5-amino-4-(3-(4-formylphenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-
-oxopentanoate (300 mg, crude) as a solid. MS (ESI) m/z=457.2
[M+H].sup.+.
[0223] To a solution of (S)-tert-butyl
5-amino-4-(3-(4-formylphenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-
-oxopentanoate (300 mg, 0.68 mmol, crude) and morpholine (115 mg,
1.32 mmol) in DCM (10 mL) was added sodium triacetoxyborohydride
(420 mg, 1.98 mmol). After 2 h, the mixture was concentrated, and
the residue was purified using prep-TLC eluting with PE/EA (1:1) to
give (S)-tert-butyl
5-amino-4-(3-(4-(morpholinomethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-
-5(6H)-yl)-5-oxopentanoate (200 mg, 58% yield) as a solid. MS (ESI)
m/z=528.3 [M+H].sup.+.
[0224] To a solution of (S)-tert-butyl
5-amino-4-(3-(4-(morpholinomethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-
-5(6H)-yl)-5-oxopentanoate (200 mg, 0.38 mmol) in DCM (4 mL) was
added TFA (2 mL). After 1 h, the mixture was concentrated to give
(S)-5-amino-4-(3-(4-(morpholinomethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]py-
rrol-5(6H)-yl)-5-oxopentanoic acid (200 mg, 0.38 mmol, crude) which
was used in the next step without purification. MS (ESI) m/z=472.2
[M+H].sup.+.
[0225] To a solution
(S)-5-amino-4-(3-(4-(morpholinomethyl)phenethyl)-6-oxo-4H-thieno[2,3-c]py-
rrol-5(6H)-yl)-5-oxopentanoic acid (200 mg, 0.38 mmol, crude) in
ACN (10 mL) was added CDI (250 mg, 1.52 mmol). The mixture was
stirred at 90.degree. C. overnight then concentrated, and the
residue was purified using prep-HPLC as previously described to
afford Compound 4 (36 mg, 21% yield) as a solid. MS (ESI) m/z=454.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.96 (s,
1H), 7.65 (s, 1H), 7.16-7.21 (m, 4H), 4.98 (dd, J=4.8, 13.2 Hz,
1H), 4.11-4.26 (m, 2H), 3.55 (t, J=4.4 Hz, 4H), 3.40 (s, 2H),
2.84-2.92 (m, 5H), 2.56-2.61 (m, 1H), 2.28-2.34 (m, 5H), 1.96-1.99
(m, 1H).
Example 5
Compound 5:
(S)-3-(3-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,3-c]pyrr-
ol-5(6H)-yl)piperidine-2,6-dione
##STR00078##
[0227] To a solution of methyl
4-bromo-3-methylthiophene-2-carboxylate (10.0 g, 42.5 mmol) in
CCl.sub.4 (50 mL) was added 1-bromo-2,5-pyrrolidinedione (9.09 g,
51.1 mmol) and benzoyl peroxide (1.03 g, 4.25 mmol). The mixture
was stirred at 85.degree. C. for 16 h. The mixture was filtered and
the filter cake was washed with DCM. The combined organic layers
were concentrated, and the residue was purified using silica gel
eluting with PE/EA (1:1) to give methyl
4-bromo-3-(bromomethyl)thiophene-2-carboxylate (10.42 g, crude) as
a solid, which was used in the next step without further
purification.
[0228] To a solution of methyl
4-bromo-3-(bromomethyl)thiophene-2-carboxylate (10.42 g, 33.17
mmol, crude) in DMF (50 mL) at 0.degree. C. was added
(S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride (9.50 g,
39.8 mmol) and TEA (7.37 g, 72.9 mmol). The mixture was stirred at
RT overnight and concentrated. The residue was purified using
silica gel eluting with PE/EA (1:2) to give (S)-methyl
3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromoth-
iophene-2-carboxylate (11.53 g, 80% yield) as oil. MS (ESI) m/z
435.1, 437.1 [M+H].sup.+.
[0229] To a solution of (S)-methyl
3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bromoth-
iophene-2-carboxylate (11.53 g, 26.49 mmol) in THF (110 mL) was
added LiOH monohydrate (1.67 g, 39.7 mmol) and water (66 mL). The
mixture was stirred for 3 h then concentrated. The residue was
diluted with water and acidified with 1M HCl to a pH of 6. After
stirring 0.5 h, the mixture was filtered and the filter cake was
washed with water and dried to afford
(S)-3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bro-
mothiophene-2-carboxylic acid (14.7 g, crude) as a solid. MS (ESI)
m/z 421.0, 423.0 [M+H].sup.+.
[0230] To a solution of
(S)-3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-4-bro-
mothiophene-2-carboxylic acid (6.70 g, crude, 15.9 mmol) in DMF
(150 mL) at 0.degree. C. was added 1-hydroxybenzotriazole (3.22 g,
23.9 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (4.58 g, 23.9 mmol) and DIEA (6.17 g, 47.7 mmol). The
mixture was stirred at RT for 2 h then concentrated. The residue
was purified using silica gel eluting with PE/EA (1:1) to give
(S)-tert-butyl
5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(2.73 g, 43% yield) as a solid. MS (ESI) m/z 347.0, 349.0
[M-55].sup.+.
[0231] To a solution of (S)-tert-butyl
5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.00 g, 2.48 mmol) in DMF (6 mL) was added zinc cyanide (320 mg,
2.73 mmol), tris(dibenzylideneacetone)dipalladium (229 mg, 0.25
mmol) and 1,1'-bis(diphenylphosphino)ferrocene (302 mg, 0.55 mmol).
The mixture was stirred at 150.degree. C. under microwave for 1 h
then concentrated. The residue was purified using silica gel
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(3-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(428 mg, 50% yield) as a solid. MS (ESI) m/z 294.0
[M-55].sup.+.
[0232] To (S)-tert-butyl
5-amino-4-(3-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.12 g, 3.21 mmol) and sodium dihydric hypophosphite (1.66 g,
19.26 mmol) in a solution of AcOH (5 mL), pyridine (10 mL) and
water (5 mL) was added Raney-Ni (200 mg). The mixture was stirred
for 1 h then filtered and the filter cake was washed with DCM. The
combined organic layers were washed with 1N HCl and concentrated.
The residue was purified using silica gel eluting with PE/EA (1:2)
to give (S)-tert-butyl
5-amino-4-(3-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (550 mg, 49% yield) as a solid. MS (ESI) m/z 297.1, 299.1
[M-55].sup.+.
[0233] To a solution of (S)-tert-butyl
5-amino-4-(3-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (550 mg, 1.56 mmol) in MeOH (40 mL) was added sodium borohydride
(24 mg, 0.63 mmol) at 0.degree. C. The mixture was stirred at RT
for 2 h then concentrated. The residue was diluted with water and
extracted with DCM. The combined organic layers were concentrated
to give (S)-tert-butyl
5-amino-4-(3-(hydroxymethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (497 mg, 91% yield) as a solid. MS (ESI) m/z 299.1,
300.1 [M-55].sup.+.
[0234] To a solution of (S)-tert-butyl
5-amino-4-(3-(hydroxymethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (180 mg, 0.51 mmol), 4-dimethylaminopyridine (6.0 mg,
0.05 mmol) and TEA (103 mg, 1.02 mmol) in DCM (10 mL) was added
p-toluenesulfonyl chloride (145 mg, 0.76 mmol). After 3 h, the
reaction was quenched with aqueous ammonium chloride solution and
extracted with DCM. The combined organic layers were concentrated
and purified using silica gel eluting with PE/EA (1:2) to give
(S)-tert-butyl
5-amino-4-(3-(chloromethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (100 mg, 53% yield) as an oil. MS (ESI) m/z 317.0, 319.0
[M-55].sup.+.
[0235] To a solution of (S)-tert-butyl
5-amino-4-(3-(chloromethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (100 mg, 0.27 mmol) in ACN (10 mL) was added
4-(morpholinomethyl)phenol (104 mg, 0.54 mmol) and K.sub.2CO.sub.3
(75 mg, 0.54 mmol). The mixture was stirred at 80.degree. C. for 16
h then concentrated. The residue was purified using silica gel
eluting with PE/EA (1:2 to 100% EA) to give (S)-tert-butyl
5-amino-4-(3-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (70 mg, 49% yield) as an oil. MS
(ESI) m/z 474.1, 476.1 [M-55].sup.+.
[0236] A mixture of (S)-tert-butyl
5-amino-4-(3-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (70 mg, 0.13 mmol) in TFA (1.0 mL)
and DCM (4.0 mL) was stirred for 1 h then concentrated to give
(S)-5-amino-4-(3-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,-
3-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (62 mg, 0.13 mmol, crude)
as an oil, which was used in the next step without further
purification. MS (ESI) m/z 474.2 [M+H].sup.+.
[0237] A mixture of
(S)-5-amino-4-(3-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,-
3-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (62 mg, 0.13 mmol, crude)
and CDI (84 mg, 0.52 mmol) in ACN (5 mL) was heated at reflux for
72 h then concentrated. The residue was purified by prep-HPLC as
previously described to afford Compound 5 (28 mg, 47% yield) as a
solid. MS (ESI) m/z 456.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.98 (s, 1H), 8.02 (s, 1H), 7.22 (d, J=8.8,
2H), 6.98 (d, J=8.4, 2H), 5.15 (s, 2H), 5.01 (dd, J=13.2, 4.8, 1H),
4.36 (dd, J=48.0, 18.0, 2H), 3.55 (t, J=4.4, 4H), 3.38 (s, 2H),
2.93-2.84 (m, 1H), 2.67-2.55 (m, 1H), 2.51-2.31 (m, 5H), 2.01-1.98
(m, 1H).
Example 6
Compound 6:
(S)-3-(1-(4-(morpholinomethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6-
H)-yl)piperidine-2,6-dione
##STR00079##
[0239] To a solution of (S)-tert-butyl
5-amino-4-(1-bromo-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(500 mg, 1.24 mmol) in toluene (30 mL) and water (3 mL) was added
(E)-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)benzaldehyde
(640 mg, 2.48 mmol), K.sub.2CO.sub.3 (514 mg, 3.72 mmol) and
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (181 mg,
0.25 mmol). After heating at 100.degree. C. overnight, the mixture
was filtered and the filter cake was washed with DCM. The combined
organic layers were concentrated, and the residue was purified
using silica gel eluting with PE/EA (1:1) to give (S,E)-tert-butyl
5-amino-4-(1-(4-formylstyryl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-ox-
opentanoate (337 mg, 60% yield) as a solid. MS (ESI) m/z 399.0
[M-55].sup.+.
[0240] To a solution of (S,E)-tert-butyl
5-amino-4-(1-(4-formylstyryl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-ox-
opentanoate (420 mg, 0.93 mmol) in isopropanol (30 mL) under
N.sub.2 was added Pd/C (1.27 g, 10%, 0.28 mmol). The mixture was
degassed and purged with H.sub.2 then stirred overnight. After
filtration, the filter cake was washed with EA. The combined
organic layers were concentrated to give (S)-tert-butyl
5-amino-4-(1-(4-(hydroxymethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(-
6H)-yl)-5-oxopentanoate (crude) as an oil, which was used in the
next step without further purification. MS (ESI) m/z 403
[M-55].sup.+.
[0241] To a solution of (S)-tert-butyl
5-amino-4-(1-(4-(hydroxymethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(-
6H)-yl)-5-oxopentanoate (0.93 mmol, crude) in DCM (30.0 mL) was
added Dess-Martin periodinane (394 mg, 0.93 mmol). After 2 h, the
mixture was quenched with saturated sodium thiosulfate and
extracted with DCM. The combined organic layers were washed with
saturated aqueous NaHCO.sub.3, and brine, then concentrated to give
(S)-tert-butyl
5-amino-4-(1-(4-formylphenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-
-oxopentanoate (1.0 mmol, crude) as an oil, which was use in the
next step without further purification. MS (ESI) m/z 401
[M-55].sup.+.
[0242] To a solution of (S)-tert-butyl
5-amino-4-(1-(4-formylphenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-
-oxopentanoate (1.0 mmol, crude), morpholine (174 mg, 2.0 mmol) in
DCM (30 mL) was added sodium borohydride acetate (636 mg, 3.0
mmol). The mixture was stirred overnight then quenched with
saturated sodium thiosulfate and extracted with DCM. The combined
organic layers were washed with saturated aqueous NaHCO.sub.3, and
brine, then concentrated and purified using silica gel eluting with
PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-(4-(morpholinomethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-
-5(6H)-yl)-5-oxopentanoate (150 mg, 28% yield) as an oil. MS (ESI)
m/z 472 [M-55].sup.+.
[0243] A mixture of (S)-tert-butyl
5-amino-4-(1-(4-(morpholinomethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-
-5(6H)-yl)-5-oxopentanoate (100 mg, 0.19 mmol) and TFA (2 mL) in
DCM (8 mL) was stirred for 2 h then concentrated to give
(S)-5-amino-4-(1-(4-(morpholinomethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]py-
rrol-5(6H)-yl)-5-oxopentanoic acid (0.19 mmol, crude) as an oil,
which was used in the next step without further purification. MS
(ESI) m/z 472 [M+H].sup.+.
[0244] A mixture of
(S)-5-amino-4-(1-(4-(morpholinomethyl)phenethyl)-4-oxo-4H-thieno[3,4-c]py-
rrol-5(6H)-yl)-5-oxopentanoic acid (0.19 mmol, crude) and CDI (123
mg, 0.76 mmol) in ACN (10 mL) was heated at 80.degree. C. overnight
then concentrated. The residue was purified by prep-HPLC as
previously described to afford Compound 6 (19 mg, 22% yield) as a
solid. MS (ESI) m/z 454.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.94 (s, 1H), 7.78 (s, 1H), 7.21-7.16 (m,
4H), 4.98 (dd, J=13.2, 5.2 Hz, 1H), 4.04 (dd, J=38.8, 15.2 Hz, 2H),
3.56-3.54 (m, 4H), 3.41 (s, 2H), 3.09-3.05 (m, 2H), 2.92-2.85 (m,
3H), 2.60-2.55 (m, 1H), 2.33-2.24 (m, 5H), 1.95-1.90 (m, 1H).
Example 7
Compound 7:
(S)-3-(1-((3-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrr-
ol-5(6H)-yl)piperidine-2,6-dione
##STR00080##
[0246] To a solution of
(S)-tert-butyl-5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5-
(6H)-yl)-5-oxopentanoate (110 mg, 0.30 mmol) in ACN (3 mL) was
added 3-(morpholinomethyl)phenol (87 mg, 0.45 mmol) and
K.sub.2CO.sub.3 (83 mg, 0.60 mmol). After heating at 90.degree. C.
for 4 h, the mixture was diluted with water (5 mL) and extracted
with EA (5 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified using silica gel eluting with PE/EA (1:4) to give
(S)-tert-butyl
5-amino-4-(1-((3-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (114 mg, 72% yield) as an solid.
MS (ESI) m/z 530.2 [M+H].sup.+.
[0247] To a solution of (S)-tert-butyl
5-amino-4-(1-((3-(morpholinomethyl)
phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(114 mg, 0.22 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture
was stirred for 2 h then concentrated to give
(S)-5-amino-4-(1-((3-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (104 mg, quant) as a
solid. MS (ESI) m/z 474.1 [M+H].sup.+.
[0248] To a solution of
(S)-5-amino-4-(1-((3-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (104 mg, 0.22 mmol) in ACN
(6 mL) was added CDI (1.78 mg, 1.10 mmol). After heating at
90.degree. C. for 16 h, the mixture was filtered, and the filtrate
was concentrated. The residue was purified by prep-HPLC as
previously described to afford Compound 7 (18.6 mg, 19% yield) as a
solid. MS (ESI) m/z 456.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 11.00 (s, 1H), 8.03 (s, 1H), 7.26 (t, J=8.0
Hz, 1H), 6.96-6.91 (m, 3H), 5.31 (s, 2H), 5.05-5.01 (m, 1H),
4.37-4.20 (m, 2H), 3.56 (t, J=4.4 Hz, 4H), 3.43 (s, 2H), 2.94-2.85
(m, 1H), 2.61-2.51 (m, 1H), 2.39-2.27 (m, 5H), 2.00-1.97 (m,
1H).
Example 8
Compound 8:
(S)-3-(1-((2-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3-
,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00081##
[0250] A mixture of 2-fluoro-4-hydroxybenzaldehyde (1.4 g, 10 mmol)
and morpholine (1.3 g, 15 mmol) in DCM (30 mL) was stirred for 0.5
h then NaBH.sub.3CN (1.3 g, 20 mmol) was added. After 0.5 h, the
mixture was washed with water and the organic layer was
concentrated. The residue was purified using silica gel eluting
with PE/EA (1:12) to give 3-fluoro-4-(morpholinomethyl)phenol (660
mg, 32% yield) as a solid. MS (ESI) m/z 212 [M+H].sup.+.
[0251] To a solution of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (100 mg, 0.27 mmol) and
2-fluoro-4-(morpholinomethyl)phenol (85 mg, 0.42 mmol) in ACN (5
mL) was added K.sub.2CO.sub.3 (75 mg, 0.54 mmol). After heating at
reflux for 3 h, the mixture was quenched with water and extracted
with EA. The combined organic layers were concentrated to give
(S)-tert-butyl
5-amino-4-(1-((2-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thie-
no[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (163 mg, crude) as an
oil. MS (ESI) m/z 548 [M+H].sup.+.
[0252] To a solution of (S)-tert-butyl
5-amino-4-(1-((2-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thie-
no[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (148 mg, 0.27 mmol,
crude) in DCM (5 mL) was added TFA (2 mL). The mixture was stirred
for 3 h then concentrated. The residue was dissolved in ACN (5 mL)
and CDI was added (66 mg, 0.41 mmol). After heating at reflux
overnight, the mixture was cooled to RT, washed with water, and
extracted with EA. The combined organic layers were concentrated
and purified by prep-HPLC as previously described to afford
Compound 8 (21.3 mg, 18% yield) as a solid. MS (ESI) m/z 474.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.97 (s,
1H), 8.03 (s, 1H), 7.18 (m, 2H), 7.06 (m, 1H), 5.35 (s, 2H), 5.02
(m, 1H), 4.27 (q, 2H), 3.55 (t, 4H), 3.39 (s, 2H), 2.88 (m, 1H),
2.58 (m, 1H), 2.32 (m, 1H), 2.31 (t, 4H), 1.99 (m, 1H).
Example 9
Compound 9: (S)-3-(1-(((4-(morpholinomethyl)benzyl)oxy)
methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00082##
[0254] To a solution of (S)-tert-butyl
5-amino-4-(1-(hydroxymethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (370 mg, 1.05 mmol) and 4-(bromomethyl)benzaldehyde (420
mg, 2.1 mmol) in ACN (10 mL) was added K.sub.2CO.sub.3 (580 mg, 4.2
mmol). After heating at reflux for 1 h, the mixture was
concentrated, and the residue was purified using silica gel eluting
with EA to give (S)-tert-butyl
5-amino-4-(1-(((4-formylbenzyl)oxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5-
(6H)-yl)-5-oxopentanoate (60 mg, 13% yield) as an oil. MS (ESI) m/z
473.2 [M+H].sup.+.
[0255] To a solution of (S)-tert-butyl
5-amino-4-(1-(((4-formylbenzyl)oxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5-
(6H)-yl)-5-oxopentanoate (60 mg, 0.127 mmol) in DCM (2 mL) was
added TFA (0.5 mL). After 2 h, the mixture was concentrated to give
(S)-5-amino-4-(1-(((4-formylbenzyl)oxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrr-
ol-5(6H)-yl)-5-oxopentanoic acid (0.127 mmol, crude) as a solid,
which was used in the next step without further purification. MS
(ESI) m/z 417.1 [M+H].sup.+.
[0256] To a solution
(S)-5-amino-4-(1-(((4-formylbenzyl)oxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrr-
ol-5(6H)-yl)-5-oxopentanoic acid (0.127 mmol, crude) in ACN (2 mL)
was added CDI (81 mg, 0.5 mmol). After heating at 90.degree. C. for
2 h, the mixture was concentrated, and the residue was purified by
prep-TLC eluting with PE/EA (1:2) to give
(S)-4-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]py-
rrol-1-yl)methoxy)methyl)benzaldehyde (40 mg, 80% yield) as a
solid. MS (ESI) m/z 399.1 [M+H].sup.+.
[0257] To a solution 4-hydroxybenzaldehyde
(S)-4-(((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]py-
rrol-1-yl)methoxy)methyl)benzaldehyde (40 mg, 0.10 mmol) and
morpholine (26 mg, 0.30 mmol) in DCM (4 mL) was added sodium
triacetoxyborohydride (106 mg, 0.50 mmol). After 1 h, the mixture
was concentrated, and the residue was purified by prep-HPLC as
previously described to afford Compound 9 (5.3 mg, 11% yield) as a
solid. MS (ESI) m/z 470.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.96 (s, 1H), 7.98 (s, 1H), 7.28 (s, 4H),
5.28 (s, 2H), 5.01 (dd, J=5.2, 12.8 Hz, 1H), 4.68 (s, 2H), 4.53 (s,
2H), 4.30 (d, J=15.6 Hz, 1H), 4.16 (d, J=16.0 Hz, 1H), 3.55 (t,
J=4.4 Hz, 4H), 3.44 (s, 2H), 2.55-2.60 (m, 1H), 2.51-2.52 (m, 1H),
2.29-2.33 (m, 5H), 1.96-2.00 (m, 1H).
Example 10
Compound 10:
(S)-3-(1-(((4-(morpholinomethyl)phenyl)amino)methyl)-4-oxo-4H-thieno[3,4--
c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00083##
[0259] To a solution of (S)-tert-butyl
5-amino-4-(1-formyl-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (140 mg, 0.397 mmol) and 4-(morpholinomethyl)aniline (92.0 mg,
0.477 mmol) in DCM (5 mL) was added NaBH(OAc).sub.3 (253 mg, 1.197
mmol). The mixture was stirred for 2 h then concentrated, and the
residue was purified using silica gel eluting with PE/EA (1:2) give
(S)-tert-butyl
5-amino-4-(1-(((4-(morpholinomethyl)phenyl)amino)methyl)-4-oxo-4H-thieno
[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (130 mg, 62% yield) as a
solid. MS (ESI) m/z 529.3 [M+H].sup.+.
[0260] To a solution of (S)-tert-butyl
5-amino-4-(1-(((4-(morpholinomethyl)phenyl)amino)methyl)-4-oxo-4H-thieno[-
3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (130 mg, 0.246 mmol) in DCM
(4 mL) was added TFA (1 mL). The mixture was stirred overnight then
concentrated and dissolved in ACN (6 mL). CDI (120 mg, 0.738 mmol)
was added, and the mixture was heated at 90.degree. C. for 3 h.
After concentration, the residue was purified by prep-HPLC as
previously described to afford Compound 10 (25.2 mg 22% yield) as a
solid. MS (ESI) m/z 455.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.97 (s, 1H), 7.83 (s, 1H), 6.99 (d, J=8.4
Hz, 2H), 6.56 (d, J=8.8 Hz, 2H), 6.27 (t, J=6.0 Hz, 1H), 5.01-4.97
(m, 1H), 4.42 (d, J=5.6 Hz, 2H), 4.27-4.13 (m, 2H), 3.52 (s, 4H),
3.27 (s, 2H), 2.87-2.86 (m, 1H), 2.59-2.54 (m, 1H), 2.32-2.27 (m,
5H), 1.96-1.90 (m, 1H).
Example 11
Compound 11:
(S)-3-(3-(((4-(morpholinomethyl)phenyl)amino)methyl)-6-oxo-4H-thieno[2,3--
c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00084##
[0262] To a mixture of (S)-tert-butyl
5-amino-4-(3-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.50 g, 3.73 mmol), Pd.sub.2(dba).sub.3 (355 mg, 0.37 mmol) and
dppf (401 mg, 0.74 mmol) in DMF (22 mL) under N.sub.2 was added
Zn(CN).sub.2 (481 mg, 4.10 mmol). The mixture was heated at
150.degree. C. under microwave for 1 h. After cooling to RT, the
mixture was diluted with water, filtered, and extracted with EA.
The organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified using silica gel eluting with PE/EA (1:2) to give
(S)-tert-butyl
5-amino-4-(3-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(300 mg, 23% yield) as an oil. MS (ESI) m/z 294.1
[M+H-56].sup.+.
[0263] To (S)-tert-butyl
5-amino-4-(3-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(300 mg, 0.86 mmol) in a solution of AcOH (1 mL), pyridine (5 mL),
and water (1 mL) at 0.degree. C. was added NaH.sub.2PO.sub.2 (370
mg, 4.30 mmol) and Raney Ni (200 mg). The mixture was stirred for 4
h then filtered. The filtrate was extracted with EA and the
combined organic layers were washed with 1 N HCl, and brine, then
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified using silica gel eluting with PE/EA (1:2) to
give (S)-tert-butyl
5-amino-4-(3-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (170 mg, 56% yield) as a solid. MS (ESI) m/z 297.1
[M+H-56].sup.+.
[0264] To a solution of (S)-tert-butyl
5-amino-4-(3-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (170 mg, 0.483 mmol) and 4-(morpholinomethyl)aniline (130 mg,
0.676 mmol) in DCM (4 mL) was added NaBH(OAc).sub.3 (307 mg, 1.45
mmol). The mixture was stirred for 2 h then concentrated. The
residue was purified using silica gel eluting with PE/EA (1:2) to
give (S)-tert-butyl
5-amino-4-(3-(((4-(morpholinomethyl)phenyl)amino)methyl)-6-oxo-4H-thieno[-
2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate (220 mg, 86% yield) as a
solid. MS (ESI) m/z 529.3 [M+H].sup.+.
[0265] To a solution of (S)-tert-butyl
5-amino-4-(3-(((4-(morpholinomethyl)
phenyl)amino)methyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoa-
te (220 mg, 0.416 mmol) in DCM (4 mL) was added TFA (1 mL). The
mixture was stirred overnight then concentrated. The residue was
dissolved in ACN (6 mL) and CDI (203 mg, 1.250 mmol) was added. The
mixture was heated at 90.degree. C. for 3 h then concentrated. The
residue was purified by prep-HPLC as previously described to afford
Compound 11 (45.1 mg 23% yield) as a solid. MS (ESI) m/z 455.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.95 (s,
1H), 7.80 (s, 1H), 6.97 (d, J=8.0 Hz, 2H), 6.56 (d, J=8.8 Hz, 2H),
6.07 (t, J=6.0 Hz, 1H), 5.01-4.96 (m, 1H), 4.36-4.22 (m, 4H), 3.52
(t, J=4.4 Hz, 4H), 3.26 (s, 2H), 2.87-2.86 (m, 1H), 2.60-2.57 (m,
1H), 2.31-2.27 (m, 5H), 2.00-1.90 (m, 1H).
Example 12
Compound 12:
(S)-3-(1-(((5-(morpholinomethyl)pyridin-2-yl)oxy)methyl)-4-oxo-4H-thieno[-
3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00085##
[0267] To a mixture of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (150 mg, 0.27 mmol) and 5-(morpholinomethyl)pyridin-2-ol
(92 mg, 0.32 mmol), in ACN (10 mL) was added K.sub.2CO.sub.3 (75
mg, 0.54 mmol). After heating at reflux for 8 h, the mixture was
concentrated, and the residue was purified by prep-TLC eluting with
PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-(((5-(morpholinomethyl)pyridin-2-yl)oxy)methyl)-4-oxo-4H-thi-
eno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (40 mg, 19% yield) as a
solid.
[0268] To a solution of (S)-tert-butyl
5-amino-4-(1-(((5-(morpholinomethyl)pyridin-2-yl)oxy)methyl)-4-oxo-4H-thi-
eno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (40 mg, 0.087 mmol) in
DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 2 h
then concentrated. The residue was dissolved in ACN (3 mL) and CDI
(43 mg, 0.262 mmol) was added. The mixture was heated at reflux for
8 h then diluted with water and extracted with EA. The combined
organic layers were concentrated, and the residue was purified by
prep-HPLC as previously described to afford Compound 12 (4.5 mg,
12% yield) as a solid. MS (ESI) m/z 456.8 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.99 (s, 1H), 7.93 (s, 1H), 7.76
(d, 1H), 7.40 (m, 1H), 6.41 (d, 1H), 5.20 (q, 2H), 5.00 (m, 1H),
4.25 (q, 2H), 3.55 (t, 4H), 2.20 (s, 2H), 2.87 (m, 1H), 2.57 (m,
1H), 2.27 (t, 4H), 1.97 (m, 1H).
Example 13
Compound 13:
(S)-3-(4-oxo-1-((4-(pyrrolidin-1-ylmethyl)phenoxy)methyl)-4H-thieno[3,4-c-
]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00086##
[0270] To a solution of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (300 mg, 0.80 mmol) in ACN (10 mL) was added
4-hydroxybenzaldehyde (108 mg, 0.88 mmol), K.sub.2CO.sub.3 (166 mg,
1.20 mmol) and KI (133 mg, 0.80 mmol). The mixture was stirred for
3 h then concentrated. The residue was purified using silica gel
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]
pyrrol-5(6H)-yl)-5-oxopentanoate (350 mg, 95% yield) as a solid. MS
(ESI) m/z 403.1 [M+H-56].sup.+.
[0271] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (150 mg, 0.327 mmol) and pyrrolidine (70 mg,
0.982 mmol) in DCM (6 mL) was added NaBH(OAc).sub.3 (208 mg, 0.982
mmol). The mixture was stirred for 10 h then concentrated, and the
residue was purified using silica gel eluting with PE/EA (1:2) to
give (S)-tert-butyl
5-amino-5-oxo-4-(4-oxo-1-((4-(pyrrolidin-1-ylmethyl)phenoxy)methyl)-4H-th-
ieno[3,4-c]pyrrol-5(6H)-yl)pentanoate (140 mg, 83% yield) as a
solid. MS (ESI) m/z 514.2 [M+H].sup.+.
[0272] To a solution of (S)-tert-butyl
5-amino-5-oxo-4-(4-oxo-1-((4-(pyrrolidin-1-ylmethyl)phenoxy)methyl)-4H-th-
ieno[3,4-c]pyrrol-5(6H)-yl)pentanoate (140 mg, 0.273 mmol) in DCM
(4 mL) was added TFA (1 mL). The mixture was stirred overnight then
concentrated. The residue was dissolved in ACN (8 mL) and CDI (133
mg, 0.818 mmol) was added. The mixture was heated at reflux for 4 h
then concentrated. The residue was purified by prep-HPLC as
previously described to afford Compound 13 (49.6 mg 41% yield) as a
solid. MS (ESI) m/z 440.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.97 (s, 1H), 8.01 (s, 1H), 7.21 (d, J=8.4
Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 5.28 (s, 2H), 5.04-4.99 (m, 1H),
4.36-4.20 (m, 2H), 3.49 (s, 2H), 2.94-2.84 (m, 1H), 2.60-2.56 (m,
1H), 2.38-2.31 (m, 5H), 2.00-1.96 (m, 1H), 1.68-1.65 (m, 4H).
Example 14
Compound 14:
(S)-3-(1-((4-((diethylamino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]-
pyrrol-5 (6H)-yl)piperidine-2,6-dione
##STR00087##
[0274] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (200 mg, 0.436 mmol) and DIEA (96 mg, 1.31
mmol) in DCM (6 mL) was added NaBH(OAc).sub.3 (278 mg, 1.31 mmol).
The mixture was stirred for 10 h then concentrated. The residue was
purified using silica gel eluting with PE/EA (1:2) to give
(S)-tert-butyl
5-amino-4-(1-((4-((diethylamino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (230 mg, crude) as an oil. MS
(ESI) m/z 516.3 [M+H].sup.+.
[0275] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-((diethylamino)
methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentan-
oate (230 mg, 0.446 mmol) in DCM (4 mL) was added TFA (1 mL). The
mixture was stirred overnight then concentrated. The residue was
dissolved in ACN (6 mL) and CDI (289 mg, 1.786 mmol) was added. The
mixture was heated at reflux for 3 h then concentrated. The residue
was purified by prep-HPLC as previously described to afford the
trifluoroacetic acid salt of Compound 14 (25.8 mg, 13% yield) as a
solid. MS (ESI) m/z 442.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.97 (s, 1H), 9.31 (s, 1H), 8.03 (s, 1H),
7.46 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 5.35 (s, 2H),
5.05-5.00 (m, 1H), 4.338-4.20 (m, 4H), 3.08-3.00 (m, 4H), 2.90-2.85
(m, 1H), 2.61-2.56 (m, 1H), 2.35-2.30 (m, 1H), 1.99-1.97 (m, 1H),
1.23-1.19 (m, 6H).
Example 15
Compound 15:
(S)-3-(1-((4-(2-morpholinoethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyr-
rol-5(6H)-yl)piperidine-2,6-dione
##STR00088##
[0277] To a solution of 2-(4-(benzyloxy)phenyl)ethanol (2.4 g, 10.5
mmol) in DCM (20 mL) at 0.degree. C. was added PBr.sub.3 (3.4 g,
12.6 mmol) dropwise. The mixture was stirred at RT for 30 m, then
water was added, and the mixture was extracted with DCM. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give
1-(benzyloxy)-4-(2-bromoethyl)benzene (2.6 g, 85% yield) as an oil
which was used in the next step without purification.
[0278] To a solution of 1-(benzyloxy)-4-(2-bromoethyl)benzene (2.6
g, 8.93 mmol) in DMF (15 mL) was added morpholine (1.16 g, 13.3
mmol) and potassium carbonate (1.84 g, 13.3 mmol). The mixture was
heated at 50.degree. C. overnight then quenched with water and
extracted with EA. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified using silica gel eluting with PE/EA (1:1) to give
4-(4-(benzyloxy)phenethyl)morpholine (1.5 g, 57% yield) as a solid.
MS (ESI) m/z 298[M+H].sup.+.
[0279] To a solution of 4-(4-(benzyloxy)phenethyl)morpholine (500
mg, 1.68 mmol) in MeOH (10 mL) was added Pd/C (200 mg). The mixture
was degassed and purged with H.sub.2. After stirring overnight, the
mixture was filtered and concentrated to give
4-(2-morpholinoethyl)phenol (340 mg, yield: 98%) as an oil. MS
(ESI) m/z 208[M+H].sup.+.
[0280] To a stirred solution of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (80 mg, 0.21 mmol) and 4-(2-morpholinoethyl)phenol (66
mg, 0.32 mmol) in ACN (8 mL) was added potassium carbonate (58 mg,
0.42 mmol). After 2 h at 80.degree. C., the mixture was
concentrated, and the residue was purified using silica gel eluting
with PE/EA (1:1) to give (S)-tert-butyl
5-amino-4-(1-((4-(2-morpholinoethyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c-
]pyrrol-5(6H)-yl)-5-oxopentanoate (100 mg, 85% yield) as a solid.
MS (ESI) m/z=544 [M+H].sup.+.
[0281] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-(2-morpholinoethyl)p
henoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(100 mg, 0.22 mmol) in DCM (5 mL) was added TFA (2 mL). After 2 h,
the mixture was concentrated, and the residue was dissolved in ACN
(8 mL), and CDI (143 mg, 0.88 mmol) was added. After 3 h at
95.degree. C., the mixture was washed with water. The organic phase
was concentrated, and the residue was purified using prep-HPLC as
previously described to afford Compound 15 (27 mg, 26% yield) as a
solid. MS (ESI) m/z 470 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.97 (s, 1H), 8.01 (s, 1H), 7.15 (d, J=8.4
Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.26 (s, 2H), 5.02 (dd, J=5.2, 5.2
Hz, 1H), 4.19-4.36 (q, 2H), 3.56 (t, 4H), 2.84-2.92 (m, 1H), 2.66
(t, 2H), 2.60 (m, 1H), 2.50 (m, 1H), 2.40 (t, 4H), 2.36 (m, 1H),
1.97-1.99 (m, 1H).
Example 16
Compound 16: (S)-3-(2-((4-(morpholinomethyl)phenoxy)
methyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)
piperidine-2,6-dione
##STR00089##
[0283] To a solution of 5-bromo-3-methylthiophene-2-carboxylic acid
(4.4 g, 20 mmol) in DCM at 0.degree. C. was added oxalyl chloride
(5.1 g, 40 mmol) and DMF (10 drops). The mixture was stirred at
0.degree. C. for 2 h then MeOH (20 mL) was added. After 1 h at
0.degree. C., the mixture was concentrated, and the residue was
purified using silica gel eluting with PE/EA (1:1) to give methyl
5-bromo-3-methylthiophene-2-carboxylate (2.615 g, 56% yield) as a
solid.
[0284] To a solution of methyl
5-bromo-3-methylthiophene-2-carboxylate (2.615 g, 11.18 mmol) in
CCl.sub.4 (30 mL) was added NBS (2.387 g, 13.41 mmol) and benzoyl
peroxide (270.5 mg, 1.12 mmol). The mixture was stirred at
85.degree. C. for 16 h then cooled to RT, filtered, and washed with
DCM. The combined organic layers were concentrated, and the residue
was purified using silica gel eluting with PE/EA (1:1) to give
methyl 5-bromo-3-(bromomethyl)thiophene-2-carboxylate (2.784 g, 80%
yield) as a solid.
[0285] To a solution of methyl
5-bromo-3-(bromomethyl)thiophene-2-carboxylate (2.784 g, 8.92 mmol)
in DMF (20 mL) at 0.degree. C. was added (S)-tert-butyl
4,5-diamino-5-oxopentanoate (3.186 g, 13.39 mmol) and TEA (1.8 g,
17.84 mmol). The mixture was stirred for 16 h then concentrated.
The residue was purified using silica gel eluting with PE/EA (1:2)
to give (S)-methyl
3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bromoth-
iophene-2-carboxylate (3.439 g, 89% yield) as an oil. MS (ESI) m/z
435.1, 437.1 [M+H].sup.+.
[0286] To a solution of (S)-methyl
3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bromoth-
iophene-2-carboxylate (2.51 g, 5.79 mmol) in THF (15 mL) and water
(15 mL) was added LiOH monohydrate (365 mg, 8.68 mmol). After 3 h,
the mixture was concentrated, and the residue was diluted with
water. The aqueous layer was acidified with 1M HCl to a pH of 6.
After stirring for 0.5 h, the mixture was filtered and the filter
cake was washed with water then dried to give
(S)-3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bro-
mothiophene-2-carboxylic acid (2.43 g, crude) as a solid. MS (ESI)
m/z 421.0, 423.0 [M+H].sup.+.
[0287] To a solution of
(S)-3-(((1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)amino)methyl)-5-bro-
mothiophene-2-carboxylic acid (2.43 g, crude, 5.79 mmol) in DMF (20
mL) at 0.degree. C. was added HATU (3.29 g, 8.68 mmol) and DIEA
(1.49 g, 11.6 mmol). The mixture was stirred at RT for 2 h then
concentrated. The residue was purified using silica gel eluting
with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(2-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.50 g, 65% yield) as a solid. MS (ESI) m/z 403.0, 405.0
[M+H].sup.+.
[0288] To a solution of (S)-tert-butyl
5-amino-4-(2-bromo-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(1.50 g, 3.72 mmol) in DMF (24 mL) was added zinc cyanide (480 mg,
4.11 mmol), tris(dibenzylideneacetone)dipalladium (342 mg, 0.36
mmol) and 1,1'-bis(diphenylphosphino)ferrocene (453 mg, 0.81 mmol).
The mixture was heated at 150.degree. C. under microwave for 1 h
then concentrated. The residue was purified using silica gel
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(2-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(956 mg, 71% yield) as a solid. MS (ESI) m/z 350.1 [M+H].sup.+.
[0289] To (S)-tert-butyl
5-amino-4-(2-cyano-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoate
(850 mg, 2.44 mmol) and sodium dihydric hypophosphite (1.07 g, 12.2
mmol) in a solution of AcOH (5 mL), pyridine (10 mL) and water (5
mL) was added Raney-Ni (300 mg). After 1 h, the mixture was
filtered, and the filtrate was washed with 1M HCl then
concentrated. The residue was purified using silica gel eluting
with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(2-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (533 mg, 62% yield) as a solid. MS (ESI) m/z 353.1
[M+H].sup.+.
[0290] To a solution of (S)-tert-butyl
5-amino-4-(2-formyl-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxopentanoat-
e (594 mg, 1.69 mmol) in MeOH (20 mL) at 0.degree. C. was added
sodium borohydride (26 mg, 0.68 mmol). The mixture was stirred at
RT for 2 h then concentrated. The residue was diluted with water
and extracted with DCM. The combined organic layers were
concentrated to give (S)-tert-butyl
5-amino-4-(2-(hydroxymethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxo-
pentanoate (408 mg, 68% yield) as a solid. MS (ESI) m/z 355.1
[M+H].sup.+.
[0291] To a solution of (S)-tert-butyl
5-amino-4-(2-(hydroxymethyl)-6-oxo-4H-thieno[2,3-c]
pyrrol-5(6H)-yl)-5-oxopentanoate (308 mg, 0.87 mmol),
4-dimethylaminopyridine (10.9 mg, 0.08 mmol) and TEA (219 mg, 2.18
mmol) in DCM (10 mL) was added p-toluenesulfonyl chloride (249 mg,
1.31 mmol). The mixture was stirred for 3 h then quenched with
aqueous ammonium chloride and extracted with DCM. The combined
organic layers were concentrated and purified using silica gel
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(2-(chloromethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (200 mg, 62% yield) as a solid. MS (ESI) m/z 373.1
[M+H].sup.+.
[0292] To a solution of (S)-tert-butyl
5-amino-4-(2-(chloromethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (268 mg, 0.72 mmol) in ACN (10 mL) was added
4-(morpholinomethyl)phenol (278 mg, 1.44 mmol) and K.sub.2CO.sub.3
(198 mg, 1.44 mmol). The mixture was heated at 80.degree. C. for 4
h then concentrated. The residue was purified using silica gel
eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(2-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (145 mg, 38% yield) as a solid. MS
(ESI) m/z 530.2 [M+H].sup.+.
[0293] A mixture of (S)-tert-butyl
5-amino-4-(2-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,3-c]-
pyrrol-5(6H)-yl)-5-oxopentanoate (145 mg, 0.27 mmol) and TFA (4 mL)
in DCM (8 mL) was stirred for 12 h then concentrated to give
(S)-5-amino-4-(2-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,-
3-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (129 mg, 0.27 mmol, crude)
as an oil, which was used in the next step without further
purification. MS (ESI) m/z 474.2 [M+H].sup.+.
[0294] A mixture of
(S)-5-amino-4-(2-((4-(morpholinomethyl)phenoxy)methyl)-6-oxo-4H-thieno[2,-
3-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (129 mg, 0.27 mmol, crude)
and CDI (176 mg, 1.09 mmol) in ACN (10 mL) was stirred at
90.degree. C. for 4 h. After concentration, the residue was
purified by prep-HPLC as previously described to afford Compound 16
(28.1 mg, 23% yield) as a solid. MS (ESI) m/z 456.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.97 (s, 1H), 7.34 (s,
1H), 7.24-7.22 (m, 2H), 7.01-6.99 (m, 2H), 5.38 (s, 2H), 5.00 (dd,
J=8.4, 13.2 Hz, 1H), 4.55 (dd, J=36.4, 54.4 Hz, 2H), 3.58-3.52 (m,
4H), 3.38 (s, 2H), 2.92-2.84 (m, 1H), 2.60-2.56 (m, 1H), 2.41-2.31
(m, H), 2.02-1.98 (m, 1H).
Example 17
Compound 17: (3S)-3-(1-((4-((2,6-dimethylmorpholino)
methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2-
,6-dione
##STR00090##
[0296] To a mixture of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno
[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (372 mg, 1.0 mmol) with
4-hydroxybenzaldehyde (134 mg, 1.1 mmol) in ACN (10 mL) was added
K.sub.2CO.sub.3 (269 mg, 1.5 mmol) and KI (83 mg, 0.5 mmol). After
heating at reflux for 2 h, the mixture was diluted with water and
extracted with EA. The combined organic layers were concentrated,
and the residue was purified using silica gel eluting with DCM/MeOH
(30:1 to 15:1) to give (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (423 mg, 92% yield) as a solid.
[0297] To a mixture of (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (200 mg, 0.44 mmol) and 2,6-dimethylmorpholine
(50 mg, 0.44 mmol) in DCM (10 mL) was added NaBH.sub.3CN (33 mg,
0.54 mmol). After stirring overnight, the mixture was concentrated,
and the residue was purified by prep-TLC eluting with PE/EA (1:2)
to give (4S)-tert-butyl
5-amino-4-(1-((4-((2,6-dimethylmorpholino)methyl)phenoxy)methyl)-4-oxo-4H-
-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (62 mg, 30% yield)
as a solid. MS (ESI) m/z 557 [M+H].sup.+.
[0298] To a solution of (4S)-tert-butyl
5-amino-4-(1-((4-((2,6-dimethylmorpholino)methyl)phenoxy)methyl)-4-oxo-4H-
-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (62 mg, 0.11 mmol)
in DCM (3 mL) was added TFA (1 mL). After stirring for 2 h, the
mixture was concentrated. The residue was dissolved in ACN (5 mL)
and CDI (89 mg, 0.55 mmol) was added. The mixture was heated at
reflux overnight then concentrated. The residue was purified by
prep-HPLC as previously described to afford Compound 17 (15 mg, 28%
yield) as a solid. MS (ESI) m/z 484.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.98 (s, 1H), 8.02 (s, 1H), 7.21 (d,
2H), 6.97 (d, 2H), 5.28 (s, 2H), 5.02 (m, 1H), 4.27 (q, 2H), 3.53
(t, 2H), 3.36 (t, 2H), 2.88 (m, 1H), 2.63 (m, 2H), 2.56 (m, 1H),
2.34 (m, 1H), 1.98 (m, 1H), 1.59 (m, 1H), 1.00 (s, 6H).
Example 18
Compound 18:
(S)-3-(1-((4-((dimethylamino)methyl)phenoxy)methyl)-4-oxo-4H-thieno[3,4-c-
]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00091##
[0300] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)
methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (493
mg, 1.0 mmol) in DCM (10 mL) was added TFA (5 mL). After 2 h, the
mixture was concentrated. The residue was dissolved in ACN (10 mL)
and CDI (810 mg, 5 mmol) was added. The resulting mixture was
heated at reflux overnight. After adding water, the mixture was
extracted with EA, and the combined organic layers were
concentrated to give
(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyr-
rol-1-yl)methoxy)benzaldehyde (150 mg, 39% yield) as a solid. MS
(ESI) m/z 385 [M+H].sup.+.
[0301] To a mixture of
(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyr-
rol-1-yl)methoxy)benzaldehyde (80 mg, 0.21 mmol) with dimethylamine
(0.12 mL, 0.25 mmol) in THF (3 mL) was added NaBH.sub.3CN (27 mg,
0.42 mmol). After stirring overnight, the mixture was concentrated,
and the residue was purified by prep-HPLC as previously described
to afford Compound 18 (19.4 mg, 22% yield) as a solid. MS (ESI) m/z
414.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.97 (s, 1H), 8.01 (s, 1H), 7.20 (d, 2H), 6.97 (d, 2H), 5.28 (s,
2H), 5.01 (m, 1H), 4.28 (q, 2H), 2.87 (m, 1H), 2.56 (m, 1H), 2.34
(m, 1H), 2.11 (s, 6H), 1.99 (m, 1H).
Example 19
Compound 19:
(3S)-3-(1-((4-((3,5-dimethylmorpholino)methyl)phenoxy)methyl)-4-oxo-4H-th-
ieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00092##
[0303] To a solution of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (300 mg, 0.805 mmol) in ACN (7 mL) was added
4-hydroxybenzaldehyde (108.2 mg, 0.8859 mmol) and K.sub.2CO.sub.3
(222.3 mg, 0.4027 mmol). After heating at 80.degree. C. for 2 h,
the mixture was concentrated, and the residue was purified using
silica gel eluting with PE/EA (1:2) to give (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (358 mg, 97% yield) as a solid. MS (ESI) m/z
459 [M+H].sup.+.
[0304] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-formylphenoxy)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-
-yl)-5-oxopentanoate (257 mg, 0.561 mmol) in DCM (8 mL) at
0.degree. C. was added TFA (3 mL). After 8 h at RT, the mixture was
concentrated. The residue was dissolved with ACN (8 mL) and CDI
(363.6 mg, 2.244 mmol) was added. The mixture was heated at
80.degree. C. overnight then concentrated. The residue was purified
using silica gel eluting with PE/EA (1:2) to give
(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyr-
rol-1-yl)methoxy)benzaldehyde (188 mg, 87% yield) as a solid. MS
(ESI) m/z 385 [M+H].sup.+.
[0305] To a solution of
(S)-4-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyr-
rol-1-yl)methoxy)benzaldehyde (143 mg, 0.372 mmol) in THF (5 mL) at
0.degree. C. was added 3,5-dimethylmorpholine (85.7 mg, 0.745
mmol), tetraethyl titanate (254.8 mg, 1.117 mmol) and
NaBH(OAc).sub.3 (394.7 mg, 1.862 mmol). After heating at reflux for
2 d, the mixture was concentrated. The residue was purified using
silica gel eluting with MeOH in DCM (0% to 8%) then further
purified by prep-HPLC as previously described to afford Compound 19
(52.1 mg, 23% yield) as a solid. MS (ESI) m/z 484 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.97 (s, 1H), 8.02 (s,
1H), 7.26 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.27 (s, 2H),
4.99-5.04 (m, 1H), 4.24-4.37 (m, 2H), 3.84 (d, J=13.6 Hz, 1H),
3.53-3.56 (m, 2H), 3.21-3.26 (m, 3H), 2.84-2.93 (m, 1H), 2.67 (s,
2H), 2.56-2.65 (m, 1H), 2.31-2.35 (s, 1H), 1.97-2.00 (s, 1H), 0.92
(d, J=6.4 Hz, 6H).
Example 20
Compound 20:
(S)-5-(2,6-dioxopiperidin-3-yl)-1-((4-(morpholinomethyl)phenoxy)methyl)-4-
H-thieno[3,4-c]pyrrole-4,6(5H)-dione
##STR00093##
[0307] To dimethyl 2-cyanothiophene-3,4-dicarboxylate (1.90 g, 8.44
mmol) in a solution of AcOH (8 mL), pyridine (16 mL), and water (8
mL) at 0.degree. C. was added NaH.sub.2PO.sub.2 (5.80 g, 67.6 mmol)
and Raney Ni (1.0 g). The mixture was stirred at RT for 3 h then
filtered. The filtrate was extracted with DCM, and the combined
organic layers were washed with 1 N HCl, dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give dimethyl
2-formylthiophene-3,4-dicarboxylate (1.0 g, 52% yield) which was
used in the next step without purification. MS (ESI) m/z
229.0[M+1].sup.+.
[0308] To a solution of dimethyl
2-formylthiophene-3,4-dicarboxylate (1.0 g, 4.4 mmol) in MeOH (10
mL) at 0.degree. C. was added sodium borohydride (250 mg, 6.6 mmol)
in portions. After 2 h at RT, the mixture was concentrated to give
dimethyl 2-(hydroxymethyl)thiophene-3,4-dicarboxylate (1.0 g,
crude) as a gum which was used in the next step without
purification. MS (ESI) m/z 231.1 [M+H].sup.+.
[0309] To a solution of dimethyl
2-(hydroxymethyl)thiophene-3,4-dicarboxylate (1.0 g, 4.4 mmol,
crude) in toluene (10 mL) was added thionyl chloride (10 mL, 50
mmol) dropwise. The mixture was stirred at 80.degree. C. overnight
then concentrated, and the residue was purified using silica gel
eluting with PE/EA (4:1) to give dimethyl
2-(chloromethyl)thiophene-3,4-dicarboxylate (905 mg, 83% yield). MS
(ESI) m/z 249.0 [M+H].sup.+.
[0310] To a solution of dimethyl
2-(chloromethyl)thiophene-3,4-dicarboxylate (810 mg, 3.26 mmol) in
THF (5 mL) at 0.degree. C. was added sodium hydride (60% dispersion
in mineral oil, 196 mg, 3.92 mmol) in portions. The mixture was
degassed and purged with N.sub.2. After 30 m at 0.degree. C., a
solution of 4-(morpholinomethyl)phenol (756 mg, 3.92 mmol) in THF
(5 ml) was added. After 16 h at 80.degree. C., the mixture was
concentrated, and the residue was purified using silica gel eluting
with PE/EA (4:1) to give dimethyl
2-((4-(morpholinomethyl)phenoxy)methyl)thiophene-3,4-dicarboxyla-
te (604 mg, 46% yield) as a solid. MS (ESI) m/z 406.1
[M+H].sup.+.
[0311] To a mixture of dimethyl
2-((4-(morpholinomethyl)phenoxy)methyl)thiophene-3,4-dicarboxylate
(857 mg, 2.12 mmol) in THF (4 mL) and H.sub.2O (4 mL) was added
LiOH monohydrate (444 mg, 10.58 mmol). After 16 h, the mixture was
concentrated then diluted with water and acidified with 1N HCl to a
pH of 2. The mixture was filtered and the filter cake was washed
with water and dried to give a
2-((4-(morpholinomethyl)phenoxy)methyl)thiophene-3,4-dicarboxylic
acid (604 mg, 76% yield) as a solid which was used in the next step
without purification. MS (ESI) m/z 378.1 [M+H].sup.+.
[0312] A mixture of
2-((4-(morpholinomethyl)phenoxy)methyl)thiophene-3,4-dicarboxylic
acid (604 mg, 1.6 mmol) in acetic anhydride (15 mL) was heated at
80.degree. C. for 4 h then concentrated to give
4-((4-(morpholinomethyl)phenoxy)methyl)thieno[3,4-c]furan-1,3-dione
(574 mg, crude) as an oil which was used in the next step without
purification.
[0313] To a solution of
4-((4-(morpholinomethyl)phenoxy)methyl)thieno[3,4-c]furan-1,3-dione
(574 mg, 1.6 mmol, crude) in THF (20 mL) was added (S)-t-butyl
4,5-diamino-5-oxopentanoate hydrochloride (381 mg, 1.6 mmol) and
DIEA (250 mg, 1.92 mmol). After 4 h, CDI (312 mg, 1.92 mmol) and
DMAP (20 mg, 0.16 mmol) were added, and the mixture was heated at
reflux for 6 h then concentrated. The residue was purified using
silica gel column eluting with PE/EA (1:1) to give (S)-tert-butyl
5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4,6-dioxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (260 mg, 28% yield) as a
solid. MS (ESI) m/z 544.2 [M+H].sup.+.
[0314] To a solution of (S)-tert-butyl
5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4,6-dioxo-4H-thieno[3,-
4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (260 mg, 0.48 mmol) in DCM (6
mL) was added TFA (2 mL). After 16 h, the mixture was concentrated
to give
(S)-5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4,6-dioxo-4H-thien-
o[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (233 mg, quant.) as a
solid. MS (ESI) m/z 488.1 [M+H].sup.+.
[0315] To a solution of
(S)-5-amino-4-(1-((4-(morpholinomethyl)phenoxy)methyl)-4,6-dioxo-4H-thien-
o[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoic acid (233 mg, 0.48 mmol) in
ACN (10 mL) was added CDI (233 mg, 1.44 mmol). After 16 h at
80.degree. C., the mixture was concentrated then purified using
silica gel eluting with PE/EA (1:1) followed by prep-HPLC as
previously described to afford Compound 20 (64 mg, 29% yield) as a
solid. MS (ESI) m/z 469.9 [M+H].sup.+. .sup.1HNMR (DMSO-d.sub.6,
400 MHz) .delta. 11.09 (s, 1H), .delta. 8.40 (s, 1H), 7.24 (d,
J=8.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 5.50 (s, 2H), 5.07 (dd,
J=5.6, 7.2 Hz, 1H), 3.55 (t, J=4.8 Hz, 4H), 3.39 (s, 2H), 2.91-2.83
(m, 1H), 2.60-2.54 (m, 1H), 2.50-2.47 (m, 1H), 2.32 (t, J=4.4 Hz,
4H), 2.07-2.02 (m, 1H).
Example 21
Compound 21:
(S)-3-(1-((3-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thieno[3-
,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione
##STR00094##
[0317] A mixture of 3-fluoro-4-hydroxybenzaldehyde (1.4 g, 10 mmol)
and morpholine (1.3 g, 15 mmol) in DCM (30 mL) was stirred for 0.5
h then NaBH.sub.3CN (1.3 g, 20 mmol) was added. After 0.5 h, the
mixture was washed with water and the organic layer was
concentrated. The residue was purified using silica gel eluting
with PE/EA (1:1) to give 3-fluoro-4-(morpholinomethyl)phenol (1.1
g, 52% yield) as an oil. MS (ESI) m/z 212 [M+H].sup.+.
[0318] To a solution of (S)-tert-butyl
5-amino-4-(1-(chloromethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-5-oxop-
entanoate (100 mg, 0.27 mmol) and
3-fluoro-4-(morpholinomethyl)phenol (68 mg, 0.32 mmol) in ACN (5
mL), was added K.sub.2CO.sub.3 (75 mg, 0.54 mmol). After heating at
reflux for 4 h, the reaction was quenched with water and extracted
with EA. The combined organic layers were concentrated to give
(S)-tert-butyl
5-amino-4-(1-((3-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thie-
no[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (180 mg, crude) an oil.
MS (ESI) m/z 548 [M+H].sup.+.
[0319] To a solution of (S)-tert-butyl
5-amino-4-(1-((3-fluoro-4-(morpholinomethyl)phenoxy)methyl)-4-oxo-4H-thie-
no[3,4-c]pyrrol-5(6H)-yl)-5-oxopentanoate (160 mg, 0.27 mmol,
crude) in DCM (5 mL) was added TFA (2 mL). After 3 h, the mixture
was concentrated. The residue was dissolved in ACN (5 mL) and CDI
(216 mg, 1.35 mmol) was added. After heating at reflux for 2 d, the
mixture was washed with water and extracted with EA. The combined
organic layers were concentrated and purified by prep-HPLC as
previously described to afford Compound 21 (36.7 mg, 29% yield) as
a solid. MS (ESI) m/z 474.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.97 (s, 1H), 8.03 (s, 1H), 7.30 (dd, 1H),
6.91 (dd, 1H), 6.85 (dd, 1H), 5.31 (s, 2H), 5.02 (m, 1H), 4.27 (q,
2H), 3.54 (t, 4H), 3.43 (s, 2H), 2.87 (m, 1H), 2.58 (m, 1H), 2.33
(m, 1H), 2.32 (t, 4H), 1.99 (m, 1H).
[0320] Compounds 22-31 may be prepared following similar synthetic
procedures described in Examples 1-21
Example 22. Biological Assays
Western Blot Analysis
[0321] MV-4-11 cells were grown in RPMI 1640 media supplemented
with 10% fetal bovine serum, streptomycin and penicillin.
[0322] Cells were cultured at approximately 10.sup.6 cells per mL
and incubated in DMSO or the indicated compound for 6-8 hours.
Whole cell extracts were prepared using RIPA buffer according to
manufacturer's protocol (Pierce). Briefly, 3.times.10.sup.6 cells
were washed once in PBS, the cell pellets were resuspended in RIPA
buffer and allowed to incubate for 15 minutes on ice. Cells debris
was removed by centrifugation and the cleared whole cell lysates
were transferred to new tubes for further analysis.
[0323] For Western blot analysis, whole cell protein extracts were
separated on 4-12% SDS-polyacrylamide gels, transferred to
nitrocellulose and probed with the indicated primary antibodies.
Membranes were subsequently washed and probed with the appropriate
IRDye secondary antibodies (LI-COR). The signal was detected using
the Odyssey Imaging System (LI-COR).
[0324] The following antibodies were used in these studies:
Anti-eRF3/GSPT1: Abcam, ab126090 (Cambridge, Mass.); Anti-Ikaros:
Abcam, ab191394 (Cambridge, Mass.); Anti-CK1.alpha.: Abcam,
ab108296 (Cambridge, Mass.); 3-actin (8H.sub.10D10) mouse
monoclonal antibody: Cell Signaling Technology, #3700 (Danvers,
Mass.); IRDye 680RD Goat anti-rabbit antibody: LI-COR, 926-68071
(Lincoln, Nebr.); IRDye 800CW Goat anti-mouse antibody: LI-COR,
926-32210 (Lincoln, Nebr.).
[0325] IKAROS activity is shown in Table 1 and 2. CK-1.alpha.
activity is shown in Table 3. GSPT1 activity is shown in Table 4.
In each of Tables 1-4, the % degradation values are reported as
"A", "B", "C", or "D". "A" represents a % degradation value of less
than 25% (value<25%). "B" represents a % degradation value of
equal to or more than 25% and less than 50%
(25%.ltoreq.value<50%). "C" represents a % degradation value of
equal to or more than 50% and less than 75% (50%.ltoreq.value
<75%). "D" represents a % degradation value of equal to or more
than 75% (value.gtoreq.75%).
TABLE-US-00003 TABLE 1 Activity of Compounds in IKAROS degradation
assay. Compounds tested at 10 .mu.M. Compound No. IKAROS %
Degradation at 10 .mu.M 3 C 14 B 16 A 18 C 20 B
TABLE-US-00004 TABLE 2 Activity of Compounds in IKAROS degradation
assay. Compounds tested at 1 .mu.M. Compound No. IKAROS %
Degradation at 1 .mu.M 1 D 4 B 6 B 7 C 8 B 13 B 15 B 17 C 19 C
TABLE-US-00005 TABLE 3 Activity of Compounds * in CK1.alpha.
degradation assay. Compounds tested at 1 .mu.M. Compound No.
CK1.alpha. % Degradation at 1 .mu.M 1 D 4 B 13 C 14 C 15 B 17 D 18
D 19 D
TABLE-US-00006 TABLE 4 Activity of Compounds * in GSPT1 degradation
assay. Compounds tested at 1 .mu.M. Compound No. GSPT1 %
Degradation at 1 .mu.M 1 C 2 B 4 B 19 C
Cell-Based Assay
[0326] Either frozen primary blood mononuclear cells (PBMCs) or
frozen CD14+ mobilized peripheral blood monocytes were purchased
from AllCells (PB003F, Normal Peripheral Blood MNC (Alameda,
Calif.)). Cells were quick thawed, washed 1-time with RPMI-1640
(10% FBS/1% Pen-Strep) and plated in 96 well plates at 200,000
cells per well. Cells were pretreated with DMSO only or with the
indicated compound for 1 h and then induced with 100 ng/mL
lipopolysaccharide (LPS) for 18-24 h. The supernatant was analyzed
for IL-1.beta., IL-6, and TNF.alpha., using Meso Scale assay
according to manufacturer's protocol. The negative control wells
were treated with DMSO.
[0327] For the IL-2 analysis, 96 well plates were precoated with 1
.mu.g/mL anti-human CD3 antibody (OKT3, eBioscience Inc., San
Diego, Calif.). After washing with PBS, the indicated compound was
added (50 .mu.L/well) followed by PBMCs diluted at 3-4 million
cells/mL (150 .mu.L/well). Plates were incubated for 24 h and the
supernatants collected for Mesoscale IL-2 analysis. IL-2 activity
is measured as fold difference from the DMSO control.
[0328] IL-1.beta. activity is shown in Table 5. IL-6 activity is
shown in Table 6. TNF.alpha. activity is shown in Table 7. IL-2
activity is shown in Table 8. In each of Tables 5-7, the %
inhibition values are reported as "A", "B", "C", or "D". "A"
represents a % inhibition value of less than 50% (value <50%).
"B" represents a % inhibition value of equal to or more than 50%
and less than 70% (50%.ltoreq.value<70%). "C" represents a %
inhibition value of equal to or more than 70% and less than 90%
(70%.ltoreq.value<90%). "D" represents a % inhibition value of
equal or more than 90% (value.gtoreq.90%). In Table 8, the
fold-change values are reported as "A", "B", "C", or "D". "A"
represents a fold-change value of equal to or less than 1
(value.ltoreq.1). "B" represents a fold-change value of more than 1
and equal to or less than 2 (1.ltoreq.value.ltoreq.2). "C"
represents a fold-change value of more than 2 and equal to or less
than 3 (2<value.ltoreq.3). "D" represents a fold-change value of
more than 3 (value>3).
TABLE-US-00007 TABLE 5 Activity of Compounds in IL-1.beta.
inhibition assay. Compounds tested at 10 .mu.M. Compound No.
IL-1.beta. % Inhibition at 10 .mu.M 1 D 2 A 6 C 7 C 8 D 9 C 10 C 13
D 14 C 15 D 17 C 18 B 19 C 20 B
TABLE-US-00008 TABLE 6 Activity of Compounds * in IL-6 inhibition
assay. Compounds tested at 10 .mu.M. Compound No. IL-6 % Inhibition
at 10 .mu.M 1 B 6 A 8 C 9 A 10 A 13 B 14 A 15 B 17 A 19 A
TABLE-US-00009 TABLE 7 Activity of Compounds in TNF-.alpha.
inhibition assay. Compounds tested at 10 .mu.M. Compound No.
TNF-.alpha. % Inhibition at 10 .mu.M 2 A 3 A 6 C 7 C 8 D 9 D 10 D
11 A 12 A 13 D 14 C 15 C 16 A 17 D 18 C 19 C 20 B
TABLE-US-00010 TABLE 8 Activity of Compounds * in IL-2 fold-change
assay. Compounds tested at 10 .mu.M. Compound No. IL-2 Fold-Change
at 10 .mu.M 1 B 2 B 3 A 4 C 5 B 6 C 7 C 8 C 9 D 10 C 11 B 12 B 13 C
14 C 15 D 16 A 17 B 18 C 19 A 20 B
Cell Viability Assay
[0329] MOLM-13 cells were cultured in RPMI 1640 media supplemented
with 10% fetal bovine serum, streptomycin and penicillin, and were
plated in white walled 96-well plates at 2500 cells/well. Cells
were incubated in DMSO (control) or the indicated compound for 3
days at 37.degree. C. and 5% CO.sub.2. Following the incubation
period, 100 .mu.L of CellTiterGlow (CTG) reagent
(CellTiter-Glo.RTM. Luminescent Cell Viability Assay, Promega
(Madison, Wis.)) was added to each well. Following a 10 minutes
incubation with shaking, luminescence was measured using the
EnVision Multimode plate reader.
[0330] Antiproliferative activity of compounds in MOLM-13 cell
viability assay is shown in Table 9. The MOLM-13 cell viability
values as % DMSO are reported as "A", "B", "C", or "D". "A"
represents a % viability value of less than 25% (value<25%). "B"
represents a % viability value of equal to or more than 25% and
less than 50% (25%.ltoreq.value<50%). "C" represents a %
viability value of equal to or more than 50% and less than 75%
(50%.ltoreq.value<75%). "D" represents a % viability value of
equal or more than 75% (value.gtoreq.75%). The results indicated
that the compounds inhibited cancer cell viability, such as
leukemia cell viability.
TABLE-US-00011 TABLE 9 Activity of Compounds in MOLM-13 cell
viability assays. Compounds tested at 10 .mu.M. Compound No.
MOLM-13 Cell Viability % DMSO at 10 .mu.M 1 C 10 B 11 A 13 C 14 C
17 C 18 A 19 C 20 A
* * * * *