U.S. patent application number 16/462200 was filed with the patent office on 2020-09-24 for inhibitors of interleukin-1 receptor-associated kinases and uses thereof.
This patent application is currently assigned to Dana-Farber Cancer Institute, Inc.. The applicant listed for this patent is Dana-Farber Cancer Institute, Inc.. Invention is credited to Sara Jean Buhrlage, Nathanael S. Gray, John Hatcher, Tinghu Zhang.
Application Number | 20200299257 16/462200 |
Document ID | / |
Family ID | 1000005073985 |
Filed Date | 2020-09-24 |
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United States Patent
Application |
20200299257 |
Kind Code |
A9 |
Gray; Nathanael S. ; et
al. |
September 24, 2020 |
INHIBITORS OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASES AND USES
THEREOF
Abstract
The present invention provides novel compounds of Formula (I'),
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, prodrugs, and compositions thereof. Also
provided are methods and kits involving the inventive compounds or
compositions for treating and/or preventing proliferative diseases
(e.g., cancers (e.g., leukemia, lymphoma)), inflammatory diseases,
autoinflammatory diseases, and autoimmune diseases in a subject.
Treatment of a subject with a proliferative disease using a
compound or composition of the invention may inhibit the aberrant
activity of a kinase, such as an interleukin-1 receptor-associated
kinase (IRAK) (e.g., IRAKI and/or IRAK4) in the subject.
##STR00001##
Inventors: |
Gray; Nathanael S.; (Boston,
MA) ; Zhang; Tinghu; (Brookline, MA) ;
Hatcher; John; (Marlborough, MA) ; Buhrlage; Sara
Jean; (Somerville, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dana-Farber Cancer Institute, Inc. |
Boston |
MA |
US |
|
|
Assignee: |
Dana-Farber Cancer Institute,
Inc.
Boston
MA
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20190276426 A1 |
September 12, 2019 |
|
|
Family ID: |
1000005073985 |
Appl. No.: |
16/462200 |
Filed: |
November 22, 2017 |
PCT Filed: |
November 22, 2017 |
PCT NO: |
PCT/US2017/063139 PCKC 00 |
371 Date: |
May 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62425503 |
Nov 22, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 413/04 20130101;
A61P 35/00 20180101; C07D 213/81 20130101; C07D 401/04 20130101;
C07D 401/14 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; A61P 35/00 20060101 A61P035/00; C07D 413/04 20060101
C07D413/04; C07D 401/14 20060101 C07D401/14; C07D 213/81 20060101
C07D213/81 |
Claims
1. A compound of Formula (I'): ##STR00213## or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, or stereoisomer
thereof, wherein: R.sup.1 is an optionally substituted monocyclic
heteroaryl ring; R.sup.2 is a warhead of formula: ##STR00214##
##STR00215## ##STR00216## ##STR00217## ##STR00218## wherein:
L.sup.3 is a bond or an optionally substituted C.sub.1-4
hydrocarbon chain, optionally wherein one or more carbon units of
the hydrocarbon chain are independently replaced with --C.dbd.O--,
--O--, --S--, --NR.sup.L3a--, --NR.sup.L3aC(.dbd.O)--,
--C(.dbd.O)NR.sup.L3a--, --SC(.dbd.O)--, --C(.dbd.O)S--,
--OC(.dbd.O)--, --C(.dbd.O)O--, --NR.sup.L3aC(.dbd.S)--,
--C(.dbd.S)NR.sup.L3a--, trans-CR.sup.L3b.dbd.CR.sup.L3b--,
cis-CR.sup.L3b.dbd.CR.sup.L3b--, --C.ident.C--, --S(.dbd.O)--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.L3a--,
--NR.sup.L3aS(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--,
--OS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.L3a--, or
--NR.sup.L3aS(.dbd.O).sub.2--, wherein R.sup.L3a is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group, and wherein each occurrence of R.sup.L3b is
independently hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, or two R.sup.L3b groups are joined to form
an optionally substituted carbocyclic or optionally substituted
heterocyclic ring; L.sup.4 is a bond or an optionally substituted,
branched or unbranched C.sub.1-6 hydrocarbon chain; each of
R.sup.E1, R.sup.E2, and R.sup.E3 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --CN,
--CH.sub.2OR.sup.EE, --CH.sub.2N(R.sup.EE).sub.2,
--CH.sub.2SR.sup.EE, --OR.sup.EE, --N(R.sup.EE).sub.2,
--Si(R.sup.EE).sub.3, or --SR.sup.EE, wherein each instance of
R.sup.EE is independently hydrogen, optionally substituted alkyl,
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.EE groups are
joined to form an optionally substituted heterocyclic ring; or
R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; R.sup.E4 is a leaving
group; R.sup.E5 is halogen; R.sup.E6 is hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each
instance of Y is independently O, S, or NR.sup.E7, wherein R.sup.E7
is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; a is 1 or 2; each instance of z is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; L.sup.1A
is .sup.la--NR.sup.L1C(.dbd.O)--.sup.lb,
.sup.la--C(.dbd.O)NR.sup.L1--.sup.lb, or an unsubstituted
5-membered heteroaryl ring; wherein .sup.la indicates the point of
attachment is to Ring A; and .sup.lb indicates the point of
attachment is to Ring B; each instance of R.sup.3, if present, is
independently selected from the group consisting of hydrogen,
halogen, optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1,
wherein R.sup.D1 is independently selected from hydrogen,
optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, an oxygen protecting group when attached to an oxygen
atom, and a sulfur protecting group when attached to a sulfur atom;
wherein each occurrence of R.sup.D1a is independently selected from
the group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, and a nitrogen protecting group;
or optionally two instances of R.sup.D1a are taken together with
their intervening atoms to form a substituted or unsubstituted
heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R.sup.3 groups are joined to form an optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, or optionally substituted heteroaryl ring; each
instance of R.sup.4, if present, is independently selected from the
group consisting of hydrogen, halogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.D1,
--N(R.sup.D1a).sub.2, and --SR.sup.D1; R.sup.L1 is independently
hydrogen, optionally substituted C.sub.1-6 alkyl, or a nitrogen
protecting group; Ring A1 is optionally substituted carbocyclyl,
optionally substituted phenyl, optionally substituted 5-membered
heterocyclyl, or optionally substituted 6-membered heterocyclyl; n
is 0, 1, 2, or 3; and p is 0, 1, 2, 3, or 4.
2. The compound of claim 1, wherein the compound is of Formula (I):
##STR00219## or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, or stereoisomer thereof, wherein: R.sup.1 is an
optionally substituted monocyclic heteroaryl ring; R.sup.2 is a
warhead of formula: ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## wherein: L.sup.3 is a bond or an
optionally substituted C.sub.1-4 hydrocarbon chain, optionally
wherein one or more carbon units of the hydrocarbon chain are
independently replaced with --C.dbd.O--, --O--, --S--,
--NR.sup.L3a--, --NR.sup.L3aC(.dbd.O)--, --C(.dbd.O)NR.sup.L3a--,
--SC(.dbd.O)--, --C(.dbd.O)S--, --OC(.dbd.O)--, --C(.dbd.O)O--,
--NR.sup.L3aC(.dbd.S)--, --C(.dbd.S)NR.sup.L3a--,
trans-CR.sup.L3b.dbd.CR.sup.L3b--, cis-CR.sup.L3b.dbd.CR.sup.L3b--,
--C.ident.C--, --S(.dbd.O)--, --S(.dbd.O)O--, --OS(.dbd.O)--,
--S(.dbd.O)NR.sup.L3a--, --NR.sup.L3aS(.dbd.O)--,
--S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.L3a--, or --NR.sup.L3aS(.dbd.O).sub.2--,
wherein R.sup.L3a is hydrogen, substituted or unsubstituted C.sub.1
6 alkyl, or a nitrogen protecting group, and wherein each
occurrence of R.sup.L3b is independently hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.L3b groups are
joined to form an optionally substituted carbocyclic or optionally
substituted heterocyclic ring; L.sup.4 is a bond or an optionally
substituted, branched or unbranched C.sub.1-6 hydrocarbon chain;
each of R.sup.E1, R.sup.E2, and R.sup.E3 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --CN,
--CH.sub.2OR.sup.EE, --CH.sub.2N(R.sup.EE).sub.2,
--CH.sub.2SR.sup.EE, --OR.sup.EE, --N(R.sup.EE).sub.2,
--Si(R.sup.EE).sub.3, or --SR.sup.EE, wherein each instance of
R.sup.EE is independently hydrogen, optionally substituted alkyl,
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.EE groups are
joined to form an optionally substituted heterocyclic ring; or
R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; R.sup.E4 is a leaving
group; R.sup.E5 is halogen; R.sup.E6 is hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each
instance of Y is independently O, S, or NR.sup.E7, wherein R.sup.E7
is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; a is 1 or 2; each instance of z is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; L.sup.1
is .sup.la--NR.sup.L1C(.dbd.O)--.sup.lb or an unsubstituted
5-membered heteroaryl ring; wherein .sup.la indicates the point of
attachment is to Ring A; and .sup.lb indicates the point of
attachment is to Ring B; each instance of R.sup.3, if present, is
independently selected from the group consisting of hydrogen,
halogen, optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1,
wherein R.sup.D1 is independently selected from hydrogen,
optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, an oxygen protecting group when attached to an oxygen
atom, and a sulfur protecting group when attached to a sulfur atom;
wherein each occurrence of R.sup.D1a is independently selected from
the group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, and a nitrogen protecting group;
or optionally two instances of R.sup.D1a are taken together with
their intervening atoms to form a substituted or unsubstituted
heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R.sup.3 groups are joined to form an optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, or optionally substituted heteroaryl ring; each
instance of R.sup.4, if present, is independently selected from the
group consisting of hydrogen, halogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.D1,
--N(R.sup.D1a).sub.2, and --SR.sup.D1; R.sup.L1 is independently
hydrogen, optionally substituted C.sub.1-6 alkyl, or a nitrogen
protecting group; n is 0, 1, 2, or 3; and p is 0, 1, 2, 3, or
4.
3. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring
A1 is optionally substituted cyclohexyl, optionally substituted
bicyclo[1.1.1]pentane, optionally substituted phenyl, or optionally
substituted piperidine.
4. (canceled)
5. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.1 is an optionally substituted 5-membered heteroaryl
ring.
6. The compound of claim 5, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.1 is optionally substituted thiazole, oxazole, imidazole, or
pyrazole.
7. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.1 is of formula: ##STR00225## wherein: R.sup.A2 is hydrogen,
halogen, optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --OR.sup.A2a, --N(R.sup.A2b).sub.2, or SR.sup.A2a; each
occurrence of R.sup.A2a is independently selected from the group
consisting of hydrogen, optionally substituted acyl, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, an oxygen protecting group when attached to
an oxygen atom, and a sulfur protecting group when attached to a
sulfur atom; each occurrence of R.sup.A2b is independently selected
from the group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, and a nitrogen protecting group;
or optionally two instances of R.sup.A2b are taken together with
their intervening atoms to form a substituted or unsubstituted
heterocyclic or substituted or unsubstituted heteroaryl ring;
R.sup.6 is hydrogen, optionally substituted acyl, optionally
substituted alkyl, or a nitrogen protecting group; and m is 0, 1,
2, or 3.
8. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.1 is of formula: ##STR00226##
9. The compound of claim 7, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.1 is of formula: ##STR00227##
10. The compound of claim 1, wherein the compound is of formula:
##STR00228## or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, or stereoisomer thereof.
11. (canceled)
12. The compound of claim 1, wherein the compound is of formula:
##STR00229## or a pharmaceutically acceptable salt, solvate,
hydrate, tautomer, or stereoisomer thereof.
13. (canceled)
14. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
R.sup.2 is of formula: ##STR00230##
15. (canceled)
16. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein n is
0.
17. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein p is
0.
18. The compound of claim 2, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
L.sup.1 is of formula ##STR00231## .sup.la--C(.dbd.O)NH--.sup.lb,
or .sup.la--NHC(.dbd.O)--.sup.lb.
19. (canceled)
20. The compound of claim 1, or a pharmaceutically acceptable salt,
solvate, hydrate, tautomer, or stereoisomer thereof, wherein
L.sup.1A is .sup.la--NHC(.dbd.O).sup.lb.
21. (canceled)
22. The compound of claim 1, wherein the compound is of formula:
##STR00232## ##STR00233## ##STR00234## or a pharmaceutically
acceptable salt, solvate, hydrate, tautomer, or stereoisomer
thereof.
23. (canceled)
24. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
or stereoisomer thereof, and optionally a pharmaceutically
acceptable excipient.
25. (canceled)
26. A method of treating a proliferative disease in a subject in
need thereof, the method comprising administering to the subject a
therapeutically effective amount of a compound of claim 1, or a
pharmaceutically acceptable salt, solvate, hydrate, tautomer, or
stereoisomer thereof, or a pharmaceutical composition thereof.
27-41. (canceled)
42. A method of inhibiting the activity of an interleukin-1
receptor-associated kinase (IRAK) in a biological sample or
subject, the method comprising administering to the subject or
contacting the biological sample with a therapeutically effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a
pharmaceutical composition thereof.
43-44. (canceled)
45. A method of inhibiting cell growth in a biological sample or
subject, the method comprising: administering to the subject or
contacting the biological sample with a therapeutically effective
amount of a compound of claim 1, or a pharmaceutically acceptable
salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a
pharmaceutical composition thereof.
46-52. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application, U.S. Ser. No. 62/425,503,
filed Nov. 22, 2016, which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] IRAK1 is a serine/threonine kinase that was originally
identified in 1994. Altogether there are four IRAK kinases: IRAK1
and IRAK4, which are catalytically active kinases, and IRAK2 and
IRAK3, which are believed to be catalytically inactive and are
hence classified as `pseudokinases.` IRAK1 is ubiquitously
expressed with its highest expression observed in blood and immune
tissues (for example, bone marrow, lymph nodes, thymus and
peripheral blood) and hematological malignancies. IRAK signaling
contributes to multiple signaling pathways downstream of the
Toll-interleukin receptors (TIRs) that ultimately regulate
NF-.kappa.B and IFN regulatory factors (IRFs). In the case of
NF-.kappa.B, IRAK1 mediates the downstream signals of TIRs through
an interaction with MYD88 which is rapidly recruited to the
receptor upon ligand binding to either IL-1R or a TLR. Subsequent
phosphorylation on IRAK1 by upstream signals or through
autophosphorylation is the key post-translational modification and
hallmark of its activation which allows IRAK1 to bind to TRAF6
resulting in release of the IRAK1 homodimer from MYD88 and
downstream NF-.kappa.B activation.
[0003] The participation of IRAK1 in signaling networks of the
innate immune response has defined the enzyme as a critical
regulator of inflammation, the antiviral response, and the
subsequent activation of the adaptive immune response.
Consequently, an extensive investigation into physiological and
pathological functions of IRAK1 in regulating these processes has
been performed. In particular, these studies have implicated IRAK1
inhibition as potential treatment for myocardial contractile
dysfunction following burn, autoimmune conditions associated with
hyper inflammation, myocardial dysfunction, microbial septic
response, human myelodysplastic syndrome (MDS), and acute myeloid
leukemia (AML). In Waldenstrom macroglobulinemia cells, the MYD88
L265P somatic mutation is highly prevalent and responsible for
malignant growth through activation of nuclear factor NF-.kappa.B.
Two downstream signaling branches, one including BTK and one
including IRAK1, both regulate NF-.kappa.B activation in Myd88L265P
expressing WM cell lines. IRAK1 inhibitors should be pursued for
the disease since genetic knockdown of either BTK or IRAK1 leads to
modest cell killing; and IRAK1 is activated in viable cells
isolated from WM patient currently receiving Ibrutinib therapy WM
cell lines, and primary patient samples treated with an IRAK1/4
inhibitor and a BTK inhibitor display augmented inhibition of
NF-.kappa.B signaling and more robust cell killing. Although IRAK1
was identified over twenty years ago, and its critical function in
autoimmunity and inflammation has been widely recognized, medicinal
chemistry efforts directed at the development of selective
inhibitors of IRAK1 have not been reported. Thus, it is important
to develop selective inhibitors of IRAK (e.g., IRAK1 and IRAK4) for
use as research tools as well as therapeutic agents in the
treatment of diseases.
SUMMARY OF THE INVENTION
[0004] The present invention provides compounds of Formula (I'),
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, prodrugs, and compositions thereof. The
compounds of Formula (I'), and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
compositions thereof, may inhibit the activity of a kinase. In
certain embodiments, the kinase is an interleukin-1
receptor-associated kinase (IRAK). In certain embodiments, the
kinase is IRAK1. In certain embodiments, the kinase is IRAK4. In
certain embodiments, the compounds of Formula (I') are selective
for IRAK1 compared to other kinases. The present invention further
provides methods of using the inventive compounds, and
pharmaceutically acceptable salts, solvates, hydrates, polymorphs,
co-crystals, tautomers, stereoisomers, isotopically labeled
derivatives, prodrugs, and compositions thereof, to study the
inhibition of a kinase (e.g., IRAK1) and as therapeutics for the
prevention and/or treatment of diseases associated with the
overexpression and/or aberrant (e.g., increased or unwanted)
activity of a kinase (e.g., IRAK1). In certain embodiments, the
inventive compounds are used for the prevention and/or treatment of
proliferative diseases (e.g., cancers (e.g., leukemia, lymphoma),
inflammatory diseases, autoinflammatory diseases, and autoimmune
diseases in a subject.
[0005] In one aspect, the present disclosure provides compounds of
Formula (I'):
##STR00002##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein Ring A1,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, L.sup.1A, n, and p are as
defined herein.
[0006] In one aspect, the present invention provides compounds of
Formula (I):
##STR00003##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, L.sup.1, n, and p are as defined
herein.
[0007] Exemplary compounds of Formula (I') and (I) include, but are
not limited to:
##STR00004##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof.
[0008] Other exemplary compounds of Formula (I') and (I) include,
but are not limited to:
##STR00005## ##STR00006## ##STR00007## ##STR00008##
and pharmaceutically acceptable salts, solvates, hydrates,
polymorphs, co-crystals, tautomers, stereoisomers, isotopically
labeled derivatives, and prodrugs thereof.
[0009] In another aspect, the present disclosure provides
pharmaceutical compositions including a compound described herein,
and optionally a pharmaceutically acceptable excipient. In certain
embodiments, the pharmaceutical compositions described herein
include a therapeutically or prophylactically effective amount of a
compound described herein. The pharmaceutical composition may be
useful for treating a proliferative disease in a subject in need
thereof, preventing a proliferative disease in a subject in need
thereof, or inhibiting the activity of a protein kinase (e.g.,
IRAK) in a subject, biological sample, tissue, or cell. In certain
embodiments, the proliferative disease is cancer (e.g., lymphoma,
leukemia, or myelodysplastic syndrome (MDS)). In certain
embodiments, the proliferative disease is an inflammatory disease.
In certain embodiments, the inflammatory disease is rheumatoid
arthritis, Crohn's disease, or fibrosis. In certain embodiments,
the proliferative disease is an autoimmune disease.
[0010] In another aspect, the present invention provides methods
for treating and/or preventing a proliferative disease. Exemplary
proliferative diseases which may be treated include diseases
associated with the overexpression or increased activity of an
interleukin-1 receptor-associated kinase (IRAK), e.g., cancer,
benign neoplasms, diseases associated with angiogenesis,
inflammatory diseases, autoinflammatory diseases, and autoimmune
diseases. In certain embodiments, the cancer is selected from the
group consisting of pancreatic cancer, lung cancer (e.g., small
cell lung cancer (SCLC), non-small cell lung cancer), prostate
cancer, breast cancer, ovarian cancer, kidney cancer, liver cancer,
Ewing's sarcoma, myeloma, Waldenstrom's macroglobulinemia,
myelodysplastic syndrome (MDS), osteosarcoma, brain cancer,
neuroblastoma, and colorectal cancer.
[0011] Another aspect of the invention relates to methods of
inhibiting the activity of a kinase (e.g., IRAK (e.g., IRAK1,
IRAK4)) using a compound described herein in a biological sample or
subject. In certain embodiments, the method involves the selective
inhibition of IRAK1. In certain embodiments, the method involves
the selective inhibition of IRAK4.
[0012] The present invention also provides methods of inhibiting
cell growth in a biological sample or subject. In still another
aspect, the present invention provides methods of inducing
apoptosis of a cell in a biological sample or subject.
[0013] The present invention provides methods for administering to
a subject in need thereof an effective amount of a compound, or
pharmaceutical composition thereof, as described herein. Also
described are methods for contacting a cell with an effective
amount of a compound, or pharmaceutical composition thereof, as
described herein. In certain embodiments, a method described herein
further includes administering to the subject an additional
pharmaceutical agent. In certain embodiments, a method described
herein further includes contacting the cell with an additional
pharmaceutical agent (e.g., an anti-proliferative agent). In
certain embodiments, the onal pharmaceutical agent is a kinase
inhibitor (e.g., an inhibitor of Bruton's tyrosine kinase (BTK).
The methods described herein may further include performing
radiotherapy, immunotherapy, and/or transplantation on the
subject.
[0014] In yet another aspect, the present invention provides
compounds of Formula (I'), and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
compositions thereof, for use in the treatment of a disease (e.g.,
a proliferative disease, such as cancer) in a subject.
[0015] Another aspect of the present disclosure relates to kits
comprising a container with a compound, or pharmaceutical
composition thereof, as described herein. The kits described herein
may include a single dose or multiple doses of the compound or
pharmaceutical composition. The kits may be useful in a method of
the disclosure. In certain embodiments, the kit further includes
instructions for using the compound or pharmaceutical composition.
A kit described herein may also include information (e.g.
prescribing information) as required by a regulatory agency, such
as the U.S. Food and Drug Administration (FDA).
[0016] The details of one or more embodiments of the invention are
set forth herein. Other features, objects, and advantages of the
invention will be apparent from the Detailed Description, Examples,
Figures, and Claims.
Definitions
[0017] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3.sup.rdEdition, Cambridge University
Press, Cambridge, 1987. The disclosure is not intended to be
limited in any manner by the exemplary listing of substituents
described herein.
[0018] Compounds described herein can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., enantiomers and/or diastereomers. For example, the compounds
described herein can be in the form of an individual enantiomer,
diastereomer or geometric isomer, or can be in the form of a
mixture of stereoisomers, including racemic mixtures and mixtures
enriched in one or more stereoisomer. Isomers can be isolated from
mixtures by methods known to those skilled in the art, including
chiral high pressure liquid chromatography (HPLC) and the formation
and crystallization of chiral salts; or preferred isomers can be
prepared by asymmetric syntheses. See, for example, Jacques et al.,
Enantiomers, Racemates and Resolutions (Wiley Interscience, New
York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel,
Stereochemistry of Carbon Compounds (McGraw Hill, N Y, 1962); and
Wilen, Tables of Resolving Agents and Optical Resolutions p. 268
(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind.
1972). The invention additionally encompasses compounds described
herein as individual isomers substantially free of other isomers,
and alternatively, as mixtures of various isomers.
[0019] When a range of values is listed, it is intended to
encompass each value and subrange within the range. For example,
"C.sub.1-6" is intended to encompass C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4,
C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3,
C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5, and
C.sub.5-6.
[0020] "Hydrocarbon chain" refers to a substituted or unsubstituted
divalent alkyl, alkenyl, or alkynyl group. A hydrocarbon chain
includes at least one chain, each node ("carbon unit") of which
including at least one carbon atom, between the two radicals of the
hydrocarbon chain. For example, hydrocarbon chain
--C.sup.AH(C.sup.BH.sub.2C.sup.CH.sub.3)-- includes only one carbon
unit C.sup.A. The term "C.sub.x hydrocarbon chain," wherein x is a
positive integer, refers to a hydrocarbon chain that includes x
number of carbon unit(s) between the two radicals of the
hydrocarbon chain. If there is more than one possible value of x,
the smallest possible value of x is used for the definition of the
hydrocarbon chain. For example, --CH(C.sub.2H.sub.5)-- is a C.sub.1
hydrocarbon chain, and
##STR00009##
is a C.sub.3 hydrocarbon chain. When a range of values is used,
e.g., a C.sub.1-6 hydrocarbon chain, the meaning of the range is as
described herein. A hydrocarbon chain may be saturated (e.g.,
--(CH.sub.2).sub.4--). A hydrocarbon chain may also be unsaturated
and include one or more C.dbd.C and/or C.ident.C bonds anywhere in
the hydrocarbon chain. For instance, --CH.dbd.CH(CH.sub.2).sub.2--,
--CH.sub.2--C.ident.CH.sub.2, and --C.ident.C--CH.dbd.CH-- are all
examples of a unsubstituted and unsaturated hydrocarbon chain. In
certain embodiments, the hydrocarbon chain is unsubstituted (e.g.,
--(CH.sub.2).sub.4--). In certain embodiments, the hydrocarbon
chain is substituted (e.g., --CH(C.sub.2H.sub.5)-- and
--CF.sub.2--). Any two substituents on the hydrocarbon chain may be
joined to form an optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl ring. For
##STR00010##
are all examples of a hydrocarbon chain. In contrast, in certain
embodiments
##STR00011##
are not within the scope of the hydrocarbon chains described
herein.
[0021] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group having from 1 to 20 carbon atoms
("C.sub.1-20 alkyl"). In some embodiments, an alkyl group has 1 to
10 carbon atoms ("C.sub.1-10 alkyl"). In some embodiments, an alkyl
group has 1 to 9 carbon atoms ("C.sub.1-9 alkyl"). In some
embodiments, an alkyl group has 1 to 8 carbon atoms ("C.sub.1-8
alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon
atoms ("C.sub.1-7 alkyl"). In some embodiments, an alkyl group has
1 to 6 carbon atoms ("C.sub.1-6 alkyl"). In some embodiments, an
alkyl group has 1 to 5 carbon atoms ("C.sub.1-5 alkyl"). In some
embodiments, an alkyl group has 1 to 4 carbon atoms ("C.sub.1-4
alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon
atoms ("C.sub.1-3 alkyl"). In some embodiments, an alkyl group has
1 to 2 carbon atoms ("C.sub.1-2 alkyl"). In some embodiments, an
alkyl group has 1 carbon atom ("C.sub.1 alkyl"). In some
embodiments, an alkyl group has 2 to 6 carbon atoms ("C.sub.2--
alkyl"). Examples of C.sub.1-6 alkyl groups include methyl
(C.sub.1), ethyl (C.sub.2), n-propyl (C.sub.3), isopropyl
(C.sub.3), n-butyl (C.sub.4), tert-butyl (C.sub.4), sec-butyl
(C.sub.4), iso-butyl (C.sub.4), n-pentyl (C.sub.5), 3-pentanyl
(C.sub.5), amyl (C.sub.5), neopentyl (C.sub.5), 3-methyl-2-butanyl
(C.sub.5), tertiary amyl (C.sub.5), and n-hexyl (C.sub.6).
Additional examples of alkyl groups include n-heptyl (C.sub.7),
n-octyl (C.sub.8) and the like. Unless otherwise specified, each
instance of an alkyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") with one or more substituents. In certain
embodiments, the alkyl group is unsubstituted C.sub.1-10 alkyl
(e.g., --CH.sub.3). In certain embodiments, the alkyl group is
substituted C.sub.1-10 alkyl.
[0022] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon double bonds, and no triple bonds ("C.sub.2-20
alkenyl"). In some embodiments, an alkenyl group has 2 to 10 carbon
atoms ("C.sub.2-10 alkenyl"). In some embodiments, an alkenyl group
has 2 to 9 carbon atoms ("C.sub.2-9 alkenyl"). In some embodiments,
an alkenyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In
some embodiments, an alkenyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkenyl"). In some embodiments, an alkenyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkenyl"). In some embodiments, an
alkenyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkenyl"). In
some embodiments, an alkenyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkenyl"). In some embodiments, an alkenyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkenyl"). In some embodiments, an
alkenyl group has 2 carbon atoms ("C.sub.2 alkenyl"). The one or
more carbon-carbon double bonds can be internal (such as in
2-butenyl) or terminal (such as in 1-butenyl). Examples of
C.sub.2-4 alkenyl groups include ethenyl (C.sub.2), 1-propenyl
(C.sub.3), 2-propenyl (C.sub.3), 1-butenyl (C.sub.4), 2-butenyl
(C.sub.4), butadienyl (C.sub.4), and the like. Examples of
C.sub.2-- alkenyl groups include the aforementioned C.sub.2-4
alkenyl groups as well as pentenyl (C.sub.5), pentadienyl
(C.sub.5), hexenyl (C.sub.6), and the like. Additional examples of
alkenyl include heptenyl (C.sub.7), octenyl (C.sub.8), octatrienyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkenyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl") with one or more substituents. In certain
embodiments, the alkenyl group is unsubstituted C.sub.2-10 alkenyl.
In certain embodiments, the alkenyl group is substituted C.sub.2-10
alkenyl.
[0023] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having from 2 to 20 carbon atoms, one or
more carbon-carbon triple bonds, and optionally one or more double
bonds ("C.sub.2-20 alkynyl"). In some embodiments, an alkynyl group
has 2 to 10 carbon atoms ("C.sub.2-10 alkynyl"). In some
embodiments, an alkynyl group has 2 to 9 carbon atoms ("C.sub.2-9
alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon
atoms ("C.sub.2-8 alkynyl"). In some embodiments, an alkynyl group
has 2 to 7 carbon atoms ("C.sub.2-7 alkynyl"). In some embodiments,
an alkynyl group has 2 to 6 carbon atoms ("C.sub.2-- alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms
("C.sub.2-5 alkynyl"). In some embodiments, an alkynyl group has 2
to 4 carbon atoms ("C.sub.2-4 alkynyl"). In some embodiments, an
alkynyl group has 2 to 3 carbon atoms ("C.sub.2-3 alkynyl"). In
some embodiments, an alkynyl group has 2 carbon atoms ("C.sub.2
alkynyl"). The one or more carbon-carbon triple bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
Examples of C.sub.2-4 alkynyl groups include, without limitation,
ethynyl (C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3),
1-butynyl (C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of
C.sub.2-6 alkenyl groups include the aforementioned C.sub.2-4
alkynyl groups as well as pentynyl (C.sub.5), hexynyl (C.sub.6),
and the like. Additional examples of alkynyl include heptynyl
(C.sub.7), octynyl (C.sub.8), and the like. Unless otherwise
specified, each instance of an alkynyl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
alkynyl") or substituted (a "substituted alkynyl") with one or more
substituents. In certain embodiments, the alkynyl group is
unsubstituted C.sub.2-10 alkynyl. In certain embodiments, the
alkynyl group is substituted C.sub.2-10 alkynyl.
[0024] "Carbocyclyl" or "carbocyclic" refers to a radical of a
non-aromatic cyclic hydrocarbon group having from 3 to 10 ring
carbon atoms ("C.sub.3-10 carbocyclyl") and .sub.wwero heteroatoms
in the non-aromatic ring system. In some embodiments, a carbocyclyl
group has 3 to 8 ring carbon atoms ("C.sub.3-8 carbocyclyl"). In
some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 carbocyclyl"). Exemplary C.sub.3-6 carbocyclyl groups
include, without limitation, cyclopropyl (C.sub.3), cyclopropenyl
(C.sub.3), cyclobutyl (C.sub.4), cyclobutenyl (C.sub.4),
cyclopentyl (C.sub.5), cyclopentenyl (C.sub.5), cyclohexyl
(C.sub.6), cyclohexenyl (C.sub.6), cyclohexadienyl (C.sub.6), and
the like. Exemplary C.sub.3-8 carbocyclyl groups include, without
limitation, the aforementioned C.sub.3-6 carbocyclyl groups as well
as cycloheptyl (C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl
(C.sub.7), cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8),
cyclooctenyl (C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7),
bicyclo[2.2.2]octanyl (C.sub.8), and the like. Exemplary C.sub.3-10
carbocyclyl groups include, without limitation, the aforementioned
C.sub.3-8 carbocyclyl groups as well as cyclononyl (C.sub.9),
cyclononenyl (C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl
(C.sub.10), octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl
(C.sub.10), spiro[4.5]decanyl (C.sub.10), and the like. As the
foregoing examples illustrate, in certain embodiments, the
carbocyclyl group is either monocyclic ("monocyclic carbocyclyl")
or contain a fused, bridged or spiro ring system such as a bicyclic
system ("bicyclic carbocyclyl") and can be saturated or can be
partially unsaturated. "Carbocyclyl" also includes ring systems
wherein the carbocyclic ring, as defined above, is fused with one
or more aryl or heteroaryl groups wherein the point of attachment
is on the carbocyclic ring, and in such instances, the number of
carbons continue to designate the number of carbons in the
carbocyclic ring system. Unless otherwise specified, each instance
of a carbocyclyl group is independently optionally substituted,
i.e., unsubstituted (an "unsubstituted carbocyclyl") or substituted
(a "substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is unsubstituted
C.sub.3-10 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-10 carbocyclyl.
[0025] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 10 ring carbon atoms
("C.sub.3-10 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 8 ring carbon atoms ("C.sub.3-8 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-10 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is unsubstituted C.sub.3-10 cycloalkyl. In
certain embodiments, the cycloalkyl group is substituted C.sub.3-10
cycloalkyl.
[0026] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered
heterocyclyl"). In heterocyclyl groups that contain one or more
nitrogen atoms, the point of attachment can be a carbon or nitrogen
atom, as valency permits. A heterocyclyl group can either be
monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro
ring system such as a bicyclic system ("bicyclic heterocyclyl"),
and can be saturated or can be partially unsaturated. Heterocyclyl
bicyclic ring systems can include one or more heteroatoms in one or
both rings. "Heterocyclyl" also includes ring systems wherein the
heterocyclic ring, as defined above, is fused with one or more
carbocyclyl groups wherein the point of attachment is either on the
carbocyclyl or heterocyclic ring, or ring systems wherein the
heterocyclic ring, as defined above, is fused with one or more aryl
or heteroaryl groups, wherein the point of attachment is on the
heterocyclic ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclic ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0027] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
the group consisting of nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("5-10 membered heterocyclyl"). In some
embodiments, a heterocyclyl group is a 5-8 membered non-aromatic
ring system having ring carbon atoms and 1-4 ring heteroatoms,
wherein each heteroatom is independently selected from the group
consisting of nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from the group consisting of nitrogen, oxygen, and sulfur ("5-6
membered heterocyclyl"). In some embodiments, the 5-6 membered
heterocyclyl has 1-3 ring heteroatoms selected from nitrogen,
oxygen, and sulfur. In some embodiments, the 5-6 membered
heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,
oxygen, and sulfur. In some embodiments, the 5-6 membered
heterocyclyl has one ring heteroatom selected from nitrogen,
oxygen, and sulfur.
[0028] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiiranyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary
6-membered heterocyclyl groups containing two heteroatoms include,
without limitation, triazinanyl. Exemplary 7-membered heterocyclyl
groups containing one heteroatom include, without limitation,
azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl
groups containing one heteroatom include, without limitation,
azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl
groups fused to a C.sub.6 aryl ring (also referred to herein as a
5,6-bicyclic heterocyclic ring) include, without limitation,
indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,
benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl
groups fused to an aryl ring (also referred to herein as a
6,6-bicyclic heterocyclic ring) include, without limitation,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
[0029] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 p electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Unless otherwise
specified, each instance of an aryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
aryl") or substituted (a "substituted aryl") with one or more
substituents. In certain embodiments, the aryl group is
unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl
group is substituted C.sub.6-14 aryl.
[0030] "Aralkyl" is a subset of alkyl and aryl and refers to an
optionally substituted alkyl group substituted by an optionally
substituted aryl group. In certain embodiments, the aralkyl is
optionally substituted benzyl. In certain embodiments, the aralkyl
is benzyl. In certain embodiments, the aralkyl is optionally
substituted phenethyl. In certain embodiments, the aralkyl is
phenethyl.
[0031] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 p electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from the group
consisting of nitrogen, oxygen and sulfur ("5-10 membered
heteroaryl"). In heteroaryl groups that contain one or more
nitrogen atoms, the point of attachment can be a carbon or nitrogen
atom, as valency permits. Heteroaryl bicyclic ring systems can
include one or more heteroatoms in one or both rings. "Heteroaryl"
includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more carbocyclyl or heterocyclyl groups
wherein the point of attachment is on the heteroaryl ring, and in
such instances, the number of ring members continue to designate
the number of ring members in the heteroaryl ring system.
"Heteroaryl" also includes ring systems wherein the heteroaryl
ring, as defined above, is fused with one or more aryl groups
wherein the point of attachment is either on the aryl or heteroaryl
ring, and in such instances, the number of ring members designates
the number of ring members in the fused (aryl/heteroaryl) ring
system. Bicyclic heteroaryl groups wherein one ring does not
contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and
the like) the point of attachment can be on either ring, i.e.,
either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring
that does not contain a heteroatom (e.g., 5-indolyl).
[0032] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from the group consisting of
nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-8 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from the group consisting of nitrogen,
oxygen, and sulfur ("5-6 membered heteroaryl"). In some
embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from
nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered
heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen,
and sulfur. Unless otherwise specified, each instance of a
heteroaryl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heteroaryl") or substituted (a
"substituted heteroaryl") with one or more substituents. In certain
embodiments, the heteroaryl group is unsubstituted 5-14 membered
heteroaryl. In certain embodiments, the heteroaryl group is
substituted 5-14 membered heteroaryl.
[0033] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0034] "Heteroaralkyl" is a subset of alkyl and heteroaryl and
refers to an optionally substituted alkyl group substituted by an
optionally substituted heteroaryl group.
[0035] "Partially unsaturated" refers to a group that includes at
least one double or triple bond. A "partially unsaturated" ring
system is further intended to encompass rings having multiple sites
of unsaturation, but is not intended to include aromatic groups
(e.g., aryl or heteroaryl groups) as herein defined. Likewise,
"saturated" refers to a group that does not contain a double or
triple bond, i.e., contains all single bonds.
[0036] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, which are divalent bridging groups are
further referred to using the suffix -ene, e.g., alkylene,
alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene,
and heteroarylene.
[0037] The term "optionally substituted" refers to substituted or
unsubstituted.
[0038] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups are optionally substituted (e.g.,
"substituted" or "unsubstituted" alkyl, "substituted" or
"unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl,
"substituted" or "unsubstituted" carbocyclyl, "substituted" or
"unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl
or "substituted" or "unsubstituted" heteroaryl group). In general,
the term "substituted", whether preceded by the term "optionally"
or not, means that at least one hydrogen present on a group (e.g.,
a carbon or nitrogen atom) is replaced with a permissible
substituent, e.g., a substituent which upon substitution results in
a stable compound, e.g., a compound which does not spontaneously
undergo transformation such as by rearrangement, cyclization,
elimination, or other reaction. Unless otherwise indicated, a
"substituted" group has a substituent at one or more substitutable
positions of the group, and when more than one position in any
given structure is substituted, the substituent is either the same
or different at each position. The term "substituted" is
contemplated to include substitution with all permissible
substituents of organic compounds, any of the substituents
described herein that results in the formation of a stable
compound. The present invention contemplates any and all such
combinations in order to arrive at a stable compound. For purposes
of this invention, heteroatoms such as nitrogen may have hydrogen
substituents and/or any suitable substituent as described herein
which satisfy the valencies of the heteroatoms and results in the
formation of a stable moiety.
[0039] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --SH, --SR.sup.aa, --SSR.sup.cc,
--C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO, --C(OR.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --OC(--O)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.O)R.sup.aa, --NR.sup.bbCO.sub.2R.sup.aa,
--NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.3,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.--O)R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--OP(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--OP(.dbd.O)(N(R.sup.bb).sub.2).sub.2,
--NR.sup.bbP(.dbd.O)(R.sup.aa).sub.2,
--NR.sup.bbP(.dbd.O)(.dbd.OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(N(R.sup.bb).sub.2).sub.2, --P(R.sup.cc).sub.2,
--P(OR.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.3.sup.+X.sup.-, --P(R.sup.cc).sub.4,
--P(OR.sup.cc).sub.4, --OP(R.sup.cc).sub.2,
--OP(R.sup.cc).sub.3.sup.+X.sup.-, --OP(OR.sup.cc).sub.2,
--OP(OR.sup.cc).sub.3.sup.+X.sup.-, --OP(R.sup.cc).sub.4,
--OP(OR.sup.cc).sub.4, --B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2,
--BR.sup.aa(OR.sup.cc), C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X.sup.- is a
counterion;
[0040] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0041] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10alkenyl, heteroC.sub.2-10alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.aa groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0042] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2,
--P(.dbd.O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10alkyl, heteroC.sub.2-10alkenyl,
heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,
heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5 R.sup.dd groups; wherein X.sup.- is a
counterion;
[0043] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, heteroC.sub.1-10 alkyl,
heteroC.sub.2-10 alkenyl, heteroC.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl, or two R.sup.cc groups are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0044] each instance of R.sup.dd is, independently, selected from
halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H,
--OH, --OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff, --SH,
--SR.sup.ee, --SSR.sup.ee, --C(.dbd.O)R.sup.ee, --CO.sub.2H,
--CO.sub.2R.sup.ee, --OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2OR.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O)(OR.sup.ee).sub.2, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups,
or two geminal R.sup.dd substituents can be joined to form .dbd.O
or .dbd.S; wherein X.sup.- is a counterion;
[0045] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, heteroC.sub.1-6 alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg
groups;
[0046] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, heteroC.sub.1-6alkyl,
heteroC.sub.2-6alkenyl, heteroC.sub.2-6alkynyl, C.sub.3-10
carbocyclyl, 3-10 membered heterocyclyl, C.sub.6-10 aryl and 5-10
membered heteroaryl, or two R.sup.ff groups are joined to form a
3-10 membered heterocyclyl or 5-10 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0047] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH), --SH,
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-6 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3-C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O)(OC.sub.1-6 alkyl).sub.2,
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, heteroC.sub.1-6alkyl, heteroC.sub.2-6alkenyl,
heteroC.sub.2-6alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl,
3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two
geminal R.sup.gg substituents can be joined to form .dbd.O or
.dbd.S; wherein X.sup.- is a counterion.
[0048] A "counterion" or "anionic counterion" is a negatively
charged group associated with a positively charged group in order
to maintain electronic neutrality. An anionic counterion may be
monovalent (i.e., including one formal negative charge). An anionic
counterion may also be multivalent (i.e., including more than one
formal negative charge), such as divalent or trivalent. Exemplary
counterions include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-,
I.sup.-), NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-,
H.sub.2PO.sub.4.sup.-, HCO.sub.3.sup.-, HSO.sub.4.sup.-, sulfonate
ions (e.g., methansulfonate, trifluoromethanesulfonate,
p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,
naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,
ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions
(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,
glycolate, gluconate, and the like), BF.sub.4.sup.-,
PF.sub.4.sup.-, PF.sub.6.sup.-, AsF.sub.6.sup.-, SbF.sub.6.sup.-,
B[3,5-(CF.sub.3).sub.2C.sub.6H.sub.3].sub.4].sup.-,
B(C.sub.6F.sub.5).sub.4.sup.-, BPh.sub.4.sup.-,
Al(OC(CF.sub.3).sub.3).sub.4.sup.-, and carborane anions (e.g.,
CB.sub.11H.sub.12.sup.- or (HCB.sub.11Me.sub.5Br.sub.6).sup.-).
Exemplary counterions which may be multivalent include
CO.sub.3.sup.2-, HPO.sub.4.sup.2-, PO.sub.4.sup.3-,
B.sub.4O.sub.7.sup.2-, SO.sub.4.sup.2-, S.sub.2O.sub.3.sup.2-,
carboxylate anions (e.g., tartrate, citrate, fumarate, maleate,
malate, malonate, gluconate, succinate, glutarate, adipate,
pimelate, suberate, azelate, sebacate, salicylate, phthalates,
aspartate, glutamate, and the like), and carboranes.
[0049] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0050] The term "acyl" refers to a group having the general formula
--C(.dbd.O)R.sup.X1, --C(.dbd.O)OR.sup.X1,
--C(.dbd.O)--O--C(.dbd.O)R.sup.X1, --C(.dbd.O)SR.sup.X1,
--C(.dbd.O)N(R.sup.X1).sub.2, --C(.dbd.S)R.sup.X1,
--C(.dbd.S)N(R.sup.X1).sub.2, and --C(.dbd.S)S(R.sup.X1),
--C(.dbd.NR.sup.X1)R.sup.X1, --C(.dbd.NR.sup.X1)OR.sup.X1,
--C(.dbd.NR.sup.X1)SR.sup.X1, and
--C(.dbd.NR.sup.X1)N(R.sup.X1).sub.2, wherein R.sup.X1 is hydrogen;
halogen; substituted or unsubstituted hydroxyl; substituted or
unsubstituted thiol; substituted or unsubstituted amino;
substituted or unsubstituted acyl, cyclic or acyclic, substituted
or unsubstituted, branched or unbranched aliphatic; cyclic or
acyclic, substituted or unsubstituted, branched or unbranched
heteroaliphatic; cyclic or acyclic, substituted or unsubstituted,
branched or unbranched alkyl; cyclic or acyclic, substituted or
unsubstituted, branched or unbranched alkenyl; substituted or
unsubstituted alkynyl; substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, aliphaticoxy,
heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,
heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or
di-aliphaticamino, mono- or di-heteroaliphaticamino, mono- or
di-alkylamino, mono- or di-heteroalkylamino, mono- or di-arylamino,
or mono- or di-heteroarylamino; or two R.sup.X1 groups taken
together form a 5- to 6-membered heterocyclic ring. Exemplary acyl
groups include aldehydes (--CHO), carboxylic acids (--CO.sub.2H),
ketones, acyl halides, esters, amides, imines, carbonates,
carbamates, and ureas. Acyl substituents include, but are not
limited to, any of the substituents described herein, that result
in the formation of a stable moiety (e.g., aliphatic, alkyl,
alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl,
acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro,
hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino,
alkylamino, heteroalkylamino, arylamino, heteroarylamino,
alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy,
heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy,
heteroarylthioxy, acyloxy, and the like, each of which may or may
not be further substituted).
[0051] "Alkoxy" or "alkoxyl" refers to a radical of the formula:
--O-alkyl.
[0052] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quaternary nitrogen atoms. Exemplary nitrogen atom substituents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(N(R.sup.cc).sub.2).sub.2, C.sub.1-10 alkyl, C.sub.1-10
perhaloalkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
heteroC.sub.1-10alkyl, heteroC.sub.2-10alkenyl,
heteroC.sub.2-10alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups attached to an N atom are joined to form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein
each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined above.
[0053] In certain embodiments, the substituent present on a
nitrogen atom is a nitrogen protecting group (also referred to as
an amino protecting group). Nitrogen protecting groups include, but
are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl,
heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined herein. Nitrogen protecting groups are well known in the
art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd
edition, John Wiley & Sons, 1999, incorporated herein by
reference.
[0054] For example, nitrogen protecting groups such as amide groups
(e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to,
formamide, acetamide, chloroacetamide, trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,
picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide,
o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0055] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl
carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl
carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl
carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate,
benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0056] Nitrogen protecting groups such as sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), .beta.-trimethylsilylethanesulfonamide
(SES), 9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0057] Other nitrogen protecting groups include, but are not
limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0058] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to herein as an
"hydroxyl protecting group"). Oxygen protecting groups include, but
are not limited to, --R.sup.aa, --N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.2, --P(OR.sup.cc).sub.3.sup.+X.sup.-,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, and
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein X.sup.-, R.sup.aa,
R.sup.bb, and R.sup.cc are as defined herein. Oxygen protecting
groups are well known in the art and include those described in
detail in Protecting Groups in Organic Synthesis, T. W. Greene and
P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999,
incorporated herein by reference.
[0059] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM),
t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM),
benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM),
(4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM),
t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl,
2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,
bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),
tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,
tetrahydrothiopyranyl, 1-methoxycyclohexyl,
4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide,
1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP),
1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, .alpha.-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0060] In certain embodiments, the substituent present on a sulfur
atom is a sulfur protecting group (also referred to as a "thiol
protecting group"). Sulfur protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb),
--S(.dbd.O)R.sup.bb, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3.sup.+X.sup.-,
--P(OR.sup.cc).sub.2, --P(OR.sup.cc).sub.3.sup.+X.sup.-,
--P(.dbd.O)(R.sup.aa).sub.2, --P(.dbd.O)(OR.sup.cc).sub.2, and
--P(.dbd.O)(N(R.sup.bb).sub.2).sub.2, wherein R.sup.aa, R.sup.bb,
and R.sup.cc are as defined herein. Sulfur protecting groups are
well known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0061] As used herein, a "leaving group" (LG) is an art-understood
term referring to a molecular fragment that departs with a pair of
electrons in a heterolytic bond cleavage, wherein the molecular
fragment is an anion or neutral molecule. As used herein, a leaving
group can be an atom or a group capable of being displaced by a
nucleophile. See, for example, Smith, March Advanced Organic
Chemistry 6th ed. (501-502). Exemplary leaving groups include, but
are not limited to, halo (e.g., chloro, bromo, iodo) and activated
substituted hydroxyl groups (e.g., --OC(.dbd.O)SR.sup.aa,
--OC(.dbd.O)R.sup.aa, --OCO.sub.2R.sup.aa,
--OC(.dbd.O)N(R.sup.bb).sub.2, --OC(.dbd.NR.sup.bb)R.sup.aa,
--OC(.dbd.NR.sup.bb)OR.sup.aa,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2, --OS(.dbd.O)R.sup.aa,
--OSO.sub.2R.sup.aa, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--OP(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --OP(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --OP(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein). Examples of suitable leaving
groups include, but are not limited to, halogen (such as F, Cl, Br,
or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,
alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g.,
acetoxy), arylcarbonyloxy, aryloxy, methoxy,
N,O-dimethylhydroxylamino, pixyl, and haloformates. In some cases,
the leaving group is a sulfonic acid ester, such as
toluenesulfonate (tosylate, --OTs), methanesulfonate (mesylate,
--OMs), p-bromobenzenesulfonyloxy (brosylate, --OBs), or
trifluoromethanesulfonate (triflate, --OTf). In some cases, the
leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In
some cases, the leaving group is a nosylate, such as
2-nitrobenzenesulfonyloxy. In some embodiments, the leaving group
is a sulfonate-containing group. In some embodiments, the leaving
group is a tosylate group. The leaving group may also be a
phosphineoxide (e.g., formed during a Mitsunobu reaction) or an
internal leaving group such as an epoxide or cyclic sulfate. Other
non-limiting examples of leaving groups are water, amines, ammonia,
alcohols, ether moieties, sulfur-containing moieties, thioether
moieties, zinc halides, magnesium moieties, diazonium salts, and
copper moieties.
[0062] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al., describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,
incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid, and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid, or
malonic acid or by using other methods known in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4.sup.-
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate,
and aryl sulfonate.
[0063] The term "solvate" refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction. This
physical association may include hydrogen bonding. Conventional
solvents include water, methanol, ethanol, acetic acid, DMSO, THF,
diethyl ether, and the like. The compounds of Formula (I') may be
prepared, e.g., in crystalline form, and may be solvated. Suitable
solvates include pharmaceutically acceptable solvates and further
include both stoichiometric solvates and non-stoichiometric
solvates. In certain instances, the solvate will be capable of
isolation, for example, when one or more solvent molecules are
incorporated in the crystal lattice of a crystalline solid.
"Solvate" encompasses both solution-phase and isolable solvates.
Representative solvates include hydrates, ethanolates, and
methanolates.
[0064] The term "hydrate" refers to a compound that is associated
with water. Typically, the number of the water molecules contained
in a hydrate of a compound is in a definite ratio to the number of
the compound molecules in the hydrate. Therefore, a hydrate of a
compound may be represented, for example, by the general formula
R.x H.sub.2O, wherein R is the compound and wherein x is a number
greater than 0. A given compound may form more than one type of
hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x
is a number greater than 0 and smaller than 1, e.g., hemihydrates
(R.0.5 H.sub.2O)), and polyhydrates (x is a number greater than 1,
e.g., dihydrates (R.2 H.sub.2O) and hexahydrates (R.6
H.sub.2O)).
[0065] The term "tautomers" refer to compounds that are
interchangeable forms of a particular compound structure, and that
vary in the displacement of hydrogen atoms and electrons. Thus, two
structures may be in equilibrium through the movement of .pi.
electrons and an atom (usually H). For example, enols and ketones
are tautomers because they are rapidly interconverted by treatment
with either acid or base. Another example of tautomerism is the
aci- and nitro-forms of phenylnitromethane, that are likewise
formed by treatment with acid or base.
[0066] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0067] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers." Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers."
[0068] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers." When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture."
[0069] The term "polymorphs" refers to a crystalline form of a
compound (or a salt, hydrate, or solvate thereof) in a particular
crystal packing arrangement. All polymorphs have the same elemental
composition. Different crystalline forms usually have different
X-ray diffraction patterns, infrared spectra, melting points,
density, hardness, crystal shape, optical and electrical
properties, stability, and solubility. Recrystallization solvent,
rate of crystallization, storage temperature, and other factors may
cause one crystal form to dominate. Various polymorphs of a
compound can be prepared by crystallization under different
conditions.
[0070] The term "prodrugs" refer to compounds, including
derivatives of the compounds of Formula (I'), which have cleavable
groups and become by solvolysis or under physiological conditions
the compounds of Formula (I') which are pharmaceutically active in
vivo. Such examples include, but are not limited to, ester
derivatives and the like. Other derivatives of the compounds of
this invention have activity in both their acid and acid derivative
forms, but in the acid sensitive form often offers advantages of
solubility, tissue compatibility, or delayed release in the
mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9,
21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives
well known to practitioners of the art, such as, for example,
esters prepared by reaction of the parent acid with a suitable
alcohol, or amides prepared by reaction of the parent acid compound
with a substituted or unsubstituted amine, or acid anhydrides, or
mixed anhydrides. Simple aliphatic or aromatic esters, amides, and
anhydrides derived from acidic groups pendant on the compounds of
this invention are particular prodrugs. In some cases it is
desirable to prepare double ester type prodrugs such as
(acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, aryl, C.sub.7-C.sub.12 substituted aryl, and
C.sub.7-C.sub.12 arylalkyl esters of the compounds of Formula (I')
may be preferred.
[0071] A "subject" to which administration is contemplated
includes, but is not limited to, humans (i.e., a male or female of
any age group, e.g., a pediatric subject (e.g., infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult,
or senior adult)) and/or other non-human animals, for example,
mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys);
commercially relevant mammals such as cattle, pigs, horses, sheep,
goats, cats, and/or dogs) and birds (e.g., commercially relevant
birds such as chickens, ducks, geese, and/or turkeys). In certain
embodiments, the animal is a mammal. The animal may be a male or
female and at any stage of development. A non-human animal may be a
transgenic animal.
[0072] The terms "administer," "administering," or
"administration," refers to implanting, absorbing, ingesting,
injecting, inhaling, or otherwise introducing an inventive
compound, or a pharmaceutical composition thereof.
[0073] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, delaying the onset of, or inhibiting the
progress of a "pathological condition" (e.g., a disease, disorder,
or condition, or one or more signs or symptoms thereof) described
herein. In some embodiments, treatment may be administered after
one or more signs or symptoms have developed or have been observed.
In other embodiments, treatment may be administered in the absence
of signs or symptoms of the disease or condition. For example,
treatment may be administered to a susceptible individual prior to
the onset of symptoms (e.g., in light of a history of symptoms
and/or in light of genetic or other susceptibility factors).
Treatment may also be continued after symptoms have resolved, for
example, to delay or prevent recurrence.
[0074] The terms "condition," "disease," and "disorder" are used
interchangeably.
[0075] An "effective amount" of a compound of Formula (I') refers
to an amount sufficient to elicit the desired biological response,
i.e., treating the condition. As will be appreciated by those of
ordinary skill in this art, the effective amount of a compound of
Formula (I') may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
condition being treated, the mode of administration, and the age
and health of the subject. An effective amount encompasses
therapeutic and prophylactic treatment. For example, in treating
cancer, an effective amount of an inventive compound may reduce the
tumor burden or stop the growth or spread of a tumor.
[0076] A "therapeutically effective amount" of a compound of
Formula (I') is an amount sufficient to provide a therapeutic
benefit in the treatment of a condition or to delay or minimize one
or more symptoms associated with the condition. A therapeutically
effective amount of a compound means an amount of therapeutic
agent, alone or in combination with other therapies, which provides
a therapeutic benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces, or avoids symptoms or causes of
the condition, or enhances the therapeutic efficacy of another
therapeutic agent.
[0077] A "prophylactically effective amount" of a compound of
Formula (I') is an amount sufficient to prevent a condition, or one
or more symptoms associated with the condition or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of a therapeutic agent, alone or in combination with
other agents, which provides a prophylactic benefit in the
prevention of the condition. The term "prophylactically effective
amount" can encompass an amount that improves overall prophylaxis
or enhances the prophylactic efficacy of another prophylactic
agent.
[0078] A "proliferative disease" refers to a disease that occurs
due to abnormal growth or extension by the multiplication of cells
(Walker, Cambridge Dictionary of Biology; Cambridge University
Press: Cambridge, UK, 1990). A proliferative disease may be
associated with: 1) the pathological proliferation of normally
quiescent cells; 2) the pathological migration of cells from their
normal location (e.g., metastasis of neoplastic cells); 3) the
pathological expression of proteolytic enzymes such as the matrix
metalloproteinases (e.g., collagenases, gelatinases, and
elastases); or 4) the pathological angiogenesis as in proliferative
retinopathy and tumor metastasis. Exemplary proliferative diseases
include cancers (i.e., "malignant neoplasms"), benign neoplasms,
angiogenesis, inflammatory diseases, autoinflammatory diseases, and
autoimmune diseases.
[0079] The terms "neoplasm" and "tumor" are used interchangeably
and refer to an abnormal mass of tissue wherein the growth of the
mass surpasses and is not coordinated with the growth of a normal
tissue. A neoplasm or tumor may be "benign" or "malignant,"
depending on the following characteristics: degree of cellular
differentiation (including morphology and functionality), rate of
growth, local invasion, and metastasis. A "benign neoplasm" is
generally well differentiated, has characteristically slower growth
than a malignant neoplasm, and remains localized to the site of
origin. In addition, a benign neoplasm does not have the capacity
to infiltrate, invade, or metastasize to distant sites. Exemplary
benign neoplasms include, but are not limited to, lipoma,
chondroma, adenomas, acrochordon, senile angiomas, seborrheic
keratoses, lentigos, and sebaceous hyperplasias. In some cases,
certain "benign" tumors may later give rise to malignant neoplasms,
which may result from additional genetic changes in a subpopulation
of the tumor's neoplastic cells, and these tumors are referred to
as "pre-malignant neoplasms." An exemplary pre-malignant neoplasm
is a teratoma. In contrast, a "malignant neoplasm" is generally
poorly differentiated (anaplasia) and has characteristically rapid
growth accompanied by progressive infiltration, invasion, and
destruction of the surrounding tissue. Furthermore, a malignant
neoplasm generally has the capacity to metastasize to distant
sites.
[0080] The term "metastasis," "metastatic," or "metastasize" refers
to the spread or migration of cancerous cells from a primary or
original tumor to another organ or tissue and is typically
identifiable by the presence of a "secondary tumor" or "secondary
cell mass" of the tissue type of the primary or original tumor and
not of that of the organ or tissue in which the secondary
(metastatic) tumor is located. For example, a prostate cancer that
has migrated to bone is said to be metastasized prostate cancer and
includes cancerous prostate cancer cells growing in bone
tissue.
[0081] The term "cancer" refers to a malignant neoplasm (Stedman's
Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:
Philadelphia, 1990). Exemplary cancers include, but are not limited
to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal
cancer; angiosarcoma (e.g., lymphangiosarcoma,
lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer;
benign monoclonal gammopathy; biliary cancer (e.g.,
cholangiocarcinoma); bladder cancer; breast cancer (e.g.,
adenocarcinoma of the breast, papillary carcinoma of the breast,
mammary cancer, medullary carcinoma of the breast); brain cancer
(e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,
oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid
tumor; cervical cancer (e.g., cervical adenocarcinoma);
choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer
(e.g., colon cancer, rectal cancer, colorectal adenocarcinoma);
connective tissue cancer; epithelial carcinoma; ependymoma;
endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic
hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer,
uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the
esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer
(e.g., intraocular melanoma, retinoblastoma); familiar
hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,
stomach adenocarcinoma); gastrointestinal stromal tumor (GIST);
germ cell cancer; head and neck cancer (e.g., head and neck
squamous cell carcinoma, oral cancer (e.g., oral squamous cell
carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal
cancer, nasopharyngeal cancer, oropharyngeal cancer));
hematopoietic cancers (e.g., leukemia such as acute lymphocytic
leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic
leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic
leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic
lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));
lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)
and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse
large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLUISLL), mantle cell lymphoma (MCL), marginal zone
B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT)
lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal
zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt
lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's
macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large
cell lymphoma, precursor B-lymphoblastic lymphoma and primary
central nervous system (CNS) lymphoma; and T-cell NHL such as
precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, and anaplastic large cell lymphoma); a mixture of one or
more leukemia/lymphoma as described above; and multiple myeloma
(MM)), heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease); hemangioblastoma; hypopharynx cancer;
inflammatory myofibroblastic tumors; immunocytic amyloidosis;
kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell
carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),
malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,
small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),
adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis
(e.g., systemic mastocytosis); muscle cancer; myelodysplastic
syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD)
(e.g., polycythemia vera (PV), essential thrombocytosis (ET),
agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),
chronic idiopathic myelofibrosis, chronic myelocytic leukemia
(CML), chronic neutrophilic leukemia (CNL), hypereosinophilic
syndrome (HES)); neuroblastoma; neurofibroma (e.g.,
neurofibromatosis (NF) type 1 or type 2, schwannomatosis);
neuroendocrine cancer (e.g., gastroenteropancreatic
neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma
(e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma,
ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary
adenocarcinoma; pancreatic cancer (e.g., pancreatic
andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN),
Islet cell tumors); penile cancer (e.g., Paget's disease of the
penis and scrotum); pinealoma; primitive neuroectodermal tumor
(PNT); plasma cell neoplasia; paraneoplastic syndromes;
intraepithelial neoplasms; prostate cancer (e.g., prostate
adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland
cancer; skin cancer (e.g., squamous cell carcinoma (SCC),
keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small
bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g.,
malignant fibrous histiocytoma (MFH), liposarcoma, malignant
peripheral nerve sheath tumor (MPNST), chondrosarcoma,
fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small
intestine cancer; sweat gland carcinoma; synovioma; testicular
cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid
cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid
carcinoma (PTC), medullary thyroid cancer); urethral cancer;
vaginal cancer; and vulvar cancer (e.g., Paget's disease of the
vulva).
[0082] The term "angiogenesis" refers to the formation and the
growth of new blood vessels. Normal angiogenesis occurs in the
healthy body of a subject for healing wounds and for restoring
blood flow to tissues after injury. The healthy body controls
angiogenesis through a number of means, e.g.,
angiogenesis-stimulating growth factors and angiogenesis
inhibitors. Many disease states, such as cancer, diabetic
blindness, age-related macular degeneration, rheumatoid arthritis,
and psoriasis, are characterized by abnormal (i.e., increased or
excessive) angiogenesis. Abnormal or pathological angiogenesis
refers to angiogenesis greater than that in a normal body,
especially angiogenesis in an adult not related to normal
angiogenesis (e.g., menstruation or wound healing). Abnormal
angiogenesis can provide new blood vessels that feed diseased
tissues and/or destroy normal tissues, and in the case of cancer,
the new vessels can allow tumor cells to escape into the
circulation and lodge in other organs (tumor metastases). In
certain embodiments, the angiogenesis is pathological
angiogenesis.
[0083] An "inflammatory disease" refers to a disease caused by,
resulting from, or resulting in inflammation. The term
"inflammatory disease" may also refer to a dysregulated
inflammatory reaction that causes an exaggerated response by
macrophages, granulocytes, and/or T-lymphocytes leading to abnormal
tissue damage and/or cell death. An inflammatory disease can be
either an acute or chronic inflammatory condition and can result
from infections or non-infectious causes. Inflammatory diseases
include, without limitation, atherosclerosis, arteriosclerosis,
autoimmune disorders, multiple sclerosis, systemic lupus
erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,
degenerative arthritis, tendonitis, bursitis, psoriasis, cystic
fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory
arthritis, Sjogren's syndrome, giant cell arteritis, progressive
systemic sclerosis (scleroderma), ankylosing spondylitis,
polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes
(e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves'
disease, Goodpasture's disease, mixed connective tissue disease,
sclerosing cholangitis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, pernicious anemia, inflammatory
dermatoses, usual interstitial pneumonitis (UIP), asbestosis,
silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis,
sarcoidosis, desquamative interstitial pneumonia, lymphoid
interstitial pneumonia, giant cell interstitial pneumonia, cellular
interstitial pneumonia, extrinsic allergic alveolitis, Wegener's
granulomatosis and related forms of angiitis (temporal arteritis
and polyarteritis nodosa), inflammatory dermatoses, hepatitis,
delayed-type hypersensitivity reactions (e.g., poison ivy
dermatitis), pneumonia, respiratory tract inflammation, Adult
Respiratory Distress Syndrome (ARDS), encephalitis, immediate
hypersensitivity reactions, asthma, hayfever, allergies, acute
anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,
cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic
injury), reperfusion injury, allograft rejection, host-versus-graft
rejection, appendicitis, arteritis, blepharitis, bronchiolitis,
bronchitis, cervicitis, cholangitis, chorioamnionitis,
conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,
nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,
pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,
phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, testitis,
tonsillitis, urethritis, urocystitis, uveitis, vaginitis,
vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis,
osteomyelitis, optic neuritis, temporal arteritis, transverse
myelitis, necrotizing fasciitis, and necrotizing enterocolitis.
[0084] An "autoimmune disease" refers to a disease arising from an
inappropriate immune response of the body of a subject against
substances and tissues normally present in the body. In other
words, the immune system mistakes some part of the body as a
pathogen and attacks its own cells. This may be restricted to
certain organs (e.g., in autoimmune thyroiditis) or involve a
particular tissue in different places (e.g., Goodpasture's disease
which may affect the basement membrane in both the lung and
kidney). The treatment of autoimmune diseases is typically with
immunosuppression, e.g., medications which decrease the immune
response. Exemplary autoimmune diseases include, but are not
limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing
vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus
erythematosis, rheumatoid, arthritis, psoriatic arthritis, systemic
lupus erythematosis, psoriasis, ulcerative colitis, systemic
sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody
syndrome, scleroderma, pemphigus vulgaris, ANCA-associated
vasculitis (e.g., Wegener's granulomatosis, microscopic
polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease,
Reiter's syndrome, ankylosing spondylitis, Lyme arthritis,
Guillain-Barre syndrome, Hashimoto's thyroiditis, and
cardiomyopathy.
[0085] The term "autoinflammatory disease" refers to a category of
diseases that are similar but different from autoimmune diseases.
Autoinflammatory and autoimmune diseases share common
characteristics in that both groups of disorders result from the
immune system attacking a subject's own tissues and result in
increased inflammation. In autoinflammatory diseases, a subject's
innate immune system causes inflammation for unknown reasons. The
innate immune system reacts even though it has never encountered
autoantibodies or antigens in the subject. Autoinflammatory
disorders are characterized by intense episodes of inflammation
that result in such symptoms as fever, rash, or joint swelling.
These diseases also carry the risk of amyloidosis, a potentially
fatal buildup of a blood protein in vital organs. Autoinflammatory
diseases include, but are not limited to, familial Mediterranean
fever (FMF), neonatal onset multisystem inflammatory disease
(NOMID), tumor necrosis factor (TNF) receptor-associated periodic
syndrome (TRAPS), deficiency of the interleukin-1 receptor
antagonist (DIRA), and Behcet's disease.
[0086] The term "biological sample" refers to any sample including
tissue samples (such as tissue sections and needle biopsies of a
tissue); cell samples (e.g., cytological smears (such as Pap or
blood smears) or samples of cells obtained by microdissection);
samples of whole organisms (such as samples of yeasts or bacteria);
or cell fractions, fragments or organelles (such as obtained by
lysing cells and separating the components thereof by
centrifugation or otherwise). Other examples of biological samples
include blood, serum, urine, semen, fecal matter, cerebrospinal
fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied
tissue (e.g., obtained by a surgical biopsy or needle biopsy),
nipple aspirates, milk, vaginal fluid, saliva, swabs (such as
buccal swabs), or any material containing biomolecules that is
derived from a first biological sample. Biological samples also
include those biological samples that are transgenic, such as a
transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor
cell, or cell nucleus.
[0087] A "protein" or "peptide" comprises a polymer of amino acid
residues linked together by peptide bonds. The term refers to
proteins, polypeptides, and peptides of any size, structure, or
function. Typically, a protein will be at least three amino acids
long. A protein may refer to an individual protein or a collection
of proteins. Inventive proteins preferably contain only natural
amino acids, although non-natural amino acids (i.e., compounds that
do not occur in nature but that can be incorporated into a
polypeptide chain) and/or amino acid analogs as are known in the
art may alternatively be employed. Also, one or more of the amino
acids in an inventive protein may be modified, for example, by the
addition of a chemical entity such as a carbohydrate group, a
hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl
group, a fatty acid group, a linker for conjugation or
functionalization, or other modification. A protein may also be a
single molecule or may be a multi-molecular complex. A protein may
be a fragment of a naturally occurring protein or peptide. A
protein may be naturally occurring, recombinant, or synthetic, or
any combination of these.
[0088] The term "kinase" refers to any enzyme that catalyzes the
addition of phosphate groups to an amino acid residue of a protein.
For example, a serine kinase catalyzes the addition of a phosphate
group to serine residue in a protein. In certain embodiments, the
kinase is a protein kinase. Examples of kinases include, but are
not limited to, a cyclin-dependent kinase (CDK, e.g., CDK1, CDK2,
CDK2, CDK4, CDK5, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13,
CDK14, CDK16, CDK20)), a mitogen-activated protein kinase (MAPK,
e.g., MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK10,
MAPK11, MAPK12, MAPK13, MAPK14, MAPK15), a glycogen synthase kinase
3 (GSK3, e.g., GSK3.alpha., GSK3.beta.), a CDK-like kinase (CLK,
e.g., CLK1, CLK2, CLK3, CLK4)), an AGC kinase (e.g., protein kinase
A (PKA), protein kinase C (PKC), protein kinase G (PKG)), a
Ca.sup.2+/calmodulin-dependent protein kinase (CaM kinase, e.g., a
specialized CaM kinase, a multifunctional CaM kinase), a casein
kinase 1 (CK1, e.g., CK1alpha, CK1beta 1, CK1gamma 1, CK1gamma 2,
CK1gamma 3, CK1delta, CK1epsilon), a STE kinase (e.g., a homolog of
yeast Sterile 7, Sterile 11, or Sterile 20 kinase), a tyrosine
kinase (TK, e.g., a receptor tyrosine kinase (RTK), a non-receptor
tyrosine kinase (nRTK)), and a tyrosine-kinase-like kinase (TKL,
e.g., a mixed lineage kinase (MLK), RAF, a serine threonine kinase
receptor (STKR), a leucine rich repeat kinase (LRRK), a LIM domain
kinase (LIMK), a testis expressed serine kinase (TESK), an IL1
receptor associated kinase (IRAK), a receptor interacting protein
kinase (RIPK)).
[0089] The term "IRAK" refers to interleukin-1 receptor-associated
kinases. Examples of kinases include, but are not limited to, IRAK1
and IRAK4. IRAK1 and IRAK4 are serine/threonine-protein kinases
that play a critical role in initiating innate immune response
against foreign pathogens. IRAK1 and IRAK4 are involved in
Toll-like receptor (TLR) and IL-1R signaling pathways, and are
rapidly recruited by MYD88 to the receptor-signaling complex upon
TLR activation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0090] The accompanying drawings, which constitute a part of this
specification, illustrate several embodiments of the invention and
together with the description, serve to explain the principles of
the invention.
[0091] FIGS. 1A to 1C. Figure JA shows the results of lentiviral
transduction studies performed in MYD88 mutated BCWM.1 cells, where
it was observed in an inducible model system that knockdown of
IRAK1 produced more robust apoptotic effects versus IRAK4. FIG. 1B
shows that JH-X-119-01 inhibited IRAK1 biochemically with an IC50
of 9.3 nM, while exhibiting no inhibition of IRAK4 at
concentrations up to 10 .mu.M, and showed exceptional kinome
selectivity with off-target inhibition of only two kinases, YSK4
and MEK3. FIG. 1C shows the effect of the combination of
JH-X-119-01 with Ibrutinib leading to synergistic tumor cell
killing in MYD88 mutated Waldenstrom's macroglobulinemia (WM) and
ABC-DLBCL cells, and suppression of NF-.kappa.B activation.
[0092] FIG. 2. IRAK1/4 kinase survival signaling remains intact in
WM cells from ibrutinib treated patients.
[0093] FIGS. 3A to 3D. Cell survival is more dependent on IRAK1
over IRAK4 in MYD88 mutated WM cells.
[0094] FIG. 4. In vitro kinase inhibition for IRAK1 inhibitors.
[0095] FIG. 5. Kinome tree for IRAK1 inhibitors.
[0096] FIG. 6. Cellular data for covalent IRAK1 inhibitors.
[0097] FIG. 7. Cellular data for covalent IRAK1 inhibitors.
JH-X-119-01 showed cell killing with micromolar ED50's when tested
in Waldenstrom's, DLBCL, and Burkitt Lymphoma cell lines.
[0098] FIG. 8. IRAK1 inhibitor JH-X-119-01 target engagement in
BCWM.1 cells.
[0099] FIG. 9. Synergism evaluation for Ibrutinib and compound
JH-I-025. Combination Index (CI<1.0).
[0100] FIG. 10. Synergism evaluation for Ibrutinib and compound
JH-X-119-01. Combination Index (CI<1.0).
[0101] FIG. 11. IRAK1 inhibitors reduce IRAK1 and downstream
NF-kB-p105 phosphorylation in MYD88 mutated WM cells. Following
recruitment on the activated receptor complex, phosphorylated on
Thr-209, probably by IRAK4, resulting in a conformational change of
the kinase domain, allowing further phosphorylations to take place.
Thr-387 phosphorylation in the activation loop is required to
achieve full enzymatic activity. Kollewe C, J. Biol. Chem.
279:5227-5236 (2004).
[0102] FIG. 12. IRAK1 inhibitors reduce IRAK1 and downstream
NF-kB-p105 phosphorylation in MYD88 mutated ABC-DLBCL cells.
[0103] FIG. 13. The combination of IRAK1 inhibitors with BTK
inhibitor, Ibrutinib shows more robust inhibition of NF-kB activity
in a NF-kB promoter driven Luciferase reporter assay.
[0104] FIG. 14. The combination of IRAK1 inhibitor, JH-X-119-01
with BTK inhibitor, and Ibrutinib shows more robust tumor cells
killing in WM patients' bone marrow LPCs.
[0105] FIG. 15. Synergism evaluation for Ibrutinib and compound
JH-X-198. Combination Index (CI<1.0).
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION
[0106] The present invention provides selective IRAK1 and/or IRAK4
inhibitors, which covalently modify a cysteine residue (e.g.,
Cys302) of IRAK1. Selective covalent inhibitors of these kinases
may be useful in the treatment of various proliferative diseases
including cancer.
[0107] The present invention provides compounds, which inhibit the
activity of a kinase (e.g., IRAK), for the prevention and/or
treatment of a subject with a proliferative disease. In certain
embodiments, the inventive compounds inhibit the activity of an
interleukin-1 receptor-associated kinase (IRAK). In certain
embodiments, the inventive compounds inhibit the activity of an
interleukin-1 receptor-associated kinase 1 (IRAK1). In certain
embodiments, the inventive compounds inhibit the activity of an
interleukin-1 receptor-associated kinase 4 (IRAK4). In certain
embodiments, the inventive compounds covalently modify an
interleukin-1 receptor-associated kinase 1 (IRAK1). In certain
embodiments, the inventive compounds covalently modify an
interleukin-1 receptor-associated kinase 4 (IRAK4). The present
invention also provides methods of using the compounds described
herein, e.g., as biological probes to study the inhibition of the
activity of a kinase (e.g., IRAK (e.g. IRAK1 and/or IRAK4)), and as
therapeutics, e.g., in the prevention and/or treatment of diseases
associated with the overexpression, increased activity, and/or
aberrant activity of a kinase (e.g., IRAK (e.g. IRAK1 and/or
IRAK4)). In certain embodiments, the diseases are proliferative
diseases. The proliferative diseases that may be treated and/or
prevented include, but are not limited to, (e.g., cancers (e.g.,
leukemia, lymphoma), inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases. Also provided by the present
disclosure are pharmaceutical compositions, kits, methods, and uses
including a compound of Formula (I') as described herein.
Compounds
[0108] Aspects of the present disclosure relate to the compounds
described herein. The compounds described herein may be useful in
treating and/or preventing proliferative diseases in a subject, or
inhibiting the activity of a protein kinase (e.g., IRAK) in a
subject or biological sample. In certain embodiments, a compound
described herein is a compound of any one of Formula (I'), or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof. In certain embodiments, a compound
described herein is a compound of Formula (I'), or a
pharmaceutically acceptable salt thereof.
[0109] In certain embodiments, a compound described herein is of
Formula (I'):
##STR00012##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
or stereoisomer thereof, wherein:
[0110] R.sup.1 is an optionally substituted monocyclic heteroaryl
ring;
[0111] R.sup.2 is a warhead of formula:
##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##
##STR00018##
[0112] wherein: [0113] L.sup.3 is a bond or an optionally
substituted C.sub.1-4 hydrocarbon chain, optionally wherein one or
more carbon units of the hydrocarbon chain are independently
replaced with --C.dbd.O--, --O--, --S--, --NR.sup.L3a--,
--NR.sup.L3aC(.dbd.O)--, --C(.dbd.O)NR.sup.L3a--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --OC(.dbd.O)--, --C(.dbd.O)O--,
--NR.sup.L3aC(.dbd.S)--, --C(.dbd.S)NR.sup.L3a--,
trans-CR.sup.L3b--.dbd.CR.sup.L3b--, cis-CR.sup.L3b--CR.sup.L3b--,
--C.ident.C--, --S(.dbd.O)--, --S(.dbd.O)O--, --OS(.dbd.O)--,
--S(.dbd.--O)NR.sup.L3a--, --NR.sup.L3aS(.dbd.O)--,
--S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--, --OS(.dbd.O).sub.2--,
--S(.dbd.O).sub.2NR.sup.L3a--, or --NR.sup.L3aS(.dbd.O).sub.2--,
wherein R.sup.L3a is hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group, and wherein each
occurrence of R.sup.L3b is independently hydrogen, halogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.L3b groups are
joined to form an optionally substituted carbocyclic or optionally
substituted heterocyclic ring; [0114] L.sup.4 is a bond or an
optionally substituted, branched or unbranched C.sub.1-6
hydrocarbon chain; [0115] each of R.sup.E1, R.sup.E2, and R.sup.E3
is independently hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, --CN, --CH.sub.2OR.sup.EE, --CH.sub.2N(R.sup.EE),
--CH.sub.2SR.sup.EE, --OR.sup.EE, --N(R.sup.EE).sub.2,
--Si(R.sup.EE).sub.3, or --SR.sup.EE, wherein each instance of
R.sup.EE is independently hydrogen, optionally substituted alkyl,
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.EE groups are
joined to form an optionally substituted heterocyclic ring; or
R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; [0116] R.sup.E4 is a
leaving group; [0117] R.sup.E5 is halogen; [0118] R.sup.E6 is
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; [0119] each instance of Y is
independently O, S, or NR.sup.E7, wherein R.sup.E7 is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; [0120] a is 1 or 2;
[0121] each instance of z is independently 0, 1, 2, 3, 4, 5, or 6,
as valency permits;
[0122] L.sup.1A is .sup.la--NR.sup.L1C(.dbd.O)--.sup.lb,
.sup.1a--C(.dbd.O)NR.sup.L1-.sup.lb, or an unsubstituted 5-membered
heteroaryl ring; wherein .sup.la indicates the point of attachment
is to Ring A; and .sup.lb indicates the point of attachment is to
Ring B;
[0123] each instance of R.sup.3, if present, is independently
selected from the group consisting of hydrogen, halogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1, wherein
R.sup.D1 is independently selected from hydrogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, an
oxygen protecting group when attached to an oxygen atom, and a
sulfur protecting group when attached to a sulfur atom;
[0124] wherein each occurrence of R.sup.D1a is independently
selected from the group consisting of hydrogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl, and
a nitrogen protecting group; or optionally two instances of
R.sup.D1a are taken together with their intervening atoms to form a
substituted or unsubstituted heterocyclic or substituted or
unsubstituted heteroaryl ring;
[0125] or two R.sup.3 groups are joined to form an optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl
ring;
[0126] each instance of R.sup.4, if present, is independently
selected from the group consisting of hydrogen, halogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1;
[0127] R.sup.L1 is independently hydrogen, optionally substituted
C.sub.1-6 alkyl, or a nitrogen protecting group;
[0128] Ring A1 is optionally substituted carbocyclyl, optionally
substituted phenyl, optionally substituted 5-membered heterocyclyl,
or optionally substituted 6-membered heterocyclyl;
[0129] n is 0, 1, 2, or 3; and
[0130] p is 0, 1, 2, 3, or 4.
[0131] In certain embodiments, the compound of Formula (I') is of
Formula (I).
[0132] In certain embodiments, a compound described herein is of
Formula (I):
##STR00019##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,
or stereoisomer thereof, wherein:
[0133] R.sup.1 is an optionally substituted monocyclic heteroaryl
ring;
[0134] R.sup.2 is a warhead of formula:
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025##
[0135] wherein: [0136] L.sup.3 is a bond or an optionally
substituted C.sub.1-4 hydrocarbon chain, optionally wherein one or
more carbon units of the hydrocarbon chain are independently
replaced with --C.dbd.O--, --O--, --S--, --NR.sup.L3a--,
--NR.sup.L3aC(.dbd.O)--, --C(.dbd.O)NR.sup.L3a--, --SC(.dbd.O)--,
--C(.dbd.O)S--, --OC(.dbd.O)--, --C(.dbd.O)O--,
--NR.sup.L3aC(.dbd.S)--, --C(.dbd.S)NR.sup.L3a--,
trans-CR.sup.L3b--.dbd.CR.sup.L3b--,
cis-CR.sup.L3b.dbd.CR.sup.L3b--, --C.ident.C--, --S(.dbd.O)--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.L3a--,
--NR.sup.L3aS(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--,
--OS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.L3a--, or
--NR.sup.L3aS(.dbd.O).sub.2--, wherein R.sup.L3a is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group, and wherein each occurrence of R.sup.L3b is
independently hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, or two R.sup.L3b groups are joined to form
an optionally substituted carbocyclic or optionally substituted
heterocyclic ring; [0137] L.sup.4 is a bond or an optionally
substituted, branched or unbranched C.sub.1-6 hydrocarbon chain;
[0138] each of R.sup.E1, R.sup.E2, and R.sup.E3 is independently
hydrogen, halogen, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--CN, --CH.sub.2OR.sup.EE, --CH.sub.2N(R.sup.EE),
--CH.sub.2SR.sup.EE, --OR.sup.EE, --N(R.sup.EE),
--Si(R.sup.EE).sub.3, or --SR.sup.EE, wherein each instance of
R.sup.EE is independently hydrogen, optionally substituted alkyl,
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.EE groups are
joined to form an optionally substituted heterocyclic ring; or
R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; [0139] R.sup.E4 is a
leaving group; [0140] R.sup.E5 is halogen; [0141] R.sup.E6 is
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; [0142] each instance of Y is
independently O, S, or NR.sup.E7, wherein R.sup.E7 is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; [0143] a is 1 or 2;
[0144] each instance of z is independently 0, 1, 2, 3, 4, 5, or 6,
as valency permits;
[0145] L.sup.1 is i-NR.sup.LC(.dbd.O)--.sup.lb or a 5-membered
heteroaryl ring; wherein i indicates the point of attachment to
Ring A; and .sup.lb indicates the point of attachment to Ring
B;
[0146] each instance of R.sup.3, if present, is independently
selected from the group consisting of hydrogen, halogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1, wherein
R.sup.D1 is independently selected from the group consisting of
hydrogen, optionally substituted acyl, optionally substituted
alkyl, optionally substituted alkenyl, optionally substituted
alkynyl, optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, an oxygen protecting group when attached to an oxygen
atom, and a sulfur protecting group when attached to a sulfur
atom;
[0147] wherein each occurrence of R.sup.D1a is independently
selected from the group consisting of hydrogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl,
a nitrogen protecting group, or optionally two instances of
R.sup.D1a are taken together with their intervening atoms to form a
substituted or unsubstituted heterocyclic or substituted or
unsubstituted heteroaryl ring;
[0148] or two R.sup.3 groups are joined to form an optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl
ring;
[0149] each instance of R.sup.4, if present, is independently
selected from the group consisting of hydrogen, halogen, optionally
substituted acyl, optionally substituted alkyl, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, optionally substituted heteroaryl,
--OR.sup.D1, --N(R.sup.D1a).sub.2, and --SR.sup.D1;
[0150] R.sup.L1 is independently hydrogen, optionally substituted
C.sub.1-6 alkyl, or a nitrogen protecting group;
[0151] n is 0, 1, 2, or 3; and
[0152] p is 0, 1, 2, 3, or 4.
[0153] Formulae (I) and (I') include substituent R.sup.1. As
generally defined herein, R.sup.1 is an optionally substituted
monocyclic heteroaryl ring. In certain embodiments, R.sup.1 is an
optionally substituted 5-membered heteroaryl ring. In certain
embodiments, R.sup.1 is of Formula (ii-5):
##STR00026##
In certain embodiments, V.sup.10, V.sup.11, V.sup.12, V.sup.13, and
V.sup.14 of R.sup.1 may each independently be O, S, N, NR.sup.A1,
C, or CR.sup.A2, as valency permits. In certain embodiments, only
one of V.sup.10, V.sup.11, V.sup.12, V.sup.13, and V.sup.14 is
selected from the group consisting of O, S, N, and NR.sup.A1. In
certain embodiments, R.sup.1 is of formula:
##STR00027##
[0154] In certain embodiments, R.sup.1 is of formula:
##STR00028##
[0155] In certain embodiments, R.sup.1 is of formula:
##STR00029##
[0156] In certain embodiments, only two of V.sup.10, V.sup.11,
V.sup.12, V.sup.13, and V.sup.14 are each independently selected
from the group consisting of O, S, N, and NR.sup.A1. In certain
embodiments, R.sup.1 is optionally substituted thiazole. In certain
embodiments, R.sup.1 is optionally substituted oxazole. In certain
embodiments, R.sup.1 is optionally substituted imidazole. In
certain embodiments, R.sup.1 is optionally substituted pyrazole. In
certain embodiments, R.sup.1 is optionally substituted
isoxazole.
[0157] In certain embodiments, R.sup.1 is of formula:
##STR00030##
[0158] In certain embodiments, R.sup.1 is of formula:
##STR00031##
[0159] In certain embodiments, R.sup.1 is of formula:
##STR00032##
[0160] In certain embodiments, R.sup.1 is of formula:
##STR00033##
##STR00034##
wherein R.sup.A2 is hydrogen, halogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
optionally substituted heteroaryl, --OR.sup.A2a,
--N(R.sup.A2b).sub.2, --SR.sup.A2a; each occurrence of R.sup.A2a is
independently selected from the group consisting of hydrogen,
optionally substituted acyl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, and optionally
substituted heteroaryl, an oxygen protecting group when attached to
an oxygen atom, and a sulfur protecting group when attached to a
sulfur atom; each occurrence of R.sup.A2b is independently selected
from the group consisting of hydrogen, optionally substituted acyl,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
and optionally substituted heteroaryl, and a nitrogen protecting
group; or optionally two instances of R.sup.A2b are taken together
with their intervening atoms to form a substituted or unsubstituted
heterocyclic or substituted or unsubstituted heteroaryl ring;
R.sup.6 is hydrogen, optionally substituted acyl, optionally
substituted alkyl, or a nitrogen protecting group; and m is 0, 1,
2, or 3. In certain embodiments, R.sup.1 is of formula:
##STR00035##
In certain embodiments, R.sup.A1 is R.sup.6. In certain
embodiments, R.sup.A1 is hydrogen, optionally substituted acyl,
optionally substituted alkyl, or a nitrogen protecting group. In
certain embodiments, R.sup.A1 is optionally substituted C.sub.1-6
alkyl. In certain embodiments, R.sup.A1 is optionally substituted
methyl. In certain embodiments, R.sup.A1 is unsubstituted methyl.
In certain embodiments, R.sup.A1 is substituted methyl. In certain
embodiments, R.sup.1 is of formula
##STR00036##
In certain embodiments, R.sup.1 is of formula
##STR00037##
In certain embodiments, only three of V.sup.10, V.sup.11, V.sup.12,
V.sup.13, and V.sup.14 are each independently selected from the
group consisting of O, S, N, and NR.sup.A1. In certain embodiments,
R.sup.1 is of formula:
##STR00038##
[0161] In certain embodiments, R.sup.1 is of formula:
##STR00039##
[0162] In certain embodiments, R.sup.1 is of formula:
##STR00040##
[0163] In certain embodiments, R.sup.1 is of formula:
##STR00041##
In certain embodiments, R.sup.1 is of formula:
##STR00042##
[0164] In certain embodiments, R.sup.6 is hydrogen. In certain
embodiments, R.sup.6 is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, R.sup.6 is substituted or
unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6
alkyl). In certain embodiments, R.sup.6 is a nitrogen protecting
group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl
carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc),
trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide
(Ts)).
[0165] In certain embodiments, R.sup.1 is an optionally substituted
6-membered heteroaryl ring. In certain embodiments, R.sup.1 is of
the formula:
##STR00043##
wherein each of V.sup.10, V.sup.11, V.sup.12, V.sup.13, V.sup.14,
and V.sup.15 is independently N, C, or CR.sup.A2, as valency
permits, wherein R.sup.A2 is as defined herein. In certain
embodiments, only one of V.sup.10, V.sup.11, V.sup.12, V.sup.13,
V.sup.14, and V.sup.15 is N. In certain embodiments, R.sup.1 is of
the formula:
##STR00044##
wherein k is 0, 1, 2, 3, or 4, and R.sup.A2 is as defined herein.
In certain embodiments, R.sup.1 is of the formula:
##STR00045##
In certain embodiments, R.sup.1 is of the formula:
##STR00046##
In certain embodiments, R.sup.1 is of the formula:
##STR00047##
In certain embodiments, only three of V.sup.10, V.sup.11, V.sup.12,
V.sup.13, V.sup.14, and V.sup.15 are N. In certain embodiments,
R.sup.1 is of the formula:
##STR00048##
In certain embodiments, only three of V.sup.10, V.sup.11, V.sup.12,
V.sup.13, V.sup.14, and V.sup.15 are N. In certain embodiments,
R.sup.1 is of the formula:
##STR00049##
In certain embodiments, only three of V.sup.10, V.sup.11, V.sup.12,
V.sup.13, V.sup.14, and V.sup.15 are N. In certain embodiments,
R.sup.1 is of formula:
##STR00050##
In certain embodiments, R.sup.1 is of formula:
##STR00051##
[0166] In certain embodiments, R.sup.1 includes zero or more
instances of R.sup.A2. In certain embodiments, m is 0. In certain
embodiments, m is 1. In certain embodiments, m is 2. In certain
embodiments, m is 3. In certain embodiments, at least one instance
of R.sup.A2 is hydrogen. In certain embodiments, at least one
instance of R.sup.A2 is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, at least one instance of
R.sup.A2 is halogen (e.g., F, Cl, Br, or I). In certain
embodiments, at least one R.sup.A2 is substituted or unsubstituted
alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In
certain embodiments, at least one instance of R.sup.A2 is
substituted or unsubstituted methyl. In certain embodiments, at
least one instance of R.sup.A2 is substituted or unsubstituted
ethyl. In certain embodiments, at least one instance of R.sup.A2 is
substituted or unsubstituted propyl. In certain embodiments, at
least one instance of R.sup.A2 is substituted or unsubstituted
alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In
certain embodiments, at least one instance of R.sup.A2 is
substituted or unsubstituted alkynyl (e.g., substituted or
unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least
one instance of R.sup.A2 is substituted or unsubstituted
carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic carbocyclyl comprising zero, one, or two double bonds in
the carbocyclic ring system). In certain embodiments, at least one
instance of R.sup.A2 is substituted or unsubstituted heterocyclyl
(e.g., substituted or unsubstituted, 5- to 10-membered monocyclic
or bicyclic heterocyclic ring, wherein one or two atoms in the
heterocyclic ring are independently nitrogen, oxygen, or sulfur).
In certain embodiments, at least one instance of R.sup.A2 is
substituted or unsubstituted aryl (e.g., substituted or
unsubstituted, 6- to 10-membered aryl). In certain embodiments, at
least one instance of R.sup.A2 is benzyl. In certain embodiments,
at least one instance of R.sup.A2 is substituted or unsubstituted
phenyl. In certain embodiments, at least one instance of R.sup.A2
is substituted or unsubstituted heteroaryl (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur; or substituted or
unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one,
two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur). In certain embodiments,
at least one instance of R.sup.A2 is --OR.sup.A2a (e.g., --OH or
--OMe). In certain embodiments, at least one instance of R.sup.A2
is --N(R.sup.A2b).sub.2 (e.g., --NMe.sub.2). In certain
embodiments, at least one instance of R.sup.A2 is --SR.sup.A2a
(e.g., --SMe).
[0167] In certain embodiments, at least one instance of R.sup.A2a
is hydrogen. In certain embodiments, at least one instance of
R.sup.A2a is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, at least one R.sup.A2a is
substituted or unsubstituted alkyl (e.g., substituted or
unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least
one instance of R.sup.A2a is substituted or unsubstituted methyl.
In certain embodiments, at least one instance of R.sup.A2a is
substituted or unsubstituted ethyl. In certain embodiments, at
least one instance of R.sup.A2a is substituted or unsubstituted
propyl. In certain embodiments, at least one instance of R.sup.A2a
is substituted or unsubstituted alkenyl (e.g., substituted or
unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least
one instance of R.sup.A2a is substituted or unsubstituted alkynyl
(e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain
embodiments, at least one instance of R.sup.A2a is substituted or
unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3-
to 7-membered, monocyclic carbocyclyl comprising zero, one, or two
double bonds in the carbocyclic ring system). In certain
embodiments, at least one instance of R.sup.A2a is substituted or
unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-
to 10-membered monocyclic or bicyclic heterocyclic ring, wherein
one or two atoms in the heterocyclic ring are independently
nitrogen, oxygen, or sulfur). In certain embodiments, at least one
instance of R.sup.A2a is substituted or unsubstituted aryl (e.g.,
substituted or unsubstituted, 6- to 10-membered aryl). In certain
embodiments, at least one instance of R.sup.A2a is benzyl. In
certain embodiments, at least one instance of R.sup.Aa2 is
substituted or unsubstituted phenyl. In certain embodiments, at
least one instance of R.sup.A2a is substituted or unsubstituted
heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered,
monocyclic heteroaryl, wherein one, two, three, or four atoms in
the heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.A2a
is an oxygen protecting group when attached to an oxygen atom. In
certain embodiments, at least one instance of R.sup.A2a is a sulfur
protecting group when attached to a sulfur atom.
[0168] In certain embodiments, at least one instance of R.sup.A2b
is hydrogen. In certain embodiments, at least one instance of
R.sup.A2b is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, at least one R.sup.A2b is
substituted or unsubstituted alkyl (e.g., substituted or
unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least
one instance of R.sup.A2b is substituted or unsubstituted methyl.
In certain embodiments, at least one instance of R.sup.A2b is
substituted or unsubstituted ethyl. In certain embodiments, at
least one instance of R.sup.A2b is substituted or unsubstituted
propyl. In certain embodiments, at least one instance of R.sup.A2b
is substituted or unsubstituted alkenyl (e.g., substituted or
unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least
one instance of R.sup.A2b is substituted or unsubstituted alkynyl
(e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain
embodiments, at least one instance of R.sup.A2b is substituted or
unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3-
to 7-membered, monocyclic carbocyclyl comprising zero, one, or two
double bonds in the carbocyclic ring system). In certain
embodiments, at least one instance of R.sup.A2b is substituted or
unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-
to 10-membered monocyclic or bicyclic heterocyclic ring, wherein
one or two atoms in the heterocyclic ring are independently
nitrogen, oxygen, or sulfur). In certain embodiments, at least one
instance of R.sup.A2b is substituted or unsubstituted aryl (e.g.,
substituted or unsubstituted, 6- to 10-membered aryl). In certain
embodiments, at least one instance of R.sup.A2b is benzyl. In
certain embodiments, at least one instance of R.sup.A2b is
substituted or unsubstituted phenyl. In certain embodiments, at
least one instance of R.sup.A2b is substituted or unsubstituted
heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered,
monocyclic heteroaryl, wherein one, two, three, or four atoms in
the heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.A2b
is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl
carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl
carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl,
orp-toluenesulfonamide (Ts)). In certain embodiments, two instances
of R.sup.A2b are taken together with their intervening atoms to
form a substituted or unsubstituted heterocyclic ring (e.g.,
substituted or unsubstituted, 5- to 10-membered monocyclic or
bicyclic heterocyclic ring, wherein one or two atoms in the
heterocyclic ring are independently nitrogen, oxygen, or sulfur) or
substituted or unsubstituted heteroaryl ring (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur; or substituted or
unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one,
two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur).
[0169] As generally defined herein, Formulae (I') and (I) include
substituent R.sup.2, wherein R.sup.2 is a warhead of formula:
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057##
wherein:
[0170] L.sup.3 is a bond or an optionally substituted C.sub.1-4
hydrocarbon chain, optionally wherein one or more carbon units of
the hydrocarbon chain are independently replaced with --C.dbd.O--,
--O--, --S--, --NR.sup.L3a--, --NR.sup.L3aC(.dbd.O)--,
--C(.dbd.O)NR.sup.L3a--, --SC(.dbd.O)--, --C(.dbd.O)S--,
--OC(.dbd.O)--, --C(.dbd.O)O--, --NR.sup.L3aC(.dbd.S)--,
--C(.dbd.S)NR.sup.L3a--, trans-CR.sup.L3b.dbd.CR.sup.L3b--,
cis-CR.sup.L3b.dbd.CR.sup.L3b--, --C.ident.C--, --S(.dbd.O)--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.L3a--,
--NR.sup.L3aS(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--,
--OS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.L3a--, or
--NR.sup.L3aS(.dbd.O).sub.2--, wherein R.sup.L3a is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group, and wherein each occurrence of R.sup.L3b is
independently hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, or two R.sup.L3b groups are joined to form
an optionally substituted carbocyclic or optionally substituted
heterocyclic ring; L.sup.4 is a bond or an optionally substituted,
branched or unbranched C.sub.1-6 hydrocarbon chain; each of
R.sup.E1, R.sup.E2, and R.sup.E3 is independently hydrogen,
halogen, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, --CN,
--CH.sub.2OR.sup.EE, --CH.sub.2N(R.sup.EE).sub.2,
--CH.sub.2SR.sup.EE, --OR.sup.EE, --N(R.sup.EE).sub.2,
--Si(R.sup.EE).sub.3, or --SR.sup.EE, wherein each instance of
R.sup.EE is independently hydrogen, optionally substituted alkyl,
optionally substituted alkoxy, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted carbocyclyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl, or two R.sup.EE groups are
joined to form an optionally substituted heterocyclic ring; or
R.sup.E1 and R.sup.E3, or R.sup.E2 and R.sup.E3, or R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
or optionally substituted heterocyclic ring; R.sup.E4 is a leaving
group; R.sup.E5 is halogen; R.sup.E6 is hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each
instance of Y is independently O, S, or NR.sup.E7, wherein R.sup.E7
is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; a is 1 or 2; and each instance of z is
independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.
[0171] In certain embodiments, R.sup.2 is a warhead of formula
(i-1) through (i-41). In certain embodiments, the warhead is of
formula:
##STR00058##
In certain embodiments, R.sup.2 is a warhead of formula:
##STR00059##
In certain embodiments, R.sup.2 is a warhead of formula:
##STR00060##
In certain embodiments, R.sup.2 is a warhead of formula:
##STR00061##
In certain embodiments, the warhead is of formula:
##STR00062##
In certain embodiments, the warhead is of formula:
##STR00063##
In certain embodiments, the warhead is of formula:
##STR00064##
In certain embodiments, the warhead is of formula:
##STR00065##
In certain embodiments, the warhead is of formula:
##STR00066##
In certain embodiments, the warhead is of formula:
##STR00067##
In certain embodiments, the warhead is of formula:
##STR00068##
In certain embodiments, the warhead is of formula:
##STR00069##
In certain embodiments, the warhead is of formula:
##STR00070##
In certain embodiments, the warhead is of formula:
##STR00071##
In certain embodiments, the warhead is of formula:
##STR00072##
In certain embodiments, the warhead is of formula:
##STR00073##
In certain embodiments, the warhead is of formula:
##STR00074##
In certain embodiments, the warhead is of formula:
##STR00075##
[0172] In certain embodiments, the warhead is of formula:
##STR00076##
In certain embodiments, the warhead is of formula:
##STR00077##
In certain embodiments, the warhead is of formula:
##STR00078##
In certain embodiments, the warhead is of formula:
##STR00079##
In certain embodiments, the warhead is of formula:
##STR00080##
In certain embodiments, the warhead is of formula:
##STR00081##
In certain embodiments, the warhead is of formula:
##STR00082##
In certain embodiments, the warhead is of formula:
##STR00083##
In certain embodiments, the warhead is of formula:
##STR00084##
In certain embodiments, the warhead is of formula:
##STR00085##
In certain embodiments, the warhead is of formula:
##STR00086##
In certain embodiments, the warhead is of formula:
##STR00087##
In certain embodiments, the warhead is of formula:
##STR00088##
In certain embodiments, the warhead is of formula:
##STR00089##
[0173] In certain embodiments, the warhead is of formula:
##STR00090##
In certain embodiments, the warhead is of formula:
##STR00091##
In certain embodiments, the warhead is of formula:
##STR00092##
In certain embodiments, the warhead is of formula:
##STR00093##
In certain embodiments, the warhead is of formula:
##STR00094##
In certain embodiments, the warhead is of formula:
##STR00095##
In certain embodiments, the warhead is of formula:
##STR00096##
In certain embodiments, the warhead is of formula:
##STR00097##
In certain embodiments, the warhead is of formula:
##STR00098##
In certain embodiments, the warhead is of formula:
##STR00099##
In certain embodiments, the warhead is of formula:
##STR00100##
In certain embodiments, the warhead is of formula:
##STR00101##
[0174] In certain embodiments, L.sup.3 is a bond (e.g., a single
bond, a double bond, a triple bond). In certain embodiments,
L.sup.3 is a single bond. In certain embodiments, L.sup.3 is a
double bond. In certain embodiments, L.sup.3 is a triple bond. In
certain embodiments, L.sup.3 is an optionally substituted C.sub.1-4
hydrocarbon chain, optionally wherein one or more carbon units of
the hydrocarbon chain are independently replaced with --C.dbd.O--,
--O--, --S--, --NR.sup.L3a--, --NR.sup.L3aC(.dbd.O)--,
--C(.dbd.O)NR.sup.L3a--, --SC(.dbd.O)--, --C(.dbd.O)S--,
--OC(.dbd.O)--, --C(.dbd.O)O--, --NR.sup.L3aC(.dbd.S)--,
--C(.dbd.S)NR.sup.L3a--, trans-CR.sup.L3b.dbd.CR.sup.L3b--,
cis-CR.sup.L3b.dbd.CR.sup.L3b--, --C.ident.C--, --S(.dbd.O)--,
--S(.dbd.O)O--, --OS(.dbd.O)--, --S(.dbd.O)NR.sup.L3a--,
--NR.sup.L3aS(.dbd.O)--, --S(.dbd.O).sub.2--, --S(.dbd.O).sub.2O--,
--OS(.dbd.O).sub.2--, --S(.dbd.O).sub.2NR.sup.L3a--, or
--NR.sup.L3aS(.dbd.O).sub.2--, wherein R.sup.L3a is hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group, and wherein each occurrence of R.sup.L3b is
independently hydrogen, halogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted carbocyclyl, optionally substituted
heterocyclyl, optionally substituted aryl, or optionally
substituted heteroaryl, or two R.sup.L3b groups are joined to form
an optionally substituted carbocyclic or optionally substituted
heterocyclic ring. In certain embodiments, L.sup.4 is a bond (e.g.,
a single bond, a double bond, or a triple bond). In certain
embodiments, L.sup.4 is an optionally substituted branched
C.sub.1-6 hydrocarbon chain (e.g., i-Pr). In certain embodiments,
L.sup.4 is an optionally substituted unbranched C.sub.1-6
hydrocarbon chain (e.g., n-Pr, or n-Bu). In certain embodiments, at
least one instance of R.sup.E1 is H. In certain embodiments, at
least one instance of R.sup.E1 is halogen (e.g., F, Cl, Br, or I).
In certain embodiments, at least one instance of R.sup.E1 is
optionally substituted alkyl (e.g., Me, or Et). In certain
embodiments, at least one instance of R.sup.E1 is optionally
substituted alkenyl (e.g., optionally substituted vinyl). In
certain embodiments, at least one instance of R.sup.E1 is
optionally substituted alkynyl. In certain embodiments, at least
one instance of R.sup.E1 is substituted or unsubstituted
carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic carbocyclyl comprising zero, one, or two double bonds in
the carbocyclic ring system). In certain embodiments, at least one
instance of R.sup.E1 is substituted or unsubstituted heterocyclyl
(e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic
heterocyclyl comprising zero, one, or two double bonds in the
heterocyclic ring system, wherein one, two, or three atoms in the
heterocyclic ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.E1
is substituted or unsubstituted aryl (e.g., substituted or
unsubstituted, 6- to 10-membered aryl). In certain embodiments, at
least one instance of R.sup.E1 is substituted or unsubstituted
phenyl. In certain embodiments, at least one instance of R.sup.E1
is substituted or unsubstituted heteroaryl (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur). In certain embodiments,
at least one instance of R.sup.E1 is --CN. In certain embodiments,
at least one instance of R.sup.E1 is --CH.sub.2OR.sup.EE, wherein
each instance of R.sup.EE is independently hydrogen, optionally
substituted alkyl, optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl.
In certain embodiments, at least one instance of R.sup.E1 is
--CH.sub.2N(R.sup.EF).sub.2 or --N(R.sup.EF).sub.2, wherein each
instance of REF is independently hydrogen, optionally substituted
alkyl, optionally substituted alkoxy, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
carbocyclyl, optionally substituted heterocyclyl, optionally
substituted aryl, or optionally substituted heteroaryl, optionally
wherein two R.sup.EF groups are joined to form an optionally
substituted heterocyclic ring. In certain embodiments, at least one
instance of R.sup.E1 is --CH.sub.2SR.sup.EE or --SR.sup.EE (e.g.,
--CH.sub.2SMe or --SMe). In certain embodiments, at least one
instance of R.sup.E1 is --OR.sup.EE (e.g., --OMe). In certain
embodiments, at least one instance of R.sup.E1 is
--Si(R.sup.EG).sub.3, wherein each instance of R.sup.EG is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkoxy, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl (e.g., --Si(Me).sub.3).
[0175] In certain embodiments, at least one instance of R.sup.E2 is
H. In certain embodiments, at least one instance of R.sup.E2 is
halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least
one instance of R.sup.E2 is optionally substituted alkyl (e.g., Me,
or Et). In certain embodiments, at least one instance of R.sup.E2
is optionally substituted alkenyl (e.g., optionally substituted
vinyl). In certain embodiments, at least one instance of R.sup.E2
is optionally substituted alkynyl. In certain embodiments, at least
one instance of R.sup.E2 is substituted or unsubstituted
carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic carbocyclyl comprising zero, one, or two double bonds in
the carbocyclic ring system). In certain embodiments, at least one
instance of R.sup.E2 is substituted or unsubstituted heterocyclyl
(e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic
heterocyclyl comprising zero, one, or two double bonds in the
heterocyclic ring system, wherein one, two, or three atoms in the
heterocyclic ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.E2
is substituted or unsubstituted aryl (e.g., substituted or
unsubstituted, 6- to 10-membered aryl). In certain embodiments, at
least one instance of R.sup.E2 is substituted or unsubstituted
phenyl. In certain embodiments, at least one instance of R.sup.E2
is substituted or unsubstituted heteroaryl (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur). In certain embodiments,
at least one instance of R.sup.E2 is --CN. In certain embodiments,
at least one instance of R.sup.E2 is --CH.sub.2OR.sup.EE, wherein
each instance of R.sup.EE is independently hydrogen, optionally
substituted alkyl, optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl.
In certain embodiments, at least one instance of R.sup.E2 is
--CH.sub.2N(R.sup.EF).sub.2 or --N(R.sup.EF).sub.2, wherein each
instance of R.sup.EF is independently hydrogen, optionally
substituted alkyl, optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl,
optionally wherein two R.sup.EF groups are joined to form an
optionally substituted heterocyclic ring. In certain embodiments,
at least one instance of R.sup.E2 is --CH.sub.2SR.sup.EE or
--SR.sup.EE (e.g., CH.sub.2SMe or --SMe). In certain embodiments,
at least one instance of R.sup.E2 is --OR.sup.EE (e.g., --OMe). In
certain embodiments, at least one instance of R.sup.E2 is
--Si(R.sup.EG).sub.3, wherein each instance of R.sup.EG is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkoxy, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl (e.g., --Si(Me).sub.3). In
certain embodiments, at least one instance of R.sup.E3 is H. In
certain embodiments, at least one instance of R.sup.E3 is halogen
(e.g., F, Cl, Br, or I). In certain embodiments, at least one
instance of R.sup.E3 is optionally substituted alkyl (e.g., Me, or
Et). In certain embodiments, at least one instance of R.sup.E3 is
optionally substituted alkenyl (e.g., optionally substituted
vinyl). In certain embodiments, at least one instance of R.sup.E3
is optionally substituted alkynyl. In certain embodiments, at least
one instance of R.sup.E3 is substituted or unsubstituted
carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic carbocyclyl comprising zero, one, or two double bonds in
the carbocyclic ring system). In certain embodiments, at least one
instance of R.sup.E3 is substituted or unsubstituted heterocyclyl
(e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic
heterocyclyl comprising zero, one, or two double bonds in the
heterocyclic ring system, wherein one, two, or three atoms in the
heterocyclic ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.E3
is substituted or unsubstituted aryl (e.g., substituted or
unsubstituted, 6- to 10-membered aryl). In certain embodiments, at
least one instance of R.sup.E3 is substituted or unsubstituted
phenyl. In certain embodiments, at least one instance of R.sup.E3
is substituted or unsubstituted heteroaryl (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur). In certain embodiments,
at least one instance of R.sup.E3 is --CN. In certain embodiments,
at least one instance of R.sup.E3 is --CH.sub.2OR.sup.EE, wherein
each instance of R.sup.EE is independently hydrogen, optionally
substituted alkyl, optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl.
In certain embodiments, at least one instance of R.sup.E3 is
--CH.sub.2N(R.sup.EF).sub.2 or --N(R.sup.EF).sub.2, wherein each
instance of R.sup.EF is independently hydrogen, optionally
substituted alkyl, optionally substituted alkoxy, optionally
substituted alkenyl, optionally substituted alkynyl, optionally
substituted carbocyclyl, optionally substituted heterocyclyl,
optionally substituted aryl, or optionally substituted heteroaryl,
optionally wherein two R.sup.EF groups are joined to form an
optionally substituted heterocyclic ring. In certain embodiments,
at least one instance of R.sup.E3 is --CH.sub.2SR.sup.EE or
--SR.sup.EE (e.g., --CH.sub.2SMe or --SMe). In certain embodiments,
at least one instance of R.sup.E3 is --OR.sup.EE (e.g., --OMe). In
certain embodiments, at least one instance of R.sup.E3 is
--Si(R.sup.EG).sub.3, wherein each instance of R.sup.EG is
independently hydrogen, optionally substituted alkyl, optionally
substituted alkoxy, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl (e.g., --Si(Me).sub.3). In
certain embodiments, R.sup.E1 and R.sup.E3 are joined to form an
optionally substituted carbocyclic ring (e.g., substituted or
unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising
zero, one, or two double bonds in the carbocyclic ring system). In
certain embodiments, R.sup.E1 and R.sup.E3 are joined to form an
optionally substituted heterocyclic ring (e.g., substituted or
unsubstituted, 3- to 7-membered, monocyclic heterocyclyl comprising
zero, one, or two double bonds in the heterocyclic ring system,
wherein one, two, or three atoms in the heterocyclic ring system
are independently nitrogen, oxygen, or sulfur). In certain
embodiments, R.sup.E2 and R.sup.E3 are joined to form an optionally
substituted carbocyclic ring (e.g., substituted or unsubstituted,
3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or
two double bonds in the carbocyclic ring system). In certain
embodiments, R.sup.E2 and R.sup.E3 are joined to form an optionally
substituted heterocyclic ring (e.g., substituted or unsubstituted,
3- to 7-membered, monocyclic heterocyclyl comprising zero, one, or
two double bonds in the heterocyclic ring system, wherein one, two,
or three atoms in the heterocyclic ring system are independently
nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted carbocyclic
ring (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic carbocyclyl comprising zero, one, or two double bonds in
the carbocyclic ring system). In certain embodiments, R.sup.E1 and
R.sup.E2 are joined to form an optionally substituted heterocyclic
ring (e.g., substituted or unsubstituted, 3- to 7-membered,
monocyclic heterocyclyl comprising zero, one, or two double bonds
in the heterocyclic ring system, wherein one, two, or three atoms
in the heterocyclic ring system are independently nitrogen, oxygen,
or sulfur). In certain embodiments, R.sup.E4 is a leaving group
(e.g., halogen, or a sulfonic acid ester, e.g., --O(tosylate) or
--O(mesylate)). In certain embodiments, R.sup.E5 is halogen (e.g.,
F, Cl, Br, or I). In certain embodiments, R.sup.E6 is H. In certain
embodiments, R.sup.E6 is substituted or unsubstituted C.sub.1-6
alkyl (e.g., Me, is --CF.sub.3, Bn, Et, perfluoroethyl, Pr,
perfluoropropyl, Bu, or perfluorobutyl). In certain embodiments,
R.sup.E6 is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,
trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain
embodiments, at least one instance of Y is O. In certain
embodiments, at least one instance of Y is S. In certain
embodiments, at least one instance of Y is NR.sup.E7, wherein
R.sup.E7 is hydrogen, substituted or unsubstituted C.sub.1-6 alkyl,
or a nitrogen protecting group (e.g., NMe). In certain embodiments,
a is 1. In certain embodiments, a is 2. In certain embodiments, at
least one instance of z is 0. In certain embodiments, at least one
instance of z is 1. In certain embodiments, at least one instance
of z is 2. In certain embodiments, at least one instance of z is 3.
In certain embodiments, at least one instance of z is 4. In certain
embodiments, at least one instance of z is 5. In certain
embodiments, at least one instance of z is 6.
[0176] Formulae (I') and (I) include zero or more instances of
substituent R.sup.3 on Ring C. In certain embodiments, n is 0. In
certain embodiments, n is 1. In certain embodiments, n is 2. In
certain embodiments, n is 3. In certain embodiments, at least one
instance of R.sup.3 is hydrogen. In certain embodiments, at least
one instance of R.sup.3 is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, at least one instance of
R.sup.3 is halogen (e.g., F, Cl, Br, or I). In certain embodiments,
at least one R.sup.3 is substituted or unsubstituted alkyl (e.g.,
substituted or unsubstituted C.sub.1-6 alkyl). In certain
embodiments, at least one instance of R.sup.3 is substituted or
unsubstituted methyl. In certain embodiments, at least one instance
of R.sup.3 is substituted or unsubstituted ethyl. In certain
embodiments, at least one instance of R.sup.3 is substituted or
unsubstituted propyl. In certain embodiments, at least one instance
of R.sup.3 is substituted or unsubstituted alkenyl (e.g.,
substituted or unsubstituted C.sub.2-6 alkenyl). In certain
embodiments, at least one instance of R.sup.3 is substituted or
unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6
alkynyl). In certain embodiments, at least one instance of R.sup.3
is substituted or unsubstituted carbocyclyl (e.g., substituted or
unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising
zero, one, or two double bonds in the carbocyclic ring system). In
certain embodiments, at least one instance of R.sup.3 is
substituted or unsubstituted heterocyclyl (e.g., substituted or
unsubstituted, 5- to 10-membered monocyclic or bicyclic
heterocyclic ring, wherein one or two atoms in the heterocyclic
ring are independently nitrogen, oxygen, or sulfur). In certain
embodiments, at least one instance of R.sup.3 is substituted or
unsubstituted aryl (e.g., substituted or unsubstituted, 6- to
10-membered aryl). In certain embodiments, at least one instance of
R.sup.3 is benzyl. In certain embodiments, at least one instance of
R.sup.3 is substituted or unsubstituted phenyl. In certain
embodiments, at least one instance of R.sup.3 is substituted or
unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to
6-membered, monocyclic heteroaryl, wherein one, two, three, or four
atoms in the heteroaryl ring system are independently nitrogen,
oxygen, or sulfur; or substituted or unsubstituted, 9- to
10-membered, bicyclic heteroaryl, wherein one, two, three, or four
atoms in the heteroaryl ring system are independently nitrogen,
oxygen, or sulfur). In certain embodiments, at least one instance
of R.sup.3 is --OR.sup.D1 (e.g., --OH or --OMe). In certain
embodiments, at least one instance of R.sup.3 is
--N(R.sup.D1a).sub.2 (e.g., --NMe.sub.2). In certain embodiments,
at least one instance of R.sup.3 is --SR.sup.D1 (e.g., --SMe). In
certain embodiments, two R.sup.3 groups are joined to form an
optionally substituted carbocyclyl (e.g., substituted or
unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising
zero, one, or two double bonds in the carbocyclic ring system),
optionally substituted heterocyclyl (e.g., substituted or
unsubstituted, 5- to 10-membered monocyclic or bicyclic
heterocyclic ring, wherein one or two atoms in the heterocyclic
ring are independently nitrogen, oxygen, or sulfur), optionally
substituted aryl (e.g., substituted or unsubstituted, 6- to
10-membered aryl), or optionally substituted heteroaryl ring (e.g.,
substituted or unsubstituted, 5- to 6-membered, monocyclic
heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur).
[0177] In certain embodiments, R.sup.D1 is hydrogen. In certain
embodiments, R.sup.D1 is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, R.sup.D1 is substituted or
unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6
alkyl). In certain embodiments, R.sup.D1 is substituted or
unsubstituted methyl. In certain embodiments, R.sup.D1 is
substituted or unsubstituted ethyl. In certain embodiments,
R.sup.D1 is substituted or unsubstituted propyl. In certain
embodiments, R.sup.D1 is substituted or unsubstituted alkenyl
(e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain
embodiments, R.sup.D1 is substituted or unsubstituted alkynyl
(e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain
embodiments, R.sup.D1 is substituted or unsubstituted carbocyclyl
(e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic
carbocyclyl comprising zero, one, or two double bonds in the
carbocyclic ring system). In certain embodiments, R.sup.D1 is
substituted or unsubstituted heterocyclyl (e.g., substituted or
unsubstituted, 5- to 10-membered monocyclic or bicyclic
heterocyclic ring, wherein one or two atoms in the heterocyclic
ring are independently nitrogen, oxygen, or sulfur). In certain
embodiments, R.sup.D1 is substituted or unsubstituted aryl (e.g.,
substituted or unsubstituted, 6- to 10-membered aryl). In certain
embodiments, R.sup.D1 is benzyl. In certain embodiments, R.sup.D1
is substituted or unsubstituted phenyl. In certain embodiments,
R.sup.D1 is substituted or unsubstituted heteroaryl (e.g.,
substituted or unsubstituted, 5- to 6-membered, monocyclic
heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, R.sup.D1 is an oxygen protecting
group when attached to an oxygen atom. In certain embodiments,
R.sup.D1 is a sulfur protecting group when attached to a sulfur
atom.
[0178] In certain embodiments, at least one instance of R.sup.D1a
is hydrogen. In certain embodiments, at least one instance of
R.sup.D1 is substituted or unsubstituted acyl (e.g.,
--C(.dbd.O)Me). In certain embodiments, at least one R.sup.D1a is
substituted or unsubstituted alkyl (e.g., substituted or
unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least
one instance of R.sup.D1a is substituted or unsubstituted methyl.
In certain embodiments, at least one instance of R.sup.D1a is
substituted or unsubstituted ethyl. In certain embodiments, at
least one instance of R.sup.D1a is substituted or unsubstituted
propyl. In certain embodiments, at least one instance of R.sup.D1a
is substituted or unsubstituted alkenyl (e.g., substituted or
unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least
one instance of R.sup.D1a is substituted or unsubstituted alkynyl
(e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain
embodiments, at least one instance of R.sup.D1a is substituted or
unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3-
to 7-membered, monocyclic carbocyclyl comprising zero, one, or two
double bonds in the carbocyclic ring system). In certain
embodiments, at least one instance of R.sup.D1a is substituted or
unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-
to 10-membered monocyclic or bicyclic heterocyclic ring, wherein
one or two atoms in the heterocyclic ring are independently
nitrogen, oxygen, or sulfur). In certain embodiments, at least one
instance of R.sup.D1a is substituted or unsubstituted aryl (e.g.,
substituted or unsubstituted, 6- to 10-membered aryl). In certain
embodiments, at least one instance of R.sup.D1a is benzyl. In
certain embodiments, at least one instance of R.sup.D1a is
substituted or unsubstituted phenyl. In certain embodiments, at
least one instance of R.sup.D1a is substituted or unsubstituted
heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered,
monocyclic heteroaryl, wherein one, two, three, or four atoms in
the heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.D1a
is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl
carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl
carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or
p-toluenesulfonamide (Ts)). In certain embodiments, two instances
of R.sup.D1a are taken together with their intervening atoms to
form a substituted or unsubstituted heterocyclic ring (e.g.,
substituted or unsubstituted, 5- to 10-membered monocyclic or
bicyclic heterocyclic ring, wherein one or two atoms in the
heterocyclic ring are independently nitrogen, oxygen, or sulfur) or
substituted or unsubstituted heteroaryl ring (e.g., substituted or
unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur; or substituted or
unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one,
two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur).
[0179] Formula (I') includes linker L.sup.1A which is attached to
Ring A1 at one end of L.sup.1A and attached to Ring B at the other
end of L.sup.1A. In certain embodiments, L.sup.1A is L.sup.1. In
certain embodiments, L.sup.1A is of formula
.sup.la--NR.sup.L1C(.dbd.O)--.sup.lb,
.sup.la--NR.sup.L1C(.dbd.O)--.sup.lb, or a 5-membered heteroaryl
ring; wherein .sup.la indicates the point of attachment to Ring A;
.sup.lb indicates the point of attachment to Ring B; and R.sup.L1
is independently hydrogen, optionally substituted C.sub.1-6 alkyl,
or a nitrogen protecting group. In certain embodiments, L.sup.1A is
of formula .sup.la--NHC(.dbd.O)--.sup.lb. In certain embodiments,
L.sup.1A is of formula .sup.la--C(.dbd.O)NH--.sup.lb. In certain
embodiments, L.sup.1A is an optionally substituted heteroarylene
(e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic
heteroarylene, wherein one, two, three, or four atoms in the
heteroarylene are independently nitrogen, oxygen, or sulfur; or
substituted or unsubstituted, 9- to 10-membered, bicyclic
heteroaryl, wherein one, two, three, or four atoms in the
heteroarylene are independently nitrogen, oxygen, or sulfur). In
certain embodiments, L.sup.1A is an optionally substituted
5-membered heteroarylene (e.g., pyrrolylene, furanylene,
thiophenylene, imidazolylene, pyrazolylene, oxazolylene,
isoxazolylene, thiazolylene, isothiazolylene, dimethyloxazolylene,
triazolylene, oxadiazolylene, or thiadiazolylene, all of which are
optionally substituted). In certain embodiments, L.sup.1A is of
formula
##STR00102##
In certain embodiments, L.sup.1A is of formula
##STR00103##
In certain embodiments, L.sup.1A is of formula
##STR00104##
In certain embodiments, L.sup.1A is of formula
##STR00105##
In certain embodiments, L.sup.1A is of formula
##STR00106##
[0180] As generally defined herein, Formula (I) includes linker
L.sup.1 which is attached to Ring A at one end of L.sup.1 and
attached to Ring B at the other end of L.sup.1. In certain
embodiments, L.sup.1 is .sup.la--NR.sup.L1C(.dbd.O)--.sup.lb or a
5-membered heteroaryl ring; wherein .sup.la indicates the point of
attachment to Ring A; .sup.lb indicates the point of attachment to
Ring B; and R.sup.L1 is independently hydrogen, optionally
substituted C.sub.1-6 alkyl, or a nitrogen protecting group. In
certain embodiments, R.sup.L1 is hydrogen. In certain embodiments,
R.sup.L1 is optionally substituted C.sub.1-6 alkyl (e.g. optionally
substituted methyl or optionally substituted ethyl). In certain
embodiments, R.sup.L1 is a nitrogen protecting group (e.g., benzyl
(Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz),
9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl,
triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain
embodiments, L.sup.1 is .sup.la--NHC(.dbd.O)--.sup.lb. In certain
embodiments, L.sup.1 is an unsubstituted 5-membered heteroaryl
ring. In certain embodiments, L.sup.1 is an unsubstituted
5-membered heteroarylene. In certain embodiments, L.sup.1 is of
formula:
##STR00107##
[0181] Formula (I') includes zero or more instances of substituent
R.sup.4 on Ring A1. Formula (I) includes zero or more instances of
substituent R.sup.4 on Ring A. In certain embodiments, p is 0. In
certain embodiments, p is 1. In certain embodiments, p is 2. In
certain embodiments, p is 3. In certain embodiments, p is 4. In
certain embodiments, at least one instance of R.sup.4 is hydrogen.
In certain embodiments, at least one instance of R.sup.4 is
substituted or unsubstituted acyl (e.g., --C(.dbd.O)Me). In certain
embodiments, at least one instance of R.sup.4 is halogen (e.g., F,
Cl, Br, or I). In certain embodiments, at least one R.sup.4 is
substituted or unsubstituted alkyl (e.g., substituted or
unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least
one instance of R.sup.4 is substituted or unsubstituted methyl. In
certain embodiments, at least one instance of R.sup.4 is
substituted or unsubstituted ethyl. In certain embodiments, at
least one instance of R.sup.4 is substituted or unsubstituted
propyl. In certain embodiments, at least one instance of R.sup.4 is
substituted or unsubstituted alkenyl (e.g., substituted or
unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least
one instance of R.sup.4 is substituted or unsubstituted alkynyl
(e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain
embodiments, at least one instance of R.sup.4 is substituted or
unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3-
to 7-membered, monocyclic carbocyclyl comprising zero, one, or two
double bonds in the carbocyclic ring system). In certain
embodiments, at least one instance of R.sup.4 is substituted or
unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5-
to 10-membered monocyclic or bicyclic heterocyclic ring, wherein
one or two atoms in the heterocyclic ring are independently
nitrogen, oxygen, or sulfur). In certain embodiments, at least one
instance of R.sup.4 is substituted or unsubstituted aryl (e.g.,
substituted or unsubstituted, 6- to 10-membered aryl). In certain
embodiments, at least one instance of R.sup.4 is benzyl. In certain
embodiments, at least one instance of R.sup.4 is substituted or
unsubstituted phenyl. In certain embodiments, at least one instance
of R.sup.4 is substituted or unsubstituted heteroaryl (e.g.,
substituted or unsubstituted, 5- to 6-membered, monocyclic
heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur; or substituted or unsubstituted, 9- to 10-membered,
bicyclic heteroaryl, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, at least one instance of R.sup.4
is --OR.sup.D1 (e.g., --OH or --OMe). In certain embodiments, at
least one instance of R.sup.4 is --N(R.sup.D1a).sub.2 (e.g.,
--NMe.sub.2). In certain embodiments, at least one instance of
R.sup.4 is --SR.sup.D1 (e.g., --SMe).
[0182] Formula (I') includes Ring A1. In certain embodiments, Ring
A1 is Ring A. In certain embodiments, Ring A1 is optionally
substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to
10-membered, monocyclic or bicyclic carbocyclyl comprising zero,
one, or two double bonds in the carbocyclic ring system). In
certain embodiments, Ring A1 is optionally substituted cyclohexyl.
In certain embodiments, Ring A1 is optionally substituted
cyclopentyl. In certain embodiments, Ring A1 is optionally
substituted cyclohexyl. In certain embodiments, Ring A1 is
unsubstituted cyclohexyl.
[0183] In certain embodiments, Ring A1 is
##STR00108##
In certain embodiments, Ring A1 is
##STR00109##
[0184] In certain embodiments, Ring A1 is optionally substituted
cyclopropyl, optionally substituted cycloheptyl, or optionally
substituted cyclooctyl. In certain embodiments, Ring A1 is
optionally substituted bicyclic carbocyclyl. In certain
embodiments, Ring A1 is optionally substituted
bicyclo[1.1.1]pentane. In certain embodiments, Ring A1 is
unsubstituted bicyclo[1.1.1]pentane. In certain embodiments, Ring
A1 is optionally substituted bicyclo[2.2.1]heptanyl, or optionally
substituted bicyclo[2.2.2]octanyl.
[0185] In certain embodiments, Ring A1 is
##STR00110##
In certain embodiments, Ring A1 is
##STR00111##
[0186] In certain embodiments, Ring A1 is optionally substituted
aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl).
In certain embodiments, Ring A1 is optionally substituted phenyl.
In certain embodiments, Ring A1 is unsubstituted phenyl. In certain
embodiments, Ring A1 is optionally substituted benzyl.
[0187] In certain embodiments, Ring A1 is optionally substituted
heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered
monocyclic or bicyclic heterocyclic ring, wherein one or two atoms
in the heterocyclic ring are independently nitrogen, oxygen, or
sulfur). In certain embodiments, Ring A1 is optionally substituted
heterocyclyl, wherein one or two atoms in the heterocyclic ring are
independently nitrogen, oxygen, or sulfur. In certain embodiments,
Ring A1 is optionally substituted 5-membered heterocyclyl. In
certain embodiments, Ring A1 is optionally substituted 6-membered
heterocyclyl. In certain embodiments, Ring A1 is optionally
substituted 5-6 membered heterocyclyl, wherein one or two atoms in
the heterocyclic ring are independently nitrogen, oxygen, or
sulfur. In certain embodiments, Ring A1 is optionally substituted
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,
pyrrolyl-2,5-dione, dioxolanyl, oxasulfuranyl, disulfuranyl,
triazolinyl, oxadiazolinyl, thiadiazolinyl, tetrahydropyranyl,
dihydropyridinyl, piperazinyl, morpholinyl, dioxanyl, or thianyl.
In certain embodiments, Ring A1 is optionally substituted
piperidine. In certain embodiments, Ring A1 is unsubstituted
piperidine. In certain embodiments, Ring A1 is unsubstituted
cyclohexyl, unsubstituted bicyclo[1.1.1]pentane, unsubstituted
phenyl, or unsubstituted piperidine.
[0188] In certain embodiments, Ring A1 is
##STR00112##
In certain embodiments, Ring A1 is
##STR00113##
[0189] In certain embodiments, Ring A is:
##STR00114##
In certain embodiments, Ring A is:
##STR00115##
[0190] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00116##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0191] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00117##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0192] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00118##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0193] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00119##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0194] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00120##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0195] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00121## ##STR00122##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0196] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00123## ##STR00124##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0197] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00125## ##STR00126##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0198] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00127## ##STR00128##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0199] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00129##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0200] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00130##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0201] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00131## ##STR00132##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0202] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00133##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0203] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00134##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0204] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00135##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0205] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00136##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0206] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00137## ##STR00138##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0207] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00139##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0208] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00140##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0209] In certain embodiments, the compound of Formula (I') is of
the formula:
##STR00141## ##STR00142## ##STR00143##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0210] In certain embodiments, the compound of Formula (I) is of
the formula:
##STR00144##
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof.
[0211] In certain embodiments, the compound of Formulae (I') or (I)
is a compound provided in any one of Tables 1-4 below.
[0212] In certain embodiments, a compound described herein is a
compound of Formula (I'), or a pharmaceutically acceptable salt,
solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,
isotopically labeled derivative, or prodrug thereof. In certain
embodiments, a compound described herein is a compound of Formula
(I'), or a pharmaceutically acceptable salt thereof.
[0213] Certain compounds described herein bind, covalently modify,
and/or inhibit a protein kinase. In certain embodiments, the
protein kinase is an IRAK. In certain embodiments, the protein
kinase is IRAK1. In certain embodiments, the protein kinase is
IRAK4. In certain embodiments, the compounds described herein
covalently bind to the protein kinase (e.g., IRAK (e.g., IRAK1 or
IRAK4)). In certain embodiments, the compounds described herein
reversibly bind to the protein kinase (e.g., IRAK (e.g., IRAK1 or
IRAK4)). In certain embodiments, the compounds described herein
non-reversibly bind to the protein kinase (e.g., IRAK (e.g., IRAK1
or IRAK4). In certain embodiments, the compounds described herein
modulate the activity of the protein kinase (e.g., IRAK (e.g.,
IRAK1 or IRAK4)). In certain embodiments, the compounds described
herein inhibit the activity of the protein kinase (e.g., IRAK
(e.g., IRAK1 or IRAK4)).
[0214] The binding affinity of a compound described herein to a
protein kinase (e.g., IRAK, (e.g., IRAK1 or IRAK4)) may be measured
by the dissociation constant (K.sub.d) value of an adduct of the
compound and the protein kinase (e.g., IRAK, (e.g., IRAK1 or
IRAK4)) using methods known in the art (e.g., isothermal titration
calorimetry (ITC)). In certain embodiments, the K.sub.d value of
the adduct is not more than about 100 .mu.M, not more than about 10
.mu.M, not more than about 1 .mu.M, not more than about 100 nM, not
more than about 10 nM, or not more than about 1 nM.
[0215] In certain embodiments, the activity of a protein kinase
(e.g., IRAK (e.g., IRAK1 or IRAK4)) is inhibited by a compound
described herein. The inhibition of the activity of a protein
kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)) by a compound described
herein may be measured by determining the half maximal inhibitory
concentration (IC.sub.50) of the compound when the compound, or a
pharmaceutical composition thereof, is contacted with the protein
kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)). The IC.sub.50 values
may be obtained using methods known in the art (e.g., by a
competition binding assay). In certain embodiments, the IC.sub.50
value of a compound described herein is not more than about 1 mM,
not more than about 100 .mu.M, not more than about 10 .mu.M, not
more than about 1 .mu.M, not more than about 100 nM, not more than
about 10 nM, or not more than about 1 nM.
[0216] The compounds described herein may selectively modulate the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)).
In certain embodiments, the compounds selectively increase the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)).
In certain embodiments, the compounds selectively inhibit the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)).
In certain embodiments, the compounds inhibit the activity of two
or more protein kinases (e.g., IRAK (e.g., IRAK1 or IRAK4)) to the
same extent. In certain embodiments, the compounds increase the
activity of two or more protein kinases (e.g., IRAK (e.g., IRAK1 or
IRAK4)) to the same extent.
[0217] The selectivity of a compound described herein in inhibiting
the activity of a first protein kinase (e.g., IRAK) over a second
protein kinase may be measured by the quotient of the IC.sub.50
value of the compound in inhibiting the activity of the second
protein kinase (e.g., IRAK) over the IC.sub.50 value of the
compound in inhibiting the activity of the first protein kinase
(e.g., IRAK). The selectivity of a compound described herein in
modulating the activity of a first protein kinase (e.g., IRAK) over
a second protein kinase may also be measured by the quotient of the
K.sub.d value of an adduct of the compound and the second protein
kinase over the K.sub.d value of an adduct of the compound and the
first protein kinase (e.g., IRAK). In certain embodiments, the
selectivity is at least about 1-fold, at least about 3-fold, at
least about 10-fold, at least about 30-fold, at least about
100-fold, at least about 300-fold, at least about 1,000-fold, at
least about 3,000-fold, at least about 10,000-fold, at least about
30,000-fold, or at least about 100,000-fold.
[0218] It is expected that the compounds described herein may be
useful in treating and/or preventing diseases associated with
aberrant activity (e.g., increased activity, undesired activity,
abnormal activity) of a protein kinase (e.g., IRAK (e.g., IRAK1 or
IRAK4)). It is known in the art that protein kinases are implicated
in a wide range of diseases, such as proliferative diseases,
inflammatory diseases, and autoimmune diseases. Therefore, the
compounds described herein are expected to be useful in treating
and/or preventing proliferative diseases, inflammatory diseases,
and autoimmune diseases.
Pharmaceutical Compositions, Kits, and Administration
[0219] The present disclosure also provides pharmaceutical
compositions comprising a compound described herein and optionally
a pharmaceutically acceptable excipient. In certain embodiments, a
compound described herein is a compound of Formula (I'), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient.
[0220] In certain embodiments, the compound described herein is
provided in an effective amount in the pharmaceutical composition.
In certain embodiments, the effective amount is a therapeutically
effective amount. In certain embodiments, the effective amount is a
prophylactically effective amount. In certain embodiments, a
therapeutically effective amount is an amount effective for
inhibiting the aberrant activity of a protein kinase (e.g., IRAK
(e.g., an IRAK (e.g., IRAK1 or IRAK4)). In certain embodiments, a
therapeutically effective amount is an amount effective for
treating a disease (e.g., a disease associated with aberrant
activity of an IRAK (e.g., proliferative disease)). In certain
embodiments, a therapeutically effective amount is an amount
effective for inhibiting the aberrant activity of an IRAK (e.g.,
IRAK1 or IRAK4) and treating a disease (e.g., a disease associated
with aberrant activity of a protein kinase (e.g., IRAK (e.g., an
IRAK (e.g., proliferative disease))). In certain embodiments, a
therapeutically effective amount is an amount effective for
inducing apoptosis of a cell (e.g., cell in vivo or in vitro). In
certain embodiments, a prophylactically effective amount is an
amount effective for inhibiting the aberrant activity of a protein
kinase (e.g., IRAK (e.g., an IRAK (e.g., IRAK1 or IRAK4)). In
certain embodiments, a prophylactically effective amount is an
amount effective for preventing or keeping a subject in need
thereof in remission of a disease (e.g., a disease associated with
aberrant activity of an IRAK (e.g., proliferative disease)). In
certain embodiments, a prophylactically effective amount is an
amount effective for inhibiting the aberrant activity of an IRAK
(e.g., IRAK1 or IRAK4), and preventing or keeping a subject in need
thereof in remission of a disease (e.g., a disease associated with
aberrant activity of an IRAK (e.g., proliferative disease)). In
certain embodiments, a prophylactically effective amount is an
amount effective for inducing apoptosis of a cell (e.g., cell in
vivo or in vitro).
[0221] In certain embodiments, the effective amount is an amount
effective for inhibiting the activity of a protein kinase (e.g.,
IRAK (e.g., an IRAK (e.g., IRAK1 or IRAK4)) by at least 10%, at
least 20%, at least 30%, at least 40%, at least 50%, at least 60%,
at least 70%, at least 80%, at least 90%, at least 95%, or at least
98%. In certain embodiments, the effective amount is an amount
effective for inhibiting the activity of an IRAK (e.g., IRAK1 or
IRAK4) by not more than 10%, not more than 20%, not more than 30%,
not more than 40%, not more than 50%, not more than 60%, not more
than 70%, not more than 80%, not more than 90%, not more than 95%,
or not more than 98%.
[0222] In certain embodiments, the subject is an animal. The animal
may be of either sex and may be at any stage of development. In
certain embodiments, the subject described herein is a human. In
certain embodiments, the subject is a non-human animal. In certain
embodiments, the subject is a mammal. In certain embodiments, the
subject is a non-human mammal. In certain embodiments, the subject
is a domesticated animal, such as a dog, cat, cow, pig, horse,
sheep, or goat. In certain embodiments, the subject is a companion
animal, such as a dog or cat. In certain embodiments, the subject
is a livestock animal, such as a cow, pig, horse, sheep, or goat.
In certain embodiments, the subject is a zoo animal. In another
embodiment, the subject is a research animal, such as a rodent
(e.g., mouse, rat), dog, pig, or non-human primate. In certain
embodiments, the animal is a genetically engineered animal. In
certain embodiments, the animal is a transgenic animal (e.g.,
transgenic mice and transgenic pigs). In certain embodiments, the
subject is a fish or reptile.
[0223] In certain embodiments, the cell being contacted with a
compound or composition described herein is in vitro. In certain
embodiments, the cell being contacted with a compound or
composition described herein is in vivo.
[0224] Pharmaceutical compositions described herein can be prepared
by any method known in the art of pharmacology. In general, such
preparatory methods include bringing the compound described herein
(i.e., the "active ingredient") into association with a carrier or
excipient, and/or one or more other accessory ingredients, and
then, if necessary and/or desirable, shaping, and/or packaging the
product into a desired single- or multi-dose unit.
[0225] Pharmaceutical compositions can be prepared, packaged,
and/or sold in bulk, as a single unit dose, and/or as a plurality
of single unit doses. A "unit dose" is a discrete amount of the
pharmaceutical composition comprising a predetermined amount of the
active ingredient. The amount of the active ingredient is generally
equal to the dosage of the active ingredient which would be
administered to a subject and/or a convenient fraction of such a
dosage, such as one-half or one-third of such a dosage.
[0226] Relative amounts of the active ingredient, the
pharmaceutically acceptable excipient, and/or any additional
ingredients in a pharmaceutical composition described herein will
vary, depending upon the identity, size, and/or condition of the
subject treated and further depending upon the route by which the
composition is to be administered. The composition may comprise
between 0.1% and 100% (w/w) active ingredient.
[0227] Pharmaceutically acceptable excipients used in the
manufacture of provided pharmaceutical compositions include inert
diluents, dispersing and/or granulating agents, surface active
agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering agents, lubricating agents, and/or oils.
Excipients such as cocoa butter and suppository waxes, coloring
agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present in the composition.
[0228] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and mixtures thereof.
[0229] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose, and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and
mixtures thereof.
[0230] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g., acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g., stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g., carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene
sorbitan monolaurate (Tween.RTM. 20), polyoxyethylene sorbitan
(Tween.RTM. 60), polyoxyethylene sorbitan monooleate (Tween.RTM.
80), sorbitan monopalmitate (Span.RTM. 40), sorbitan monostearate
(Span.RTM. 60), sorbitan tristearate (Span.RTM. 65), glyceryl
monooleate, sorbitan monooleate (Span.RTM. 80), polyoxyethylene
esters (e.g., polyoxyethylene monostearate (Myrj.RTM. 45),
polyoxyethylene hydrogenated castor oil, polyethoxylated castor
oil, polyoxymethylene stearate, and Solutol.RTM.), sucrose fatty
acid esters, polyethylene glycol fatty acid esters (e.g.,
Cremophor.RTM.), polyoxyethylene ethers, (e.g., polyoxyethylene
lauryl ether (Brij.RTM. 30)), poly(vinyl-pyrrolidone), diethylene
glycol monolaurate, triethanolamine oleate, sodium oleate,
potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium
lauryl sulfate, Pluronic.RTM. F-68, poloxamer P-188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and/or mixtures thereof.
[0231] Exemplary binding agents include starch (e.g., cornstarch
and starch paste), gelatin, sugars (e.g., sucrose, glucose,
dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.),
natural and synthetic gums (e.g., acacia, sodium alginate, extract
of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum.RTM.),
and larch arabogalactan), alginates, polyethylene oxide,
polyethylene glycol, inorganic calcium salts, silicic acid,
polymethacrylates, waxes, water, alcohol, and/or mixtures
thereof.
[0232] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
antiprotozoan preservatives, alcohol preservatives, acidic
preservatives, and other preservatives. In certain embodiments, the
preservative is an antioxidant. In other embodiments, the
preservative is a chelating agent.
[0233] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, and sodium sulfite.
[0234] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, dipotassium edetate, and the like),
citric acid and salts and hydrates thereof (e.g., citric acid
monohydrate), fumaric acid and salts and hydrates thereof, malic
acid and salts and hydrates thereof, phosphoric acid and salts and
hydrates thereof, and tartaric acid and salts and hydrates thereof.
Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, and thimerosal.
[0235] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, and sorbic acid.
[0236] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
[0237] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, and phytic acid.
[0238] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant.RTM. Plus, Phenonip.RTM., methylparaben,
Germall.RTM. 115, Germaben.RTM. II, Neolone.RTM., Kathon.RTM., and
Euxyl.RTM..
[0239] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof.
[0240] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0241] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and mixtures thereof.
[0242] Liquid dosage forms for oral and parenteral administration
include pharmaceutically acceptable emulsions, microemulsions,
solutions, suspensions, syrups and elixirs. In addition to the
active ingredients, the liquid dosage forms may comprise inert
diluents commonly used in the art such as, for example, water or
other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ,
olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions
can include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents. In
certain embodiments for parenteral administration, the conjugates
described herein are mixed with solubilizing agents such as
Cremophor.RTM., alcohols, oils, modified oils, glycols,
polysorbates, cyclodextrins, polymers, and mixtures thereof.
[0243] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension, or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.,
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or di-glycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0244] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0245] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0246] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates described herein with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol, or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active ingredient.
[0247] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or (a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
(b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia,
(c) humectants such as glycerol, (d) disintegrating agents such as
agar, calcium carbonate, potato or tapioca starch, alginic acid,
certain silicates, and sodium carbonate, (e) solution retarding
agents such as paraffin, (f) absorption accelerators such as
quaternary ammonium compounds, (g) wetting agents such as, for
example, cetyl alcohol and glycerol monostearate, (h) absorbents
such as kaolin and bentonite clay, and (i) lubricants such as talc,
calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate, and mixtures thereof. In the case of
capsules, tablets, and pills, the dosage form may include a
buffering agent.
[0248] Solid compositions of a similar type can be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the art of pharmacology. They may optionally
comprise opacifying agents and can be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of encapsulating compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type can be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polethylene glycols and the like.
[0249] The active ingredient can be in a micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings, and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active ingredient can be admixed with at least one inert diluent
such as sucrose, lactose, or starch. Such dosage forms may
comprise, as is normal practice, additional substances other than
inert diluents, e.g., tableting lubricants and other tableting aids
such a magnesium stearate and microcrystalline cellulose. In the
case of capsules, tablets and pills, the dosage forms may comprise
buffering agents. They may optionally comprise opacifying agents
and can be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
encapsulating agents which can be used include polymeric substances
and waxes.
[0250] Dosage forms for topical and/or transdermal administration
of a compound described herein may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants,
and/or patches. Generally, the active ingredient is admixed under
sterile conditions with a pharmaceutically acceptable carrier or
excipient and/or any needed preservatives and/or buffers as can be
required. Additionally, the present disclosure contemplates the use
of transdermal patches, which often have the added advantage of
providing controlled delivery of an active ingredient to the body.
Such dosage forms can be prepared, for example, by dissolving
and/or dispensing the active ingredient in the proper medium.
Alternatively or additionally, the rate can be controlled by either
providing a rate controlling membrane and/or by dispersing the
active ingredient in a polymer matrix and/or gel.
[0251] Suitable devices for use in delivering intradermal
pharmaceutical compositions described herein include short needle
devices. Intradermal compositions can be administered by devices
which limit the effective penetration length of a needle into the
skin. Alternatively or additionally, conventional syringes can be
used in the classical mantoux method of intradermal administration.
Jet injection devices which deliver liquid formulations to the
dermis via a liquid jet injector and/or via a needle which pierces
the stratum corneum and produces a jet which reaches the dermis are
suitable. Ballistic powder/particle delivery devices which use
compressed gas to accelerate the compound in powder form through
the outer layers of the skin to the dermis are suitable.
[0252] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi-liquid preparations such
as liniments, lotions, oil-in-water and/or water-in-oil emulsions
such as creams, ointments, and/or pastes, and/or solutions and/or
suspensions. Topically administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0253] A pharmaceutical composition described herein can be
prepared, packaged, and/or sold in a formulation suitable for
pulmonary administration via the buccal cavity. Such a formulation
may comprise dry particles which comprise the active ingredient and
which have a diameter in the range from about 0.5 to about 7
nanometers, or from about 1 to about 6 nanometers. Such
compositions are conveniently in the form of dry powders for
administration using a device comprising a dry powder reservoir to
which a stream of propellant can be directed to disperse the powder
and/or using a self-propelling solvent/powder dispensing container
such as a device comprising the active ingredient dissolved and/or
suspended in a low-boiling propellant in a sealed container. Such
powders comprise particles wherein at least 98% of the particles by
weight have a diameter greater than 0.5 nanometers and at least 95%
of the particles by number have a diameter less than 7 nanometers.
Alternatively, at least 95% of the particles by weight have a
diameter greater than 1 nanometer and at least 90% of the particles
by number have a diameter less than 6 nanometers. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0254] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0255] Pharmaceutical compositions described herein formulated for
pulmonary delivery may provide the active ingredient in the form of
droplets of a solution and/or suspension. Such formulations can be
prepared, packaged, and/or sold as aqueous and/or dilute alcoholic
solutions and/or suspensions, optionally sterile, comprising the
active ingredient, and may conveniently be administered using any
nebulization and/or atomization device. Such formulations may
further comprise one or more additional ingredients including, but
not limited to, a flavoring agent such as saccharin sodium, a
volatile oil, a buffering agent, a surface active agent, and/or a
preservative such as methylhydroxybenzoate. The droplets provided
by this route of administration may have an average diameter in the
range from about 0.1 to about 200 nanometers.
[0256] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a pharmaceutical
composition described herein. Another formulation suitable for
intranasal administration is a coarse powder comprising the active
ingredient and having an average particle from about 0.2 to 500
micrometers. Such a formulation is administered by rapid inhalation
through the nasal passage from a container of the powder held close
to the nares.
[0257] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) to as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A pharmaceutical
composition described herein can be prepared, packaged, and/or sold
in a formulation for buccal administration. Such formulations may,
for example, be in the form of tablets and/or lozenges made using
conventional methods, and may contain, for example, 0.1 to 20%
(w/w) active ingredient, the balance comprising an orally
dissolvable and/or degradable composition and, optionally, one or
more of the additional ingredients described herein. Alternately,
formulations for buccal administration may comprise a powder and/or
an aerosolized and/or atomized solution and/or suspension
comprising the active ingredient. Such powdered, aerosolized,
and/or aerosolized formulations, when dispersed, may have an
average particle and/or droplet size in the range from about 0.1 to
about 200 nanometers, and may further comprise one or more of the
additional ingredients described herein.
[0258] A pharmaceutical composition described herein can be
prepared, packaged, and/or sold in a formulation for ophthalmic
administration. Such formulations may, for example, be in the form
of eye drops including, for example, a 0.1-1.0% (w/w) solution
and/or suspension of the active ingredient in an aqueous or oily
liquid carrier or excipient. Such drops may further comprise
buffering agents, salts, and/or one or more other of the additional
ingredients described herein. Other opthalmically-administrable
formulations which are useful include those which comprise the
active ingredient in microcrystalline form and/or in a liposomal
preparation. Ear drops and/or eye drops are also contemplated as
being within the scope of this disclosure.
[0259] Although the descriptions of pharmaceutical compositions
provided herein are principally directed to pharmaceutical
compositions which are suitable for administration to humans, it
will be understood by the skilled artisan that such compositions
are generally suitable for administration to animals of all sorts.
Modification of pharmaceutical compositions suitable for
administration to humans in order to render the compositions
suitable for administration to various animals is well understood,
and the ordinarily skilled veterinary pharmacologist can design
and/or perform such modification with ordinary experimentation.
[0260] Compounds provided herein are typically formulated in dosage
unit form for ease of administration and uniformity of dosage. It
will be understood, however, that the total daily usage of the
compositions described herein will be decided by a physician within
the scope of sound medical judgment. The specific therapeutically
effective dose level for any particular subject or organism will
depend upon a variety of factors including the disease being
treated and the severity of the disorder; the activity of the
specific active ingredient employed; the specific composition
employed; the age, body weight, general health, sex, and diet of
the subject; the time of administration, route of administration,
and rate of excretion of the specific active ingredient employed;
the duration of the treatment; drugs used in combination or
coincidental with the specific active ingredient employed; and like
factors well known in the medical arts.
[0261] The compounds and compositions provided herein can be
administered by any route, including enteral (e.g., oral),
parenteral, intravenous, intramuscular, intra-arterial,
intramedullary, intrathecal, subcutaneous, intraventricular,
transdermal, interdermal, rectal, intravaginal, intraperitoneal,
topical (as by powders, ointments, creams, and/or drops), mucosal,
nasal, bucal, sublingual; by intratracheal instillation, bronchial
instillation, and/or inhalation; and/or as an oral spray, nasal
spray, and/or aerosol. Specifically contemplated routes are oral
administration, intravenous administration (e.g., systemic
intravenous injection), regional administration via blood and/or
lymph supply, and/or direct administration to an affected site. In
general, the most appropriate route of administration will depend
upon a variety of factors including the nature of the agent (e.g.,
its stability in the environment of the gastrointestinal tract),
and/or the condition of the subject (e.g., whether the subject is
able to tolerate oral administration). In certain embodiments, the
compound or pharmaceutical composition described herein is suitable
for topical administration to the eye of a subject.
[0262] The exact amount of a compound required to achieve an
effective amount will vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of the
particular compound, mode of administration, and the like. An
effective amount may be included in a single dose (e.g., single
oral dose) or multiple doses (e.g., multiple oral doses). In
certain embodiments, when multiple doses are administered to a
subject or applied to a biological sample, tissue, or cell, any two
doses of the multiple doses include different or substantially the
same amounts of a compound described herein. In certain
embodiments, when multiple doses are administered to a subject or
applied to a biological sample, tissue, or cell, the frequency of
administering the multiple doses to the subject or applying the
multiple doses to the biological sample, tissue, or cell is three
doses a day, two doses a day, one dose a day, one dose every other
day, one dose every third day, one dose every week, one dose every
two weeks, one dose every three weeks, or one dose every four
weeks. In certain embodiments, the frequency of administering the
multiple doses to the subject or applying the multiple doses to the
biological sample, tissue, or cell is one dose per day. In certain
embodiments, the frequency of administering the multiple doses to
the subject or applying the multiple doses to the biological
sample, tissue, or cell is two doses per day. In certain
embodiments, the frequency of administering the multiple doses to
the subject or applying the multiple doses to the biological
sample, tissue, or cell is three doses per day. In certain
embodiments, when multiple doses are administered to a subject or
applied to a biological sample, tissue, or cell, the duration
between the first dose and last dose of the multiple doses is one
day, two days, four days, one week, two weeks, three weeks, one
month, two months, three months, four months, six months, nine
months, one year, two years, three years, four years, five years,
seven years, ten years, fifteen years, twenty years, or the
lifetime of the subject, tissue, or cell. In certain embodiments,
the duration between the first dose and last dose of the multiple
doses is three months, six months, or one year. In certain
embodiments, the duration between the first dose and last dose of
the multiple doses is the lifetime of the subject, tissue, or cell.
In certain embodiments, a dose (e.g., a single dose, or any dose of
multiple doses) described herein includes independently between 0.1
.mu.g and 1 .mu.g, between 0.001 mg and 0.01 mg, between 0.01 mg
and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between
3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg,
between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between
1 g and 10 g, inclusive, of a compound described herein. In certain
embodiments, a dose described herein includes independently between
1 mg and 3 mg, inclusive, of a compound described herein. In
certain embodiments, a dose described herein includes independently
between 3 mg and 10 mg, inclusive, of a compound described herein.
In certain embodiments, a dose described herein includes
independently between 10 mg and 30 mg, inclusive, of a compound
described herein. In certain embodiments, a dose described herein
includes independently between 30 mg and 100 mg, inclusive, of a
compound described herein.
[0263] Dose ranges as described herein provide guidance for the
administration of provided pharmaceutical compositions to an adult.
The amount to be administered to, for example, a child or an
adolescent can be determined by a medical practitioner or person
skilled in the art and can be lower or the same as that
administered to an adult.
[0264] A compound or composition, as described herein, can be
administered in combination with one or more additional
pharmaceutical agents (e.g., therapeutically and/or
prophylactically active agents). The compounds or compositions can
be administered in combination with additional pharmaceutical
agents that improve their activity (e.g., activity (e.g., potency
and/or efficacy) in treating a disease in a subject in need
thereof, in preventing a disease in a subject in need thereof, in
inhibiting the activity of a protein kinase (e.g., IRAK) in a
subject, biological sample, tissue, or cell), improve
bioavailability, improve safety, reduce drug resistance, reduce
and/or modify metabolism, inhibit excretion, and/or modify
distribution in a subject, biological sample, tissue, or cell. It
will also be appreciated that the therapy employed may achieve a
desired effect for the same disorder, and/or it may achieve
different effects. In certain embodiments, a pharmaceutical
composition described herein including a compound described herein
and an additional pharmaceutical agent shows a synergistic effect
that is absent in a pharmaceutical composition including one of the
compound and the additional pharmaceutical agent, but not both.
[0265] The compound or composition can be administered concurrently
with, prior to, or subsequent to one or more additional
pharmaceutical agents, which may be useful as, e.g., combination
therapies. Pharmaceutical agents include therapeutically active
agents. Pharmaceutical agents also include prophylactically active
agents. Pharmaceutical agents include small organic molecules such
as drug compounds (e.g., compounds approved for human or veterinary
use by the U.S. Food and Drug Administration as provided in the
Code of Federal Regulations (CFR)), peptides, proteins,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides
or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides,
oligonucleotides, antisense oligonucleotides, lipids, hormones,
vitamins, and cells. In certain embodiments, the additional
pharmaceutical agent is a pharmaceutical agent useful for treating
and/or preventing a disease (e.g., proliferative disease,
inflammatory disease, autoimmune disease, genetic disease,
hematological disease, neurological disease, painful condition,
psychiatric disorder, or metabolic disorder). Each additional
pharmaceutical agent may be administered at a dose and/or on a time
schedule determined for that pharmaceutical agent. The additional
pharmaceutical agents may also be administered together with each
other and/or with the compound or composition described herein in a
single dose or administered separately in different doses. The
particular combination to employ in a regimen will take into
account compatibility of the compound described herein with the
additional pharmaceutical agent(s) and/or the desired therapeutic
and/or prophylactic effect to be achieved. In general, it is
expected that the additional pharmaceutical agent(s) in combination
be utilized at levels that do not exceed the levels at which they
are utilized individually. In some embodiments, the levels utilized
in combination will be lower than those utilized individually.
[0266] The additional pharmaceutical agents include, but are not
limited to, anti-proliferative agents, anti-cancer agents,
anti-angiogenesis agents, anti-inflammatory agents,
immunosuppressants, anti-bacterial agents, anti-viral agents,
cardiovascular agents, cholesterol-lowering agents, anti-diabetic
agents, anti-allergic agents, contraceptive agents, pain-relieving
agents, and a combination thereof. In certain embodiments, the
additional pharmaceutical agent is an anti-proliferative agent
(e.g., anti-cancer agent). In certain embodiments, the additional
pharmaceutical agent is an anti-leukemia agent. In certain
embodiments, the additional pharmaceutical agent is ABITREXATE
(methotrexate), ADE, Adriamycin RDF (doxorubicin hydrochloride),
Ambochlorin (chlorambucil), ARRANON (nelarabine), ARZERRA
(ofatumumab), BOSULIF (bosutinib), BUSULFEX (busulfan), CAMPATH
(alemtuzumab), CERUBIDINE (daunorubicin hydrochloride), CLAFEN
(cyclophosphamide), CLOFAREX (clofarabine), CLOLAR (clofarabine),
CVP, CYTOSAR-U (cytarabine), CYTOXAN (cyclophosphamide), ERWINAZE
(Asparaginase Erwinia chrysanthemi), FLUDARA (fludarabine
phosphate), FOLEX (methotrexate), FOLEX PFS (methotrexate), GAZYVA
(obinutuzumab), GLEEVEC (imatinib mesylate), Hyper-CVAD, ICLUSIG
(ponatinib hydrochloride), IMBRUVICA (ibrutinib), LEUKERAN
(chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristine
sulfate liposome), METHOTREXATE LPF (methorexate), MEXATE
(methotrexate), MEXATE-AQ (methotrexate), mitoxantrone
hydrochloride, MUSTARGEN (mechlorethamine hydrochloride), MYLERAN
(busulfan), NEOSAR (cyclophosphamide), ONCASPAR (Pegaspargase),
PURINETHOL (mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin
(daunorubicin hydrochloride), SPRYCEL (dasatinib), SYNRIBO
(omacetaxine mepesuccinate), TARABINE PFS (cytarabine), TASIGNA
(nilotinib), TREANDA (bendamustine hydrochloride), TRISENOX
(arsenic trioxide), VINCASAR PFS (vincristine sulfate), ZYDELIG
(idelalisib), or a combination thereof. In certain embodiments, the
additional pharmaceutical agent is an anti-lymphoma agent. In
certain embodiments, the additional pharmaceutical agent is
ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC, ADCETRIS
(brentuximab vedotin), ADRIAMYCIN PFS (doxorubicin hydrochloride),
ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN
(chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine),
BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR
(tositumomab and iodine I 131 tositumomab), BICNU (carmustine),
BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN
(cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN
(cyclophosphamide), DEPOCYT (liposomal cytarabine), DTIC-DOME
(dacarbazine), EPOCH, FOLEX (methotrexate), FOLEX PFS
(methotrexate), FOLOTYN (pralatrexate), HYPER-CVAD, ICE, IMBRUVICA
(ibrutinib), INTRON A (recombinant interferon alfa-2b), ISTODAX
(romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil),
Lomustine, MATULANE (procarbazine hydrochloride), METHOTREXATE LPF
(methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate),
MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethamine
hydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukin
diftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN
(rituximab), STANFORD V, TREANDA (bendamustine hydrochloride),
VAMP, VELBAN (vinblastine sulfate), VELCADE (bortezomib), VELSAR
(vinblastine sulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN
(ibritumomab tiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib),
or a combination thereof. In certain embodiments, the additional
pharmaceutical agent is REVLIMID (lenalidomide), DACOGEN
(decitabine), VIDAZA (azacitidine), CYTOSAR-U (cytarabine),
IDAMYCIN (idarubicin), CERUBIDINE (daunorubicin), LEUKERAN
(chlorambucil), NEOSAR (cyclophosphamide), FLUDARA (fludarabine),
LEUSTATIN (cladribine), or a combination thereof. In certain
embodiments, the additional pharmaceutical agent is ABITREXATE
(methotrexate), ABRAXANE (paclitaxel albumin-stabilized
nanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS
(doxorubicin hydrochloride), ADRUCIL (fluorouracil), AFINITOR
(everolimus), AFINITOR DISPERZ (everolimus), ALDARA (imiquimod),
ALIMTA (pemetrexed disodium), AREDIA (pamidronate disodium),
ARIMIDEX (anastrozole), AROMASIN (exemestane), AVASTIN
(bevacizumab), BECENUM (carmustine), BEP, BICNU (carmustine),
BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecan hydrochloride),
CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL, CARMUBRIS
(carmustine), CASODEX (bicalutamide), CEENU (lomustine), CERUBIDINE
(daunorubicin hydrochloride), CERVARIX (recombinant HPV bivalent
vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ
(cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS
(ifosfamide), CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine),
CYTOXAN (cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL
(doxorubicin hydrochloride liposome), DOXORUBICIN HYDROCHLORIDE,
DOX-SL (doxorubicin hydrochloride liposome), DTIC-DOME
(dacarbazine), EFUDEX (fluorouracil), ELLENCE (epirubicin
hydrochloride), ELOXATIN (oxaliplatin), ERBITUX (cetuximab),
ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate), EVACET
(doxorubicin hydrochloride liposome), FARESTON (toremifene),
FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX
(fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate),
FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX,
FOLFOX, FU-LV, GARDASIL (recombinant human papillomavirus (HPV)
quadrivalent vaccine), GEMCITABINE-CISPLATIN,
GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabine hydrochloride),
GILOTRIF (afatinib dimaleate), GLEEVEC (imatinib mesylate), GLIADEL
(carmustine implant), GLIADEL WAFER (carmustine implant), HERCEPTIN
(trastuzumab), HYCAMTIN (topotecan hydrochloride), IFEX
(ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A
(recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA
(ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA
(cabazitaxel), KADCYLA (ado-trastuzumab emtansine), KEYTRUDA
(pembrolizumab), KYPROLIS (carfilzomib), LIPODOX (doxorubicin
hydrochloride liposome), LUPRON (leuprolide acetate), LUPRON DEPOT
(leuprolide acetate), LUPRON DEPOT-3 MONTH (leuprolide acetate),
LUPRON DEPOT-4 MONTH (leuprolide acetate), LUPRON DEPOT-PED
(leuprolide acetate), MEGACE (megestrol acetate), MEKINIST
(trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF
(methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate),
MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL
(plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN
(mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine
tartrate), NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate),
NOLVADEX (tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF,
PAD, PARAPLAT (carboplatin), PARAPLATIN (carboplatin), PEG-INTRON
(peginterferon alfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab),
PLATINOL (cisplatin), PLATINOL-AQ (cisplatin), POMALYST
(pomalidomide), prednisone, PROLEUKIN (aldesleukin), PROLIA
(denosumab), PROVENGE (sipuleucel-t), REVLIMID (lenalidomide),
RUBIDOMYCIN (daunorubicin hydrochloride), SPRYCEL (dasatinib),
STIVARGA (regorafenib), SUTENT (sunitinib malate), SYLATRON
(peginterferon alfa-2b), SYLVANT (siltuximab), SYNOVIR
(thalidomide), TAC, TAFINLAR (dabrafenib), TARABINE PFS
(cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA
(nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR
(temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide),
TORISEL (temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB
(lapatinib ditosylate), VECTIBIX (panitumumab), VEIP, VELBAN
(vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastine
sulfate), VEPESID (etoposide), VIADUR (leuprolide acetate), VIDAZA
(azacitidine), VINCASAR PFS (vincristine sulfate), VOTRIENT
(pazopanib hydrochloride), WELLCOVORIN (leucovorin calcium),
XALKORI (crizotinib), XELODA (capecitabine), XELOX, XGEVA
(denosumab), XOFIGO (radium 223 dichloride), XTANDI (enzalutamide),
YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF
(vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic
acid), ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate),
ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258),
BIBW 2992 (TOVOK.TM.), SGX523, PF-04217903, PF-02341066, PF-299804,
BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF.RTM.), AP24534,
JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib
(AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228),
proteasome inhibitors (e.g., bortezomib (Velcade)), mTOR inhibitors
(e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001),
ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235
(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502
(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),
oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,
cyclophosphamide, dacarbazine, procarbizine, prednisolone,
dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,
methopterin, porfiromycin, melphalan, leurosidine, leurosine,
chlorambucil, trabectedin, procarbazine, discodermolide,
carminomycin, aminopterin, and hexamethyl melamine, or a
combination thereof. In certain embodiments, the additional
pharmaceutical agent is ibrutinib. In certain embodiments, the
additional pharmaceutical agent is a protein kinase inhibitor
(e.g., tyrosine protein kinase inhibitor). In certain embodiments,
the additional pharmaceutical agent is a binder or inhibitor of an
IRAK (e.g., IRAK1 or IRAK4). In certain embodiments, the additional
pharmaceutical agent is a binder or inhibitor of IRAK1. In certain
embodiments, the additional pharmaceutical agent is a binder or
inhibitor of IRAK4. In certain embodiments, the additional
pharmaceutical agent is a binder or inhibitor of Bruton's tyrosine
kinase (BTK). In certain embodiments, the additional pharmaceutical
agent is selected from the group consisting of epigenetic or
transcriptional modulators (e.g., DNA methyltransferase inhibitors,
histone deacetylase inhibitors (HDAC inhibitors), lysine
methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and
vinca alkaloids), hormone receptor modulators (e.g., estrogen
receptor modulators and androgen receptor modulators), cell
signaling pathway inhibitors (e.g., tyrosine protein kinase
inhibitors), modulators of protein stability (e.g., proteasome
inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic
acids, and other agents that promote differentiation. In certain
embodiments, the compounds described herein or pharmaceutical
compositions can be administered in combination with an anti-cancer
therapy including, but not limited to, surgery, radiation therapy,
transplantation (e.g., stem cell transplantation, bone marrow
transplantation), immunotherapy, and chemotherapy.
[0267] Also encompassed by the disclosure are kits (e.g.,
pharmaceutical packs). The kits provided may comprise a
pharmaceutical composition or compound described herein and a
container (e.g., a vial, ampule, bottle, syringe, and/or dispenser
package, or other suitable container). In some embodiments,
provided kits may optionally further include a second container
comprising a pharmaceutical excipient for dilution or suspension of
a pharmaceutical composition or compound described herein. In some
embodiments, the pharmaceutical composition or compound described
herein provided in the first container and the second container are
combined to form one unit dosage form.
[0268] Thus, in one aspect, provided are kits including a first
container comprising a compound or pharmaceutical composition
described herein. In certain embodiments, the kits are useful for
treating a disease (e.g., proliferative disease, inflammatory
disease, autoimmune disease, genetic disease, hematological
disease, neurological disease, painful condition, psychiatric
disorder, or metabolic disorder) in a subject in need thereof. In
certain embodiments, the kits are useful for preventing a disease
(e.g., proliferative disease, inflammatory disease, autoimmune
disease, genetic disease, hematological disease, neurological
disease, painful condition, psychiatric disorder, or metabolic
disorder) in a subject in need thereof. In certain embodiments, the
kits are useful for inhibiting the activity (e.g., aberrant or
unwanted activity, such as increased activity) of a protein kinase
(e.g., IRAK) in a subject, biological sample, tissue, or cell. In
certain embodiments, the kits are useful for inducing apoptosis of
a cell (e.g., cell in vivo or in vitro).
[0269] In certain embodiments, a kit described herein further
includes instructions for using the compound or pharmaceutical
composition included in the kit. A kit described herein may also
include information as required by a regulatory agency such as the
U.S. Food and Drug Administration (FDA). In certain embodiments,
the information included in the kits is prescribing information. In
certain embodiments, the kits and instructions provide for treating
a disease (e.g., proliferative disease, inflammatory disease,
autoimmune disease, genetic disease, hematological disease,
neurological disease, painful condition, psychiatric disorder, or
metabolic disorder) in a subject in need thereof. In certain
embodiments, the kits and instructions provide for preventing a
disease (e.g., proliferative disease, inflammatory disease,
autoimmune disease, genetic disease, hematological disease,
neurological disease, painful condition, psychiatric disorder, or
metabolic disorder) in a subject in need thereof. In certain
embodiments, the kits and instructions provide for modulating
(e.g., inhibiting) the activity (e.g., aberrant activity, such as
increased activity) of a protein kinase (e.g., IRAK) in a subject,
biological sample, tissue, or cell. In certain embodiments, the
kits and instructions provide for inducing apoptosis of a cell. A
kit described herein may include one or more additional
pharmaceutical agents described herein as a separate
composition.
Methods of Treatment and Uses
[0270] The present disclosure provides methods of modulating (e.g.,
inhibiting or increasing) the activity (e.g., aberrant activity,
such as increased or decreased activity) of a protein kinase (e.g.,
IRAK). The present disclosure provides methods of modulating (e.g.,
inhibiting or increasing) the activity (e.g., aberrant activity,
such as increased or decreased activity) of an IRAK (e.g., IRAK1 or
IRAK4) in a subject, biological sample, or cell. The present
disclosure also provides methods for the treatment of a wide range
of diseases, such as diseases associated with the aberrant activity
(e.g., increased activity) of a protein kinase, e.g., proliferative
diseases, musculoskeletal diseases, genetic diseases, hematological
diseases, neurological diseases, painful conditions, psychiatric
disorders, and metabolic disorders in a subject in need thereof.
The present disclosure provides methods for the treatment and/or
prevention of a proliferative disease (e.g., cancers (e.g.,
leukemia, lymphoma), inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases.
[0271] In another aspect, the present disclosure provides methods
of modulating the activity of a protein kinase (e.g., IRAK (e.g.,
IRAK1 or IRAK4)) in a subject, biological sample, or cell. In
certain embodiments, provided are methods of inhibiting the
activity of a protein kinase in a subject. In certain embodiments,
provided are methods of inhibiting the activity of a protein kinase
in a cell. In certain embodiments, provided are methods of
increasing the activity of a protein kinase (e.g., IRAK (e.g.,
IRAK1 or IRAK4) in a subject. The compounds described herein may
exhibit kinase inhibitory activity; the ability to inhibit
interleukin-1 receptor-associated kinase (IRAK); the ability to
inhibit interleukin-1 receptor-associated kinase (IRAK) 1 (IRAK1);
the ability to inhibit IRAK1, without inhibiting another kinase
(e.g., an interleukin-1 receptor-associated kinase (e.g., IRAK));
the ability to inhibit IRAK4, without inhibiting another kinase
(e.g., an interleukin-1 receptor-associated kinase (e.g., IRAK)); a
therapeutic effect and/or preventative effect in the treatment of
cancers; a therapeutic effect and/or preventative effect in the
treatment of proliferative diseases; and/or a therapeutic profile
(e.g., optimum safety and curative effect) that is superior to
existing chemotherapeutic agents.
[0272] In certain embodiments, provided are methods of increasing
the activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or
IRAK4)) in a subject or cell by a method described herein. In
certain embodiments, provided are methods of decreasing the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)) in
a subject or cell by a method described herein by at least about
1%, at least about 3%, at least about 10%, at least about 20%, at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70%, at least about 80%, or at least
about 90%. In certain embodiments, the activity of a protein kinase
(e.g., IRAK (e.g., IRAK1 or IRAK4)) in a subject or cell is
decreased by a method described herein by at least about 1%, at
least about 3%, at least about 10%, at least about 20%, at least
about 30%, at least about 40%, at least about 50%, at least about
60%, at least about 70%, at least about 80%, or at least about 90%.
In some embodiments, the activity of a protein kinase (e.g., IRAK
(e.g., IRAK1 or IRAK4)) in a subject or cell is selectively
inhibited by the method. In some embodiments, the activity of a
protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)) in a subject or
cell is selectively decreased by the method.
[0273] Without wishing to be bound by any particular theory, the
compounds described herein are able to bind (e.g., covalently
modify) the protein kinase being inhibited. In certain embodiments,
a compound described herein is able to bind (e.g., covalently
modify) the protein kinase. In certain embodiments, the compound
described herein is able to covalently bind a cysteine residue of
the protein kinase. In certain embodiments, the compound is capable
of covalently modifying IRAK1 (e.g., Cys302) of IRAK1. In certain
embodiments, the compound is capable of covalently modifying
IRAK4.
[0274] In another aspect, the present disclosure provides methods
of inhibiting the activity of a protein kinase in a subject, the
methods comprising administering to the subject an effective amount
(e.g., therapeutically effective amount) of a compound, or
pharmaceutical composition thereof, as described herein. In another
aspect, the present disclosure provides methods of inhibiting the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4) in
a biological sample, the methods comprising contacting the
biological sample with an effective amount of a compound, or
pharmaceutical composition thereof, as described herein. In another
aspect, the present disclosure provides methods of inhibiting the
activity of a protein kinase in a tissue or cell, the methods
comprising contacting the tissue or cell with an effective amount
of a compound, or pharmaceutical composition thereof, as described
herein.
[0275] In another aspect, the present disclosure provides methods
of inhibiting the activity of a protein kinase (e.g., IRAK (e.g.,
IRAK1 or IRAK4) in a cell, the methods comprising contacting the
cell with an effective amount of a compound, or pharmaceutical
composition thereof, as described herein.
[0276] In certain embodiments, the subject being treated is a
mammal. In certain embodiments, the subject is a human. In certain
embodiments, the subject is a domesticated animal, such as a dog,
cat, cow, pig, horse, sheep, or goat. In certain embodiments, the
subject is a companion animal such as a dog or cat. In certain
embodiments, the subject is a livestock animal such as a cow, pig,
horse, sheep, or goat. In certain embodiments, the subject is a zoo
animal. In another embodiment, the subject is a research animal
such as a rodent, dog, or non-human primate. In certain
embodiments, the subject is a non-human transgenic animal such as a
transgenic mouse or transgenic pig.
[0277] In certain embodiments, the biological sample being
contacted with the compound or composition is breast tissue, bone
marrow, lymph node, lymph tissue, spleen, or blood. In certain
embodiments, the biological sample being contacted with the
compound or composition is a tumor or cancerous tissue. In certain
embodiments, the biological sample being contacted with the
compound or composition is serum, cerebrospinal fluid, interstitial
fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained
by a surgical biopsy or needle biopsy), nipple aspirates, milk,
vaginal fluid, saliva, swabs (such as buccal swabs), or any
material containing biomolecules that is derived from a first
biological sample.
[0278] In certain embodiments, the cell or tissue being contacted
with the compound or composition is present in vitro. In certain
embodiments, the cell or tissue being contacted with the compound
or composition is present in vivo. In certain embodiments, the cell
or tissue being contacted with the compound or composition is
present ex vivo. In certain embodiments, the cell or tissue being
contacted with the compound or composition is a malignant cell
(e.g., malignant blood cell). In certain embodiments, the cell
being contacted with the compound or composition is a malignant
hematopoietic stem cell (e.g., malignant myeloid cell or malignant
lymphoid cell). In certain embodiments, the cell being contacted
with the compound or composition is a malignant lymphocyte (e.g.,
malignant T-cell or malignant B-cell). In certain embodiments, the
cell being contacted with the compound or composition is a
malignant white blood cell. In certain embodiments, the cell being
contacted with the compound or composition is a malignant
neutrophil, malignant macrophage, or malignant plasma cell. In
certain embodiments, the cell being contacted with the compound or
composition is a carcinoma cell. In certain embodiments, the cell
being contacted with the compound or composition is a breast
carcinoma cell. In certain embodiments, the cell being contacted
with the compound or composition is a sarcoma cell. In certain
embodiments, the cell being contacted with the compound or
composition is a sarcoma cell from breast tissue.
[0279] The proliferative disease to be treated or prevented using
the compounds described herein may be associated with the
overexpression of a kinase, such as an interleukin-1
receptor-associated kinase (IRAK). IRAK1 and IRAK4 are
serine/threonine-protein kinases that play a role in initiating
innate immune response against foreign pathogens. They are involved
in Toll-like receptor (TLR) and IL-1R signaling pathways, and are
rapidly recruited by MYD88 to the receptor-signaling complex upon
TLR activation. Association with MYD88 leads to IRAK1
phosphorylation by IRAK4 and subsequent autophosphorylation and
kinase activation of IRAK1 (Immunity, 1997, 7(6), 837-47). IRAK4-/-
mice have abolished cellular responses to various IL-1 and TLR
ligands and are severely impaired in their response to viral and
bacterial challenges. IRAK1-/- mice show a similar but partial
response.
[0280] In certain embodiments, the proliferative disease to be
treated or prevented using the compounds described herein may be
associated with the overexpression of an IRAK (e.g., IRAK1 or
IRAK4).
[0281] A proliferative disease may be associated with aberrant
activity of an IRAK (e.g., IRAK1 or IRAK4). Aberrant activity of an
IRAK (e.g., IRAK1 or IRAK4) may be elevated and/or inappropriate or
undesired activity of the IRAK. Deregulation of cell cycle
progression is a characteristic of a proliferative disease, and a
majority of proliferative diseases have abnormalities in some
component of IRAK (e.g., IRAK1 or IRAK4) activity, frequently
through elevated and/or inappropriate IRAK activation. In certain
embodiments, IRAK is not overexpressed, and the activity of IRAK is
elevated and/or inappropriate. In certain embodiments, IRAK1 is
overexpressed, and the activity of IRAK1 is elevated and/or
inappropriate. In certain embodiments, IRAK4 is overexpressed, and
the activity of IRAK4 is elevated and/or inappropriate. The
compounds described herein, and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
compositions thereof, may inhibit the activity of IRAK1 and be
useful in treating and/or preventing proliferative diseases. The
compounds described herein, and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
compositions thereof, may inhibit the activity of IRAK4 and be
useful in treating and/or preventing proliferative diseases. The
compounds described herein, and pharmaceutically acceptable salts,
solvates, hydrates, polymorphs, co-crystals, tautomers,
stereoisomers, isotopically labeled derivatives, prodrugs, and
compositions thereof, may inhibit the activity of IRAK1 and be
useful in treating and/or preventing proliferative diseases.
[0282] All types of biological samples described herein or known in
the art are contemplated as being within the scope of the
invention. In certain embodiments, the proliferative disease to be
treated or prevented using the compounds described herein is
cancer. All types of cancers disclosed herein or known in the art
are contemplated as being within the scope of the invention. In
certain embodiments, the proliferative disease is a hematological
malignancy. In certain embodiments, the proliferative disease is a
blood cancer. In certain embodiments, the proliferative disease is
a hematological malignancy. In certain embodiments, the
proliferative disease is leukemia. In certain embodiments, the
proliferative disease is chronic lymphocytic leukemia (CLL). In
certain embodiments, the proliferative disease is acute
lymphoblastic leukemia (ALL). In certain embodiments, the
proliferative disease is T-cell acute lymphoblastic leukemia
(T-ALL). In certain embodiments, the proliferative disease is
chronic myelogenous leukemia (CML). In certain embodiments, the
proliferative disease is acute myeloid leukemia (AML). In certain
embodiments, the proliferative disease is acute monocytic leukemia
(AMoL). In certain embodiments, the proliferative disease is
Waldenstrim's macroglobulinemia. In certain embodiments, the
proliferative disease is Waldenstrim's macroglobulinemia associated
with the MYD88 L265P somatic mutation. In certain embodiments, the
proliferative disease is myelodysplastic syndrome (MDS). In certain
embodiments, the proliferative disease is lymphoma. In some
embodiments, the proliferative disease is Burkitt's lymphoma. In
certain embodiments, the proliferative disease is a Hodgkin's
lymphoma. In certain embodiments, the proliferative disease is a
non-Hodgkin's lymphoma. In certain embodiments, the proliferative
disease is multiple myeloma. In certain embodiments, the
proliferative disease is melanoma. In certain embodiments, the
proliferative disease is colorectal cancer. In certain embodiments,
the proliferative disease is breast cancer. In certain embodiments,
the proliferative disease is recurring breast cancer. In certain
embodiments, the proliferative disease is mutant breast cancer. In
certain embodiments, the proliferative disease is HER2+ breast
cancer. In certain embodiments, the proliferative disease is HER2-
breast cancer. In certain embodiments, the proliferative disease is
triple-negative breast cancer (TNBC). In certain embodiments, the
proliferative disease is a bone cancer. In certain embodiments, the
proliferative disease is osteosarcoma. In certain embodiments, the
proliferative disease is Ewing's sarcoma. In some embodiments, the
proliferative disease is a brain cancer. In some embodiments, the
proliferative disease is neuroblastoma. In some embodiments, the
proliferative disease is a lung cancer. In some embodiments, the
proliferative disease is small cell lung cancer (SCLC). In some
embodiments, the proliferative disease is non-small cell lung
cancer. In some embodiments, the proliferative disease is a benign
neoplasm. All types of benign neoplasms disclosed herein or known
in the art are contemplated as being within the scope of the
invention. In some embodiments, the proliferative disease is
associated with angiogenesis. All types of angiogenesis disclosed
herein or known in the art are contemplated as being within the
scope of the invention. In certain embodiments, the proliferative
disease is an inflammatory disease. All types of inflammatory
diseases disclosed herein or known in the art are contemplated as
being within the scope of the invention. In certain embodiments,
the inflammatory disease is rheumatoid arthritis.
[0283] In certain embodiments, the proliferative disease is an
acute inflammatory disease. In certain embodiments, the
proliferative disease is an inflammatory disease. In certain
embodiments, the acute inflammatory disease is rheumatoid
arthritis, Crohn's disease, or fibrosis. In some embodiments, the
proliferative disease is an autoinflammatory disease. All types of
autoinflammatory diseases disclosed herein or known in the art are
contemplated as being within the scope of the invention. In some
embodiments, the proliferative disease is an autoimmune disease.
All types of autoimmune diseases disclosed herein or known in the
art are contemplated as being within the scope of the
invention.
[0284] Another aspect of the invention relates to methods of
inhibiting the activity of a kinase in a biological sample, tissue,
cell, or subject. In certain embodiments, the kinase is an IRAK. In
certain embodiments, the kinase is IRAK1. In certain embodiments,
the kinase is IRAK4. In certain embodiments, the activity of the
kinase is aberrant activity of the kinase. In certain embodiments,
the activity of the kinase is increased activity of the kinase. In
certain embodiments, the inhibition of the activity of the kinase
is irreversible. In other embodiments, the inhibition of the
activity of the kinase is reversible. In certain embodiments, the
methods of inhibiting the activity of the kinase include attaching
a compound described herein to the kinase.
[0285] The present invention provides methods of inhibiting cell
growth in a biological sample, tissue, cell, or subject.
[0286] In certain embodiments, the methods described herein include
administering to a subject or contacting a biological sample with
an effective amount of a compound described herein, or a
pharmaceutically acceptable salt, solvate, hydrate, polymorph,
co-crystal, tautomer, stereoisomer, isotopically labeled
derivative, or prodrug thereof, or a pharmaceutical composition
thereof. In certain embodiments, the methods described herein
include administering to a subject or contacting a biological
sample with an effective amount of a compound described herein, or
a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition thereof. In certain embodiments, the compound is
contacted with a biological sample. In certain embodiments, the
compound is administered to a subject. In certain embodiments, the
compound is administered in combination with one or more additional
pharmaceutical agents described herein. The additional
pharmaceutical agent may be an anti-proliferative agent. In certain
embodiments, the additional pharmaceutical agent is an anti-cancer
agent. The additional pharmaceutical agent may also be a kinase
inhibitor. In certain embodiments, the additional pharmaceutical
agent is an inhibitor of an IRAK. In certain embodiments, the
additional pharmaceutical agent is an inhibitor of IRAK1. In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of IRAK4. In certain embodiments, the additional
pharmaceutical agent is a selective inhibitor of IRAK1. In certain
embodiments, the additional pharmaceutical agent is a selective
inhibitor of IRAK4. In certain embodiments, the additional
pharmaceutical agent is a non-selective inhibitor of IRAK1. In
certain embodiments, the additional pharmaceutical agent is a
non-selective inhibitor of IRAK4. In certain embodiments, the
additional pharmaceutical agent includes an anti-cancer agent
(e.g., chemotherapeutics), anti-inflammatory agent, steroids,
immunosuppressant, radiation therapy, or other agents. In certain
embodiments, the additional pharmaceutical agent is an
anti-proliferative agent. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a kinase. In certain
embodiments, the additional pharmaceutical agent is a non-selective
inhibitor of Bruton's tyrosine kinase (BTK). In certain
embodiments, the additional pharmaceutical agent is a selective
inhibitor of BTK. In certain embodiments, the additional
pharmaceutical agent is flavopiridol, triptolide, SNS-032
(BMS-387032), PHA-767491, PHA-793887, BS-181, (S)-CR8, (R)-CR8, or
NU6140. In certain embodiments, the additional pharmaceutical agent
is an inhibitor of a mitogen-activated protein kinase (MAPK). In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of a glycogen synthase kinase 3 (GSK3). In certain
embodiments, the additional pharmaceutical agent is an inhibitor of
an AGC kinase. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a calmodulin-dependent
kinase (CaM Kinase). In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a casein kinase 1. In
certain embodiments, the additional pharmaceutical agent is an
inhibitor of a STE kinase. In certain embodiments, the additional
pharmaceutical agent is an inhibitor of a tyrosine kinase.
[0287] In some embodiments, the additional pharmaceutical agent is
a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2 inhibitor, a
BCL-xL inhibitor, a BRD4 inhibitor, a BRCA1 inhibitor, BRCA2
inhibitor, HER1 inhibitor, HER2 inhibitor, a CDK9 inhibitor, a
Jumonji histone demethylase inhibitor, or a DNA damage inducer. In
some embodiments, the additional pharmaceutical agent is etoposide,
obatoclax, navitoclax, JQ1,
4-(((5'-chloro-2'-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl-
)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitr-
ile, JIB04, or cisplatin. In some embodiments, the additional
pharmaceutical agent is etoposide, obatoclax, or navitoclax, and
the disease to be treated is breast cancer, e.g., triple-negative
breast cancer, HER2 positive breast cancer, HER2 negative breast
cancer, ER-positive breast cancer, ER-negative breast cancer, or
ER/PR-positive breast cancer. In some embodiments, the additional
pharmaceutical agent is etoposide, JIB04, or cisplatin, and the
disease to be treated is Ewing's sarcoma. In some embodiments, the
additional pharmaceutical agent is JQ1 or NVP2, and the disease to
be treated is leukemia, e.g., acute myelogenous leukemia,
myeloblastic leukemia, promyelocytic leukemia, myelomonocytic
leukemia, monocytic leukemia, monoblastic leukemia, or
megakaryoblastic leukemia. Exemplary chemotherapeutic agents
include alkylating agents such as nitrogen mustards, ethylenimines,
methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes;
antimetabolites such as folic acid analogs, pyrimidine analogs, in
particular fluorouracil and cytosine arabinoside, and purine
analogs; natural products such as vinca alkaloids
epi-podophyllotoxins, antibiotics, enzymes, and biological response
modifiers; and miscellaneous products such as platinum coordination
complexes, anthracenedione, substituted urea such as hydroxyurea,
methyl hydrazine derivatives, and adrenocorticoid suppressant.
Exemplary chemotherapeutic agents also include anthracycline
antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D,
paclitaxel, colchicine, cytochalasin B, emetine, maytansine,
amsacrine, cisplatin, carboplatin, mitomycin, altretamine,
cyclophosphamide, lomustine, and carmustine. In certain
embodiments, a pharmaceutical composition described herein further
comprises a combination of the additional pharmaceutical agents
described herein.
[0288] The inventive compounds or compositions may synergistically
augment inhibition of IRAK1 induced by the additional
pharmaceutical agent(s) in the biological sample or subject. Thus,
the combination of the inventive compounds or compositions and the
additional pharmaceutical agent(s) may be useful in treating
proliferative diseases resistant to a treatment using the
additional pharmaceutical agent(s) without the inventive compounds
or compositions.
[0289] In some embodiments, the activity of a protein kinase is
non-selectively inhibited by the compounds or pharmaceutical
compositions described herein. In some embodiments, the activity of
the protein kinase being inhibited is selectively inhibited by the
compounds or pharmaceutical compositions described herein, compared
to the activity of a different protein (e.g., a different protein
kinase). In certain embodiments, the activity of IRAK (e.g., IRAK1)
is selectively inhibited by a compound or pharmaceutical
composition described herein, compared to the activity of a
different protein. In certain embodiments, the activity of IRAK1 is
selectively inhibited by a compound or pharmaceutical composition
described herein, compared to the activity of another IRAK (e.g.,
IRAK4). In certain embodiments, the activity of IRAK4 is
selectively inhibited by a compound or pharmaceutical composition
described herein, compared to the activity of another IRAK (e.g.,
IRAK1).
[0290] The selectivity of a compound or pharmaceutical composition
described herein in inhibiting the activity of a protein kinase
over a different protein (e.g., a different protein kinase) may be
measured by the quotient of the IC.sub.50 value of the compound or
pharmaceutical composition in inhibiting the activity of the
different protein over the IC.sub.50 value of the compound or
pharmaceutical composition in inhibiting the activity of the
protein kinase. The selectivity of a compound or pharmaceutical
composition described herein for a protein kinase over a different
protein may also be measured by the quotient of the K.sub.d value
of an adduct of the compound or pharmaceutical composition and the
different protein over the K.sub.d value of an adduct of the
compound or pharmaceutical composition and the protein kinase. In
certain embodiments, the selectivity is at least 2-fold, at least
3-fold, at least 5-fold, at least 10-fold, at least 30-fold, at
least 100-fold, at least 300-fold, at least 1,000-fold, at least
3,000-fold, at least 10,000-fold, at least 30,000-fold, or at least
100,000-fold. In certain embodiments, the selectivity is not more
than 100,000-fold, not more than 10,000-fold, not more than
1,000-fold, not more than 100-fold, not more than 10-fold, or not
more than 2-fold. Combinations of the above-referenced ranges
(e.g., at least 2-fold and not more than 10,000-fold) are also
within the scope of the disclosure.
[0291] In certain embodiments, a kit described herein includes a
first container comprising a compound or pharmaceutical composition
described herein. In certain embodiments, a kit described herein is
useful in treating a proliferative disease (e.g., cancers (e.g.,
leukemia, lymphoma), inflammatory diseases, autoinflammatory
diseases, and autoimmune diseases in a subject in need thereof,
preventing a proliferative disease in a subject in need thereof,
inhibiting the activity of a protein kinase (e.g., IRAK (e.g.,
IRAK1 or IRAK4)) in a subject, biological sample, tissue, or cell,
and/or inducing apoptosis in a cell.
[0292] In certain embodiments, a kit described herein further
includes instructions for using the compound or pharmaceutical
composition included in the kit. A kit described herein may also
include information as required by a regulatory agency such as the
U.S. Food and Drug Administration (FDA). In certain embodiments,
the information included in the kits is prescribing information. In
certain embodiments, the kits and instructions provide for treating
a proliferative disease in a subject in need thereof, preventing a
proliferative disease in a subject in need thereof, inhibiting the
activity of a protein kinase (e.g., IRAK (e.g., IRAK1 or IRAK4)) in
a subject, biological sample, tissue, or cell, and/or inducing
apoptosis in a cell. A kit described herein may include one or more
additional pharmaceutical agents described herein as a separate
composition.
EXAMPLES
[0293] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described in this application are
offered to illustrate the compounds, pharmaceutical compositions,
and methods provided herein and are not to be construed in any way
as limiting their scope.
Structure-Activity Analyses for Selected Compounds
[0294] Select compounds described herein were evaluated for
structure-activity analyses. Exemplary results are shown in Table
1. For IRAK1, the following Alexa kinase assay procedure was
followed: in the absence of an inhibitor, ADP formed by a kinase
reaction will displace an Alexa Fluor 647 dye-labeled ADP tracer
from an Eu3+-labeled anti-ADP antibody, resulting in a decrease in
the time-resolved fluorescence resonance energy transfer (TR-FRET)
signal. In the presence of an inhibitor, the amount of ADP formed
by the kinase reaction is reduced, and the resulting intact
antibody-tracer interaction produces a high TR-FRET signal. For
IRAK4, the following Z-lyte kinase assay procedure was followed:
phosphorylation-dependent protease susceptibility of a
double-labeled peptide substrate is detected using fluorescence
resonance energy transfer (FRET).
TABLE-US-00001 TABLE 1 IC.sub.50 values of exemplary compounds
described herein. Compound IRAK1 (nM) IRAK4 (nM) ##STR00145##
JH-X-119-01 9 >10,000 ##STR00146## JH-X-119-03 55 >10,000
##STR00147## JH-X-159 259 >10,000 ##STR00148## JH-X-119-02 47
>10,000 ##STR00149## JH-X-119-04 25 >10,000 ##STR00150##
JH-X-198 51 >10,000 ##STR00151## JH-XII-205-1 88 1,110
##STR00152## JH-XII-205-2 72 >10,000 ##STR00153## JH-XIII-80-1
12 >10,000 ##STR00154## JH-XIII-80-2 67 >10,000 ##STR00155##
JH-XIII-77 80 >10,000 ##STR00156## JH-XIII-80-3 22 >10,000
##STR00157## JH-XII-200-1 46 154 ##STR00158## JH-XII-200-2 24 648
##STR00159## JH-XII-200-3 51 607 ##STR00160## JH-XIII-96-2 40
>10,000 ##STR00161## ##STR00162## ##STR00163## ##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168## ##STR00169##
##STR00170##
Preparation of the Compounds Described Herein
[0295] The compounds provided herein can be prepared from readily
available starting materials using the following general methods
and procedures. Where typical or preferred process conditions
(i.e., reaction temperatures, times, mole ratios of reactants,
solvents, pressures, etc.) are given, other process conditions can
also be used unless otherwise stated. Optimum reaction conditions
may vary with the particular reactants or solvents used, but such
conditions can be determined by those skilled in the art by routine
optimization procedures.
##STR00171##
tert-butyl (4-(6-bromopicolinamido)phenyl)carbamate
[0296] To a solution of 6-bromopicolinic acid (1.6 g, 7.92 mmol) in
DCM (100 mL) was added tert-butyl (4-aminophenyl)carbamate (1.81 g,
8.71 mmol) and HATU (6.02 g, 15.84 mmol) followed by DIEA (6.90 mL,
39.60 mmol). The mixture was stirred for 1 hour at room
temperature. Water (50 mL) was added and the mixture was extracted
with DCM (2.times.50 mL). The combined organic layer was washed
with brine, dried over MgSO.sub.4, and condensed. The crude
material was triturated with EtOAc (20 mL), filtered and dried
under N.sub.2 to give a white powder that was used without further
purification (1.58 g, 51% yield) m/z expected: 392.25, observed:
392.64
[0297] The following compound was synthesized according to the
above procedure:
##STR00172##
White powder (1.73 g, 56% yield) m/z expected: 392.25, observed:
392.53
##STR00173##
tert-butyl
(4-((4-(6-bromopicolinamido)phenyl)carbamoyl)phenyl)carbamate
[0298] To a solution of tert-butyl
(4-(6-bromopicolinamido)phenyl)carbamate (1.58 g, 4.03 mmol) in DCM
(100 mL) was added TFA (10 mL). The mixture was stirred for 1 hour.
The solvent was removed in vacuo and the material was dissolved in
DCM (100 mL). 4-((tert-butoxycarbonyl)amino)benzoic acid (1.05 g,
4.43 mmol) and HATU (3.06 g, 8.06 mmol) followed by DIEA (2.75 mL,
20.14 mmol). The mixture was stirred for 1 hour at room
temperature. Water (50 mL) was added and the mixture was extracted
with DCM (2.times.50 mL). The combined organic layer was washed
with brine, dried over MgSO.sub.4, and condensed. The crude
material was purified by flash chromatography using a gradient of
20-80% EtOAc in Hexanes to give the desired compound as a white
solid. (0.70 g, 34% yield) m/z expected: 511.38, observed:
512.47
[0299] The following compounds in Table 2 were synthesized
according to the above procedure.
TABLE-US-00002 TABLE 2 Structure Yield LCMS ##STR00174## 30% 512.78
##STR00175## 42% 512.68 ##STR00176## 48% 512.35
##STR00177##
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide
[0300] To a solution of tert-butyl
(4-((4-(6-bromopicolinamido)phenyl)carbamoyl) phenyl)carbamate (100
mg, 0.19 mmol) in DCM (10 mL) was added TFA (1 mL). The mixture was
stirred for 1 hour then the solvent was removed in vacuo. The
material was dissolved in THF (5 mL) and NaHCO.sub.3 sat. aq. (5
mL). Acryloyl chloride (19 .mu.L, 0.23 mmol) was added and the
mixture stirred for 30 minutes. Water (20 mL) was added and the
mixture was extracted with EtOAc (2.times.50 mL). The combined
organic layer was washed with brine, dried over MgSO.sub.4, and
condensed to give a white solid that was used without further
purification. (84 mg, 92% yield) m/z expected: 465.31, observed:
467.52
[0301] The following compounds in Table 3 were synthesized
according to the above procedure.
TABLE-US-00003 TABLE 3 Structure Yield LCMS ##STR00178## 96% 467.19
##STR00179## 88% 467.23 ##STR00180## 84% 467.51 ##STR00181## 79%
522.71 ##STR00182## 82% 522.32
##STR00183##
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
[0302] N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide (84
mg, 0.18 mmol) was dissolved in 1,4-Dioxane (5 mL).
1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2--
yl)-1H-pyrazole (55 mg, 0.19 mmol) was added followed by
Na.sub.2CO.sub.3 2M aqueous solution (0.54 mL, 1.08 mmol). The
mixture was degassed in a sonicator for 2 minutes. Pd(dppf)Cl.sub.2
(16 mg, 0.021 mmol) and t-BuXPhos (13 mg, 0.032 mmol) were added
and the mixture heated to 90.degree. C. in a sealed vial for 1
hour. The reaction was quenched with water (10 mL) and extracted
with EtOAC (2.times.50 mL) washed with brine, dried over MgSO.sub.4
and condensed. The crude material was dissolved in DCM (10 mL) and
TFA (1 mL) was added. The mixture was stirred for 30 minutes and
the solvent removed in vacuo. The crude material was purified by
reversed phase HPLC to give the desired compound as a white solid
(46 mg, 56% yield) m/z expected: 452.47, observed: 453.19; .sup.1H
NMR (500 MHz DMSO) .delta. 14.06, (Br, 1H), 10.67 (Br, 1H), 10.35
(d, J=20 Hz, 2H), 8.18 (s, 1H), 8.15-8.08 (m, 3H), 7.94 (d, J=9 Hz,
1H), 7.85 (q, J=12 Hz, 4H) 7.75 (Br, 1H), 7.69 (d, J=10 Hz, 1H),
7.50 (t, J=9 Hz, 1H), 7.18 (Br, 1H), 6.47 (dd, J=10 Hz, 15 Hz, 1H),
6.33-6.28 (m, 1H), 5.80 (dd, J=3 Hz, 10 Hz, 1H).
[0303] The following compounds in Table 4 were synthesized
according to the above procedure.
TABLE-US-00004 TABLE 4 .sup.1H NMR (500 MHz Structure Yield LCMS
DMSO) ##STR00184## 49% 453.36 .delta. 14.04 (Br, 1H), 10.66, (s,
1H), 10.44 (s, 1H), 10.19 (s, 1H), 8.14-8.07 (m, 3H), 7.98 (d, J =
9Hz, 2H), 7.87-7.81 (m, 6H), 7.75 (Br, 1H), 7.19 (Br, 1H), 6.48
(dd, J = 10 Hz, 16 Hz, 1H), 6.34-6.29 (m, 1H), 5.82 (dd, J = 3 Hz,
11 Hz, 1H) ##STR00185## 58% 453.07 .delta. 10.69 (s, 1H), 10.37 (d,
J = 10 Hz, 2H), 8.38 (s, 1H), 8.19 (s, 1H), 8.15-8.08 (m, 3H), 7.93
(d, J = 9 Hz, 1H), 7.74 (Br, 1H), 7.69 (d, J = 8 Hz, 1H), 7.62 (d,
J = 7 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.50 (t, J = 8 Hz, 1H), 7.40
(t, J = 8 Hz, 1H), 7.17 (Br, 1H), 6.47 (dd, J = 11 Hz, 17 Hz, 1H),
6.33-6.28 (m, 1H), 5.80 (dd, J = 2Hz, 10 Hz, 1H) ##STR00186## 54%
453.56 .delta. 10.69 (s, 1H), 10.45 (s, 1H), 10.26 (s, 1H), 8.40
(s, 1H), 8.14- 8.08 (m, 3H), 8.00 (d, J = 9 Hz, 2H), 7.82 (d, J = 9
Hz, 2H), 7.74 (Br, 1H), 7.59 (t, J = 10 Hz, 2H), 7.39 (t, J = 7 Hz,
1H), 7.17 (Br, 1H), 6.48 (dd, J = 10 Hz, 16 Hz, 1H), 6.35-6.29 (m,
1H), 5.82 (dd, J = 3 Hz, 10 Hz, 1H) ##STR00187## 45% 510.27
##STR00188## 47% 510.38
Preparation of Further Compounds Described Herein
##STR00189##
[0304] N-(4-azidophenyl)-6-bromopicolinamide
[0305] Prepared using the same procedure as for the synthesis of
tert-butyl (4-(6-bromopicolinamido)phenyl)carbamate described above
to give a yellow solid that was used without further purification
(72% yield). M/z expected: 318.13, observed: 318.57
##STR00190##
tert-butyl
(3-(1-(4-(6-bromopicolinamido)phenyl)-1H-1,2,3-triazol-4-yl)phenyl)carbam-
ate
[0306] N-(4-azidophenyl)-6-bromopicolinamide (200 mg, 0.629 mmol)
and tert-butyl (3-ethynylphenyl)carbamate (137 mg, 0.629 mmol) were
dissolved in a 1:1:1 solution of t-BuOH, DMF and H.sub.2O (6 mL).
CuSO.sub.4 Pentahydrate (157 mg, 0.629 mmol) and Na Ascorbate (125
mg, 0.629 mmol) were added and the mixture stirred at 80.degree. C.
for 1 hour. Water was added and the precipitate filtered, washed
with water and dried under vacuum to give the desired product as a
yellow solid that was used without further purification (268 mg,
80% yield). M/z expected: 535.40, observed: 537.39
##STR00191##
N-(4-(4-(3-acrylamidophenyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-bromopicolin-
amide
[0307] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (93% yield). M/z expected: 489.33, observed:
491.36
##STR00192##
N-(4-(4-(3-acrylamidophenyl)-1H-1,2,3-triazol-1-yl)phenyl)-6-(1H-pyrazol--
5-yl)picolinamide
[0308] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (58% yield). M/z expected: 476.50,
observed: 477.26. .sup.1H NMR (500 MHz DMSO) .delta. 10.81, (Br,
1H), 10.26 (s, 1H), 9.22 (s, 1H), 8.29 (s, 1H), 8.13-8.04 (m, 6H),
7.98 (d, J=9 Hz, 2H), 7.64 (d, J=7 Hz, 2H), 7.56 (d, J=7 Hz, 1H),
7.39 (t, J=10 Hz, 1H), 6.42 (dd, J=10 Hz, 15 Hz, 1H), 6.26-6.22 (m,
1H), 5.73 (dd, J=3 Hz, 10 Hz, 1H). IRAK1 IC50=40 nM, IRAK4
IC50>10,000 nM.
##STR00193##
tert-butyl 4-(6-bromopicolinamido)benzoate
[0309] Prepared using the same procedure as for the synthesis of
tert-butyl (4-(6-bromopicolinamido)phenyl)carbamate described above
to give a white solid that was used without further purification
(54% yield). M/z expected: 377.24, observed: 377.56
##STR00194##
tert-butyl
((1r,4r)-4-(4-(6-bromopicolinamido)benzamido)cyclohexyl)carbamate
[0310] To a solution of tert-butyl 4-(6-bromopicolinamido)benzoate
(250 mg, 0.66 mmol) in DCM (10 mL) was added TFA (1 mL). The
solution was stirred for 3 hours at room temperature and the
solvent removed. The residue was dissolved in DCM (10 mL) and
tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (156 mg, 0.73 mmol)
was added along with HATU (503 mg, 1.32 mmol) and DIEA (577 .mu.L,
3.31 mmol). The solution was stirred for 1 hour at which time the
resulting precipitate was filtered and washed with cold DCM and
dried under vacuum to give the desired product as a yellow solid
that was used without further purification (246 mg, 78% yield). M/z
expected: 517.42, observed: 517.39
##STR00195##
tert-butyl
((1S,3R)-3-(4-(6-bromopicolinamido)benzamido)cyclohexyl)carbamate
[0311] Prepared using the same procedure as above to give a white
solid that was used without further purification (260 mg, 75%
yield) M/z expected: 517.42, observed: 517.32
##STR00196##
tert-butyl
(3-(4-(6-bromopicolinamido)benzamido)bicyclo[1.1.1]pentan-1-yl)carbamate
[0312] Prepared using the same procedure as above to give a white
solid that was used without further purification (260 mg, 87%
yield) M/z expected: 501.38, observed: 501.63
##STR00197##
N-(4-(((1r,4r)-4-acrylamidocyclohexyl)carbamoyl)phenyl)-6-bromopicolinami-
de
[0313] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (91% yield). M/z expected: 471.36, observed:
471.58
##STR00198##
N-(4-(((1R,3S)-3-acrylamidocyclohexyl)carbamoyl)phenyl)-6-bromopicolinami-
de
[0314] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (91% yield). M/z expected: 471.36, observed:
471.64
##STR00199##
N-(4-((3-acrylamidobicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)-6-bromopic-
olinamide
[0315] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (91% yield). M/z expected: 455.31, observed:
455.73
##STR00200##
N-(4-(((1r,4r)-4-acrylamidocyclohexyl)carbamoyl)phenyl)-6-(1H-pyrazol-5-y-
l)picolinamide
[0316] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (14% yield). M/z expected: 458.52,
observed: 459.32. .sup.1H NMR (500 MHz DMSO) .delta. 10.83, (Br,
1H), 8.20 (d, J=6 Hz, 1H), 8.12 (m, 2H), 8.03-7.90 (m, 4H), 7.68
(br, 1H), 7.09 (br, 1H), 6.21 (dd, J=10 Hz, 15 Hz, 1H), 6.16-6.08
(m, 1H), 5.57 (dd, J=3 Hz, 10 Hz, 1H), 3.83-3.56 (m, 2H), 1.88 (m,
4H), 1.51-1.26 (m, 6H). IRAK1 IC50=46 nM, IRAK4 IC50=154 nM.
##STR00201##
N-(4-(((1R,3S)-3-acrylamidocyclohexyl)carbamoyl)phenyl)-6-(1H-pyrazol-5-y-
l)picolinamide
[0317] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (12% yield). M/z expected: 458.52,
observed: 459.32. .sup.1H NMR (500 MHz DMSO) .delta. 10.82, (Br,
1H), 8.25 (d, J=5 Hz, 1H), 8.17-8.03 (m, 3H), 7.99 (d, J=10 Hz,
2H), 7.92 (d, J=10 Hz, 2H), 7.71 (br, 1H), 7.12 (br, 1H), 6.20 (dd,
J=10 Hz, 15 Hz, 1H), 6.16-6.08 (m, 1H), 5.57 (dd, J=3 Hz, 10 Hz,
1H), 3.93-3.66 (m, 2H), 1.86-1.74 (m, 3H), 1.46-1.09 (m, 6H). IRAK1
IC50=24 nM, IRAK4 IC50=648 nM.
##STR00202##
N-(4-((3-acrylamidobicyclo[1.1.1]pentan-1-yl)carbamoyl)phenyl)-6-(1H-pyra-
zol-5-yl)picolinamide
[0318] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (12% yield). M/z expected: 442.48,
observed: 443.29. .sup.1H NMR (500 MHz DMSO) .delta. 10.77, (Br,
1H), 8.99 (s, 1H), 8.72 (s, 1H), 8.19-8.08 (m, 3H), 7.99 (d, J=10
Hz, 2H), 7.92 (d, J=10 Hz, 2H), 7.75 (br, 1H), 7.20 (br, 1H), 6.16
(dd, J=10 Hz, 15 Hz, 1H), 6.18-6.09 (m, 1H), 5.59 (dd, J=3 Hz, 10
Hz, 1H), 2.36 (s, 6H). IRAK1 IC50=51 nM, IRAK4 IC50=607 nM.
##STR00203##
tert-butyl
((1r,4r)-4-((4-(6-bromopicolinamido)phenyl)carbamoyl)cyclohexyl)carbamate
[0319] N-(4-aminophenyl)-6-bromopicolinamide (200 mg, 0.51 mmol)
was dissolved in DCM (10 mL).
(1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid
(136 mg, 0.561 mmol) and HATU (388 mg, 1.02 mmol) were added
followed by DIEA (444 .mu.L, 2.55 mmol). The mixture was stirred
for 2 hours and the resulting precipitate was filtered and washed
with DCM (5 mL) to give the desired product as a white solid (226
mg, 86% yield) that was used without further purification. M/z
expected: 517.42, observed: 517.34
##STR00204##
tert-butyl
((1S,3R)-3-((4-(6-bromopicolinamido)phenyl)carbamoyl)cyclohexyl)carbamate
[0320] Prepared using the same procedure as the above compound to
give a white solid (218 mg, 83% yield) that was used without
further purification. M/z expected: 517.42, observed: 517.56
##STR00205##
N-(4-((1r,4r)-4-acrylamidocyclohexane-1-carboxamido)phenyl)-6-bromopicoli-
namide
[0321] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (91% yield). M/z expected: 471.36, observed:
471.61
##STR00206##
N-(4-((1R,3S)-3-acrylamidocyclohexane-1-carboxamido)phenyl)-6-bromopicoli-
namide
[0322] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-bromopicolinamide described
above to give a brown solid that was used without further
purification (91% yield). M/z expected: 471.36, observed:
471.43
##STR00207##
N-(4-((1r,4r)-4-acrylamidocyclohexane-1-carboxamido)phenyl)-6-(1H-pyrazol-
-5-yl)picolinamide
[0323] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (8% yield). M/z expected: 458.52,
observed: 459.71. .sup.1H NMR (500 MHz DMSO) .delta. 10.64, (Br,
1H), 9.88 (s, 1H), 8.15-8.05 (m, 3H), 7.99 (d, J=10 Hz, 2H), 7.79
(d, J=10 Hz, 2H), 7.65 (d, J=10 Hz, 2H), 6.20 (dd, J=10 Hz, 15 Hz,
1H), 6.12-6.03 (m, 1H), 5.57 (dd, J=3 Hz, 10 Hz, 1H), 3.60 (m, 2H),
2.30 (m, 1H), 1.90 (m, 4H), 1.53 (m, 2H), 1.26 (m, 2H). IRAK1
IC50=88 nM, IRAK4 IC50=1,110 nM.
##STR00208##
N-(4-((1R,3S)-3-acrylamidocyclohexane-1-carboxamido)phenyl)-6-(1H-pyrazol-
-5-yl)picolinamide
[0324] Prepared using the same procedure as for the synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above to give a brown oil that was purified by reverse
phase HPLC using a gradient of 1 to 70% ACN in H.sub.2O to give the
desired product as a white solid (8% yield). M/z expected: 458.52,
observed: 459.62. .sup.1H NMR (500 MHz DMSO) .delta. 10.62, (Br,
1H), 9.93 (s, 1H), 8.14-8.04 (m, 4H), 7.78 (d, J=10 Hz, 2H), 7.73
(s, 1H), 7.67 (d, J=10 Hz, 2H), 7.18 (br, 1H), 6.20 (dd, J=10 Hz,
15 Hz, 1H), 6.12-6.03 (m, 1H), 5.57 (dd, J=3 Hz, 10 Hz, 1H),
3.81-3.67 (m, 2H), 1.98-1.77 (m, 4H), 1.42-1.32 (m, 3H), 1.15 (m,
1H). IRAK1 IC50=72 nM, IRAK4 IC50>10,000 nM.
[0325] Other compounds prepared using the same procedure as for the
synthesis of
N-(4-(4-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-5-yl)picolinamide
described above.
##STR00209##
N-(4-(4-acrylamidobenzamido)phenyl)-[2,3'-bipyridine]-6-carboxamide
[0326] Brown solid (33% yield). M/z expected: 463.50, observed:
463.72. .sup.1H NMR (500 MHz DMSO) .delta. 10.61, (s, 1H), 10.38
(s, 1H), 10.32 (s, 1H), 9.70 (s, 1H), 9.0 (d, J=5 Hz, 1H), 8.81 (s,
1H), 8.39 (d, J=9 Hz, 2H), 8.26-8.18 (m, 3H), 7.94-7.77 (m, 5H),
7.68 (d, J=6 Hz, 1H), 7.49 (t, J=10 Hz, 1H), 6.47 (dd, J=10 Hz, 15
Hz, 1H), 6.38-6.27 (m, 1H), 5.80 (dd, J=3 Hz, 10 Hz, 1H). IRAK1
IC50=80 nM, IRAK4 IC50>10,000 nM.
##STR00210##
N-(4-(3-acrylamidobenzamido)phenyl)-6-(isoxazol-4-yl)picolinamide
[0327] Yellow solid (10% yield). M/z expected: 453.46, observed:
453.38. .sup.1H NMR (500 MHz DMSO) .delta. 10.82, (s, 1H), 10.37
(s, 1H), 10.31 (s, 1H), 9.03 (d, J=5 Hz, 1H), 8.17 (s, 1H), 8.01
(t, J=10 Hz, 1H), 7.94-7.11 (m, 2H), 7.84-7.75 (m, 4H), 7.67 (d,
J=9 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.50 (t, J=10 Hz, 1H), 6.54 (br,
1H), 6.47 (dd, J=10 Hz, 15 Hz, 1H), 6.38-6.27 (m, 1H), 5.79 (dd,
J=3 Hz, 10 Hz, 1H). IRAK1 IC50=12 nM, IRAK4 IC50>10,000 nM.
##STR00211##
N-(4-(3-acrylamidobenzamido)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)picolinam-
ide
[0328] Brown solid (33% yield). M/z expected: 466.50, observed:
466.41. .sup.1H NMR (500 MHz DMSO) .delta. 10.45, (s, 1H), 10.37
(s, 1H), 10.31 (s, 1H), 8.65, (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H),
8.01 (t, J=10 Hz, 1H), 7.95-7.87 (m, 5H), 7.81 (d, J=9 Hz, 2H),
7.68 (d, J=7 Hz, 1H), 7.49 (t, J=10 Hz, 1H), 6.47 (dd, J=10 Hz, 15
Hz, 1H), 6.38-6.27 (m, 1H), 5.80 (dd, J=3 Hz, 10 Hz, 1H), 3.93 (s,
3H). IRAK1 IC50=67 nM, IRAK4 IC50>10,000 nM.
##STR00212##
N-(4-(3-acrylamidobenzamido)phenyl)-6-(1H-pyrazol-4-yl)picolinamide
[0329] Brown solid (28% yield). M/z expected: 452.47, observed:
452.75. .sup.1H NMR (500 MHz DMSO) .delta. 10.47, (s, 1H), 10.37
(s, 1H), 10.31 (s, 1H), 8.56, (s, 1H), 8.18 (s, 1H), 8.04-7.87 (m,
6H), 7.80 (d, J=9 Hz, 2H), 7.69 (d, J=7 Hz, 2H), 7.50 (t, J=10 Hz,
1H), 6.47 (dd, J=10 Hz, 15 Hz, 1H), 6.38-6.27 (m, 1H), 5.79 (dd,
J=3 Hz, 10 Hz, 1H). IRAK1 IC50=22 nM, IRAK4 IC50>10,000 nM.
Biological Assays
[0330] A novel, highly selective IRAK1 inhibitor Jh-X-119-01 shows
synergistic tumor cell killing with Ibrutinib in MYD88. Activating
mutations in MYD88 are present in many B-cell lymphoproliferative
disorders including WM (95%), ABC DLBCL (39%), Primary CNS Lymphoma
(80-90%), Marginal Zone Lymphoma (6-10%) and Chronic Lymphocytic
Leukemia (4-8%). In MYD88 mutated WM and ABC DLBCL cells, MYD88
triggers NF-kB pro-growth and survival signaling through divergent
pathways driven by BTK and IRAK4/IRAK1 (Ngo et al, Nature 2011;
Yang et al, Blood 2013). Ibrutinib targets BTK, and has shown high
levels of activity in MYD88 mutated WM, ABC DLBCL and PCNSL.
Responses however are partial, and complete remissions are lacking.
It was therefore sought to be clarified if persistent IRAK4/IRAK1
signaling was responsible for survival of malignant
lymphoplasmacytic cells (LPC) in WM patients on ibrutinib. It was
observed by flow cytometric analysis that while BTK activation was
suppressed in WM patients on ibrutinib for >6 months, both IRAK4
and IRAK1 remained hyperactivated. Treatment of LPC from patients
on ibrutinib with a toolbox IRAK4/IRAK1 inhibitor resulted in
marked reduction of NF-kB and induction of apoptosis. Subsequently,
lentiviral transduction studies were performed in MYD88 mutated
BCWM.1 cells, and it was observed in an inducible model system that
knockdown of IRAK1 produced more robust apoptotic effects versus
IRAK4 (FIGS. 1A and 3C). Given these findings, a medical chemistry
campaign has been pursued to develop a potent and highly selective
inhibitor of IRAK1 kinase activity, JH-X-119-01. JH-X-119-01
inhibited IRAK1 biochemically with an IC50 of 9.3 nM while
exhibiting no inhibition of IRAK4 at concentrations up to 10 .mu.M,
and showed exceptional kinome selectivity with off-target
inhibition of only two kinases, YSK4 and MEK3 (FIGS. 1B and 5).
Mass spec labelling studies were used to confirm that JH-X-119-01
irreversibly labelled IRAK1 at cysteine 302. JH-X-119-01 showed
antiproliferative effects on MYD88 mutated WM and ABC DLBCL cells.
Importantly, the combination of JH-X-119-01 with Ibrutinib led to
synergistic tumor cell killing in MYD88 mutated WM and ABC-DLBCL
cells, and suppression of NF-KB activation (FIGS. 1C and 9). In
vivo PK studies revealed a favorable profile for JH-X-119-01 with a
moderate half-life of 1.61 hours, a Cmax of 9.95 .mu.M, and a low
clearance of 18.84 mL/min/kg when dosed IV. The present findings
evidence the development of a novel, highly selective IRAK1 kinase
inhibitor, JH-X-119-01, that shows specific inhibition of IRAK1
kinase activity and a reduction of tumor cell survival in MYD88
mutated WM. Importantly, JH-X-119-01 shows synergistic tumor cell
killing with ibrutinib in MYD88 mutated WM and ABC-DLBCL cells.
This study provides a framework for the development of highly
selective IRAK1 inhibitors for use alone, and in combination with
ibrutinib in MYD88 mutated B-cell lymphomas.
EQUIVALENTS AND SCOPE
[0331] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The invention includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The invention includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0332] Furthermore, the invention encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the invention,
or aspects of the invention, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
invention or aspects of the invention consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the invention, to the tenth of the unit of the lower
limit of the range, unless the context clearly dictates
otherwise.
[0333] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present invention that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the invention can be excluded from any claim, for any
reason, whether or not related to the existence of prior art.
[0334] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
invention, as defined in the following claims.
* * * * *